Dapoxetine

Brand Obolensky OP

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Available since: 2019-09-19

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Clinical Pharmacology

Pharmacotherapeutic group

A treatment for premature ejaculation.

ATX code: G04BX14

Pharmacological properties

Pharmacodynamics

It is assumed that the mechanism of action of dapoxetine during premature ejaculation is associated with inhibition of serotonin reuptake by neurons with subsequent enhancement of the action of the neurotransmitter on pre- and postsynaptic receptors.

The mechanism of ejaculation is regulated mainly by the sympathetic nervous system. Postganglionic sympathetic nerve fibers innervate the seminal vesicles, vas deferens, prostate gland, muscles of the urethra and bladder neck, causing their coordinated contraction to achieve ejaculation. Dapoxetine affects the ejaculation reflex, increasing the latent period and reducing the duration of the reflex impulses of the motor neurons of the perineal ganglia. The stimulus that triggers ejaculation is generated in the spinal reflex center, which through the brain stem is controlled by several nuclei of the brain, including the preoptic and paraventricular.

Pharmacokinetics

Suction

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

Eating fatty foods moderately reduces Cmax of dapoxetine (by 10%) and increases AUC (area under the concentration-time curve) and time to reach maximum plasma concentration by 12%. However, the degree of absorption of dapoxetine does not change. These changes are not clinically significant. The drug Primaxetine® can be taken regardless of the meal.

Distribution

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

Metabolism

In vitro studies suggest that dapoxetine is metabolized by many liver and kidney enzymes, especially CYP2D6, CYP3A4, and flavin-containing monooxygenase (PMO1) of the kidneys. In a clinical study, during which the metabolism of 14C-dapoxetine was studied, dapoxetine after oral administration was extensively metabolized mainly by N-oxidation, N-demethylation, naphtho-group hydroxylation, sulfo-group addition. After oral administration, signs of presystemic metabolism were found in the liver. The main components circulating in the blood plasma were intact dapoxetine and dapoxetine-N-oxide. In vitro studies have revealed that dapoxetine-N-oxide is inactive. In addition, desmethyldioxetine and didesmethyldipoxetine were detected in an amount of less than 3% of the total number of circulating metabolites of dapoxetine. In an in vitro study, it was found that desmethyldapoxetine is comparable in activity to dapoxetine, and didemetmethyldiadoxetine is about 2 times less active than dapoxetine. Exposure (AUC and C max) of unbound desmethyldipoxetine was 50% and 23% of unbound dapoxetine, respectively. Removal

Metabolites of dapoxetine are derived mainly from the urine in the form of conjugates. Unchanged active substance is not detected in the urine. Dapoxetine is rapidly excreted, as evidenced by the low concentration of the substance in the blood plasma (less than 5% of the maximum) 24 hours after the dose. With daily intake, the accumulation of a substance in the body is minimal. When administered orally, the final half-life is approximately 19 hours.

Special patient groups

Race

A single dose of 60 mg of dapoxetine did not reveal statistically significant differences in rates among Europeans, Negroids, Hispanics, and Asians. Comparison of the pharmacokinetics of dapoxetine in Europeans and Japanese showed higher C max and AUC values, the latter (by 10–20%) due to lower body weight. A higher level of systemic exposure is unlikely to cause a significant difference in clinical effect.

Elderly patients (65 years and older)

A single dose of 60 mg of dapoxetine did not reveal a significant difference in pharmacokinetics (Cmax, AUC, Tmax) in healthy elderly men and younger men.

The mean AUC values of dapoxetine and the terminal half-life were higher, respectively, by 12% and 46% in older men compared with younger men.

Renal dysfunction

A single dose of 60 mg of dapoxetine did not reveal a relationship between creatinine clearance and Cmax or AUC of dapoxetine in patients with weak (creatinine clearance 50-80 ml / min) moderately pronounced (creatinine clearance from 30 to

Liver dysfunction

In patients with mild hepatic impairment, the pharmacokinetics of dapoxetine and desmethyldapoxetine did not change. In patients with impaired moderate liver function (Child-Pugh class B), Cmax and AUC of unbound dapoxetine are increased by 55% and 120%, respectively. Cmax of the unbound active fraction of dapoxetine was unchanged, and AUC - 2 times increased.

