Dapoxetin

presentation on molecule dapoxetin by anant kumar rathi

1. DAPOXETINE IN SEXUAL DYSFUNCTIONS PRESENTOR DR. ANANT KUMAR RATHI 2 nd 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 NERVOUS SYSTEM PARASYMPATHETIC SYSTEM SYMPATHETIC SYSTEM AFFERENT PUDENDAL NERVE & SACRAL PLEXUS PUDENDAL NERVE RELAY SACRAL SEGMENTS OF SPINAL CORD LUMBAR SEGMENTS OF SPINAL CORD EFFERENT PELVIC SPLANCHNIC NERVE (NERVI ERIGENTIS) HYPOGASTRIC & PELVIC SYMPATHETIC 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 & personality; characterized by sexual fantasies & desire to have sex Hypoactive sexual desire disorder; sexual aversion disorder (male or female) 2. Excitement Subjective sense of sexual pleasure & accompanying physiological responses (sexual flush, erection by vasocongestion, tightening & lifting of scrotal sac, increase size of testes ) Female sexual arousal disorder Male erectile disorder; dyspareunia 3. Orgasm Peaking of sexual pleasure, release of sexual tension & rhythmic contraction of perineal muscles and pelvic reproductive organs Orgasmic disorder (male & female); premature ejaculation 4. Resolution A sense of general relaxation, wellbeing & muscle relaxation Post coital dysphoria ; post 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 organs

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 Resolution Excitement Sexual Interest/ Stimulation Ejaculation Accompanied by Orgasm Orgasm Penile tumescence High arousal/ Erection Penetration Penile Detumesence Time Plateau

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

9. Premature Ejaculation (PE) [ICD-10 F52.4] WHO 2 nd 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) (IELT - time interval between penetration & ejaculation)

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 anxious personality

12. Etiology of Premature Ejaculation Low 5HT neurotransmission Hyposensitivity of 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 label treatment represented substantial unmet treatment need

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

24. 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) hepatic impairment leads to increased Cmax & AUC

25. 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

26. 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

27. 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 (n=145) 40 mg (n=141) Placebo (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 effect 2

28. 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 (n=144) 100 mg (n=155) Placebo (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 adverse effect 9 1

29. 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

30. 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 Treatment duration Randomized subjects Inclusion criteria U.S. Study Multicentre, D/B, randomized, placebo controlled 12 weeks 1294 IELT less than 2 mins during 2 wks baseline period , met DSM IV TR criteria U.S. Study Multicentre, D/B, randomized, placebo controlled 12 weeks 1320 Same as above International Study Multicentre, D/B, randomized, placebo controlled 24 weeks 1162 IELT less than 2 mins during 4 week baseline period, met DSM IV TR criteria Asia Pacific Study Multicentre, D/B, randomized, placebo controlled 12 weeks 1067 Same as above North American Study Multicentre, D/B, randomized, placebo controlled 9 weeks 1238 Same as above except no IELT criterion

31. 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)

32. Dapoxetine dose 30 mg (n=1613) 60 mg (n=1611) Placebo (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 % baseline 38.5 38.8 36.1 % study end 16.0 12.3 23.8 Discontinuation due to A/E 3.5 8.8 1.0

33. Changes in IELT ( mins ) over time Placebo Dapoxetine 30 mg

34. Percentage of subjects reporting that their PE was better/much better at 12 weeks (CGIC) Placebo Dapoxetine 30 mg Dapoxetine 60 mg

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

36. 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 )

37. 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

38. 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)

39. Adverse Events

40. 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

41. 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 dapoxetin

42. 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 1 st dose Can be increased up to 60 mg Not to use more than once in 24 hrs

43. 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

44. 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

45. 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

46. PE SYNDROME Marcel Waldinger F

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