presentation on molecule dapoxetin by anant kumar rathi

1. DAPOXETINE IN SEXUAL
DYSFUNCTIONS
PRESENTOR
DR. ANANT KUMAR RATHI
2nd YEAR RESIDENT
GUIDE
DR. D. K. SHARMA
PROF. & HEAD, DEPTT. OF PSYCHIATRY
GOVT. MEDICAL COLLEGE & N.M.C. HOSPITAL, KOTA

2. NORMAL PHYSIOLOGY (Ganong Physiology)
ERECTION EJACULATION
AUTONOMIC PARASYMPATHETIC SYMPATHETIC
NERVOUS SYSTEM SYSTEM SYSTEM
AFFERENT PUDENDAL NERVE & PUDENDAL NERVE
SACRAL PLEXUS
RELAY SACRAL SEGMENTS LUMBAR SEGMENTS
OF SPINAL CORD OF SPINAL CORD
EFFERENT PELVIC SPLANCHNIC HYPOGASTRIC &
NERVE (NERVI PELVIC SYMPATHETIC
ERIGENTIS) PLEXUS
NEUROTRANSMITOR NITRIC OXIDE (NO) CARBON MONOXIDE
(CO)

3. Phases of Sexual Response Cycle & Associated
Sexual Dysfunctions
PHASES CHARACTERSTICS DYSFUNCTION
1. Desire Reflects person’s motivations, drives & Hypoactive sexual desire
personality; characterized by sexual disorder; sexual aversion
fantasies & desire to have sex disorder (male or female)
2. Subjective sense of sexual pleasure & Female sexual arousal
Excitement accompanying physiological responses disorder
(sexual flush, erection by vasocongestion, Male erectile disorder;
tightening & lifting of scrotal sac, increase dyspareunia
size of testes )
3. Orgasm Peaking of sexual pleasure, release of Orgasmic disorder (male &
sexual tension & rhythmic contraction of female); premature
perineal muscles and pelvic reproductive ejaculation
organs
4. A sense of general relaxation, wellbeing & Post coital dysphoria; post
Resolution muscle relaxation coital headache

4. PHYSIOLOGY OF
EJACULATION
 Normal ante grade ejaculation:- 3 basic mechanism
(Lipshultz 1981)
(1) Emission:- Result of a sympathetic spinal cord reflex
Initiated by genital/cerebral erotic stimuli
Involves sequential contraction of accessory sexual organs
(2) Ejection:- Involve bladder neck closure
Rhythmic contraction of bulbocavernosus, bulbospongiosus
and other pelvic floor muscles
Relaxation of external urethral sphincter (Yeates 1987)
(3) Orgasm:- Result of cerebral processing of pudendal nerve
sensory stimuli resulting from increased pressure in posterior
urethra, contraction of urethral bulb & accessory sexual

5. Neurology of ejaculation
 Seminal emission & ejection are
integrated by medial preoptic
area(MPOA) and nucleus
paragigantocellularis (nPGI)
 Descending serotonergic pathway
from nPGI to lumbosacral motor
nuclei tonically inhibit ejaculation
(Yells 1992)
 Disinhibition of nPGI by MPOA
facilitates ejaculation
 Lumbar spinothalamic neurons
send projection to autonomic nuclei
& motor neurons involved in
emission and ejection, while they
receive sensory projection from
pelvis

6. Neurobiology of ejaculation (Ahlenius
1981)
 Ejaculatory reflex is controlled by central
serotonergic & dopaminegric neurons with
secondary involvement of cholinergic,
adrenergic, nitregic, oxytocinergic neurons
 Speed of ejaculation appears to be
determined by 5HT2C & 5HT1A receptors
 Stimulation of postsynaptic 5HT2C receptor
by its agonist delays ejaculation
 Stimulation of somatodendritic 5HT1A
receptors decreases ejaculation latency

7. The Male Sexual Response
Sexual Ejaculation
Interest/ Orgasm Accompanied by
Stimulation Orgasm
Penile Penile
Penetration
tumescence Detumesence
Plateau Resolution
High arousal/
Erection
Excitement
Time