In patients with severe hepatic impairment, C max of unbound dapoxetine was unchanged, and the AUC of unbound dapoxetine was increased more than 3 times. AUC of the active fraction was also increased several times.

CYP2D6 Polymorphism

The concentration of dapoxetine in the blood plasma after a single dose of the drug Primaxetin® in a dose of 60 mg in patients with low CYP2D6 activity was higher than in patients with high CYP2D6 activity (Cmax approximately 31%, AUC approximately 36%). Similarly, C max of desmethyl adapoxetine in patients with low CYP2D6 activity was increased by 98%, and AUC - by 161%. The average terminal 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. Cmax of the active fraction of dapoxetine increased by - 46%, a AUC by - 90%. This increase may be accompanied by increased frequency and severity of dose-related adverse events. The safety of the use of Primaxetin® in patients with low CYP2D6 activity may raise doubts while taking other medications that can inhibit the metabolism of dapoxetine, in particular, active and moderately active CYP3A4 inhibitors.

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

Indications

The drug Primaxetine® is intended for the treatment of premature ejaculation in men aged 18 to 64 years.

Composition

1 tablet contains:

active ingredient: dapoxetine hydrochloride 33.6 mg / 67.2 mg in terms of dapoxetine 30 mg / 60 mg;

excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, anhydrous colloidal silicon dioxide, magnesium stearate;

shell auxiliaries: [hypromellose (hydroxypropylmethylcellulose), macrogol 6000 (polyethylene glycol 6000), titanium dioxide, ferric oxide black, ferrous oxide yellow].

Round biconvex pills, film coated gray. In cross section, the core is white or almost white.

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Dosage and Administration

For oral administration. The tablet should be swallowed whole with a minimum of one full glass of water. The drug Primaxetine® can be taken regardless of the meal.

Adult men from 18 to 64 years

The recommended starting dose for all men is 30 mg; This dose is taken 1-3 hours before the intended sexual intercourse. With insufficient effect and good tolerability of a dose of 30 mg, it can be increased to 60 mg. The maximum recommended dose frequency is 1 time per 24 hours.

The physician prescribing the drug Primaxetine® for treating premature ejaculation should evaluate the risk and benefit of using the drug after the first 4 weeks of treatment or after taking 6 doses and should determine the risk-benefit ratio for deciding whether to further treat Primaxetin®.

Patients with impaired renal function

For patients with mild or moderate renal impairment, dose adjustment is not required, but caution is advised. Primaxetine® is not recommended for patients with severely impaired renal function.

Patients with impaired liver function

For patients with mild hepatic impairment, dose adjustment is not required. The drug Primaxetine® is contraindicated in patients with moderately severe and severe liver dysfunction (classes B and C, Child-Pugh classification).

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

Caution should be exercised when increasing the dose of the drug Primaxetin® to 60 mg in individuals with low CYP2D6 activity or in patients simultaneously with the drug Primaxetin® taking active CYP2D6 inhibitors.

Patients receiving active or moderately active CYP3A4 inhibitors Simultaneous administration of active CYP3A4 inhibitors is contraindicated. At the same time taking the drug Primaxetine® with moderately active inhibitors of CYP3A4, the dose of the drug should be reduced to 30 mg.

Adverse reactions

The following side effects were observed in clinical studies, which were observed frequently and were dose-dependent: nausea (11.0% and 22.2% when taking 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 events requiring cessation of treatment.

The adverse reactions observed during clinical trials are listed below:

Mental disorders

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

Uncommon: depression, depressed mood, a state of euphoria, mood swings, nervousness, apathy, lethargy, confusion, disorientation, abnormal thinking, somatosensory amplification, sleep disorder, initial insomnia, intrasomnicheskoe disorder, nightmares, bruxism, loss of libido, anorgasmia.

Violations of the central nervous system

Very often: dizziness, headache.

Often: drowsiness, impaired concentration, tremor, paresthesia.

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

Seldom: dizziness at an exercise stress, sudden falling asleep.

Violations by the organ of vision

Often: blurred vision.

Infrequently: mydriasis, pain in the eye area, blurred vision.

Disturbances from an organ of hearing and labyrinth disturbances

Often: ringing in the ears.

Infrequently: vertigo.

