- Pharmacological properties
- Indications for Priligy
- Use of Priligy
- Side Effects
- Special Instructions
- Storage Conditions
Mechanism of action. Dapoxetine is a potent selective serotonin reuptake inhibitor (SSRI). Ejaculation in humans is primarily regulated by the sympathetic nervous system. Ejaculation is triggered by the spinal reflex center involving the brainstem, which is primarily influenced by a number of brain nuclei (medial preoptic and paraventricular nuclei).
The mechanism of action of dapoxetine in premature ejaculation (PE) is probably associated with inhibition reuptake of serotonin by neurons and subsequent enhancement of the effect of neurotransmitters on pre- and postsynaptic receptors.
Clinical efficacy and safety. The efficacy of dapoxetine in the treatment of PE was established in 5 double-blind, placebo-controlled clinical trials in which a total of 6081 patients were randomized. The age of patients is from 18 years. 6 months before the inclusion of these individuals in the study, they had PE in most sexual acts. PE was determined in accordance with the DSM-IV diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders): a short period before the onset of ejaculation (intravaginal ejaculatory latency time (IELT) - the period from vaginal penetration to the moment of intravaginal ejaculation) is less than 2 minutes as measured using a stopwatch in 4 studies, poor control of ejaculation, and significant stress or difficulty in interpersonal relationships due to this condition.
Persons with other types of sexual dysfunction, including erectile dysfunction, as well as individuals using other drugs for the treatment of PE were excluded from all studies.
The results of all randomized trials are comparable. Efficacy was found after 12 weeks of treatment. One study included patients from both the EU and non-EU countries and their treatment duration was 24 weeks. The study randomized 1162 patients: 385 received placebo, 388 received dapoxetine 30 mg as needed, and 389 patients received dapoxetine 60 mg as needed. The mean value and mean IELT at the end of the study are presented in Table. 1, and the overall distribution of patients who achieved at least a certain level of mean IELT at the end of the study is presented in table. 2. Other studies and pooled data analysis at week 12 showed similar results.
Table 1. Least-squares mean and median IELT score at the end of the study*
|Average IELT||Placebo||Dapoxetine 30 mg||Dapoxetine 60 mg|
|Median||1.05 min||1.72 min||1.91 min|
|Difference vs placebo (95% confidence interval (CI))||0.6 min**
|Least squares mean||1.7 min||2.9 min||3.3 min|
|Difference vs placebo (95% CI)||1.6 min**
|1.2 min** (0.59; 1.72)|
*Background (baseline) value carried over to patients with no baseline data.
* *The difference was statistically significant (p value ≤ 0.001).
Table 2. Patients who achieved at least a representative mean IELT level at the end of the study*
|IELT, min||Placebo, %||Dapoxetine 30 mg%||Dapoxetine 60 mg%|
*Baseline value carried over to patients with no baseline data.
The amount of IELT prolongation was associated with baseline IELT and was variable in individual patients: the clinical relevance of dapoxetine treatment efficacy was demonstrated in the reported scores efficacy and data analysis of patients with therapeutic effect.
A patient with therapeutic effect was defined as having at least a category 2 increase in ejaculation control plus at least a category 1 improvement in ejaculatory disorders. Statistically, the majority of patients had a therapeutic effect in each of the groups using dapoxetine compared with the placebo group at the end of the study: 12th or 24th week. Most of the patients with a therapeutic effect were found in the group receiving dapoxetine at a dose of 30 mg (11.1%, 95% CI 7.24; 14.87) and dapoxetine at a dose of 60 mg (16.4%, 95% CI 13.01 ; 19.75) compared with the placebo group at week 12 (pooled analysis).
The clinical significance of the effect of dapoxetine therapy is presented in the example of a group to measure the outcome of the overall clinical impression of the patient, in which patients were asked to compare them PE from the beginning of the study, with responses ranging from "much better" to "much worse". At the end of the study (week 24), 28.4% of patients in the 30 mg dapoxetine group and 35.5% of patients in the 60 mg dapoxetine group reported that their condition was better or much better compared to 14% in placebo group. 53.4 and 65.6% of patients treated with dapoxetine 30 mg and 60 mg, respectively, reported that their condition was at least somewhat better, compared with 28.8% in the placebo group.