8. Spectrum of Ejaculatory Dysfunctions
Adapted from pereman. Atlas of Male Sexual dysfunction.2004

9. Premature Ejaculation (PE) [ICD-10
F52.4]
 WHO 2nd International consultation on sexual health:- “Persistent
or recurrent ejaculation with minimal stimulation before, on, or shortly
after penetration, and before the person wishes it, over which the
sufferer has little or no voluntary control, which causes the sufferer
and/or his partner bother or distress” (Leu et al 2004)
 International Society for Sexual Medicine(ISSM) :- “ Male sexual
dysfunction characterized by ejaculation which always or nearly
always occurs before or within approximately 1 minute of vaginal
penetration; the inability to delay ejaculation on all or nearly all
vaginal penetration; and negative personal consequences such as
distress, bother, frustration and/or the avoidance of sexual intimacy”
 Recent normative data suggest that men with an :-
Intravaginal Ejaculatory Latency Time (IELT) less than 1 min have
“definite PE”
IELT between 1 and 1.5 min have “probable PE” (Waldiner, Zwinderman
2005)

10. DSM IV TR Diagnostic criteria for
PE
 A. Persistent or recurrent ejaculation with minimal
stimulation before, on, or shortly after penetration, and
before the person wishes it. The clinician must take into
account factors that affect duration of excitement phase,
such as age, novelty of sexual partner or situation, and
recent frequency of sexual activity.
 B. The disturbance causes marked distress or
interpersonal difficulty.
 C. The premature ejaculation is not due to exclusively to
the direct effect of the substance (e.g., withdrawal from
opioids)

11.  PE sub classification:- (Schapiro1943)
Lifelong(Primary) PE :- Commences with onset of sexual
activity
Acquired(secondary) PE :- Develops following a period
of normal ejaculatory response. Most cases are due to
performance anxiety
Etiology:- Combination of Psychogenic and Organic
factor is presumed, with role of endocrinopathy,
Peyronie disease & Prostatitis
PE is a psychosomatic disturbance & due to over Biological
anxious personality Young
Genes
age
Cultural

12. Etiology of Premature Ejaculation
Low 5HT Hyposensitivity of
neurotransmission 5HT2C
Ejaculatory threshold genetically "set" at a lower point
Ejaculate quickly and with minimal stimulation

13. Epidemiology:- PE is the most prevalent male
sexual dysfunction (4-39% of men in general community)
Distribution of IELT values in a random
cohort of 491 men demonstrated median
IELT of 5.4 min. (range 1-45 min)
Median IELT decreased with age
Median IELT varied between countries
(Waldinger, Quinn 2005)
In a study of 1326 men with PE:-
lifelong PE was present in 74.4% men
acquired PE was found in 25.6% men
(McMohan 2002)
Men with PE appear younger than those
without. (Fasolo, Mirone 2005)
No association found with HTN, Cardiac
disease, Peripheral or central neuropathy

14. What is Normal & what is desired?

15. MANAGEMENT OF PE
 Detailed medical & sexual history should be taken
 Physical examination
 Appropriate investigation
 Identify obvious biological causes as genital &
urinary tract infection
 Treatment encompasses:-
Behavioral aspect
Pharmacological aspect
Psychological aspect

16. TREATMENT OF PREMATURE
EJACUALTION
 Incorporate into sexual practice
 Behavioural techniques - stop/start, squeeze
 Oral medication - SSRI, clomipramine, PDE5i
 Intra-cavernosal injections
 Anaesthetic cream
 Pelvic floor exercises
 Surgery to dorsal nerve (Brazil)

17. Treatment PE cont’d
 Sensate focus: Tailor to clients, work on
intimacy
 Sexual script change: Extend foreplay,
modify rigid sex patterns, “partner first”
 Treatment aim: Restore IELT, address
relationship issues, restore confidence

18. Pharmacological management
 SSRIs has been used as off the label drugs for the
treatment of PE for past 15 to 20 years utilizing its side
effect delayed ejaculation as therapeutic effect
 Paroxetin, Fluoxetin, Sertraline, Cetalopram,
Fluvoxamine and Clomipramine has revolutionized the
approach to treat PE
 Yet daily dosing, long half life, accumulation of drug,
gradual receptor desensitization and other side effects of
long acting SSRIs were the drawbacks
 However lack of approved drug & total reliance on off