Violations of the cardiovascular system

Often: "tides" of blood.

Infrequently: cessation of sinus node activity, sinus bradycardia, tachycardia, reduction in blood pressure, systolic hypertension.

Rarely: "tides" of heat.

Respiratory disorders

Often: nasal congestion, yawning.

Disorders of the gastrointestinal tract

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

Violations of the skin and subcutaneous tissue

Often: hyperhidrosis.

Infrequently: itch, cold sweat.

Reproductive system disorders

Often: erectile dysfunction.

Infrequently: lack of ejaculation, impaired orgasm, including anorgasmia in men, paresthesia of male genitals.

General state

Often: weakness, irritability.

Infrequently: asthenia, fever, anxiety, malaise, intoxication.

Changes in laboratory parameters

Often: increase in blood pressure.

Infrequently: increase in heart rate, increase in diastolic arterial pressure, increase in orthostatic arterial pressure.

Description of individual side effects

Fainting with loss of consciousness, with bradycardia, or stopping the sinus node was observed in patients with Holter monitoring and were recorded in clinical studies. These adverse events are regarded as associated with the use of the drug. Most cases were observed during the first 3 hours after taking the drug, after taking the first dose, or are associated with medical procedures (blood sampling, changes in body position, blood pressure measurement). Prodromal symptoms often preceded syncope.

The incidence of syncope and prodromal symptoms depended on the dose, which was demonstrated in patients who received higher doses of the drug.

Effects of drug withdrawal

With the sudden cancellation of long-term selective serotonin reuptake inhibitors for the treatment of chronic depressive disorders, the following symptoms were observed: dysphoric state, irritability, agitation, dizziness, sensory disturbances (eg, paresthesia), anxiety, confusion, headache, lethargy, emotional lability, insomnia and hypomania. The results of a safety study showed a higher frequency of withdrawal symptoms in the form of insomnia and mild and moderate dizziness after discontinuation of the drug after 62 days of use.

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

- Severe heart disease (for example, NYHA class II-IV heart failure, impaired cardiac conduction (2-3 degree atrioventricular conduction block or sinus weakness syndrome) in the absence of a permanent pacemaker, severe ischemic heart disease or valvular lesion).

- Simultaneous administration of monoamine oxidase inhibitors (MAO-I) and administration within 14 days after discontinuation of their use. Similarly, MAO-I should not be taken within 7 days after discontinuation of taking Primaxetin®.

- Simultaneous administration of thioridazine and for 14 days after discontinuation of its use. Similarly, thioridazine should not be taken within 7 days after discontinuation of the drug Primaxetin®.

- Concurrent use of serotonin reuptake inhibitors (selective serotonin reuptake inhibitors - SSRIs), serotonin and noradrenaline reuptake inhibitors and tricyclic antidepressants and other drugs that have serotonergic effects (for example, L-tryptophan, triptans, tramadol, trimetroins, serptonergic (for example, L-tryptophan, tryptans, tramadol, serotonergic) (Hypericum perforatum) and within 14 days after discontinuation of these drugs. Similarly, these drugs should not be taken within 7 days after discontinuation of the drug Primaxet ®.

- Simultaneous administration with active inhibitors of CYP3A4, for example, ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, atazanavir, etc.

- Moderate and severe liver dysfunction.

- Severe renal dysfunction.

- Children and teenagers younger than 18 years old.

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

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

Carefully

- mild or moderate renal dysfunction;

- simultaneous use with potent inhibitors of CYP2D6 isoenzyme and moderate CYP3A4 inhibitors in patients with genotypically low CYP2D6 isoenzyme activity and patients with high CYP2D6 isoenzyme activity (in combination with moderate inhibitors of CYP3A4 isoenzyme);

- simultaneous use with drugs that affect platelet aggregation and anticoagulants due to the risk of bleeding.

Drug interactions

Interaction with monoamine oxidase inhibitors

In patients who received both the SSRI and monoamine oxidase inhibitor (MAO-I), serious, sometimes fatal reactions were described, including hyperthermia, rigidity, myoclonus, instability of the vegetative system with possible rapid fluctuation of vital signs, as well as changes in mental state, including including severe agitation, progressing to delirium and coma. These reactions were also observed in patients who recently stopped taking SSRIs and started treatment with MAO-I. In some cases, the symptoms resembled a neuroleptic malignant syndrome. Data on the combined use of SSRIs and MAO-I in animals suggest that these drugs can synergistically increase blood pressure and cause behavioral arousal. Therefore, the drug Primaxetine® should not be taken simultaneously with MAO-I and for 14 days after stopping their administration. Similarly, MAO-I should not be taken within 7 days after discontinuation of taking Primaxetin®.

