Dapoxetine is a potent selective serotonin reuptake inhibitor. Human ejaculation is regulated, first, by the sympathetic nervous system. Ejaculation is triggered by the spinal reflex center with the involvement of the brainstem, which is mainly affected by a number of brain nuclei (medium preoptic and paraventricular nuclei). The mechanism of action of dapoxetine in premature ejaculation is likely associated with inhibition of serotonin reuptake by neurons and the consequent increase in the effect of neurotransmitters on pre and post-synaptic receptors.
Clinical effectiveness and safety.
The effectiveness of Priligy in the treatment of premature ejaculation was established in five double-blind clinical trials with placebo control, in which there were a randomized total of 6081 patients. Patients were over 18 years old. 6 months before the inclusion of these people in the study, they had premature ejaculation in most sexual acts. Early ejaculation was determined according to the DSM-IV diagnostic criteria (Guidelines for the diagnosis and statistics of mental disorders): the short start time of ejaculation (latent time of intravaginal ejaculation [IELT, time from vaginal penetration to the time of intravaginal ejaculation ] is less than two minutes, which was measured with the use of a stopwatch in four studies) , poor control over ejaculation,
People with other types of sexual dysfunction, including erectile dysfunction, as well as people who use other drugs to treat PE, were excluded from all studies. The results of all randomized trials are comparable. Efficacy was observed after 12 weeks of treatment. One study included patients from EU countries and other countries, the duration of treatment was 24 weeks. In the study, 1162 patients were randomly assigned, 385 took a placebo, 388 patients took Priligy 30 mg if necessary, 389 patients took Priligy 60 mg if necessary. The average value and average IELT (intravaginal ejaculation latency time) at the end of the study are presented in Table 1, and the total patient distribution.
The magnitude of IELT elongation was associated with IELT output and was variable in individual patients: the clinical importance of the efficacy of Priligy treatment was demonstrated in efficacy rates and analysis of data from patients with therapeutic effect.
A patient with a therapeutic effect was defined as having at least one category 2 increase in ejaculation control plus a decrease of at least one category 1 in ejaculation disorders. Statistically, most patients had a therapeutic effect in each group used by Priligy compared to the placebo group at the end of the study: week 12 or 24. A higher percentage of patients with a therapeutic effect in the Priligy group was 30 mg (11.1 % - 95%). IC [7.24; 14.87]) and Priligy 60 mg (16.4% - 95% CI [13.01; 19.75]) compared to the placebo group at week 12 (generalized analysis).
The clinical importance of the effect of Priligy treatment is presented as an example of a group to measure the outcome of a patient's general clinical impression (CGIC), in which patients were asked to compare their premature ejaculation from the beginning of the study. , with a gradation of answers from "much better" to "much worse". At the end of the study (week 24), 28.4% (30 mg group) and 35.5% (60 mg group) reported that their condition was better or much more preferable compared to 14% in the placebo group. In addition, 53.4% and 65.6% of patients taking Priligy 30 mg and 60 mg, respectively, reported that their condition was at least slightly better compared to 28.8% in the placebo group.
Dapoxetine is rapidly absorbed and reaches a maximum plasma concentration (Cmax) approximately 1-2 hours after administration. Bioavailability is 42% (range 15-76%), and in the range of 30 mg to 60 mg, C max and AUC (area under the curve) increased in proportion to the dose. After repeated administration, AUC values for dapoxetine and the active metabolite demethyldoxetine increased by approximately 50% compared to AUC values after taking the drug in a single dose. Consumption of fatty foods decreased slightly to C max (by 10%) and slightly increased dapoxetine's AUC (by 12%), and also slightly extended the time to reach the maximum dapoxetine concentration. These changes were not clinically significant. Priligy can be taken regardless of meals.
Distribution. In vitro, 99% of dapoxetine binds to plasma proteins in humans. The active metabolite desmethyldoxetine binds to proteins by 98.5%. The average volume of distribution of dapoxetine in balance is 162 liters.
