Primaxetine, 30 mg 6 pcs

Pharmacotherapeutic group:

A treatment for premature ejaculation.

The ATX code: G04BX14

Pharmacological properties

Pharmacodynamics

The mechanism of action of dapoxetine in premature ejaculation is thought to involve inhibition of serotonin reuptake by neurons, with subsequent enhancement of neurotransmitter action at pre- and postsynaptic receptors.

The mechanism of ejaculation is regulated primarily by the sympathetic nervous system. Postganglionic sympathetic nerve fibers innervate the seminal vesicles, seminal duct, prostate, urethral and bladder neck muscles, causing their coordinated contraction to achieve ejaculation.

Dapoxetine affects the ejaculation reflex by increasing the latent period and decreasing the duration of reflex impulse of the motoneurons of the perineal ganglia. The stimulus that triggers ejaculation is generated in the spinal reflex center, which is controlled through the brain stem by several brain nuclei, including the preoptic and paraventricular.

Pharmacokinetics

absorption

Dapoxetine is rapidly absorbed, and the maximum plasma concentration (Cmax) is reached 1-2 hours after taking the drug. Absolute bioavailability is 42% (range 15-76%). After a single oral dapoxetine dose of 30 mg and 60 mg on an empty stomach, the maximum plasma concentration is 297 ng/ml (after 1.01 hours) and 498 ng/ml (after 1.27 hours), respectively.

Eating a fatty meal moderately decreases the Cmax of dapoxetine (by 10%) and increases the AUC (area under the concentration-time curve) and time to reach maximum plasma concentration by 12%. However, the degree of absorption of dapoxetine is not changed. These changes are not clinically significant. Primaxetine® may be taken regardless of meals.

Distribution

More than 99% of dapoxetine is bound to plasma proteins in vitro. The active metabolite, desmethyldapoxetine, binds 98.5% to plasma proteins. Dapoxetine is rapidly distributed throughout the body with an average equilibrium volume of distribution of 162 liters. When administered intravenously in humans, the average half-life in the initial, intermediate and terminal phases of excretion is 0.10, 2.19 and 19.3 hours, respectively.

Metabolism

In vitro studies suggest that dapoxetine is metabolized by many liver and renal enzymes, especially CYP2D6, CYP3A4, and flavin-containing monooxygenase (FMO1) of the kidneys. In a clinical study that examined the metabolism of 14C-dapoxetine, dapoxetine was actively metabolized after oral administration primarily by the N-oxidation, N-demethylation, naphtho-group hydroxylation, glucuronidation, and sulfo-group attachment routes. After oral administration, there are signs of presystemic metabolism in the liver. The main components circulating in plasma were intact dapoxetine and dapoxetine-N-oxide. In in vitro studies, dapoxetine-N-oxide was found to be inactive. In addition, desmethyldapoxetine and didesmethyldapoxetine were detected in amounts of less than 3% of the total circulating metabolites of dapoxetine. In an in vitro study, desmethyldapoxetine was found to be comparable in activity to dapoxetine, while didesmethyldapoxetine was about half as active as dapoxetine. Exposure (AUC and Cmax) of unbound desmethyldapoxetine was 50% and 23% of unbound dapoxetine, respectively. Elimation

Dapoxetine metabolites are excreted mainly in the urine as conjugates. The unchanged active ingredient is not detected in the urine. Dapoxetine is rapidly excreted, as evidenced by the low plasma concentration of the substance (less than 5% of maximum) 24 hours after taking the dose. When administered daily, the accumulation of the substance in the body is minimal. When administered orally, the terminal elimination half-life is approximately 19 hours.

Special patient groups

Race

A single administration of dapoxetine at a dose of 60 mg showed no statistically significant difference in performance among Europeans, persons of the Negro race, Hispanics, and persons of the Asian race. Comparison of dapoxetine pharmacokinetics in Europeans and Japanese showed higher Cmax and AUC values in the latter (by 10-20%) due to lower body weight. Higher systemic exposure is unlikely to cause a significant difference in clinical effect.

Elderly patients (65 years and older)

. A single dose of dapoxetine 60 mg showed no significant difference in pharmacokinetics (Cmax, AUC, Tmax) between healthy older men and younger men.

The mean AUC of dapoxetine and the final half-life were 12% and 46% higher, respectively, in older men compared to younger men.