Interaction with Thioridazine

Thioridazine extends the QTc interval, which is accompanied by ventricular arrhythmia. Preparations like Primaxetin®, which inhibit the CYP2D6 enzyme, appear to inhibit the metabolism of thioridazine. It is expected that the increase in thioridazine caused by this will enhance the prolongation of the QTc interval. The drug Primaxetine® should not be taken simultaneously with thioridazine and for 14 days after discontinuation. Similarly, thioridazine should not be taken within 7 days after discontinuation of the drug Primaxetin®.

Drugs with serotonergic action

As in the case of SSRIs, taking Primaxetin® simultaneously with serotonergic drugs (including MAO-I, L-tryptophan, tryptans, tramadol,

linezolid, SSRIs, serotonin and noradrenaline uptake inhibitors, lithium, and Hypericum perforatum drugs may increase the incidence of serotonergic side effects. The drug Primaxetine® should not be taken simultaneously with other SSRIs, MAO-I and other serotonergic drugs and for 14 days after discontinuation of these drugs. Similarly, these drugs should not be taken within 7 days after stopping the drug intake of Primaxetin®.

Drugs acting on CHC

Reception of the drug Primaxetine® simultaneously with drugs acting on the central nervous system has not been studied in patients with premature ejaculation. It is recommended that caution be taken when taking these drugs at the same time.

Effect of other drugs on dapoxetine hydrochloride

Studies in human microsomes of the liver, kidneys and intestines in vitro showed that dapoxetine is metabolized predominantly by CYP2D6, CYP3A4 and flavin-containing monooxygenase 1 (PMO1). Therefore, inhibitors of these enzymes can reduce the clearance of dapoxetine.

CYP3A4 inhibitors

Active inhibitors of CYP3A4

Taking ketoconazole at a dose of 200 mg twice a day for 7 days increased Cmax and AUC of dapoxetine (60 mg once) by 35% and 99%, respectively. Considering the fraction of unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction (the amount of unbound dapoxetine and desmethyldipoxetine) in the presence of active CYP3A4 inhibitors can increase by about 25%, and AUC can double. This increase in Cmax and AUC of the active fraction may be significantly more pronounced in a subpopulation of patients who do not have the functionally active CYP2D6 enzyme, as well as with the simultaneous use of active CYP2D6 inhibitors.

The drug Primaxetine® should not be taken simultaneously with active inhibitors of CYP3A4, for example, ketoconazole, intraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir and atazanavir.

Moderately active inhibitors of CYP3A4

Simultaneous administration of moderately active inhibitors of CYP3A4, for example, erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, or diltiazem, can significantly increase the level of systemic exposure to dapoxetine and desmethylpanoxetine, especially in patients with low CYP2D6 activity. The maximum dose of the drug Primaxetine®, taken simultaneously with these drugs, should be limited to 30 mg and taken with caution.

Active inhibitors of CYP2D6

Taking fluoxetine in a dose of 60 mg / day for 7 days has increased Cmax and AUC of dapoxetine (60 mg once) by 50% and 88%, respectively. Taking into account the proportion of unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction (the amount of unbound dapoxetine and desmethydipoxetine) in the presence of active CYP2D6 inhibitors can increase by about 50%, and AUC can double. This increase in Cmax and AUC of the active fraction is close to that expected in patients with low CYP2D6 activity and may lead to an increase in the frequency and severity of dose-related adverse reactions. Therefore, it is recommended to exercise caution when increasing the dose of the drug Primaxetin® to 60 mg in patients receiving active CYP2D6 inhibitors, and in patients with low CYP2D6 activity.