Absorption. Dapoxetine is rapidly absorbed and reaches Cmax in blood plasma 1–2 hours after taking the tablet. Bioavailability is 42% (range 15-76%), and in the range of 30-60 mg Cmax and AUC increased in proportion to the dose. After repeated administration, the AUC values of dapoxetine and the active metabolite desmethyldapoxetine increased by approximately 50% compared with the AUC values after administration of dapoxetine in a single dose. Fatty meals slightly reduced Cmax (by 10%) and slightly increased the AUC of dapoxetine (by 12%), and also slightly prolonged the Tmax of dapoxetine. These changes were not clinically significant. Dapoxetine can be taken with or without food.
Distribution. 99% of dapoxetine in vitro binds to plasma proteins. The active metabolite desmethyldapoxetine is 98.5% protein bound. The average Vd of dapoxetine at steady state is 162 L.
Metabolism. According to in vitro studies, dapoxetine is metabolized by numerous enzyme systems in the liver and kidneys, primarily CYP 2D6, CYP 3A4 and flavin-dependent monooxygenase (FMO1). After oral administration of 14C-dapoxetine, the latter was actively metabolized, primarily involving such biotransformation pathways as N-oxidation, N-demethylation, naphthyl hydroxylation, glucuronization, and sulfation. There are indications of a presystemic first pass effect after oral administration.
The main components that circulate in blood plasma were intact dapoxetine and dapoxetine-N-oxide. in vitro binding and transport data showed that dapoxetine N-oxide is inactive. Additional metabolites, including desmethyldapoxetine and didesmethyldapoxetine, accounted for less than 3% of total plasma substances. Data from in vitro binding studies have shown that desmethyldapoxetine and dapoxetine have similar potency, with didesmethyldapoxetine having an activity of about 50% that of dapoxetine. The concentration of unbound desmethyldapoxetine (AUC and Cmax) is 50 and 23% of the concentration of unbound dapoxetine, respectively.
Removal. Metabolites of dapoxetine are excreted primarily in the urine as conjugates. The active substance in unchanged form was not detected in the urine. After oral administration, the initial T½ of dapoxetine is about 1.5 hours, the plasma level is less than 5% Cmax 24 hours after administration, and the final T ½ is about 19 hours, as is the final T½ of desmethyldapoxetine.
Pharmacokinetics in special patient groups. The metabolite of desmethyldapoxetine contributes to the pharmacological effect of dapoxetine, in particular when the effect of desmethyldapoxetine is increased. Below is an increase in the active fraction in some groups of patients. This is the result of the influence of unbound dapoxetine and desmethyldapoxetine. Desmethyldapoxetine has the same potency as dapoxetine. Preliminary calculation assumes uniform distribution of desmethyldapoxetine in the CNS.
Patients of different races. Analysis of the clinical pharmacology of a single dose of 60 mg of dapoxetine did not show statistically significant differences in patients of various races.
Analysis of a clinical pharmacology study after a single dose of dapoxetine at a dose of 60 mg did not find a statistically significant difference between representatives of Hispanic origin, as well as Caucasian , Negroid and Mongoloid races. Clinical studies comparing the pharmacokinetics of dapoxetine in individuals of Japanese descent and Caucasians found that patients of Japanese descent had higher plasma levels of dapoxetine (by 10–20%) (AUC and Cmax ) due to lower body weight. A significant clinical effect, if the concentration is slightly higher, is not expected.
Elderly patients (over 65 years old). Pharmacology analysis of single dose studies of 60 mg dapoxetine showed no significant differences in pharmacokinetic parameters (Cmax, AUCinf, Tmax) in healthy elderly men age and healthy young men. Efficacy and safety have not been established for patients in this group.
Patients with impaired renal function. A clinical pharmacology study on a single dose of 60 mg dapoxetine was conducted in patients with mild (creatinine clearance 50–80 ml/min), moderate (creatinine clearance 30–
Patients with impaired liver function. In patients with moderate hepatic impairment, Cmax of unbound dapoxetine is reduced by 28%, and its AUC value is unchanged. The Cmax and AUC values of the unbound active fraction (sum of exposure to unbound dapoxetine and desmethyldapoxetine) were reduced by 30% and 5%, respectively. In patients with moderate hepatic impairment, Cmax of unbound dapoxetine remains practically unchanged (3% decrease), and its AUC value increases by 66%. The Cmax and AUC values of the unbound active fraction of dapoxetine and desmethyldapoxetine were practically unchanged and increased by 2 times, respectively.