Kidney function impairment

. A single dose of dapoxetine 60 mg showed no relationship between creatinine clearance and Cmax or AUC of dapoxetine in patients with mild (creatinine clearance 50-80 ml/min), moderately severe (creatinine clearance 30 to <50 ml/min) and severe (creatinine clearance <30 ml/min) renal dysfunction. The AUC of dapoxetine in patients with severe renal impairment was approximately 2 times higher than in patients with normal renal function. There are limited data on the use of the drug in patients with severe renal impairment. The pharmacokinetics of dapoxetine have not been studied in patients requiring hemodialysis.

Hepatic impairment

In patients with mild hepatic impairment, the pharmacokinetics of dapoxetine and desmethyldapoxetine have not changed. In patients with moderate hepatic impairment (Child-Pugh class B), the Cmax and AUC of unbound dapoxetine were increased by 55% and 120%, respectively. The cmax of the unbound active fraction of dapoxetine was unchanged, and the AUC was doubled.

In patients with severe hepatic impairment, the Cmax of unbound dapoxetine was unchanged and the AUC of unbound dapoxetine was more than 3-fold increased. The AUC of the active fraction was also increased several-fold.

CYP2D6 polymorphism

. Plasma concentrations of dapoxetine after a single dose of Primaxetine® at 60 mg were higher in patients with low CYP2D6 activity than in patients with high CYP2D6 activity (Cmax by approximately 31%, AUC by approximately 36%). Similarly, the Cmax of desmethyldapoxetine in patients with low CYP2D6 activity was increased by 98% and the AUC by 161%. The mean final half-life of dapoxetine was increased by 2.4 hours in patients with low CYP2D6 isoenzyme activity compared with patients with high CYP2D6 isoenzyme activity. The cmax of the active fraction of dapoxetine is increased by – 46% and the AUC by – 90%. This increase may be accompanied by an increased frequency and severity of dose-dependent adverse events. The safety of Primaxetine® administration in patients with low CYP2D6 activity may be in doubt in concomitant administration of other drugs that may inhibit dapoxetine metabolism, particularly active and moderately active CYP3A4 inhibitors.

Patients with ultra-high CYP2D6 activity are expected to have lower plasma concentrations of dapoxetine and desmethyldapoxetine.

Indications

Active ingredient

Composition

Tablets, coated with a film coating.

1 tablet contains:

the active ingredient:

dapoxetine hydrochloride 33.6 mg converted to dapoxetine 30 mg;

excipients:

lactose monohydrate,

microcrystalline cellulose,

croscarmellose sodium,

colloidal anhydrous silica,

magnesium stearate;

coating excipients:

[hypromellose (hydroxypropyl methylcellulose), macrogol 6000 (polyethylene glycol 6000), titanium dioxide, iron oxide black, iron oxide yellow].

How to take, the dosage

For oral administration. The tablet should be swallowed whole with at least one full glass of water. Primaxetine® can be taken regardless of meals.

Adult men 18 to 64 years of age

The recommended starting dose for all men is 30 mg; this dose is taken 1 to 3 hours before intended sexual intercourse. If the effect is insufficient and the 30 mg dose is well tolerated, it can be increased to 60 mg. The maximum recommended frequency of dosing is once every 24 hours.

The physician prescribing Primaxetine® for treatment of premature ejaculation should assess the risks and benefits of the drug after the first 4 weeks of treatment or after 6 doses and should determine the risk-benefit ratio to decide whether further treatment with Primaxetine® is appropriate.

Patients with impaired renal function

In patients with mild to moderately impaired renal function, no dose adjustment is necessary, but caution is recommended. Primaxetine® is not recommended for patients with severe renal impairment.

Patients with impaired hepatic function

Dose adjustment is not necessary in patients with mild hepatic impairment. Primaxetine® is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh grades B and C).

Patients with low CYP2D6 activity, concomitant use with active CYP2D6 inhibitors

Cautions should be taken when increasing the dose of Primaxetine® to 60 mg in people with low CYP2D6 activity or in patients taking active CYP2D6 inhibitors concomitantly with Primaxetine®.

Patients receiving active or moderately active CYP3A4 inhibitors Simultaneous use of active CYP3A4 inhibitors is contraindicated. If Primaxetine® is concomitantly taken with moderately active CYP3A4 inhibitors, the dose of the drug should be decreased to 30 mg.