Interaction with drugs metabolized by isoenzymes CYP1A and CYP2B6

Based on the comparative data of Cmax of dapoxetine when taking a dose of the drug 60 mg and concentration of dapoxetine at 50% inhibition (IC50) of the CYP1A2 isoenzyme in vitro, it was concluded that the effect of dapoxetine on the concentration of concurrent drugs metabolized by this isoenzyme is not expected. The effect of dapoxetine on the CYP2B6 isoenzyme has not been studied.

PDE5 inhibitors

The pharmacokinetics of dapoxetine taken at a dose of 60 mg simultaneously with tadalafil (20 mg) or sildenafil (100 mg) was studied. Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil slightly increased AUC and C max of dapoxetine (22% and 4% respectively), which is considered clinically insignificant. Primaxetine® should be used with caution in patients taking PDE5 inhibitors, because of the possibly reduced tolerance of these patients to orthostatic hypotension.

Effect of dapoxetine hydrochloride on concomitantly administered drugs Tamsulosin

A single and repeated administration of the drug Primaxetin® in doses of 30 mg and 60 mg in patients receiving tamsulosin daily did not change the pharmacokinetics of the latter. It also did not change the frequency of orthostatic hypotension, which was the same when taking only tamsulosin and in combination with tamsulosin and Primaxetin® 30 mg or 60 mg.The drug Primaxetine should be used with caution in patients taking alpha-blockers, because of the possibly reduced tolerance of these patients to orthostatic hypotension. Drugs metabolized by CYP2D6

Repeated intake of the drug Primaxetin® (60 mg / day for 6 days) increased the Cmax and AUC of desipramine (50 mg once) by 11% and 19%, respectively, compared to taking only desipramine. Dapoxetine can likewise increase the concentration in plasma and other drugs metabolized by CYP2D6. The clinical significance of this is likely to be small.

Drugs metabolized by CYP3A

Repeated administration of the drug Primaxetin® (60 mg / day for 6 days) reduced the AUC of midazolam (8 mg once) by about 20% (range from -60% to + 18%). The clinical significance of this phenomenon in most patients is likely to be small. However, an increase in CYP3A activity may be of clinical importance in some patients who are simultaneously taking medications that are mainly metabolized by CYP3A and have a narrow therapeutic window.

Drugs metabolized by CYP2C19

Repeated administration of the drug Primaxetin® (60 mg / day for 6 days) did not affect the pharmacokinetics of omeprazole (40 mg once). Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C19 substrates.

Drugs metabolized by CYP2C9

Repeated administration of the drug Primaxetin® (60 mg / day for 6 days) did not affect the pharmacokinetics and pharmacodynamics of glyburide (5 mg once). Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C9 substrates.

PDE5 inhibitors

According to the study, dapoxetine (60 mg) did not affect the pharmacokinetics of tadalafil (20 mg) and sildenafil (100 mg).

Warfarin

There are no data on the effects of long-term use of warfarin simultaneously with the drug Primaxetin®. It is recommended to exercise caution when prescribing the drug Primaxetin® to patients who take warfarin for a long time. In the pharmacokinetic study, repeated administration of dapoxetine (60 mg / day for 6 days) did not affect the pharmacokinetics and pharmacodynamics (PV and INR) of warfarin (25 mg once). Ethanol

A single dose of ethanol (0.5 g / kg, or about 2 doses) did not affect the pharmacokinetics of dapoxetine (60 mg once) and vice versa. The simultaneous use of the drug Primaxetin® and ethanol increased drowsiness and significantly reduced wakefulness when evaluated by the patient. Taking only ethanol and only Primaxetin® did not significantly alter cognitive functions (reaction rate in the digit recognition test and the digit character substitution test) compared with placebo, however, the combination of ethanol with Primaxetin® statistically reliably changed these indicators compared to ethanol alone . The simultaneous use of ethanol and the drug Primaxetin® increases the frequency and severity of unwanted reactions such as dizziness, drowsiness, slow reflexes, and changes in judgment. The combination of alcohol with Primaxetin® can also enhance neuro-cardiogenic side effects, in particular, the frequency of fainting, which increases the risk of accidental injury. Therefore, patients should be advised to refrain from taking alcohol during the period of treatment with Primaxetin®.

Pregnancy and Lactation

The drug Primaxetine® is not intended for use in women.

Pregnancy

Based on the limited amount of data obtained in clinical studies, there is no reason to assume that dapoxetine intake by a man may affect the partner's pregnancy. Well-controlled studies of the use of dapoxetine in pregnant women have not been conducted.

