Clinical Uses of Combined Dapoxetine Sildenafil

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 dapoxetine 60mg tablet price 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 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.

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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 dapoxetine 60mg tablet price 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 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. (Decrease in anxiety/no worsening of anxiety ) dapoxetine sex 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. Safety Adverse event occurred in 56.1% subjects v/s 35.1% in placebo. (Decrease in anxiety/no worsening of anxiety ) dapoxetine sex Effect on akathisia:- Barnes Akathisia Rating Scale (BARS) scores did not changed.

• The legal status of dapoxetine varies significantly more than sildenafil.
• In some countries, dapoxetine is not available at all, making combination impossible.
• Telemedicine consultations have made access to specialists for these issues easier.
• However, a physical examination is often still required for a first-time prescription.
• Blood tests may be ordered to rule out hormonal causes like low testosterone.
• The role of the partner in treatment success and support should not be underestimated.
• Couples therapy can address relational issues that contribute to sexual dysfunction.
• The drugs treat the symptoms, not necessarily the root cause of the problems.
• A healthy lifestyle with exercise and a good diet can improve overall sexual health.
• Smoking cessation is highly recommended, as it is a major cause of vascular ED.
• Managing stress through techniques like mindfulness can also be beneficial.

(No change in akathisia) Effect on suicidality:- BDI-II or MADRS score of 0 on suicidality item.

Safety Adverse event occurred in 56.1% subjects v/s 35.1% in placebo.

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[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 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) 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 USE IN SPECIALPOPULATION Contraindicated in Men with moderate to severe hepatic impairment, severe renal dapoxetine 60 mg tablets 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 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 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 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 PROS & CONS Potentialadvantages On demand medicine Significant improvement in IELT & PEP Less frequent side effects No withdrawal symptoms Potential disadvantages Lack of studies Not U.S.

• Dapoxetin is an SSRI used for premature ejaculation treatment.
• Sildenafil is a PDE5 inhibitor for erectile dysfunction.
• Combining dapoxetin and sildenafil may enhance sexual performance.

FDA, UK approved Several drug to drug interactions Can not be used in hepatic and renal dysfunction Future trend Development of drug that act as antagonist on 5HT 1A receptor & inhibit the serotonergic transmission at synapse A simple, specific and accurate reverse phase high performance liquid chromatographic method was developed for the simultaneous determination Sildenafil and Dapoxetine in pharmaceutical dosage form.

Possible Side Effects

[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 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) 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 USE IN SPECIALPOPULATION Contraindicated in Men with moderate to severe hepatic impairment, severe renal dapoxetine 60 mg tablets 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 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 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 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 PROS & CONS Potentialadvantages 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 Future trend Development of drug that act as antagonist on 5HT 1A receptor & inhibit the serotonergic transmission at synapse A simple, specific and accurate reverse phase high performance liquid chromatographic method was developed for the simultaneous determination Sildenafil and Dapoxetine in pharmaceutical dosage form. The column used was Kromasil C18(150mm x 4.6 mm, 5mm) in isocratic mode, with mobile phase containing phosphate buffer(accurately weighed 1.36gm of Potassium dihydrogen Ortho phosphate in a 1000ml of Volumetric flask add about 900ml of milli-Q water added and degas to sonicate, add 0.5ml of Triethylamine, finally made up the volume with water and pH adjusted to 3.5 with dil.

CAS registry number (Chemical Abstracts Service)

The column used was Kromasil C18(150mm x 4.6 mm, 5mm) in isocratic mode, with mobile phase containing phosphate buffer(accurately weighed 1.36gm of Potassium dihydrogen Ortho phosphate in a 1000ml of Volumetric flask add about 900ml of milli-Q water added and degas to sonicate, add 0.5ml of Triethylamine, finally made up the volume with water and pH adjusted to 3.5 with dil.

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