Interaction

Interaction with monoamine oxidase inhibitors

In patients receiving concomitant SSRIs, serious and sometimes fatal reactions have been described. Serious, sometimes fatal, reactions, including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations in vital signs, and altered mental status, including severe agitation progressing to delirium and coma, have been described in patients receiving concomitant SSRIs and a monoamine oxidase inhibitor (MAO-I). These reactions were also observed in patients who had recently discontinued SSRIs and started MAO-I treatment. In some cases, the symptoms resembled malignant neuroleptic syndrome. Data on co-administration of SSRIs and MAO-I in animals suggest that these drugs may synergistically increase blood pressure and induce behavioral arousal. Therefore, Primaxetine® should not be taken concomitantly with MAO-I and for 14 days after stopping their administration. Similarly, MAO-I should not be taken for 7 days after discontinuation of Primaxetine®.

Interaction with thioridazine

Thioridazine prolongs the QTc interval, which is accompanied by ventricular arrhythmias. Drugs such as Primaxetine®, which inhibit the CYP2D6 enzyme, appear to inhibit the metabolism of thioridazine. The resulting increase in thioridazine levels is expected to exacerbate QTc interval prolongation. Primaxetine® should not be taken concomitantly with thioridazine and for 14 days after its discontinuation. Similarly, thioridazine should not be taken for 7 days after discontinuation of Primaxetine®.

Drugs with serotonergic effects

As with SSRIs, taking Primaxetine® concomitantly with serotonergic drugs (including MAOIs, L-tryptophan, triptans, tramadol,

Linezolid, SSRIs, serotonin and norepinephrine uptake inhibitors, lithium, and Hypericum perforatum drugs may increase the incidence of serotonergic side effects. Primaxetine® should not be taken concomitantly with other SSRIs, MAO-I and other serotonergic drugs and for 14 days after stopping these drugs. Similarly, these drugs should not be taken for 7 days after discontinuation of Primaxetine®.

The use of Primaxetine® concomitantly with drugs acting on the central nervous system has not been studied in patients with premature ejaculation. Caution is advised if it is necessary to take these drugs concomitantly.

The effects of other drugs on dapoxetine hydrochloride

In vitro studies using human liver, kidney and intestinal microsomes have shown that dapoxetine is metabolized primarily by CYP2D6, CYP3A4 and flavin-containing monooxygenase 1 (FMO1). Therefore, inhibitors of these enzymes may decrease the clearance of dapoxetine.

CYP3A4 inhibitors

Active CYP3A4 inhibitors

Ketoconazole administration at a dose of 200 mg twice daily for 7 days increased Cmax and AUC of dapoxetine (60 mg once) by 35% and 99% respectively. Given the proportion of unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction (sum of unbound dapoxetine and desmethyldapoxetine) in the presence of active CYP3A4 inhibitors may increase by approximately 25%, and the AUC may double. This increase in Cmax and AUC of the active fraction may be significantly more pronounced in a subpopulation of patients without a functionally active CYP2D6 enzyme and when concomitant administration of active CYP2D6 inhibitors.

Primaxetine® should not be taken concomitantly with active CYP3A4 inhibitors such as ketoconazole, intraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir and atazanavir.

Moderately active CYP3A4 inhibitors

. Concomitant administration of moderately active CYP3A4 inhibitors, such as erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil or diltiazem, may significantly increase systemic exposure to dapoxetine and desmethyldapoxetine, especially in patients with low CYP2D6 activity. The maximum dose of Primaxetine® taken concomitantly with these drugs should be limited to 30 mg and should be taken with caution.

Active CYP2D6 inhibitors

Taking fluoxetine at a dose of 60 mg/day for 7 days increased the Cmax and AUC of dapoxetine (60 mg once) by 50% and 88%, respectively. Given the proportion of unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction (sum of unbound dapoxetine and desmethyldapoxetine) in the presence of active CYP2D6 inhibitors may increase by approximately 50% and the AUC may double. This increase in Cmax and AUC of the active fraction is close to that expected in patients with low CYP2D6 activity and may result in increased frequency and severity of dose-dependent adverse reactions. Therefore, caution is recommended when increasing the dose of Primaxetine® to 60 mg in patients receiving active CYP2D6 inhibitors and in patients with low CYP2D6 activity.