Metabolism. According to in vitro studies, dapoxetine is metabolised by numerous enzyme systems in the liver and renal tissue (mainly CYP2D6, CYP3A4) and flavins containing monooxygenase (FMO1). After taking 14 C-dapoxetine, the latter is actively metabolized with the formation of numerous metabolites, which involve, first, such routes of biotransformation of N-oxidation, N-demethylation, naftyl hydroxylation, glucuronidation and sulfation. There is evidence of a systemic effect of the first step after ingestion.
Most of the substances circulating in plasma were intact dapoxetine and dapoxetine N-oxide. In vitro binding and transport, studies have shown that dapoxetine N-oxide is inactive. Additional metabolites, such as desmethyldapoxetine and didesmethyldoxetine, accounted for less than 3% of the total amount of substances in plasma associated with the medicinal product. In vitro joining studies have shown that demethyl dapoxetine and dapoxetine have the same efficacy, and the activity of desmethyl dapoxetine is approximately 50% of dapoxetine activity. The concentration of free demethyl dapoxetine (AUC and C max) is, respectively, 50% and 23% of the concentration of free dapoxetine.
Conclusion. Dapoxetine metabolites are mainly excreted with urine in the form of conjugates. The active substance unchanged in the urine was not shown. After administration, the initial half-life of dapoxetine (pharmacokinetics) was approximately 1.5 hours, the plasma level was less than 5% of the maximum concentration 24 hours after administration and the final half-life was approximately 19 hours, as was the final dose. half-life of demethyl dapoxetine.
Pharmacokinetics in special groups of patients.
The metabolite desmethyldoxetine promotes the pharmacological effect of Priligy, in particular when the effect of desmethyldoxetine increases. Below is an increase in the indexes of the active fraction in some patient groups. This is the result of the effects free of dapoxetine and demethyl dapoxetine. Demethyl dapoxetine has the same potency as dapoxetine. A preliminary calculation provides a uniform distribution of demethyldoxetine in the central nervous system, but it is not known if it will.
Race. A clinical pharmacology analysis of a single dose of 60 mg dapoxetine showed no statistically significant differences in patients of different breeds.
Analysis of a clinical pharmacology study after a single dose of dapoxetine at a dose of 60 mg did not reveal a statistically significant difference between representatives of Hispanics, as well as Caucasian, negroid and breeds. Clinical studies have been conducted to compare the pharmacokinetics of dapoxetine in Japanese and Europeans and the Japanese were found to have a higher level of dapoxetine in plasma (10-20%) (area under the maximum curve and concentration) due to lower body weight. The significant clinical effect, if the concentration is slightly higher, is not expected.
Elderly (over 65 years).
A pharmacological analysis of a single dose of 60 mg dapoxetine showed no significant differences in pharmacokinetics (C max, AUC inf, T max) of healthy elderly men and healthy young men. Efficacy and safety have not been established for patients in this group.
Patients with renal impairment.
A clinical pharmacological study of the use of a single dose of 60 mg dapoxetine was conducted in patients with mild renal impairment (creatinine clearance of 50 to 80 ml / min), moderate (clearance of creatinine of 30 to <50 ml / min) and severe deterioration (creatinine clearance <30 ml / min) and patients with normal renal function (creatinine clearance> 80 ml / min). There was no tendency to increase dapoxetine AUC with decreased renal function. AUC in patients with severe renal impairment was approximately 2 times higher than in patients with normal renal function, although limited data are available for patients with severe renal impairment. The pharmacokinetics of dapoxetine have not been evaluated in patients requiring haemodialysis.
Patients with hepatic impairment.
In patients with moderate hepatic impairment, the value of dapoxetine-free C max is reduced by 28%, and the value of free AUC does not change. The free value of C max and AUC of the active fraction (the sum of the free influence of dapoxetine and demethyl dapoxetine) was reduced by 30% and 5%, respectively. In patients with moderate hepatic impairment, the value of dapoxetine-free C max remains virtually unchanged (a decrease of 3%) free AUC is increasing by 66%. The free C max and AUC of the active fraction of dapoxetine and demethyl dapoxetine were virtually unchanged and doubled, respectively.
In patients with severe hepatic impairment, the value of dapoxetine-free C max was reduced by 42%, but the value of free AUC increased by approximately 223%. C max and AUC of the active fraction had similar changes.