In patients with severe liver failure, Cmax unbound dapoxetine was reduced by 42%, but its AUC value was increased by approximately 223%. Cmax and AUC of the active fraction had similar changes.
CYP 2D6 polymorphism. A clinical pharmacological study using a single dose of 60 mg dapoxetine showed that plasma concentrations in slow CYP 2D6 metabolizers were higher than in fast CYP 2D6 metabolizers (approximately 31% higher for Cmax, 36% higher for AUCinf of dapoxetine, 98% higher for Cmax and 161% higher for AUCinf of desmethyldapoxytine). The active fraction of dapoxetine can be increased by about 46% in terms of Cmax and by about 90% in terms of AUC. This increase can lead to higher morbidity and serious dose dependent side effects such as dose dependency. The safety of dapoxetine in slow metabolizers of CYP 2D6 is of particular concern when used concomitantly with other medicinal products that may inhibit the metabolism of dapoxetine, such as moderate to strong CYP 3A4 inhibitors.
for the treatment of PE in older men 18-64 years of age who meet the following criteria:
- intravaginal ejaculation latency time (IELT) is less than 2 minutes;
- persistent or recurrent ejaculation after minimal sexual stimulation before, during or shortly after sexual penetration, which occurs earlier than the moment desired by the patient;
- severe stress or difficulties that arose in interpersonal relationships as a result of PE;
- insufficient control over the onset of ejaculation;
- PE in most attempts at sexual intercourse in the last 6 months.
The drug should be used if necessary only as a treatment before the intended sexual intercourse. The drug should not be used to delay ejaculation in men who have not been diagnosed with PE.
intended for oral use. To avoid a bitter taste, tablets should be swallowed without breaking, drinking plenty of water. The drug can be used regardless of food intake.
Adults. The drug is not intended for continuous daily use. It should only be used for intended sexual intercourse. The drug should not be taken more frequently than after 24 hours.
The recommended initial dose for all patients is 30 mg, which should be taken 1-3 hours before the intended sexual intercourse. Treatment should not be started with a dose of 60 mg.
If the individual response to dapoxetine at a dose of 30 mg is insufficient and the patient does not have moderate or severe adverse reactions, as well as prodromal symptoms suggesting the possible development of syncope, the dose can be increase to the maximum recommended dose of 60 mg, which should be taken if necessary approximately 1-3 hours before sexual intercourse. The frequency and severity of adverse reactions when taking dapoxetine at a dose of 60 mg increases. If the patient has experienced orthostatic reactions after taking dapoxetine at the initial dose, it is not recommended to increase the dose to 60 mg.
The maximum recommended dose of dapoxetine should not be exceeded.
The doctor should carefully analyze the ratio " risk/benefit after the first 4 weeks of treatment (or at least 6 doses of treatment) to determine whether continued therapy is appropriate. Data regarding the efficacy and safety of taking dapoxetine for more than 24 weeks are limited. The physician should reassess the clinical need for continued treatment and the risk/benefit ratio of the drug at least every 6 months.
Patients with impaired renal function. The drug should be used with caution in patients with mild to moderate renal impairment. The drug is not recommended for patients with severely impaired renal function.
Patients with impaired liver function. Dapoxetine is contraindicated in patients with moderate or severe hepatic impairment.
Patients who are treated with CYP 2D6 inhibitors or are slow metabolizers of CYP 2D6. In such patients, increasing the dose of dapoxetine to 60 mg should be done with caution.
Patients taking moderate CYP 3A4 inhibitors or strong CYP 3A4 inhibitors. The use of dapoxetine in patients taking concomitantly potent inhibitors of CYP 3A4 is contraindicated. The drug should be used with caution in patients who are simultaneously taking moderate inhibitors of CYP 3A4, but not to exceed the dose of dapoxetine 30 mg.
Elderly patients (over 65 years old). The efficacy and safety of dapoxetine have not been established in patients over the age of 65.
Children. Dapoxetine is contraindicated in children.
- increased sensitivity to the active substance and / or other components of the drug.
- Heart failure (NYHA (New York Heart Association) class II-IV).
- Cardiac conduction disorders such as AV - blockade or weakness of the sinus node.
- Severe coronary artery disease.
- Severe valvular insufficiency.
