Primaxetine pills 30mg, 6pcs

Composition

Film-coated tablets.

1 tablet contains:

Active ingredient:

dapoxetine hydrochloride 33.6 mg in terms of dapoxetine 30 mg;

excipients:

lactose monohydrate,

microcrystalline cellulose,

croscarmellose sodium,

colloidal anhydrous silicon dioxide,

magnesium stearate;

excipients for the shell:

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

Pharmacological action

Pharmacotherapy group:

A treatment for premature ejaculation.

ATX code: G04BX14

Pharmacological properties

Pharmacodynamics

It is suggested that the mechanism of action of dapoxetine in premature ejaculation is associated with inhibition of serotonin reuptake by neurons, followed by an increase in the effect 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, urethral and bladder neck muscles, causing their coordinated contraction to achieve ejaculation.

Dapoxetine affects the ejaculation reflex, increasing the latent period and reducing the duration of reflex impulses of motor neurons of the perineal ganglia. The stimulus that triggers ejaculation is generated in the spinal reflex center, which is controlled through the brainstem by several brain nuclei, including the preoptic and paraventricular.

Pharmacokinetics

Suction

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

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

Distribution

More than 99% of dapoxetine binds to plasma proteins in vitro. The active metabolite, desmethyldapoxetine, binds to plasma proteins by 98.5%. Dapoxetine is rapidly distributed throughout the body with an average steady-state volume of distribution of 162 liters. When administered intravenously in humans, the average elimination half-lives in the initial, intermediate, and terminal phases of elimination are 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 renal monooxygenase (PMO 1). In a clinical study that examined the metabolism of 14C-dapoxetine, dapoxetine was extensively metabolized after oral use mainly by N-oxidation, N-demethylation, naphtho-group hydroxylation, glucuronidation, and sulfo-group addition. After oral use, signs of presystemic metabolism in the liver were found. The main components circulating in the blood plasma were intact dapoxetine and dapoxetine-N-oxide. In vitro studies have shown that dapoxetine – N-oxide is inactive. In addition, desmethyldapoxetine and didezmethyldapoxetine were detected in an amount of less than 3% of the total amount of circulating dapoxetine metabolites. An in vitro study found that desmethyldapoxetine is comparable in activity to dapoxetine, and didezmethyldapoxetine is approximately 2 times less active than dapoxetine. The exposure (AUC and Cmax) of unbound desmethyldapoxetine was 50% and 23% of unbound dapoxetine, respectively. Deduction

Dapoxetine metabolites are mainly excreted in the urine as conjugates. The unchanged Active ingredient is not detected in the urine. Dapoxetine is rapidly eliminated, as indicated by a low concentration of the substance in the blood plasma (less than 5% of the maximum) 24 hours after taking the dose. With daily intake, the accumulation of substances in the body is minimal. When taken orally, the final half-life is approximately 19 hours.

Special patient groups

Race

A single dose of dapoxetine 60 mg did not reveal a statistically significant difference in indicators among Europeans, black people, Hispanics and Asian people. Comparison of the pharmacokinetics of dapoxetine in Europeans and Japanese showed higher values of Cmax and AUC, in the latter (by 10-20%) due to lower body weight. A higher level of systemic exposure is unlikely to cause a significant difference in the clinical effect.

Elderly patients (65 years and older)

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

Mean dapoxetine AUC and terminal half-life were higher, by 12% and 46%, respectively, in older men compared to younger men.

Impaired renal function

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), moderate (creatinine clearance from 30 to <50 ml/min) and severe (creatinine clearance The AUC of dapoxetine in patients with severe renal impairment was approximately 2 times higher than in patients with normal renal function. Data on the use of the drug in patients with severe renal impairment are limited. The pharmacokinetics of dapoxetine have not been studied in patients requiring hemodialysis.

Impaired liver function

In patients with mild hepatic impairment, the pharmacokinetics of dapoxetine and desmethyldapoxetine did not change. In patients with moderate hepatic impairment (Child-Pugh class B), 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 increased 2-fold.

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

CYP2D6 polymorphism

The concentration of dapoxetine in blood plasma after a single dose of Primaxetin® at a dose of 60 mg in patients with low CYP2D6 activity was higher than in patients with high CYP2D6 activity (Cmax by about 31%, AUC by about 36%). Similarly, the cmax of desmethyldapoxetine in patients with low CYP2D6 activity was increased by 98%, and AUC-by 161%. The mean terminal half-life of dapoxetine was increased by 2.4 hours in patients with low activity of the CYP2D6 isoenzyme compared to patients with high activity of the CYP2D6 isoenzyme. Cmax of the active fraction of dapoxetine was increased by -46%, and AUC by -90%. This increase may be accompanied by an increased frequency and severity of dose-dependent adverse events. The safety of Primaxetin® in patients with low CYP2D6 activity may be questionable when other drugs that can inhibit the metabolism of dapoxetine, in particular, active and moderately active CYP3A4 inhibitors, are taken simultaneously.

Plasma concentrations of dapoxetine and desmethyldapoxetine are expected to be reduced in patients with ultrahigh CYP2D6 activity.

