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Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it.

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(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.

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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.

• Dapoxetin is generally well-tolerated with minimal interactions.
• Sildenafil interacts with nitrates, causing dangerous blood pressure drops.
• Inform your doctor of all medications you are taking.

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) PE sub classification:- (Schapiro1943) Lifelong(Primary) PE :- Commences with onset of sexual activity Acquired(secondary) PE :- Develops following a period of normal ejaculatory response.

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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) PE sub classification:- (Schapiro1943) Lifelong(Primary) PE :- Commences with onset of sexual activity Acquired(secondary) PE :- Develops following a period of normal ejaculatory response.

CAS registry number (Chemical Abstracts Service)

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 Etiology of PrematureEjaculation Low 5HT Hyposensitivity of neurotransmission 5HT2C Ejaculatory threshold genetically "set" at a lower point Ejaculate quickly and with minimal stimulation Epidemiology:- PE isthe 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 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 TREATMENT OF PREMATURE EJACUALTION Incorporate into sexual priligy dapoxetine canada practice Behavioural techniques - stop/start, squeeze Oral medication - SSRI, clomipramine, PDE5i Intra-cavernosal injections Anaesthetic cream Pelvic floor exercises Surgery to dorsal nerve (Brazil) 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 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 Ejaculo-Selective Serotonin TransportInhibitor (ESSTIs) Drugs under investigation are Dapoxetine UK-390 UK-957 Tramadol 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 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 Pharmacokinetics of singledose 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 Mechanism of action Dapoxetine ↑ 5HT Activation of neurotransmission 5HT2C Elevates ejaculatory threshold "set" point Delays Ejaculation Indian J Urol 2007;23:97-108 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) 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.

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(caution-hypotension) Alcohol increased somnolence & reduced alertness Concomitant MAOI & SSRI/SNRI may result in serotonin related A/E 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 Result of dapoxetinephase 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 Result of dapoxetinephase 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 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 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 tadalafil dapoxetine 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 Phase 3 studiespooled 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) 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 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 Percentage of subjectsreporting 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 Effect of dapoxetineon 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 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. 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 Etiology of PrematureEjaculation Low 5HT Hyposensitivity of neurotransmission 5HT2C Ejaculatory threshold genetically "set" at a lower point Ejaculate quickly and with minimal stimulation Epidemiology:- PE isthe 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.

• Dapoxetin can help delay ejaculation for better control.
• Sildenafil can improve erectile firmness and duration.
• These medications target different aspects of sexual dysfunction.

(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.

• There is no evidence that this combination affects fertility or sperm quality.
• Dapoxetine, as an SSRI, has been associated with slight changes in semen parameters.
• These changes are not thought to be clinically significant for fertility.
• Sildenafil has no known negative impact on sperm count or motility.
• Men trying to conceive should discuss any medications with their doctor.
• The drugs are not known to cause birth defects if a partner is exposed to semen.
• However, this is not a well-studied area, and caution is always advised.
• The primary focus of treatment is on the male partner's sexual function.
• The female partner's satisfaction is an important secondary outcome measure.
• Open communication between partners about the treatment is encouraged.
• Sexual dysfunction is a couples' issue, and treatment should involve both partners when possible.

(Fasolo, Mirone 2005) No association found with HTN, Cardiac disease, Peripheral or central neuropathy 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 TREATMENT OF PREMATURE EJACUALTION Incorporate into sexual priligy dapoxetine canada practice Behavioural techniques - stop/start, squeeze Oral medication - SSRI, clomipramine, PDE5i Intra-cavernosal injections Anaesthetic cream Pelvic floor exercises Surgery to dorsal nerve (Brazil) 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 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 Ejaculo-Selective Serotonin TransportInhibitor (ESSTIs) Drugs under investigation are Dapoxetine UK-390 UK-957 Tramadol 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 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 Pharmacokinetics of singledose 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 Mechanism of action Dapoxetine ↑ 5HT Activation of neurotransmission 5HT2C Elevates ejaculatory threshold "set" point Delays Ejaculation Indian J Urol 2007;23:97-108 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) 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 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 Result of dapoxetinephase 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 Result of dapoxetinephase 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 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 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 tadalafil dapoxetine weeks 1294 IELT less than 2 mins during randomized, placebo 2 wks baseline period, met Study controlled DSM IV TR criteria U.S.

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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 Phase 3 studiespooled 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) 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 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 Percentage of subjectsreporting 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 Effect of dapoxetineon 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 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.

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(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.