- Moderate or severe liver dysfunction.
- History of mania or severe depression.
- Concomitant use of MAO inhibitors and within 14 days after their withdrawal. The use of the drug should be discontinued at least 7 days before the start of therapy with MAO inhibitors.
- Simultaneous administration of thioridazine and within 14 days after its withdrawal. The use of the drug should be discontinued at least 7 days before the start of treatment with thioridazine.
- Simultaneous use of serotonin reuptake inhibitors (SSRIs, selective serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants) or other drugs / herbal preparations with serotonergic action, such as L-tryptophan, triptans, tramadol, linezolid, lithium, St. John's wort (Hypericum perforatum), and within 14 days after their withdrawal. The use of the drug should be discontinued at least 7 days before the start of treatment with these drugs / herbal preparations with serotonergic action.
- Simultaneous administration of potent inhibitors of CYP 3A4, such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, atazanavir, etc. (See INTERACTIONS).
in clinical trials, cases of syncope and orthostatic hypotension were reported.
The most frequently reported dose-dependent adverse reactions in clinical trials were: nausea (11.0 and 22.2% in groups treated with dapoxetine in case of the need for a dose of 30 and 60 mg, respectively), dizziness (5.8 and 10.9%), headache (5.6 and 8.8%), diarrhea (3.5 and 6.9%), insomnia (2 .1 and 3.9%) and fatigue (2.0 and 4.1%).
Criteria for assessing the incidence of adverse reactions when using the drug: very often (≥1 / 10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); rare (≥1/10 000, <1/1000); very rare (<1/10 000); unknown (frequency cannot be determined from the available data).
On the part of the psyche: often - anxiety, agitation, restlessness, insomnia, unusual dreams, decreased libido; infrequently - depression, depressed mood, euphoric mood, changeable mood, irritability, indifference, apathy, confusion, disorientation, impaired thinking, excessive alertness, sleep disturbance, sleep disturbance, intrasomnic disorders, nightmares, bruxism, loss of libido, anorgasmia.
From the nervous system: very often - headache, dizziness; often - drowsiness, impaired attention, tremor, paresthesia; infrequently - fainting, vasovagal syncope, postural dizziness, akatsia, dysgeusia, hypersomnia, lethargy, sedation, decreased level of consciousness; rarely - dizziness during physical exertion, sudden falling asleep.
On the part of the organ of vision: often - blurred vision; infrequently - mydriasis, eye pain, visual impairment.
From the side of the organ of hearing and balance: often - ringing in the ears; infrequently - vertigo.
On the side of the heart: infrequently - blockade of the sinoatrial node, sinus bradycardia, tachycardia.
On the side of the vessels : often - hot flashes; infrequently - arterial hypotension, systolic hypertension.
On the part of the respiratory tract, chest and mediastinum: often - swelling of the paranasal sinuses, yawning.
< em> From the gastrointestinal tract: very often - nausea; often - diarrhea, vomiting, constipation, abdominal pain, epigastric pain, dyspepsia, flatulence, discomfort in the stomach, bloating, dry mouth; infrequently - a feeling of discomfort in the epigastrium, a feeling of discomfort in the abdomen; rarely - imperative urge to defecate.
On the part of the skin and subcutaneous tissues: often - excessive sweating; infrequently - itching, cold sweat.
From the reproductive system and mammary glands: often - erectile dysfunction; infrequently - insufficiency of ejaculation, orgasmic disorders in men, paresthesia in the genital area.
General disorders: often - fatigue, irritability; infrequently - weakness, a feeling of heat, a feeling of anxiety, unusual sensations, a feeling of intoxication.
Research: often - increased blood pressure; infrequently - an increase in heart rate, diastolic blood pressure, orthostatic blood pressure.
Description of individual adverse reactions. Syncope and orthostatic hypotension have been reported in clinical studies with dapoxetine.
In clinical studies, there have been cases of syncope due to bradycardia or due to cessation of sinus node activity associated with the use of dapoxetine in patients undergoing Holter monitoring. Most cases occurred within the first 3 hours after taking dapoxetine, after taking the first dose, or after clinical investigation procedures (such as blood sampling for analysis and orthostatic procedures, blood pressure measurement). Prodromal symptoms often preceded syncope.
The occurrence of syncope and possibly prodromal symptoms is dose-dependent, with a higher incidence in patients receiving higher than recommended doses.