Interaction with drugs metabolized by CYP1A and CYP2B6 isoenzymes

Based on comparative Cmax data of dapoxetine at 60 mg dose and dapoxetine concentration at 50% inhibition (IC50) of CYP1A2 isoenzyme in vitro, it is concluded that no effect of dapoxetine on the concentration of concomitantly administered drugs metabolized by this isoenzyme is expected. The effect of dapoxetine on the CYP2B6 isoenzyme has not been studied.

FDE5 inhibitors

The pharmacokinetics of dapoxetine taken at a dose of 60 mg simultaneously with tadalafil (20 mg) or sildenafil (100 mg) were studied. Tadalafil had no effect on the pharmacokinetics of dapoxetine. Sildenafil slightly increased the AUC and Cmax of dapoxetine (by 22% and 4%, respectively), which is considered clinically insignificant. Primaxetine® should be used with caution in patients taking FDE5 inhibitors because of the possible reduced tolerance of these patients to orthostatic hypotension.

The effect of dapoxetine hydrochloride on concomitantly administered drugs Tamsulosin

Single and multiple doses of Primaxetine® at 30 mg and 60 mg in patients receiving daily tamsulosin did not lead to changes in pharmacokinetics of the latter. The incidence of orthostatic hypotension did not change either and was similar when tamsulosin alone and when combined with Primaxetine® 30 mg or 60 mg. Primaxetine® should be used with caution in patients taking alpha-adrenoblockers because of possible decreased tolerance of these patients to orthostatic hypotension. Drugs metabolized by CYP2D6

Multiple administration of Primaxetine® (60 mg/day for 6 days) increased Cmax and AUC of desipramine (50 mg once) by 11% and 19%, respectively, compared with desipramine administration alone. Dapoxetine may similarly increase plasma concentrations of other drugs metabolized by CYP2D6. The clinical significance of this is likely to be small.

Drugs metabolized by CYP3A

Multiple administration of Primaxetine® (60 mg/day for 6 days) reduced the AUC of midazolam (8 mg once) by approximately 20% (range -60% to +18%). The clinical significance of this phenomenon in most patients is likely to be small. However, the increase in CYP3A activity may be clinically significant in some patients concomitantly taking drugs metabolized primarily by CYP3A and with a narrow therapeutic window.

Drugs metabolized by CYP2C19

Multiple administration of Primaxetine® (60 mg/day for 6 days) had no effect on the pharmacokinetics of omeprazole (40 mg once). Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C19 substrates.

Drugs metabolized by CYP2C9

Multiple administration of Primaxetine® (60 mg/day for 6 days) had no effect on the pharmacokinetics and pharmacodynamics of glyburide (5 mg once). Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C9 substrates.

FDE5 inhibitors

Dapoxetine (60 mg) did not affect the pharmacokinetics of tadalafil (20 mg) and sildenafil (100 mg), according to the results.

Warfarin

There are no data on the effects of long-term use of warfarin concomitantly with Primaxetine®. Caution is recommended when prescribing Primaxetine® to patients taking warfarin for a long time. In the pharmacokinetics study, multiple dapoxetine administration (60 mg/day for 6 days) did not influence pharmacokinetics and pharmacodynamics (PV and INR) of warfarin (25 mg once). Ethanol

Single administration of ethanol (0.5 g/kg, or approximately 2 doses) had no effect on the pharmacokinetics of dapoxetine (60 mg once daily) and vice versa. Simultaneous administration of Primaxetine® and ethanol increased drowsiness and significantly decreased wakefulness when assessed by the patient. Ethanol and Primaxetine® alone did not significantly alter cognitive measures (reaction rate in the number recognition test and the number symbol substitution test) compared to placebo, but the combination of ethanol and Primaxetine® statistically significantly altered these measures compared to ethanol alone. Concomitant administration of ethanol and Primaxetine® increases the frequency and severity of such adverse reactions as dizziness, somnolence, slowed reflexes, and altered judgment. The combination of alcohol with Primaxetine® may also increase neurocardiogenic side effects, particularly the frequency of syncope, which increases the risk of accidental injury. Therefore, patients should be advised to refrain from taking alcohol during treatment with Primaxetine.

Special Instructions

General

Primaxetine® is only indicated for men with premature ejaculation. The safety of the drug in men without premature ejaculation has not been established, and there are no data on delayed ejaculation.

Patients should be advised not to take Primaxetine® together with narcotic drugs. Concomitant use of Primaxetine® with drugs that have serotonergic activity, such as ketamine, methylenedioxymethamphetamine (MDMA) and lysergic acid diethylamide (LSD), may result in potentially serious reactions including, but not limited to, arrhythmias, hyperthermia and serotonin syndrome. Taking Primaxetine® together with sedatives such as opiates or benzodiazepines may increase drowsiness and dizziness.