Indications

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

Contraindications

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

– Severe heart diseases (for example, NYHA class II-IV heart failure, cardiac conduction disorders (grade 2-3 atrioventricular conduction block or sinus weakness syndrome) in the absence of a permanent pacemaker, severe coronary heart disease or valvular apparatus damage).

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

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

– Concomitant use of inhibitors of serotonin reuptake (selective reuptake inhibitors of serotonin, SSRI) reuptake inhibitors of serotonin and norepinephrine, and tricyclic antidepressants, and other drugs that have serotonergic activity (e. g., L-tryptophan, triptan, tramadol, linezolid, lithium, St. John’s wort preparations (Hypericum perforatum) and within 14 days after discontinuation of these drugs. Similarly, these medications should not be taken for 7 days after discontinuation of Primaxetin®.

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

– Moderate to severe liver function disorders.

– Severe renal impairment.

– Children and teenagers under 18 years of age.

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

If there is a history of established or suspected orthostatic hypotension, as well as a history of mania/hypomania orTaking into account the proportion of unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction (the sum of unbound dapoxetine and desmethyldapoxetine) in the presence of active CYP2D6 inhibitors can increase by about 50%, and the AUC can double. This increase in Cmax and AUC of the active fraction is close to what is expected in patients with low CYP2D6 activity and may lead to an increase in the frequency and severity of dose-dependent adverse reactions. Therefore, caution is recommended when increasing the dose of Primaxetin® to 60 mg in patients receiving active CYP2D6 inhibitors and in patients with low CYP2D6 activity.

Interaction with drugs metabolized by CYP1A and CYP2A6 isoenzymes

Based on comparative data on the Cmax of dapoxetine at a dose of 60 mg and the concentration of dapoxetine with 50% inhibition (IC50) of the CYP1A2 isoenzyme in vitro, it was concluded that no effect of dapoxetine on the concentration of concomitantly prescribed drugs metabolized by this isoenzyme is 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) were studied. Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil slightly increased the AUC and Cmax of dapoxetine (by 22% and 4%, respectively), which is considered clinically insignificant. Primaxetin® should be used with caution in patients taking PDE5 inhibitors, due to the possible reduced tolerance of these patients to orthostatic hypotension.

Effect of dapoxetine hydrochloride on concomitant medications Tamsulosin

Single and repeated use of Primaxetin® in doses of 30 mg and 60 mg to patients receiving tamsulosin daily did not lead to a change in the pharmacokinetics of the latter. At the same time, the frequency of orthostatic hypotension also did not change, which was the same when taking tamsulosin alone and in combination with tamsulosin with Primaxetin® 30 mg or 60 mg. Primaxetin® should be used with caution in patients taking alpha-blockers, due to the possible reduced tolerance of these patients to orthostatic hypotension. Drugs metabolized by CYP2D6

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

Drugs metabolized by CYP3A

Repeated use of Primaxetin® (60 mg / day for 6 days) reduced the AUC of midazolam (8 mg once) by approximately 20% (range from -60% to +18%). The clinical significance of this phenomenon in most patients is probably low. However, an increase in CYP3A activity may be of clinical significance in some patients taking concomitant drugs that are mainly metabolized by CYP3A and have a narrow therapeutic window.

Drugs metabolized by CYP2C19

Repeated use of 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 use of 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

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 concomitantly with Primaxetin®. Caution is recommended when prescribing Primaxetin to patients taking warfarin for a long time. In the pharmacokinetic study, multiple doses 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 approximately 2 doses) did not affect the pharmacokinetics of dapoxetine (60 mg once) and vice versa. Concomitant use of Primaxetin and ethanol increased drowsiness and significantly reduced the patient’s level of wakefulness. Taking only ethanol and Primaxetin® alone did not significantly change cognitive function scores (reaction rate in the digit recognition test and in the digit character replacement test) compared to placebo, but the combination of ethanol and Primaxetin® statistically significantly changed these scores compared to ethanol alone. Concomitant use of ethanol and Primaxetin increases the frequency and severity of adverse reactions such as dizziness, drowsiness, slow reflexes, and changes in judgment. The combination of alcohol with Primaxetin® may also increase neuro-cardiogenic side effects, in particular the frequency of syncope, which increases the risk of accidental injury. Therefore, patients should be advised to refrain from taking alcohol during treatment with Primaxetin.

How to take, course of use and dosage

For oral use. The tablet should be swallowed whole, washed down with at least one full glass of water. Primaxetin® can be taken regardless of food intake.

Adult males from 18 to 64 years of age

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

A doctor who prescribes Primaxetin® for the treatment of 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 to decide whether further treatment with Primaxetin®is appropriate.

Patients with impaired renal function

No dose adjustment is required in patients with mild to moderate renal impairment, but caution is recommended. Primaxetin® is not recommended for use in patients with severe renal impairment.

Patients with impaired liver function

No dose adjustment is required for patients with mild hepatic impairment. Primaxetin® is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C).