Other Special Populations. Dapoxetine should be used with caution at an increased dose of 60 mg in patients taking strong inhibitors of CYP 2D6, or with an established genotype of slow CYP 2D6 metabolizers.
Withdrawal syndrome. Sudden discontinuation of continuous use of SSRIs for the treatment of chronic depressive disorder leads to symptoms such as dysphoric disorder, irritability, agitation, dizziness, sensory disturbances (for example, paresthesias such as the sensation of "electric shock"), anxiety, confusion, headache, lethargy, emotional lability, insomnia and hypomania.
Reports of suspected adverse reactions that occur after registration of a medicinal product are very important. This allows you to constantly monitor the benefit / risk ratio when using the drug. Healthcare professionals should report any suspected adverse reactions through the national pharmacovigilance system.
general recommendations. Dapoxetine should only be used in men with PE (see INDICATIONS). The drug is not intended for use in men who have not been diagnosed with PE. The safety of use has not been established and there are no data on the effect on delayed ejaculation in men without PE.
Use in other forms of sexual disorders. Before starting treatment, patients with other forms of sexual disorders, including erectile dysfunction, should be carefully examined by doctors. Dapoxetine should not be used in men with erectile dysfunction taking phosphodiesterase 5 (PDE-5) inhibitors.
Risk of orthostatic hypotension. Cases of orthostatic hypotension have been reported in clinical trials. Before starting the use of the drug, a thorough medical examination is necessary, including a history of orthostatic reactions. An orthostatic test should be performed before starting treatment (BP and pulse rate - supine and standing). If there is a history of orthostatic reactions or in case of a suspected orthostatic reaction, the use of the drug should be avoided.
It is necessary to inform the patient in advance that if there are prodromal symptoms, such as dizziness shortly after the patient has risen, you should immediately lie down so so that the head is lower than other parts of the body, or sit with the head between the knees until the symptoms disappear. The patient should not rise quickly after prolonged lying or sitting.
Risk of suicide/suicidal ideation. Antidepressants, including SSRIs, compared with placebo increase the risk of suicidal ideation and suicidal behavior in short-term studies in children and adolescents with major depressive and other psychiatric disorders. Short-term studies do not show an increased risk of suicide with antidepressants compared with placebo in adults aged 24 years and older. In clinical trials of dapoxetine for the treatment of PE, there was no clear evidence of suicidality during treatment as measured by the Columbia Classification of Suicide Scoring (C-CASA), the Montgomery-Asberg Depression Rating Scale, or the Depression Rating Scale. Beck II.
Risk of syncope (syncope). Patients should be advised to avoid situations that could lead to injury, including driving or operating dangerous machinery, as syncope or prodromal symptoms such as dizziness or lightheadedness may occur.
It has been reported that prodromal symptoms such as nausea, dizziness/pre-syncope and increased sweating are more common in patients treated with dapoxetine compared to placebo.
In clinical studies with dapoxetine, syncope is characterized by loss of consciousness with bradycardia or cessation of activity of the sinus node. Such cases have been reported in patients undergoing Holter ECG monitoring and are considered vasovagal in etiology, but most cases are recorded within the first 3 hours after the first dose of dapoxetine or are associated with clinical examination procedures (for example, blood sampling for analysis and orthostatic procedures, measurement HELL). Possible prodromal symptoms such as nausea, dizziness, presyncope, palpitations, weakness, confusion and sweating, which usually occur within the first 3 hours after dosing, often preceded by syncope.
Patients should be informed about the possibility of syncope at any time (with or without the development of prodromal symptoms) during treatment. Patients should also be advised on the importance of maintaining adequate hydration and on how to recognize prodromal signs and symptoms to reduce the likelihood of serious injury associated with a fall due to loss of consciousness.
If a patient experiences prodromal symptoms, they should immediately lie down so that the head is lower than other parts of his body, or sit with his head between his knees, until the symptoms disappear.
Patients with cardiovascular risk factors. When using dapoxetine, the risk of adverse cardiovascular effects from syncope (cardiac syncope and syncope for other reasons) is increased in patients with underlying structural cardiovascular diseases (such as outflow obstruction, valvular heart disease, carotid stenosis and coronary artery disease). There are insufficient data to determine whether this increase in the risk of vasovagal syncope extends to patients with cardiovascular disease.