Ethanol

The combination of Primaxetine® with alcohol may increase the effects of the latter on the central nervous system and the neurocardiogenic side effects of alcohol, such as fainting, which increases the risk of accidental injury. Therefore, patients should be advised to refrain from taking alcohol while taking Primaxetine®.

Syncope

The incidence of syncope in clinical trials of Primaxetine® depended on patient category and ranged from 0.06% (for the 30 mg dose) to 0.23% (for the 60 mg dose) to 0.64% (for both doses together) in studies involving healthy volunteers.

Patients receiving Primaxetine® were more likely to experience prodromal symptoms, including nausea, dizziness/light-headedness, and sweating, compared to patients receiving placebo. At the Primaxetine® 30 mg dose, the incidence of nausea was 11.0%, the incidence of dizziness was 5.8%, and hyperhidrosis was 0.8%. At the dose of Primaxetine® 60 mg, these figures were 21.2%, 11.7% and 1.5%, respectively. The incidence of syncope and possible prodromal symptoms was dose-dependent, as evidenced by higher rates in patients receiving higher doses than the maximum recommended daily dose of 60 mg. Fainting episodes observed in clinical trials were considered to be of a vaso-vagal nature. Most of these cases occurred within the first 3 hours after the first dose or were associated with research procedures in a clinical setting (e.g., blood sampling, abrupt standing up, blood pressure measurement). Possible prodromal symptoms such as nausea, dizziness, feeling light in the head, palpitations, asthenia, confusion, and sweating were also commonly observed in the first 3 hours after drug administration and often preceded fainting. Patients should be informed that fainting with or without prodromal symptoms may occur at any time during treatment with Primaxetine®. The physician should inform the patient about the importance of adequate water exercise and the recognition of prodromal signs and symptoms to reduce the risk of serious injury if a fall due to loss of consciousness occurs. When possible prodromal symptoms occur, the patient should immediately lie down so that the head is below the torso, or sit with the head between the knees, and should remain in this position until the symptoms disappear. If fainting or other central nervous system effects occur, the patient should be warned to avoid potentially traumatic situations, including driving and operating dangerous machinery.

The combination of Primaxetine® with alcohol may increase neurocardiogenic side effects, including syncope, which increases the risk of accidental injury; therefore, patients should be advised to refrain from drinking alcohol during treatment with Primaxetine®.

Patients at risk of cardiovascular disease

Patients with cardiovascular disease have not been included in clinical studies of the drug. Patients with organic heart and vascular disease (e.g., cardiac ejection obstruction, valve lesions, carotid stenosis, coronary artery atherosclerosis) have an increased risk of adverse cardiovascular outcomes of fainting of cardiac and other origin. However, there are currently insufficient data to determine whether this risk extends to vaso-vagal syncope in patients with cardiovascular disease.

Orthostatic hypotension

In clinical studies, cases of orthostatic hypotension have been described. The physician should inform the patient beforehand that if possible prodromal symptoms occur, e.g., light-headedness immediately after standing up, immediately lie down so that the head is below the torso, or sit with the head between the knees, and remain in this posture until the symptoms disappear. In addition, the patient should be informed about the necessity of avoiding abrupt standing up after prolonged lying or sitting. In addition, Primaxetine® should be used with caution in patients taking vasodilators (e.g., alpha-adrenoblockers, nitrates, FDE5 inhibitors), because of possible reduced tolerance of such patients to orthostatic action of the drug. Moderately active CYP3A4 inhibitors

When taking Primaxetine® concomitantly with moderately active CYP3A4 inhibitors (erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem) the drug dose should be reduced to 30 mg, caution should be taken.

Active CYP2D6 inhibitors

. Caution is advised when increasing the Primaxetine® dose to 60 mg in patients receiving active CYP2D6 inhibitors and in patients with low CYP2D6 activity, as this may increase the level of systemic exposure to the drug with a corresponding increase in the frequency and severity of dose-dependent adverse events.

Suicide/suicidal ideation

In short-term studies, antidepressants, including SSRIs, compared with placebo, increased more strongly the risk of suicide and suicidal ideation in children and adolescents with generalized depression and other psychiatric disorders. No such effect was found in adults over the age of 24. In clinical trials of Primaxetine® for the treatment of premature ejaculation, there are no clear data on the association of suicidal ideation with treatment.

