Dapoxetine is a selective inhibitor of neuronal reabsorption of serotonin (SSRI), registered by the Italian Medicines Agency (AIFA) for the treatment of premature ejaculation. In addition to Italy, it has been authorized in 6 other European countries (Sweden, Finland, Austria, Germany, Spain and Portugal).
The causes of premature ejaculation have not been fully understood, but the disorder is likely to depend on a combination of psychological and physiological factors. Among the latter, a reduced availability of serotonin in the central nervous system could play an important role in the complex mechanisms involved in ejaculation1,2. In humans, the ejaculatory process originates from a center of the spinal reflex, mediated by the brain stem, which is initially influenced by numerous brain nuclei. The coordinated contraction of seminal vesicles, prostate, vas deferens and bulbourethral muscles, innervated by sympathetic fibers, leads to ejaculation. In the rat, dapoxetine modulates this ejaculatory reflex, causing an increase in the firing latency of the pudendal nerve motor neuron reflex and a reduction in the duration of firing3.
After oral administration, the drug reaches peak plasma levels in approximately 1 hour4. In the liver and kidneys, it is extensively metabolised; the two active metabolites, desmethyldapoxetine and didemetidapoxetine, are eliminated mainly in the urine, in the conjugated form4,5.
After 24 hours of intake, concentrations are below 5% of the maximum levels4.5. Minimal accumulation of dapoxetine was observed after daily administration5. The terminal half-life is approximately 20 hours4.

                                                            CLINICAL EFFICIENCY

The efficacy of dapoxetine in the treatment of premature ejaculation, taken as needed 1 to 3 hours before sexual intercourse, was evaluated in 3 randomized, double-blind, placebo-controlled studies6-8. The inclusion criteria included a history of premature ejaculation according to DSM-IV, i.e. ejaculation with minimal sexual stimulation, before, during or shortly after penetration and sooner than desired in most sexual intercourse in the 6 months preceding the enrollment and marked personal distress or interpersonal difficulty resulting from premature ejaculation. Patients over 18 years of age had an intravaginal ejaculatory latency time (IELT) of less than 2 minutes in at least three-quarters of sexual intercourse during a 2-week baseline period. Patients with other forms of sexual dysfunction or with cardiovascular pathologies, those using drugs with serotonergic effect (SSRI, SNRI, tricyclic antidepressants) were excluded.
In the first two studies, from the same experimental design, both lasting 12 weeks, analyzed cumulatively, 2,614 American males between the ages of 18 and 64 with stable heterosexual relationships and with premature ejaculation problems subjectively judged as moderate-severe, were treated with dapoxetine (30 and 60 mg) or placebo6. In 1,958 patients evaluable at follow up, the mean IELT (primary end point) measured with the aid of a stopwatch during each intercourse after the first dose, at 4, 8 and 12 weeks, increased significantly with the two dapoxetine doses (baseline 0.92 to 2.78 minutes with 30 mg and 0.91 to 3.32 minutes with 60 mg) versus placebo (baseline 0.90 to 1.75 minutes) 6. Therefore, it can be estimated that dapoxetine increases the IELT by 1.9 (30 mg) and 2.3 times (60 mg) compared to 1.2 times with placebo7. In an indirect comparison, the delaying effect of dapoxetine on ejaculation appears much lower than that induced by other SSRIs, such as paroxetine (8.8) 7 or escitalopram (4.9) 8.
In the third study with a longer observation period, 1,162 patients were randomized to dapoxetine 30 mg (n = 388), dapoxetine 60 mg (n = 389) or to placebo (n = 385) 9. After 24 weeks, the arithmetic mean of the IELT measured after the first dose and every 4 weeks thereafter (primary endpoint) increased from baseline of 0.9 minutes (in all groups) to 1.9 minutes with placebo. 3.2 minutes with 30 mg dapoxetine and 3.5 minutes with 60 mg dapoxetine. Among the secondary outcome measures, a higher percentage of patients than the placebo group reported a decrease in subjective distress (60-69% vs. 48%) and an improvement in satisfaction (48-56% vs. 36%) . At the 24th week, patients were asked to judge their condition with respect to the start of the study (CGIC); the response outcome in the two extreme parameters was: no change or worsening (28% with 60 mg, 42% with 30 mg vs. 68% with placebo), much better (10% with 30 mg, 12% with 60 mg vs. 4% with placebo) 5.9.