Concomitant use with recreational agents. The simultaneous use of dapoxetine with recreational drugs with serotonergic activity, such as ketamine, methylenedioxymethamphetamine and lysergic acid diethylamide (LSD), can lead to the development of potentially serious reactions. These reactions include arrhythmias, hyperthermia, and serotonin syndrome. Simultaneous use with recreational drugs with sedative properties, such as narcotics and benzodiazepines, may increase the severity of drowsiness and dizziness. The simultaneous use of dapoxetine with these drugs is not recommended.
Simultaneous use with alcohol. Co-administration of dapoxetine with alcohol may enhance the neurocognitive effects associated with alcohol use, as well as lead to increased neurocardiogenic side effects such as syncope, thus increasing the risk of accidental injury. Patients are not recommended to drink alcohol while using the drug.
Simultaneous use with drugs that have vasodilating properties. The drug should be used with caution in patients who are simultaneously taking drugs with vasodilatory properties (for example, alpha-adrenergic antagonists and nitrates), due to a possible decrease in orthostatic tolerance.
Patients with manic syndromeThe drug should not be used in patients with manic syndrome / hypomania or a history of bipolar affective disorder. It should be discontinued if symptoms of these disorders occur.
Risk of developing an epileptic seizure. Due to the properties of SSRIs to reduce the seizure threshold, the use of the drug should be discontinued in the event of an epileptic seizure. Patients with unstable epilepsy should avoid the use of dapoxetine. Patients with controlled epilepsy should be closely monitored during treatment.
Risk of depression and/or psychiatric disorders. If the patient has signs and symptoms of depression, an examination should be carried out before starting the use of dapoxetine to exclude the presence of an undiagnosed depressive disorder.
The simultaneous use of dapoxetine with antidepressants, including SSRIs and SNRIs, is contraindicated. Discontinuation of treatment for persistent depression or anxiety in order to initiate a drug for the treatment of PE is not recommended. Dapoxetine is not recommended for the treatment of psychiatric disorders and should not be used in men with disorders such as schizophrenia or those with hypochondria because an increase in depression-related symptoms cannot be ruled out. This may be the result of an underlying psychiatric disorder or a consequence of drug therapy. Patients should be encouraged to report any disturbing thoughts or feelings at any time during treatment. If signs and symptoms of depression occur during treatment, the drug should be discontinued.
Risk of bleeding. When using SSRIs, violations of hemostasis were recorded. Dapoxetine should be used with caution in patients who are concomitantly taking drugs that affect platelet function (eg, atypical antipsychotics and phenothiazines, acetylsalicylic acid, NSAIDs, antiplatelet agents) or anticoagulants (eg, warfarin), and in the presence of a history of bleeding or disorders coagulation.
Patients with impaired renal function. Dapoxetine is not recommended for use in patients with severe renal insufficiency; it should be used with caution in patients with mild to moderate renal impairment.
Risk of withdrawal syndrome. Sudden discontinuation of continuous use of SSRIs for the treatment of chronic depressive disorders leads to symptoms such as dysphoric disorder, irritability, agitation, dizziness, sensory disturbances (for example, paresthesias such as the sensation of "electric shock"), anxiety, confusion, headache, lethargy, emotional lability, insomnia and hypomania.
The results of the safety study showed a higher incidence of withdrawal symptoms in the form of insomnia and mild to moderate dizziness after discontinuation of dapoxetine after 62 days of use or its use at a dose of 60 mg.
Patients with diseases of the organ of vision. The use of dapoxetine has been associated with ocular adverse reactions such as mydriasis and eye pain. The drug should be used with caution in patients with elevated intraocular pressure or risk of angle-closure glaucoma.
Use in patients with lactose intolerance. The drug contains lactose, so it should not be used in patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.
Use during pregnancy or lactation. The drug is not intended for use in women.
The ability to influence the reaction rate when driving vehicles or operating other mechanisms. Dapoxetine has a minor or moderate effect on the ability to drive vehicles or other mechanisms. Dizziness, impaired attention, fainting, blurred vision and drowsiness have been reported. Patients should be warned to avoid risky situations, including driving or operating machinery.