Mania

The drug Primaxetine® should not be taken in patients with a history of mania/hypomania or bipolar disorder; if symptoms of these conditions appear, the drug should be stopped.

Convulsions

Because of the ability of SSRIs to lower the seizure threshold, the use of Primaxetine® should be avoided in patients with unstable epilepsy and the drug should be stopped if seizures occur. Patients with controlled epilepsy require close monitoring.

In children and adolescents under 18 years of age

Primaxetine® should not be taken in patients under 18 years of age.

Companion Depression and Mental Disorders

If a patient has signs and symptoms of depression, an evaluation should be done to rule out the presence of an undiagnosed depressive disorder before starting Primaxetine®. Primaxetine® should not be taken concomitantly with antidepressants, including SSRIs and serotonin and norepinephrine reuptake inhibitors. It is not recommended to stop treatment of depression or anxiety to start treatment with Primaxetine®. Primaxetine® is not intended to treat psychiatric disorders (e.g., schizophrenia or depression) and should not be taken by men with these disorders, as an increase in depression symptoms cannot be excluded. Any disturbing thoughts or feelings should be reported to your doctor immediately, and Primaxetine® should be stopped if signs and symptoms of depression appear during treatment.

Bleeding

Bleeding has been described with the use of SSRIs. Caution is recommended when taking Primaxetine® concomitantly with drugs that affect platelet function (such as atypical neuroleptics, phenothiazines, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants), and in patients with a history of bleeding or clotting disorders.

Primaxetine® is not recommended for patients with severe renal impairment; patients with moderate to mild renal impairment should exercise caution.

Withdrawal syndrome

There is evidence that abrupt withdrawal of SSRIs used for long-term treatment of chronic depressive disorders leads to the following symptoms Decreased mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia as an electric shock sensation), anxiety, confusion, headache, lethargy, emotional instability, insomnia, and hypomania.

In a clinical study conducted to evaluate the effects of dapoxetine withdrawal after 62 days of dosing at a dose of 60 mg (daily or as needed) in patients with premature ejaculation, no signs of withdrawal syndrome were found. After switching patients to placebo after daily dapoxetine administration, only minor withdrawal symptoms in the form of mild to moderate insomnia and dizziness were found. Similar results were obtained in another double-blind clinical study with a one-week follow-up period evaluating the effects of withdrawal after 24 weeks of doses of 30 mg or 60 mg as needed.

Impact on the ability to drive vehicles, operate machinery, and engage in other activities requiring increased concentration

In cases of dizziness, impaired attention, fainting, blurred vision, and drowsiness have been described while taking dapoxetine. Patients should be warned to avoid situations in which injury may occur, including driving and operating dangerous machinery.

Contraindications

– Hypersensitivity to dapoxetine hydrochloride or any other component of the drug.

– Severe heart disease (e.g., NYHA class II-IV heart failure, cardiac conduction disorders (atrioventricular conduction block of degree 2-3 or sinus weakness syndrome) in the absence of a permanent pacemaker, significant coronary heart disease or valve involvement).

– Concurrent use of monoamine oxidase inhibitors (MAO-I) and administration within 14 days of discontinuation. Similarly, MAO-I should not be taken within 7 days after discontinuation of Primaxetine®.

– Simultaneous use of thioridazine and for 14 days after discontinuation. Similarly, thioridazine should not be taken for 7 days after discontinuation of Primaxetine®.

. – Concomitant use of serotonin reuptake inhibitors (selective serotonin reuptake inhibitors – SSRIs), serotonin and noradrenaline reuptake inhibitors and tricyclic antidepressants and other drugs serotonergic drugs (e.g., L-tryptophan, triptans, tramadol, linezolid, lithium, Hypericum perforatum) and for 14 days after stopping these drugs. Similarly, these drugs should not be taken for 7 days after discontinuation of Primaxetine®.

– Concomitant use with active CYP3A4 inhibitors, e.g., ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, atazanavir, etc.

– Moderate to severe liver function abnormalities.

– Severe renal dysfunction.

– Children and adolescents under 18 years of age.

– Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

In the case of a history of established or suspected orthostatic hypotension and a history of mania/hypomania or bipolar disorder, treatment with Primaxetine® should be avoided.

With caution

– mild to moderately severe renal dysfunction;

– concomitant use with potent CYP2D6 isoenzyme inhibitors and moderate CYP3A4 inhibitors in patients with genotypically low CYP2D6 isoenzyme activity and patients with high CYP2D6 isoenzyme activity (in combination with moderate CYP3A4 isoenzyme inhibitors);

– concomitant use with drugs that affect platelet aggregation and with anticoagulants because of the risk of bleeding.

Side effects

The following adverse events were reported in clinical trials and were frequent and dose-dependent: nausea (11.0% and 22.2% for 30 mg and 60 mg dapoxetine, 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%), fatigue (2.0% and 4.1%). Nausea (in 2.2% of patients) and dizziness (1.2%) were the most frequent phenomena that required treatment withdrawal.

The undesirable adverse reactions observed in clinical trials are listed below:

Mental disorders

Often: anxiety, agitation, restlessness, unusual dreams, decreased libido.

Infrequent: depression, depressed mood, euphoric states, mood swings, nervousness, apathy, confusion, disorientation, pathological thinking, somatosensory amplification, sleep disorders, initial insomnia, intrasomnia disorder, nightmares, bruxism, loss of libido, anorgasmia.

Disorders of the central nervous system

Very common: dizziness, headache.

Often: drowsiness, impaired concentration, tremor, paresthesia.

Infrequent: syncope, including vasovagal syncope, postural dizziness, akathisia, perversion of taste, hypersomnia, lethargy, sedation, depression of consciousness.

Rarely: dizziness on physical exertion, sudden falling asleep.

Visual disorders

Often: blurred vision.

Infrequent: mydriasis, pain in the eye area, visual disturbance.

Hearing and labyrinth disorders

Often: tinnitus.

Infrequent: vertigo.

Cardiovascular system disorders

Often: “hot flashes” of blood.

Infrequent: cessation of sinus node activity, sinus bradycardia, tachycardia, decreased blood pressure, systolic hypertension.

Rarely: “flushes” of heat.

Respiratory system disorders

Often: nasal congestion, yawning.

Gastrointestinal disorders

Often: diarrhea, vomiting, constipation, abdominal pain, dyspepsia, flatulence, discomfort in the stomach, bloating, dry mouth.

Skin and subcutaneous tissue disorders

Often: hyperhidrosis.

Infrequent: itching, cold sweat.

Reproductive system disorders

Often: erectile dysfunction.

Infrequent: lack of ejaculation, impaired orgasm, including anorgasmia in men, paresthesia of the male genitalia.

General condition

Often: weakness, irritability.

Infrequent: asthenia, feeling hot, feeling anxious, feeling malaise, feeling intoxicated.

Changes in laboratory values

Often: increased blood pressure.

Infrequent: increased heart rate, increased diastolic blood pressure, increased orthostatic blood pressure.

Description of individual adverse effects

Since fainting with loss of consciousness, with bradycardia or sinus node arrest have been observed in patients on Holter monitoring and have been reported in clinical trials. These adverse events were considered to be associated with the use of the drug. Most cases were observed within the first 3 hours after taking the drug, after the first dose, or were associated with medical procedures (blood draws, body position changes, blood pressure measurement). Prodromal symptoms often preceded fainting.

The incidence of syncope and prodromal symptoms was dose-dependent, as demonstrated in patients receiving higher doses of the drug.

The effects of drug withdrawal

The following symptoms have been reported with abrupt withdrawal of long-acting selective serotonin reuptake inhibitors for the treatment of chronic depressive disorder: Dysphoric state, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. Results of a safety study showed a higher incidence of mild to moderate withdrawal symptoms in the form of insomnia and dizziness after withdrawal of the drug after 62 days of use.

Overdose

Symptoms

There have been no cases of overdose described in clinical studies.

The administration of Primaxetine® at doses up to 240 mg (2 doses of 120 mg at 3-hour intervals) has not caused any unexpected adverse events. In general, symptoms of SSRI overdose include serotonergic reactions, including drowsiness, gastrointestinal disturbances (nausea, vomiting), tachycardia, tremor, agitation, and dizziness.

Treatment

In case of overdose, standard supportive therapy should be given, if necessary. Due to significant binding of the drug to plasma proteins and the large volume of distribution of dapoxetine hydrochloride, forced diuresis, dialysis, hemoperfusion and blood transfusion are unlikely to be effective. A specific antidote is not known.

Similarities