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Premature Ejaculation (PE) And

new drug for treatment of PE

Mahdavi RProfessor of Urology and Renal Transplantation

March 2009

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Anatomical structures involved in ejaculation and the central

serotonergic of ejaculation

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Definition (1)

Consensus on definition of PE

1) The Second International Consultation on Sexual and

Erectile Dysfunction defined PE as ‘ejaculation with

minimal stimulation and earlier than desired, before or

soon after penetration, which causes bother or

distress, and over which the sufferer has little or no

voluntary control’

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Definition(2)

2) The international society for sexual medicine (ISSM)

Definition for life-long PE : Premature ejaculation is a

male sexual dysfunction characterized by ejaculation

which always or nearly always occurs prior to or within

about one minute of vaginal penetration; and 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

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Premature ejaculationclassification

a) Life long (primary) : occurred too fast before

vaginal penetration or < 1-2 minutes

b) Acquired PE (secondary): time to

ejaculation is short but not as fast as in life

long

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Epidemiology ofPremature ejaculation

PE is the most male sexual dysfunction

Prevalence rate : 20-30% overall

Prevalence of life long PE with IELT

(Intra Vaginal Ejaculatory Latency Time)

< 1-2 minutes : 2-5%

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Risk factors and PE (hypothesis)

a) Anxiety

b) Penile hypersensitivity

c) Serotonin receptor dysfunction

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The prevalence of

Premature ejaculation is

not affected by age or

countries

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Percentage of men reporting symptoms of PE in the PEPA

survey, by country and age group

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Side effects of Premature ejaculation

Effect on self-confidence and relationship

with partner

Mental distress

Anxiety

Embarrassment and depression

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Most men with premature

ejaculation do not seek

help

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Diagnostic workup

Medical and sexual history include :

a) Type of PE: Primary or secondary

b) Specific circumstance or specific partner or consistent

c) Length of time of ejaculation

d) Degree of sexual stimulus

e) Impact PE on sexual activity and QoL

f) Drug use or abuse

g) To distinguish PE from ED

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Diagnostic workup

Physical examination include : examination of

vascular , endocrine , neurologic system

Laboratory or physiological testing should be

specific finding from history or physical

examination

Continue:

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Diagnostic workup

In every day clinical practice self-

estimated IELT (intra vaginal ejaculatory

latency time) is sufficient but stop watch-

measured IELTs is necessary in clinical

trials.

Continue:

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Relationships among

measures of PE

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Treatment of Premature ejaculation

First-line treatment: Which ?

Psychological / behavioral sterategies

Topical anesthetic agent

Selective serotonin reuptake inhibitors

Phosphodiesterase types inhibitors

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Psychological / behavioral therapy

Stop-start program ( Semans technique ) or

squeeze technique (Masters – Jonson

technique)

Masturation before intercourse in younger

men

Overall success rate 50-60%

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Topical anesthetic agents

lidocaine-prilocaine cream ( 5% ) 20-30 minutes

before intercourse

To apply condom for prevention vaginal wall

numbnes in the partner

SS-cream ( made from 9 herbs ) apply 0.2 gr /

1 hour before intercourse

Side effect : mild local burning and mild pain in 18.5% of

partners

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Premature ejaculation and role of serotonin

Current evidence suggests that PE is a

neurobiological phenomen

Cerebral and their neurotransmiters like

serotonin, dopamine, oxytocine has a key role in

ejaculation and PE

In PE cases probably there is a low synaptic

levels of serotonin in CNS because of variation

in serotonin receptor sensitivity

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Proposed mechanism of action of Dapoxetine

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Selective serotonin reuptake inhibitors (SSRIs): First treatment of Premature

ejaculation

Paroxetine

Sertraline (Asentra)

Dapoxetine

These agents act to decrease the rate of removal of

serotonin from synaptic cleft , thus causing an

elevation in serotonergic activity at the synapse and

prolong IELTs.

