Efficacy and safety of dapoxetine/sildenafil combination tablets in the treatment of men with premature ejaculation and concomitant erectile dysfunction-DAP-SPEED Study

Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg.

5.1 Cardiovascular

Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels. In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil C max. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil. In healthy male volunteers, there was no evidence of a clinically significant effect of azithromycin (500 mg daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite.

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Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. These effects on the metabolite are not expected to be of clinical consequence. Effects of sildenafil tablets on Other Drugs Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µM). Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that sildenafil will alter the clearance of substrates of these isoenzymes. No significant interactions were dapoxetine 60 mg tablets shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. 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.

Figure 6 shows that regardless of the baseline levels of function subsequent function in

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In addition, N-desmethyl metabolite AUC and C maxvalues significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment:In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C max(47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [ see Dosage and Administration (2.5), and Use in Specific Populations (8.7)]. Therefore, age >65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. A starting oral dose of 25 mg should be considered in those patients [ see Dosage and Administration (2.5) Effects of Other Drugs on sildenafil tablets Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route).

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Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers. When a single 100 mg dose of sildenafil tablets was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C maxand a 182% increase in sildenafil AUC. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [ see Dosage and Administration (2.4)and Drug Interactions (7.4)]. In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C maxand a 1000% (11- fold) increase in sildenafil plasma AUC. Sildenafil tablets had no effect on ritonavir pharmacokinetics [ see Dosage and Administration (2.4)and Drug Interactions (7.4)]. patients treated with sildenafil tablets was better than that seen in patients treated with placebo.

• Sildenafil is not recommended for use by women.
• Dapoxetine is approved specifically for men with PE.
• Both drugs help improve sexual confidence and performance.
• Proper hydration can help mitigate side effects.
• Patients with retinal disorders should consult a healthcare professional.
• Use of these medications does not protect against sexually transmitted infections.
• Combining medications without medical guidance can be dangerous.
• Inform your doctor if you experience any adverse reactions.

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

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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. 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.

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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. Sexual function data were 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. 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.

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In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates. Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg). 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. 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 priligy dapoxetine canada 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). These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions.

• Consistent use of sildenafil can help maintain erectile function.
• Dapoxetine provides a pharmacological solution for PE.
• Both products should be stored in a cool, dry place away from children.
• Side effects may diminish with continued use or dose adjustment.
• Some patients may require alternative therapies if side effects occur.
• Clinical guidelines recommend consultation before combining treatments.
• Dapoxetine's short half-life minimizes residual effects.
• Patients should inform healthcare providers about all current medications.

Erectile dysfunction was attributed to organic (58%; generally not characterized, but including

• 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.

diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies.