Efficacy and safety of dapoxetine/sildenafil combination tablets in the treatment of men with premature ejaculation and concomitant erectile dysfunction-DAP-SPEED Study
Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in C maxof bosentan (125 mg b.i.d.). 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of FertilitySildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18–21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2basis in a 50 kg subject.MutagenesisSildenafil was negative in in vitrobacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitrohuman lymphocytes and in vivomouse micronucleus assays to detect clastogenicity.Impairment of FertilityThere was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.
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Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg.
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Sildenafil was not carcinogenic when administered to mice for 18–21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2basis in a 50 kg subject. There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC. 14 CLINICAL STUDIES In clinical studies, sildenafil tablets was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. Sildenafil tablets was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). Sildenafil tablets was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. Sildenafil tablets demonstrated statistically significant improvement compared to placebo in all 21 studies.
| Condition | Explanation | Alternative Approach |
|---|---|---|
| Nitrate medications | Dangerous interaction leading to hypotension | Consult healthcare provider |
| Severe liver or kidney disease | Altered drug metabolism and excretion | Dose adjustment or avoidance |
| Hypersensitivity to ingredients | Allergic reactions possible | Discontinue use immediately |
| Heart conditions | Increased cardiovascular risks | Medical evaluation required |
The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo.Efficacy Endpoints in Controlled Clinical StudiesThe effectiveness of sildenafil tablets was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function - IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction.
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Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in C maxof bosentan (125 mg b.i.d.). 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of FertilitySildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18–21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2basis in a 50 kg subject.MutagenesisSildenafil was negative in in vitrobacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitrohuman lymphocytes and in vivomouse micronucleus assays to detect clastogenicity.Impairment of FertilityThere was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC. Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18–21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2basis in a 50 kg subject.
Drugs you should not use with sildenafil
There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC. 14 CLINICAL STUDIES In clinical studies, sildenafil tablets was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. Sildenafil tablets was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). Sildenafil tablets was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. Sildenafil tablets demonstrated statistically significant improvement compared to placebo in all 21 studies.
How it works
The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo.Efficacy Endpoints in Controlled Clinical StudiesThe effectiveness of sildenafil tablets was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function - IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Sexual function data were dapoxetine sildenafil online also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered.Efficacy Results from Controlled Clinical StudiesThe effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results.
- Sildenafil helps improve erectile response in men with ED.
- Dapoxetine may enhance control over ejaculation for men with PE.
- Combining sildenafil and dapoxetine can improve sexual satisfaction.
- Use sildenafil with caution in patients with heart conditions.
- Dapoxetine has a short half-life, suitable for on-demand use.
- Patients should avoid high-fat meals immediately before taking sildenafil.
- Dapoxetine should be taken with a full glass of water.
- Both drugs are contraindicated in patients with certain heart problems.
Figure 6 shows that regardless of the baseline levels of function subsequent function in patients treated with sildenafil tablets was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline.The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 7.
12.2 Pharmacodynamics
Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were dapoxetine sildenafil online also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered.Efficacy Results from Controlled Clinical StudiesThe effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse.
-Missed Does
The titration studies, in which most patients received 100 mg, showed similar results. Figure 6 shows that regardless of the baseline levels of function subsequent function in patients treated with sildenafil tablets was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline.The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 7. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies.
Depression and anxiety
Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of sildenafil tablets, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar.Figure 7. Percentage dapoxetine order online of Patients Reporting an Improvement in Erections.The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period.In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of sildenafil on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50–100 mg of sildenafil vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on sildenafil vs about 20% on placebo.During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions.
| Parameter | Value | Notes |
|---|---|---|
| Absorption Rate | Rapid | Peak plasma in 1-2 hours |
| Half-Life | 21 hours | Longer duration for sustained effect |
| Metabolism | Liver (CYP2D6 and CYP3A4) | Biotransformation process |
| Excretion | Urine | Main route of elimination |
Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies.
- Sildenafil's effects last approximately 4-6 hours.
- Dapoxetine's onset is rapid, within 1-3 hours of intake.
- Side effects of sildenafil may include nasal congestion and visual changes.
- Dapoxetine may cause dry mouth and sweating as side effects.
- Combining these drugs might increase the risk of side effects.
- Usage should be based on a healthcare provider’s assessment.
- Patients with kidney or liver issues need dosage adjustments.
- Proper storage of medications is essential to maintain efficacy.
Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of sildenafil tablets, respectively, reported an improvement in their erections, compared to 24% on placebo.
| Side Effect | Frequency | Severity | Management Tips | Notes |
|---|---|---|---|---|
| Headache | Common | Mild | Hydration, pain relievers | Usually transient |
| Dizziness | Common | Mild | Avoid driving | May diminish over time |
| Nausea | Occasionally | Mild | Take with food | Self-limiting |
| Hypotension | Rare | Moderate | Seek medical advice | Monitor blood pressure |
In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar.Figure 7. Percentage dapoxetine order online of Patients Reporting an Improvement in Erections.The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period.In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of sildenafil on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50–100 mg of sildenafil vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on sildenafil vs about 20% on placebo.During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that sildenafil improved their erections.Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. Sildenafil improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction.One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of sildenafil; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on sildenafil compared to placebo.
8.6 Renal Impairment
At the end of the long-term study, 88% of patients reported that sildenafil improved their erections.Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. Sildenafil improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction.One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of sildenafil; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on sildenafil compared to placebo. On a global improvement question, 57% of sildenafil patients reported improved erections versus 10% on placebo.
Side Effects
Diary data indicated that on sildenafil, 48% of intercourse attempts were successful versus 12% on placebo.One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of sildenafil. On a global improvement question, 83% of patients reported improved erections on sildenafil versus 12% on placebo. Diary data indicated that on sildenafil, 59% of attempts at sexual intercourse were successful compared to 13% on placebo.Across all trials, sildenafil improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo.Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of sildenafil patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of sildenafil .Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for sildenafil and 29% for placebo.Efficacy Results in Subpopulations in Controlled Clinical StudiesA review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age.
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On a global improvement question, 57% of sildenafil patients reported improved erections versus 10% on placebo. Diary data indicated that on sildenafil, 48% of intercourse attempts were successful versus 12% on placebo.One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted.
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The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of sildenafil. On a global improvement question, 83% of patients reported improved erections on sildenafil versus 12% on placebo. Diary data indicated that on sildenafil, 59% of attempts at sexual intercourse were successful compared to 13% on placebo.Across all trials, sildenafil improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo.Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of sildenafil patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of sildenafil .Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for sildenafil and 29% for placebo.Efficacy Results in Subpopulations in Controlled Clinical StudiesA review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age.