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Selective serotonin reuptake inhibitors

(SSRIs)

Paroxetine

Sertraline (Asentra)

At least 1-2 weeks administration needs for

paroxetine and sertraline to prolong IELTS

Half-lives elimination of these agents 5h to 4days

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Pharmacokinetic profiles of Dapoxetine and

longer – acting SSRIs

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Dapoxetine for the on-demand

treatment of Premature ejaculation

It is short SSRI and administrated as

on-demand (PRN)

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Mechanism action of Dapoxetine

Inhibits the ejaculatory expulsion reflex in

the rate by cutting at supraspinal level

resulting in pudendal motor neuron reflex

discharge latency and a reduction in

PRMD duration

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Dapoxetine:Rapid absorption and elimination

Maximum plasma concentration 1-2 hours

after single dose 30-60 mg/day

By 24% plasma concentration ↓ 5% of the

peak

Daily accumulation is minimal

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Metabolism and excretion of

Dapoxetine

99% is bound to protein (in vitro)

Metabolized in liver (CYP 450)

Metabolites were eliminated in the urine

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The dapoxetine clinical development

program

5 double-blind-placebo controlled phase III

clinical studies were performed (a total

6081 subjects were randomized) in 16

countries

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Results of these studies at the 24

weekend point :

1- Dapoxetine significantly increased

ejaculatory latency time (IELT)

2- Dapoxetine improved control over

ejaculation and reduced distress relatad to

ejaculation

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Satisfaction with

sexual intercourse

with Dapoxetine

30 and 60 mg and

placebo in the

international study

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At the week 24 end point

Approximately 58% and 72% of subjects

receiving Dapoxetine 30 and 60 mg

reported that PE was slightly better, much

better compared with 32% of subjects

receiving placebo (p < o.ooo1)

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Mean average IELT (min) during traetment with Dapoxetine

30 and 60 mg or placebo over time in the international study

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Overall adverse events of Dapoxetine

The most common adversa events with dapoxetine are

nausea(16%), headache(8%) and dizziness(7.7%)

Orthostatic hypotension (O.H)

Precaution:

a) History of O.H

b) Who taking α-blocker antagonist

c) Nitrate

d) Phosphodiesterase (PDF) 5-inhibitor

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Overall adverse events of Dapoxetine

Syncope: especially in patient with

underlying structural cardiovascular

disease

Withdrawal syndrome?

Continue:

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Dapoxetine:

Contraindications

Hypersensitivity

Presence of significant pathologic cardiac

condition :

a) Heart failure (class II-IV)

b) Second or third degree A-V block or sick sinus

syndrome

c) Significant IHD or valvular disease

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Dapoxetine:

ContraindicationsUse of monoaminoxidase inhibitors, thioridazine and

agents with serotonergic effect like :

- Norepinephrine

- Tramadol

- Lithium

Concomitant treatment with certain drugs that strong

effects on CYPA4 like : ketoconazole, itraconazole

Moderate and severe hepatic impairment

Severe renal impairment

Continue:

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Dapoxetine

Precaution and drug interaction

Caution is advised in patients taking moderate

CYP3AU inhibitors like: Erythromycin,

Clarithromycin, Verapamil, Diltiazem

Dose of Dapoxetine must be restricted to 30mg

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Dapoxetine Precaution and drug interaction

Relative contraindication in patients with history of

mania / hypomania or bipolar disorder

Unstable seizure (dapoxetine lower seizure

threshold)

Psychiatric disorder

Ethanol (alcohol) : increase alcohol-related effects

and increase the risk of accidental injury

Driving or operating hazardous machinery

Continue:

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Perceived control

over ejaculation

and personal

distress related to

ejaculation

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Perceived control

over ejaculation

with Dapoxetine

30 and 60 mg and

placebo in the

international study

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CGI of change in

PE al the week 24

endpoint (LPOCF)

with Dapoxetine

30 and 60 mg and

placebo in the

international study

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Satisfaction with

sexual intercourse

and interpersonal

difficultly related

to ejaculation

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Important patient information

Take Dapoxetine 1 to 3 hours before sexual activity

Take Dapoxetine with at least one full glass of water

Do not take Dapoxetine more than once every 24

hours

Do not combine Dapoxetine with alcohol or

recreational drugs

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Premature Ejaculation and sildenafil

IELT was not significantly improved ??

However:

- Increase confidence

- Reduce anxiety

- Increase the perception of ejaculatory control

- Increase the overall sexual satisfaction

Sildenafil + SSRI is superior to SSRI

monotherapy

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