Treatment of premature ejaculation (PE) in adult men aged 18 to 64 years. Priligy is recommended only for patients who meet the following criteria: • The latent intravaginal ejaculation time (IELT) is less than two minutes; • persistent or repeated ejaculation after minimal sexual stimulation before, during or shortly after sexual penetration, which occurs before the patient's desired time; • severe stress or difficulties that arose in interpersonal relationships as a result of PE;
Lack of control over the onset of ejaculation;
The onset of premature ejaculation in most attempts at sexual intercourse in the last 6 months. Priligy should be taken if necessary only as a treatment, prior to the alleged sexual relationship. Priligy cannot be prescribed to delay ejaculation in men who have not been diagnosed with PE.
Hypersensitivity to the active substance or to some excipient of the drug.
Heart failure (NYHA Grades II-IV).
Conduction disorders, such as AV blockage or sinus node weakness syndrome.
Severe coronary heart disease.
Severe lack of heart valves.
History of fainting.
History of severe mania or depression.
Simultaneous administration of MAO inhibitors (MAO inhibitors) or if less than 14 days have elapsed after discontinuation. Priligy should be discontinued at least 7 days before initiation of MAO inhibitor therapy.
Concomitant use of thioridazine or within 14 days of the end of administration. The use of Priligy should be discontinued at least 7 days before starting thioridazine therapy.
Concomitant use of serotonin reuptake inhibitors (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SIZSN), tricyclic antidepressants (TCA)) or other herbal medications with tri-phyto-phyto-tri-phyto-tri-action triptans, tramadol, tramadol, tramadol lithium, Hypericum perforatum (Hypericum perforatum)] or within 14 days of cancellation of these medications/herbal products. These herbal medications/preparations should not be taken within 7 days of the end of taking Priligy.
Simultaneous administration of strong CYPZA4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, atazanavir, etc. (see section "Interaction with other medicines and other types of interactions").
INTERACTION WITH OTHER DRUGS AND OTHER TYPES OF INTERACTIONS
When taking SSRIs in combination with MAO inhibitors, serious reactions were reported, sometimes with a fatal outcome, which included hyperthermia, stiffness, myoclonia, autonomic nervous system disorders with the possible occurrence of rapid changes in vital functions, as well as changes in mental state, including severe agitation, rolling towards delirium and to whom. Such reactions have also been reported in patients who recently completed SSRIs and began taking MAO inhibitors. There have been isolated cases with symptoms similar to malignant antipsychotic syndrome. Data on the combined use of SSRIs and MAO inhibitors from animal studies suggest that these drugs may act synergistically, raising blood pressure and causing arousal. Therefore, Priligy should not be used in combination with MAO inhibitors or within 14 days of cancellation. MAO inhibitors should not be taken within 7 days of the end of taking Priligy.
Possible interaction with thioridazine.
Taking thioridazine causes an extension of the QTk interval, which is associated with the appearance of severe ventricular arrhythmias. Drugs like Priligy that inhibit CYP2D6 isoenzyme are likely to inhibit thioridazine metabolism. It is expected that the high level of thioridazine resulting from this will lead to a more pronounced elongation of the QTk. Priligy interval should not be used in combination with thioridazine or within 14 days of its withdrawal. Thioridazine should not be taken within 7 days after taking Priligy.
Herbal medications/preparations with serotonergic effects. As with selective serotonin reuptake inhibitors, joint administration with herbal/drug-based drugs with a serotonergic mechanism of action (including MAO inhibitors, L-Tryptophan, Trytanes, tramadol, linezolid, SSRIs, SIZZNS (selective serotonin reuptake inhibitors), lithium and Hypericum perforation-based preparations (Hypericicumtum perforate) can lead to an increase in the frequency of Serotonin effects. Priligy should not be used in combination with other SSRIs, MAO inhibitors or other herbal medications with a serotonergic mechanism of action or within 14 days of cancellation. In a similar way,
Medications that act on the central nervous system.
No systematic evaluation of Priligy intake was performed in conjunction with drugs acting on the central nervous system (such as antiepileptic drugs, antidepressants, antipsychotics, anxiolytics, hypnotics with sedative effects) in patients with premature ejaculation. Therefore, if joint administration of Priligy and these medicines is necessary, caution is recommended.