MAO inhibitors. With the simultaneous use of SSRIs with MAO inhibitors, serious reactions, sometimes fatal, have been reported, which included hyperthermia, rigidity, myoclonus, disorders of the autonomic nervous system with the occurrence of rapid changes in vital functions, as well as changes in mental status, including marked arousal, turning into delirium and to whom. Such reactions have also been noted in patients who have recently completed SSRIs and started taking MAO inhibitors. There have been isolated cases with symptoms resembling neuroleptic malignant syndrome. Animal data on the combined use of SSRIs and MAO inhibitors suggest that these drugs may act synergistically to raise blood pressure and cause agitation. Dapoxetine should not be used simultaneously with MAO inhibitors or within 14 days after their withdrawal. MAO inhibitors should not be taken within 7 days after stopping dapoxetine.
Thioridazine: thioridazine use causes a prolongation of the Q-Tc interval, which is associated with the occurrence pronounced ventricular arrhythmias. Dapoxetine inhibits the CYP 2D6 isoenzyme and probably inhibits the metabolism of thioridazine. The resulting increase in thioridazine levels is expected to result in a more pronounced prolongation of the Q-Tc interval. Dapoxetine should not be used simultaneously with thioridazine or within 14 days after its withdrawal. Thioridazine should not be taken within 7 days after stopping dapoxetine.
Medicines/herbal preparations with serotonergic effects: as with SSRIs, concomitant use with drugs/ herbal preparations with a serotonergic mechanism of action, including MAO inhibitors, L-tryptophan, triptans, tramadol, linezolid, SSRIs, SNRIs, lithium, and preparations based on St. Dapoxetine should not be used in combination with other SSRIs, MAO inhibitors, or other serotonergic drugs/herbal preparations or within 14 days of their withdrawal. Similarly, these serotonergic drugs/herbal products should not be taken within 7 days of stopping dapoxetine.
CNS-active drugs (such as antiepileptics, antidepressants, antipsychotics) , anxiolytics, sedative hypnotics): The use of dapoxetine concomitantly with CNS agents has not been studied in patients with PE. The simultaneous use of dapoxetine with such drugs requires caution.
In in vitro studies human liver and kidney tissues, as well as intestinal microsomes, it was found that dapoxetine is metabolized primarily by CYP 2D6, CYP 3A4 and flavin monooxygenase 1 (FMO1). Thus, inhibitors of these enzymes may reduce the clearance of dapoxetine.
Medications known to be potent inhibitors of CYP 3A4: Ketoconazole (200 mg twice daily for 7 days) increases Cmax and AUCinf of dapoxetine (60 mg single dose) by 35 and 99%, respectively. With respect to the distribution of both unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction may increase by approximately 25% and the AUC of the active fraction may double with potent CYP 3A4 inhibitors.
The increase in Cmax and AUC of the active fraction can significantly increase in patients with a deficiency of a functional CYP 2D6 enzyme, in particular in weak CYP 2D6 metabolizers or when used simultaneously with CYP 2D6 inhibitors.
Simultaneous Dapoxetine and potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir and atazanavir are contraindicated.
Medicines known to be mild inhibitors of CYP3A4 >: the simultaneous use of dapoxetine and moderate inhibitors of CYP 3A4 (such as erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem) can lead to a pronounced increase in the exposure of dapoxetine and desmethyldapoxetine, especially in weak metabolizers of CYP 2D6. In the case of simultaneous use with such drugs, the maximum dose of dapoxetine should not exceed 30 mg. This applies to all patients, except for those who, according to the results of geno- or phenotyping, were assigned to the group of active metabolizers of CYP 2D6. Patients in the group of active CYP 2D6 metabolizers should be cautious when using dapoxetine 60 mg and moderate CYP 3A4 inhibitors at the same time.
Medicines known to be potent inhibitors of CYP 2D6 : Cmax and AUCinf of dapoxetine (single dose of 60 mg) increase by 50 and 88%, respectively, when used simultaneously with fluoxetine (at a dose of 60 mg / day for 7 days ). With regard to the distribution of both unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction may increase by about 50%, and the AUC of the active fraction may double with the simultaneous use of potent inhibitors of CYP 2D6. This increase in Cmax and AUC of the active fraction is similar to that expected in weak metabolizers of CYP 2D6 and may cause an increase in the frequency and severity of dose-dependent adverse reactions.