19. Ejaculo-Selective Serotonin Transport Inhibitor
(ESSTIs)
 Drugs under investigation are
Dapoxetine
UK-390
UK-957
Tramadol

20.  Dapoxetine, an SSRI is
first oral pharmacological
agent indicated for
treatment of men aged 18-
64 years with PE
 Has been approved in
various European
countries, South America &
Asia Pacific
 It is novel potent SSRI
structurally similar to
Fluoxetin

21. Pharmacokinetics
 Oral formulation
 Rapidly absorbed
 Absolute bioavailability 42%
 Tmax of 1.4-2 hrs
 Cmax of 1.01-1.27 hrs
 Initial half life 1.3-1.5 hrs
 Terminal half life 15-19 hrs
 Steady state plasma conc. reaches in 4 days
 Rapid, biphasic elimination
 Less than 4% peak conc. present in plasma after 24 hrs
 Dose dependant pharmacokinetics
 Metabolized by liver via glucuronidation, N- demethylation, N-
oxidation & sulphation
 Enzymes CYT P 450 3A4, CYP2D6 are involved
 Metabolites excreted in urine

22. Pharmacokinetics of single dose of dapoxetine and effect of
food
Dapoxetine 30 mg Dapoxetine 60 mg
Cmax (ng/ml) 297 349
Tmax (h) 1.01 1.27
Initial T half 1.31 1.42
Terminal T half 18.7 21.0
Effect of high fat meal
Cmax (fasted) - 443
Cmax (high fat meal) - 398
Tmax (h) (fasted) - 1.30
Tmax (h) (high fat meal) - 1.83

23. Mechanism of action
Dapoxetine
↑ 5HT Activation of
neurotransmission 5HT2C
Elevates ejaculatory threshold "set" point
Delays Ejaculation
Indian J Urol 2007;23:97-108

25. Pharmacodynamic profile
 Inhibit neuronal reuptake of serotonin
 Potentiation of neurotransmitter’s action at pre &
post synaptic receptors
 Modulate ejaculatory expulsion reflex by elevating
latency & reducing amplitude of pudendal motor
neuron reflex discharge (Giuliano et al 2006)
 Not associated with clinically significant ECG
changes
 Blood pressure, heart rate not affected
 Moderate to severe (Child Pugh class B & C)

26. Drug interactions
 Co-administration of moderate or potent CYP3A4 inhibitor as
erythromycin, fluconazole, verapamil, ketoconazole resulted in
elevation in dapoxetin Cmax & AUC
 Concomitant potent CYP2D6 inhibitors results in higher
incidence & severity of adverse events
 Concurrent fluoxetin, desipramine therapy also increases
Cmax & AUC by 50% & 88%
 No clinically significant alteration of pharmacokinetics of
dapoxetin with co administration of sildenafil/tadalafil.
(caution-hypotension)
 Alcohol increased somnolence & reduced alertness
 Concomitant MAOI & SSRI/SNRI may result in serotonin
related A/E

27. Human clinical trials
 Phase 2 trials:- Two phase 2 randomized,
placebo controlled, double blind, cross over
designed studies
 Heterosexual men with PE diagnosed
according to DSM IV criteria and a baseline
IELT less than 2 mins.
 Study drug was administered 2 hrs prior to
planned intercourse
 Primary efficacy measure was IELT measured
by partner operated switch

28. Result of dapoxetine phase 2 study (Hellstrom et
al 2004)
 Age range (yrs)- 18-60
 Inclusion IELT- less than 2 mins estimated
 Treatment period- 4 weeks/treatment
Dapoxetine Dose 20 mg 40 mg Placebo
(n=145) (n=141) (n=142)
Mean baseline IELT 1.34 1.34 1.34
Mean treatment IELT 2.72 3.31 2.22
IELT fold increase 2 2.5 1.7
Discontinuation due to adverse 0 2 0
effect