Breastfeeding period

It is not known whether dapoxetine and its metabolites are excreted in breast milk.

Special instructions

Are common

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

Reception together with narcotic drugs

Patients should be advised not to take Primaxetin® along with narcotic drugs. Simultaneous use of the drug Primaxetin® with drugs with serotonergic activity, for example, ketamine, methylenedioxymethamphetamine (MDMA) and lysergic acid diethylamide (LSD), can lead to potentially serious reactions, including, but not limited to, arrhythmia, hyperthermia, and serotonism, in the presence of hyperthermia and serotonism, and in the case of serotononine and serotonism, and in the case of serotonism, in the presence of hypertension and serotonism, in the presence of hypertension and serotonism Taking Primaxetine® together with sedatives, such as opiates or benzodiazepines, may increase drowsiness and dizziness.

Ethanol

The combination of Primaxetin® with alcohol may enhance the effect of the latter on the central nervous system and the neuro-cardiogenic side effects of alcohol, such as syncope, which increases the risk of accidental injury. Therefore, patients should be advised to refrain from taking alcohol while taking the drug Primaxetin®.

Fainting

The frequency of fainting in clinical studies of the drug Primaxetin® depended on the category of patients and ranged from 0.06% (for a dose of 30 mg) to 0.23% (for a dose of 60 mg) to 0.64% (for both doses together) study involving healthy volunteers.

Patients who received Primaxetin® compared with patients who received a placebo, were more likely to have prodromal symptoms, including nausea, dizziness / lightness in the head, and sweating. At the dose of the drug Primaxetin® 30 mg, the frequency of nausea was 11.0%, the frequency of dizziness - 5.8%, hyperhidrosis - 0.8%. At the dose of the drug Primaxetin® 60 mg, these figures were 21.2%, 11.7% and 1.5%, respectively. The frequency of syncope and possible prodromal symptoms was dose-dependent, as evidenced by higher rates in patients who received higher doses than the maximum recommended daily dose of 60 mg. The cases of a syncope observed in clinical trials were regarded as having the vazo-vagal nature. Most of these cases occurred during the first 3 hours after the first dose, or were associated with conducting research procedures in a clinical setting (for example, taking a blood sample, rising sharply, measuring blood pressure). Possible prodromal symptoms, such as nausea, dizziness, a feeling of lightness in the head, palpitations, asthenia, confusion and sweating, were usually also observed in the first 3 hours after taking the drug and often preceded fainting. Patients should be informed that during the period of treatment with Primaxetin® at any time, fainting may develop with or without prodromal symptoms. The physician should inform the patient of the importance of sufficient water load and of recognizing prodromal signs and symptoms to reduce the risk of serious injury from falling due to loss of consciousness. When possible prodromal symptoms appear, the patient should immediately lie down so that the head is lower than the body, or sit with the head between the knees, and must remain in this position until the symptoms disappear. If fainting or other effects occur in the patient’s central nervous system, they should be warned of the need to avoid potentially traumatic situations, including driving a car and controlling dangerous machinery.

The combination of Primaxetin® with alcohol can increase neuro-cardiogenic side effects, including syncope, which increases the risk of accidental injury; therefore, patients should be advised to refrain from taking alcohol during the period of treatment with Primaxetin®.

Patients at risk for cardiovascular disease

Patients with cardiovascular diseases did not participate in clinical trials of the drug. Patients with organic diseases of the heart and blood vessels (for example, obstruction of blood ejection from the heart, valvular lesion, carotid stenosis, coronary artery atherosclerosis) increase the risk of undesirable cardiovascular effects of syncope of the heart and other origin. However, there is currently insufficient data to determine whether this risk extends to vaso-vagal syncope in patients with cardiovascular diseases.

Orthostatic hypotension

In clinical studies, cases of orthostatic hypotension are described. The doctor should inform the patient in advance that when possible prodromal symptoms appear, for example, a feeling of lightness in the head immediately after getting up, you should immediately lie down so that the head is lower than the body, or sit with your head down between your knees, and remain in this position until disappearance of symptoms. In addition, you need to inform the patient about the need to avoid a sharp rise after prolonged lying or sitting. In addition, the drug Primaxetine should be carefully prescribed to patients taking vasodilator drugs (for example, alpha-blockers, nitrates, PDE5 inhibitors), because of the possible reduced tolerance of such patients to the orthostatic effect of the drug. Moderately active inhibitors of CYP3A4

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

Active inhibitors of CYP2D6

It is recommended to exercise caution when increasing the dose of Primaxetin® 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 of the drug with a corresponding increase in the frequency and severity of dose-related adverse events.