PDE-5 inhibitors >. With simultaneous use with dapoxetine, orthostatic hypotension may develop. Efficacy and safety in patients with PE and erectile dysfunction treated concomitantly with dapoxetine and PDE-5 inhibitors have not been established. The simultaneous use of these agents is not recommended. The pharmacokinetics of dapoxetine (60 mg) in combination with tadalafil (20 mg) and sildenafil (100 mg) were also evaluated in a crossover study. Tadalafil did not affect the pharmacokinetic parameters of dapoxetine. Sildenafil caused mild changes in the pharmacokinetic parameters of dapoxetine (22% increase in AUCinf and 4% increase in Cmax), which are probably not clinically significant.
Tamsulosin: simultaneous single or multiple use of dapoxetine at doses of 30 or 60 mg in patients taking tamsulosin at a daily dose of 0.4 mg does not cause changes in the pharmacokinetic parameters of the latter. The simultaneous use of dapoxetine and tamsulosin does not cause changes in the orthostatic profile and orthostatic effects compared with taking tamsulosin in combination with dapoxetine at a dose of 30 or 60 mg and taking tamsulosin alone. However, the simultaneous use of dapoxetine with alpha-adrenergic antagonists requires caution due to a possible decrease in orthostatic tolerance.
Drugs that are metabolized by CYP 2D6: repeated use of dapoxetine at a dose of 60 mg / day for 6 days followed by a single dose of 50 mg of desipramine led to an increase in the average Cmax and AUCinf of desipramine, respectively, by 11 and 19% compared with taking desipramine alone. Dapoxetine can cause a similar increase in plasma concentrations of other drugs that are metabolized by CYP 2D6. This probably has no clinical significance.
Medicines that are metabolized by CYP 3A4: repeated administration of dapoxetine (60 mg/day for 6 days) resulted in a decrease in AUC inf midazolam (8 mg single dose) by about 20% (range -60 to +18%). For most patients, this effect with midazolam is likely to be of no clinical significance. An increase in CYP 3A activity may be of clinical importance in some patients who are concomitantly taking a drug that is metabolized primarily by CYP 3A and has a narrow therapeutic window.
Drugs that are metabolized by CYP 2C19: repeated use of dapoxetine at a dose of 60 mg / day for 6 days did not lead to inhibition of metabolism with a single dose of 40 mg of omeprazole. It is likely that dapoxetine does not affect the pharmacokinetics of other CYP 2C19 substrates.
Drugs that are metabolized by CYP 2C9: repeated use of dapoxetine at a dose of 60 mg / day for 6 days did not affect pharmacokinetics or pharmacodynamics of glibenclamide (single dose of 5 mg). Dapoxetine does not appear to affect the pharmacokinetics of other CYP 2C9 substrates.
Warfarin and other agents that affect blood coagulation and/or platelet function: Evidence from assessing the effect of regular warfarin and dapoxetine missing. In a pharmacokinetic study, dapoxetine (at a dose of 60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics of warfarin (prothrombin time or international normalized ratio) (single dose of 25 mg). However, bleeding has been reported in association with SSRIs. Caution is advised in the case of simultaneous continuous use of these agents.
Ethanol: simultaneous administration of ethanol (single dose of 0.5 g/kg) did not affect the pharmacokinetics of dapoxetine (single dose of 60 mg ). However, the simultaneous use of dapoxetine with ethanol increases drowsiness and significantly reduces vigilance. Pharmacodynamic measurements of cognitive impairment (digital attention speed test, digital symbol substitution test) also found an additive effect. Concomitant use of alcohol and dapoxetine increases the likelihood or severity of adverse reactions such as dizziness, drowsiness, slow reflexes or impaired judgment, and may increase the likelihood of neurocardiogenic adverse reactions such as fainting, thus increasing the risk of accidental injury. . It is not recommended to drink alcohol while using the drug.
symptoms. No cases of overdose were reported.
During the study of clinical pharmacology of dapoxetine, no unforeseen adverse reactions were detected when it was used at a dose of up to 240 mg (two doses of 120 mg taken with a difference of 3 hours). In general, symptoms of an SSRI overdose include serotonin-mediated adverse reactions such as drowsiness, gastrointestinal disturbances, nausea and vomiting, tachycardia, tremors, agitation, and dizziness.
Treatment. In case of overdose, symptomatic and supportive therapy should be carried out. Due to the high protein binding and large Vd of dapoxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidote.
at a temperature not exceeding 25 °C.