                                                               CONTINUOUS USE

In a double-blind, randomized, controlled study, 212 males diagnosed with premature ejaculation were treated with dapoxetine 30 mg twice daily or placebo10. After 12 weeks, the mean IELT increased 2.9 times with dapoxetine and 1.4 with placebo. After 3 months of drug discontinuation, the patients’ condition returned to that of pre-treatment10. Another randomized, double-blind study in 340 patients compared dapoxetine (60 mg) with paroxetine (20 mg) and placebo, given once daily for 12 weeks11. At the end of the study, the mean IELT increased from 38 to 179 seconds with dapoxetine, from 31 to 370 seconds with paroxetine and from 34 to 55 seconds with placebo. During treatment, the mean number of sexual intercourse per week increased from 1.4 to 2.3 with dapoxetine, from 1.3 to 2.5 with paroxetine, from 1.3 to 1.4 with placebo.
The effects of chronically discontinuing dapoxetine dosing were evaluated as a primary end point in a double-blind clinical study in which 1,238 patients were randomized12. Patients diagnosed with premature ejaculation according to DSM-IV received dapoxetine 60 mg or placebo, once daily, for 62 days. During the following week, there was no clear evidence of the onset of withdrawal symptoms and signs typically associated with stopping an SSRI.

                                                                    SIDE EFFECTS

In clinical trials where dapoxetine was used as needed, the discontinuation rate due to adverse events was 3.9% -5.3% with 30 mg and 8.2% -11.6% with 60. mg6.9. The detection of undesirable effects took place retrospectively during the control visits, not after 24-48 hours from intake as would have been appropriate for a more reliable assessment. The most frequent, dose-related adverse reactions were nausea (8.7% with 30 mg and 20.1% with 60 mg), diarrhea (3.9% with 30 mg and 6.8% with 60 mg), headache (5.9% with 30 mg and 6.8% with 60 mg), dizziness (3% with 30 mg and 6.2% with 60 mg), somnolence (3.2% with 30 mg and 3, 7% with 60 mg) 6. Sexual adverse events, particularly erectile dysfunction, affected 2.9% of patients treated with the 30 mg dose and 3.8% of those treated with 60 mg6.
The incidence of syncope, described as loss of consciousness (of presumable vaso-vagal aetiology) within the first 3 hours of taking the first dose of the drug, ranged from 0.06% (30 mg) to 0, 23% (60 mg); syncope was often preceded by symptoms such as nausea, dizziness / lightheadedness and diaphoresis5. Cases of orthostatic hypotension have also been reported.

                                                                       WARNINGS

In patients taking dapoxetine, the onset of dizziness, disturbances in attention, drowsiness and syncope can impair driving ability and be dangerous.

                                                                  INTERACTIONS

Alcohol intake can aggravate the cardiogenic adverse events of dapoxetine such as syncope, increasing the risk of falls or road accidents (for those who drive) 5. Co-administration of other serotonergic drugs such as SSRIs, SNRIs, lithium, tricyclic antidepressants, hypericum preparations, triptans, tramadol, can cause the appearance of a serotin syndrome5.
The concomitant use of potent CYP3A4 inhibitors (eg macrolides, fluconazole, anti-HIV) can lead to a marked increase in plasma levels of dapoxetine.

                                                            THERAPEUTIC USAGE

The recommended starting dose for all patients is 30 mg, to be taken as needed, approximately 1-3 hours before sexual activity. If 30 mg is not enough and the side effects are acceptable, the dose can be increased to 60 mg.

                                                                             DISTRIBUTION

Dapoxetine is commercialized under the name of Priligy (Dapoxetine 60MG), Tadapox (20MG Cialis + 60MG Dapoxetine) or Super Tadapox (40MG Cialis + 60MG Dapoxetine) and is distributed in all European Union countries by Suisse Pharma Ltd. (suisse-pharma.com).

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