Suicide / suicidal thoughts

In short-term studies, antidepressants, including SSRIs, compared with placebo, increased the risk of suicide and the appearance of suicidal thoughts in children and adolescents with generalized depression and other mental disorders. In adults older than 24 years, no such effect was found. In clinical studies of the drug Primaxetin® for the treatment of premature ejaculation, clear data on the connection of suicidal thoughts with treatment have not been obtained.

Mania

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

Cramps

Because of the ability of SSRIs to reduce the convulsive threshold, the use of Primaxetin® should be avoided in patients with unstable epilepsy, and should be discontinued when seizures appear. Patients with controlled epilepsy require careful monitoring.

Reception in children and adolescents younger than 18 years

The drug Primaxetine® can not be taken in patients younger than 18 years.

Concomitant depression and mental disorders

If the patient has signs and symptoms of depression before the use of the drug Primaxetin®, it is necessary to conduct an examination to rule out the presence of an undiagnosed depressive disorder. The drug Primaxetine® should not be taken simultaneously with antidepressants, including SSRIs and serotonin and noradrenaline reuptake inhibitors. It is not recommended to stop treatment of depression or anxiety to start treatment with Primaxetin®.The drug Primaxetine® is not intended for the treatment of mental disorders (for example, schizophrenia or depression), it should not be taken by men with these diseases, since this can not be ruled out by the increased symptoms of depression. Any disturbing thoughts or sensations should be reported to the doctor immediately, and if signs and symptoms of depression appear during treatment, Primaxetin® should be withdrawn.

Bleeding

At use of SIOZS bleeding cases are described. Caution is advised when receiving Primaxetine® drug simultaneously with drugs affecting platelet function (e.g., atypical antipsychotics, phenothiazine, acetylsalicylic acid, nonsteroidal antiinflammatory drugs (NSAIDs), anticoagulants), as well as in patients with bleeding or bleeding disorders in the anamnesis.

Renal dysfunction

Primaxetine® should not be taken in patients with severe renal dysfunction, patients with moderately severe and mild renal dysfunction should be cautious.

Cancellation syndrome

There is evidence that abrupt cancellation of SSRIs that have been long used for the treatment of chronic depressive disorders leads to the following symptoms: decrease in mood, irritability, agitation, dizziness, sensitivity disorders (for example, paresthesia in the form of electric shock), anxiety, confusion, headache, lethargy, emotional instability, insomnia, hypomania.

In a clinical study conducted to assess the effect 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 transferring patients to placebo after daily dapoxetine, only minor withdrawal symptoms were observed in the form of weak or moderately marked insomnia and dizziness. Similar results were obtained in another clinical study with double-blind control with a weekly period of evaluating the effects of withdrawal after 24 weeks of use of the drug in a dose of 30 mg or 60 mg according to need.

Influence on the ability to drive vehicles, machinery and engage in other activities that require high concentration of attention

When taking dapoxetine described cases of dizziness, attention disorders, fainting, blurred vision, drowsiness. The patient should be warned about the need to avoid situations in which injury is possible, including driving a car and controlling dangerous machinery.

Overdosage

Symptoms

In clinical studies, cases of overdose are not described.

The administration of the drug Primaxetin® in a dose of up to 240 mg (2 doses of 120 mg each with an interval of 3 hours) did not cause unforeseen undesirable effects. In general, the symptoms of an SSRI overdose include serotonergic reactions, including drowsiness, gastrointestinal disturbances (nausea, vomiting), tachycardia, tremor, agitation and dizziness.

Treatment

In case of overdose, standard maintenance therapy should be carried out, if necessary. Due to the significant binding of the drug to plasma proteins and the large distribution of dapoxetine hydrochloride, forced diuresis, dialysis, hemoperfusion and blood transfusion are unlikely to be effective. The specific antidote is unknown.