Efficacy and safety of dapoxetine in men with premature ejaculation and concomitant erectile dysfunction treated with a phosphodiesterase type 5 inhibitor: randomized, placebo-controlled, phase III study.

INTRODUCTION: Men with comorbid erectile dysfunction (ED) and premature ejaculation (PE) may be concomitantly prescribed a phosphodiesterase type 5 (PDE5) inhibitor and dapoxetine. AIM: Evaluate efficacy and safety of dapoxetine 30 mg and 60 mg on demand (prn) in men with PE and ED who were being treated with PDE5 inhibitors. METHODS: This randomized, double-blind, placebo-controlled, flexible-dose, multicenter study enrolled men ≥18 years who met diagnostic criteria for PE including intravaginal ejaculatory latency time (IELT) of ≤2 minutes in ≥75% of sexual intercourse episodes; were on stable regimen of a PDE5 inhibitor; and had International Index of Erectile Function-erectile function domain score ≥21. Subjects received placebo, dapoxetine 30 mg, or dapoxetine 60 mg prn (1-3 hours before intercourse) for 12 weeks. MAIN OUTCOME MEASURE: Stopwatch-measured average IELT, Clinical Global Impression of Change (CGIC) in PE, Premature Ejaculation Profile (PEP), and treatment-emergent adverse events (TEAEs). RESULTS: Of 495 subjects randomized, 429 completed the study. Arithmetic mean average IELT significantly increased with dapoxetine vs. placebo at end point (5.2 vs. 3.4 minutes) and weeks 4, 8, and 12 (P ≤ 0.002 for all). Men who described their PE at least "better" using the CGIC were significantly greater with dapoxetine vs. placebo at end point (56.5% vs. 35.4%) and weeks 4, 8, and 12 (P ≤ 0.001 for all). Significantly better outcomes were also reported with dapoxetine vs. placebo on PEP measures. Incidence of TEAEs was 20.0% and 29.6% in placebo- and dapoxetine-treated subjects, respectively (P = 0.0135). TEAEs led to discontinuation in 1.6% of subjects in both groups. Most frequent TEAEs were known adverse drug reactions of dapoxetine treatment including nausea (9.2%), headache (4.4%), diarrhea (3.6%), dizziness (2.4%), and dizziness postural (2.4%). CONCLUSIONS: In men with PE and comorbid ED on a stable regimen of PDE5 inhibitor, dapoxetine provided meaningful treatment benefit and was generally well tolerated.

Efficacy and safety of dapoxetine for the treatment of premature ejaculation: integrated analysis of results from five phase 3 trials.

INTRODUCTION: Dapoxetine has been evaluated for the on-demand treatment of premature ejaculation (PE) in five phase 3 studies in various populations worldwide and has recently been approved in several countries. AIM: To present integrated efficacy and safety data from phase 3 trials of dapoxetine. METHODS: Data were from five randomized, multicenter, double-blind, placebo-controlled studies conducted in over 25 countries. Men (N=6,081)≥18 years who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE; four studies required a baseline intravaginal ejaculatory latency time (IELT) of ≤2 minutes. Dapoxetine 30 and 60 mg on demand (prn; 1-3 hours before intercourse) were evaluated for either 12 or 24 weeks in four studies; one study evaluated dapoxetine 60 mg daily (qd; included in safety assessments only) or prn for 9 weeks. MAIN OUTCOME MEASURES: End points included stopwatch-measured IELT, Premature Ejaculation Profile (PEP) items, clinical global impression of change (CGIC) in PE, and adverse events (AEs). RESULTS: Average IELT (mean [standard deviation], geometric mean [standard error]) increased from baseline (across groups, 0.9 [0.49] minutes, 0.8 [1.01] minutes) to a significantly greater extent with dapoxetine 30 (3.1 [3.91] minutes, 2.0 [1.03] minutes) and 60 mg (3.6 [3.85] minutes, 2.3 [1.03] minutes) vs. placebo (1.9 [2.43] minutes, 1.3 [1.02] minutes; P<0.001 for all) at week 12 (geometric mean fold increase, 2.5, 3.0, and 1.6, respectively). All PEP items and CGIC improved significantly with both doses of dapoxetine vs. placebo (P<0.001 for all). The most common AEs included nausea, dizziness, and headache, and evaluation of validated instruments demonstrated no anxiety, akathisia, suicidality, or changes in mood with dapoxetine use and no discontinuation syndrome following abrupt withdrawal. CONCLUSIONS: In this diverse population, dapoxetine significantly improved all aspects of PE and was generally well tolerated.

Baseline characteristics and treatment outcomes for men with acquired or lifelong premature ejaculation with mild or no erectile dysfunction: integrated analyses of two phase 3 dapoxetine trials.