29. Result of dapoxetine phase 2 study (Hellstrom et
al 2005)
 Age range (yrs)- 18-65
 Inclusion IELT- less than 2 mins by stopwatch
 Treatment period- 2 weeks/treatment
Dapoxetine Dose 60 mg 100 mg Placebo
(n=144) (n=155) (n=145)
Mean baseline IELT 1.01 1.01 1.01
Mean treatment IELT 2.86 3.24 2.07
IELT fold increase 2.9 3.2 2.0
Discontinuation due to 0 9 1
adverse effect

30. Analysis
 Magnitude of effect of 20 mg dapoxetine on IELT
was small
 Adverse events were dose dependant
 Most common AE were nausea, diarrhea
headache, dizziness
 Overall 60 mg dose was better tolerated
 Most common reason of study withdrawal at dose
100 mg was nausea
 Based on these results 30, 60 mg dose were
chosen for phase 3 study

31. Phase 3 studies :- To present safety & efficacy data five
randomized, double blinded, placebo controlled studies
conducted in over 25 countries
 All studies enrolled heterosexual men & their partners who were more than
18 yrs age, in monogamous relationship and met DSMIV TR criteria for PE
Study Description Treatmen Randomiz Inclusion criteria
t duration ed
subjects
U.S. Multicentre, D/B, 12 weeks 1294 IELT less than 2 mins during
randomized, placebo 2 wks baseline period, met
Study controlled DSM IV TR criteria
U.S. Multicentre, D/B, 12 weeks 1320 Same as above
randomized, placebo
Study controlled
Internation Multicentre, D/B, 24 weeks 1162 IELT less than 2 mins during
randomized, placebo 4 week baseline period, met
al Study controlled DSM IV TR criteria
Asia Multicentre, D/B, 12 weeks 1067 Same as above
randomized, placebo
Pacific controlled
Study

32. Phase 3 studies pooled data
analysis
 This is the largest efficacy and safety database for any agent
intended to treat PE
 Overall 6081 men with mean age of 40.6 yrs (18-82) from 32
countries were enrolled & 4232 (69.6%) completed the study
(9-24 weeks)
 Baseline average IELT was 0.9 min (DSM IV TR, less than 2
mins)
 58% subjects met criteria for lifelong PE
 Primary outcome measure was stopwatch IELT
 Secondary outcome measure was Premature Ejaculation
Profile (PEP) a validated tool that includes perceived control
over ejaculation, satisfaction with intercourse, ejaculation
related personal distress & interpersonal difficulty and subject
response to Clinical Global Impression of Change (CGIC)

33. Dapoxetine dose 30 mg 60 mg Placebo
(n=1613) (n=1611) (n=1608)
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
Good/very good control over
ejaculation
% baseline 0.3 0.6 0.5
% study end 26.2 30.2 11.2
Good/very good satisfaction
% baseline 15.5 14.7 15.5
% study end 37.3 42.8 24.4
Quite a bit/extreme personal
distress
% baseline 73.5 71.3 69.7
% study end 28.2 22.2 41.9
Quite a bit/extreme interpersonal
distress

34. Changes in IELT (mins) over time
4
3.5
3
2.5
Placebo 1
Series
2
Series 2
Dapoxetine 30 mg
1.5 Series 3
Dapoxetine 60 mg
1
0.5
0
Baseline Week 4 Week 8 Week 12 Week 24

35. Percentage of subjects reporting that their
PE was better/much better at 12 weeks
(CGIC)
45 Placebo
40
Dapoxetine 30
35 mg
30
Dapoxetine 60
25 mg
20
15
10
5
0
Category 1

36. Effect of dapoxetine on female partner
Dapoxetine dose 30 mg 60 mg Placebo
Good/very good control over 26.7 % 34.3 % 11.9 %
ejaculation
Good/very good satisfaction 37.5 % 44.7 % 24.0 %
Man’s PE was better 27.5 % 35.7 % 9.0 %
Ejaculation related personal Significant Significant -
distress decrease decrease
Interpersonal difficulties Significant Significant -
decrease decrease

37. Dapoxetine analysis
 Effect on mood:- Scores for Beck Depression Inventory
(BDI-II) & Montgomery Asberg Depression Rating Scale
(MADRS) decreased slightly or stayed same over time.
(Decrease in depression symptoms/no worsening of symptoms)
 Effect on anxiety:- Mean Hamilton Anxiety Scale (HAM-
A) scores decreased slightly. (Decrease in anxiety/no worsening
of anxiety )
 Effect on akathisia:- Barnes Akathisia Rating Scale (BARS)
scores did not changed. (No change in akathisia)
 Effect on suicidality:- BDI-II or MADRS score of 0 on suicidality
item. (No evidence of suicidality)

38. Safety
 Adverse event occurred in 56.1% subjects v/s
35.1% in placebo. [Most AE were of mild to moderate category(3%)
or serious (less than 1%)]
 Nausea, diarrhea, headache, dizziness, insomnia,
somnolence, fatigue, nasopharyngitis were most
common S/Es (More than half AE were reported within 4 weeks)
 Erectile dysfunction is most common sexual S/E
(placebo,1.6%; dapoxetin 30mg prn, 2.3%; dapoxetin 60mg prn, 2.6%;
dapoxetin 60mg qd.1.2% )
 Syncope occurred in 0.05%, 0.06%, 0.23% of
subjects with placebo, dapoxetine 30mg,
dapoxetine 60mg

39. Safety
 AE led to discontinuation of 1.0%, 3.5%, 8.8%, 10.0% of
subjects with placebo, dapoxetine 30mg prn, dapoxetine
60mg prn, dapoxetine 60mg qd
 Discontinuation Emergent Signs & Symptoms (DESS):-
It comprises of 43 possible withdrawal signs &
symptoms
 Incidence of discontinuation syndrome was 3, 1.1, 1.3%
for those continuing to take dapoxetine 30, 60 mg prn &
placebo respectively (Lack of chronic serotonergic stimulation &
receptor desensitization)

40. Adverse Events

41. Doses & administration
 Starting dose is 30mg taken as needed, about
1-3 hrs before intercourse
 If effect of 30mg is insufficient and AE are
acceptable, the dose can be increased for
maximum of 60mg
 Maximum dosing frequency is once in every
24 hrs

42. USE IN SPECIAL POPULATION
 Contraindicated in
Men with moderate to severe hepatic impairment, severe
renal impairment
concomitant therapy with potent CYP3A4 inhibitors
(ketoconazole, erythromycin), thioridazine, other
SSRI/SNRI/TCA
 Use cautiously in
Mild hepatic, mild to moderate renal impairment
concomitant therapy with potent CYP2D6 inhibitor or
moderate CYP3A4 inhibitors
Alcohol or recreational drugs should be avoided with

43. TO SUMMARISE
 First & only SSRI specifically developed for treatment
of PE
 Rapid oral absorption, Rapid elimination
 Minimal accumulation
 Metabolized in liver by CYP3A4 & CYP2D6
 Metabolites excreted in urine
 Ejaculo-Selective Serotonin Transport Inhibitor (ESSTIs)
 Convenience of on demand dosing
 Starting dose is 30 mg 1-3 hrs prior to intercourse
 Efficacy appears with 1st dose
 Can be increased up to 60 mg
 Not to use more than once in 24 hrs

44. TO SUMMARISE
 Significant improvements in IELT, ejaculatory
control, sexual satisfaction
 Reduction in personal and interpersonal distress
 Improved relationships & quality of life
 Severe the illness, better the improvement
 Common AE are nausea, headache, dizziness,
somnolence, insomnia
No change in blood pressure, heart rate, ECG
No discontinuation syndrome
Rare serious side effects

45. TO SUMMARISE
 Avoid with hepatic, severe renal impairment,
concomitant potent CYP3A4 & CYP2D6 inhibitors
& alcohol
 Lack of chronic serotonergic stimulation &
receptor desensitization minimize risk of
withdrawal syndrome
 At present it has largest efficacy and safety
database for use in men with PE

46. PROS & CONS
Potential advantages
On demand medicine
Significant improvement in IELT & PEP
Less frequent side effects
No withdrawal symptoms
Potential disadvantages
Lack of studies
Not U.S. FDA, UK approved
Several drug to drug interactions
Can not be used in hepatic and renal dysfunction

47. PE SYNDROME
Marcel Waldinger
F

48. Future trend
 Development of drug that act as antagonist on
5HT 1A receptor & inhibit the serotonergic
transmission at synapse