INTRODUCTION: Premature ejaculation (PE) is classified as an acquired or lifelong condition but data on baseline characteristics and response to treatment of men with acquired or lifelong PE and mild erectile dysfunction (ED) or normal erectile function (EF) is limited. AIM: To present integrated analyses of baseline characteristics and treatment outcomes from phase 3 dapoxetine trials in men with acquired or lifelong PE and mild or no ED. METHODS: Data were analyzed from two randomized, double-blind, placebo-controlled, phase 3 clinical trials (International and Asia-Pacific) that evaluated efficacy and safety of dapoxetine (30 mg or 60 mg as needed [PRN]) in patients with PE. Men were ≥18 years, in a stable monogamous relationship for ≥6 months, met DSM-IV-TR criteria for PE for ≥6 months, had an International Index of Erectile Function EF domain score ≥21, and had an intravaginal ejaculatory latency time (IELT) ≤2 minutes in ≥75% of intercourse episodes. MAIN OUTCOME MEASURES: Demographics, sexual history, and PE symptomatology at baseline, and mean IELT and patient-reported outcomes (PROs) at study end (week 12), were analyzed for men with acquired or lifelong PE and mild or no ED (EF score 21-25 vs. ≥26). RESULTS: Baseline characteristics except duration of PE were similar in men with acquired and lifelong PE, with no other differentiating features by ED status. Dapoxetine treatment improved significantly mean IELT (arithmetic and geometric) and PRO responses (perceived control over ejaculation, satisfaction with sexual intercourse, ejaculation-related personal distress, and interpersonal difficulty) for acquired and lifelong subtypes, but presence of mild ED diminished PRO responsiveness in both subtypes, particularly those with lifelong PE. CONCLUSIONS: Baseline characteristics and treatment outcomes were generally similar in men with acquired and lifelong PE. The presence of mild ED appears to be associated with a more modest treatment response, irrespective of lifelong or acquired PE subtype.

Dapoxetine for the treatment of premature ejaculation: results from a randomized, double-blind, placebo-controlled phase 3 trial in 22 countries.

BACKGROUND: Dapoxetine is being developed for the on-demand treatment of premature ejaculation (PE). Previous clinical trials have demonstrated its safety and efficacy. OBJECTIVE: To evaluate the long-term efficacy and safety of dapoxetine in men with PE. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial, conducted in 22 countries, enrolled men (N=1162) > or = 18 yr of age who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE for > or = 6 mo, with an intravaginal ejaculatory latency time (IELT) < or = 2 min in > or = 75% of intercourse episodes at baseline. INTERVENTION: Dapoxetine 30 mg or dapoxetine 60 mg or placebo on demand (1-3 h before intercourse) for 24 wk. MEASUREMENTS: Stopwatch-measured IELT, Premature Ejaculation Profile (PEP), Clinical Global Impression (CGI) of change, adverse events (AEs). RESULTS AND LIMITATIONS: The study was completed by 618 men. Mean average IELT increased from 0.9 min at baseline (all groups) to 1.9 min, 3.2 min, and 3.5 min with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively, at study end point; geometric mean IELT increased from 0.7 min at baseline to 1.1 min, 1.8 min, and 2.3 min, respectively, at study end point. All PEP measures and IELTs improved significantly with dapoxetine versus placebo at week 12 and week 24 (p<0.001 for all). The most common AEs were nausea, dizziness, diarrhea, and headache. AEs led to discontinuation in 1.3%, 3.9%, and 8.2% of subjects with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively. Limitations of this study included the exclusion of men who were not in long-term monogamous relationships. CONCLUSIONS: Dapoxetine significantly improved all aspects of PE and was generally well tolerated in this broad population.

Intravesical resiniferatoxin for refractory detrusor hyperreflexia: a multicenter, blinded, randomized, placebo-controlled trial.

OBJECTIVE: Resiniferatoxin (RTX) is an analogue of capsaicin with more than 1,000 times its potency in desensitizing C-fiber bladder afferent neurons. This study investigated the safety and efficacy of intravesical RTX in patients with refractory detrusor hyperreflexia (DH). METHODS: Thirty-six (22 males, 14 females) neurologically impaired patients (20 spinal cord injury, 7 multiple sclerosis, 9 other neurologic diseases) with urodynamically verified DH and intractable urinary symptoms despite previous anticholinergic drug use were treated prospectively with intravesical RTX using dose escalation in a double-blind fashion at 4 centers. Patients received a single instillation of 100 mL of placebo (n = 8 patients) or 0.005, 0.025, 0.05, 0.10, 0.2, 0.5, or 1.0 microM of RTX (n = 4 each group). A visual analog pain scale (VAPS) (0-10; 10 = highest level of pain) was used to quantify discomfort of application. Treatment effect was monitored using a bladder diary and cystometric bladder capacity at weeks 1, 3, 6, and 12 posttreatment. RESULTS: Mean VAPS scores revealed minimal to mild discomfort with values of 2.85 and 2.28 for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. Due to the small sample size, there were no statistically significant changes in mean cystometric capacity (MCC) or incontinence episodes in each treatment dose group. However, at 3 weeks, MCC increased by 53% and 48% for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. Patients in the 0.5-microM and 1.0-microM groups with MCC < 300 mL at baseline showed greater improvements in MCC at 120.5% and 48%, respectively. In some patients, MCC increased up to 500% over baseline, despite a low RTX dose. Incontinence episodes decreased by 51.9% and 52.7% for the 0.5-microM and 1.0-microM RTX treatment groups, respectively. There were no long-term complications. CONCLUSION: Intravesical RTX administration, in general, is a well-tolerated new therapy for DH. This patient group was refractory to all previous oral pharmacologic therapy, yet some patients responded with significant improvement in bladder capacity and continence function shortly after RTX administration. Patients at risk for autonomic dysreflexia require careful monitoring during RTX therapy.