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

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

Patients receiving active or moderately active CYP3A4 inhibitors Concomitant use of active CYP3A4 inhibitors is contraindicated. When Primaxetin® is co-administered with moderately active CYP3A4 inhibitors, the dose of the drug should be reduced to 30 mg.

Overdose

Symptoms

No overdose cases have been reported in clinical trials.

Taking Primaxetin® in a dose of up to 240 mg (2 doses of 120 mg with an interval of 3 hours) it did not cause any unexpected adverse events. In general, symptoms of SSRI overdose include serotonergic reactions, including drowsiness, gastrointestinal disorders (nausea, vomiting), tachycardia, tremor, agitation, and dizziness.

Treatment

In case of overdose, standard maintenance therapy should be used, if necessary. Due to the 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. The specific antidote is unknown.

Special instructions

General information

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

Use with narcotic drugs

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

Ethanol

The combination of Primaxetin® with alcohol may increase the effect of the latter on the central nervous system and the neuro-cardiogenic 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 Primaxetin®.

Syncope

The frequency of syncope in clinical trials of 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) in a study with healthy volunteers.

Patients treated with Primaxetin® were more likely to experience prodromal symptoms, including nausea, dizziness/lightheadedness, and sweating, compared to patients treated with placebo.At a dose of Primaxetin 30 mg, the frequency of nausea was 11.0%, the frequency of dizziness was 5.8%, and hyperhidrosis was 0.8%. At the Primaxetin 60 mg dose, these figures were 21.2%,11.7%, and 1.5%, respectively. The frequency of syncope and possible prodromal symptoms was dose-dependent, as indicated by higher rates in patients receiving higher doses than the maximum recommended daily dose of 60 mg. Cases of syncope observed in clinical trials were considered to be of a vaso-vagal nature. Most of these cases occurred within the first 3 hours after taking the first dose, or were associated with conducting research procedures in a clinical setting (for example, taking a blood sample, standing up abruptly, measuring blood pressure). Possible prodromal symptoms, such as nausea, dizziness, lightheadedness, palpitations, asthenia, confusion, and sweating, were also usually observed in the first 3 hours after taking the drug and often preceded fainting. Patients should be informed that syncope with or without prodromal symptoms may occur at any time during treatment with Primaxetin®. The doctor should inform the patient about the importance of sufficient water load and about recognizing prodromal signs and symptoms to reduce the risk of serious injury in a fall due to loss of consciousness. If possible prodromal symptoms appear, the patient should immediately lie down so that the head is lower than the torso, or sit with the head between the knees, and should remain in this position until the symptoms disappear. If syncope or other central nervous system effects occur, the patient should be warned to avoid potentially traumatic situations, including driving a car and operating dangerous machinery.

The combination of Primaxetin® with alcohol may 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 treatment with Primaxetin®.

Patients at risk of 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 the ejection of blood from the heart, damage to the valvular apparatus, carotid artery stenosis, coronary artery atherosclerosis) have an increased risk of undesirable cardiovascular consequences of syncope of cardiac 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

Cases of orthostatic hypotension have been reported in clinical studies. The doctor should inform the patient in advance that if 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 trunk, or sit with your head between your knees and remain in this position until the symptoms disappear. In addition, the patient should be informed about the need to avoid getting up abruptly after lying down or sitting for a long time. In addition, Primaxetin® should be used with caution in patients taking vasodilators (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 CYP3A4 inhibitors

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

Active CYP2D6 inhibitors

Caution is recommended 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 to the drug with a corresponding increase in the frequency and severity of dose-dependent adverse events.

Suicide/suicidal thoughts

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

Mania

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

Convulsions

Due to the ability of SSRIs to lower the seizure threshold, Primaxetin® should be avoided in patients with unstable epilepsy, and the drug should be discontinued if seizures occur. Patients with controlled epilepsy should be carefully monitored.

Admission for children and adolescents under 18 years of age

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

Concomitant depression and psychiatric disorders

If the patient has signs and symptoms of depression before starting the use of Primaxetin®, it is necessary to conduct an examination to exclude the presence of undiagnosed depressive disorder. Primaxetin should not be taken concomitantly with antidepressants, including SSRIs and serotonin and norepinephrine reuptake inhibitors. It is not recommended to discontinue treatment for depression or anxiety before starting treatment with Primaxetin. Primaxetin® is not intended for the treatment of psychiatric disorders (for example, schizophrenia or depression), it should not be taken by men with these diseases, since this cannot exclude an increase in the symptoms of depression. You should immediately inform your doctor of any disturbing thoughts or feelings, and if signs and symptoms of depression appear during treatment, Primaxetin® should be discontinued.

Bleeding

Cases of bleeding have been reported with SSRIs. Caution is recommended when taking Primaxetin ® concomitantly with drugs that affect platelet function (for example, atypical neuroleptics, phenothiazines, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants), as well as in patients with a history of bleeding or blood clotting disorders.

Impaired renal function

Primaxetin® is not recommended for use in patients with severe renal impairment, and caution should be exercised in patients with moderate to mild renal impairment.

Withdrawal syndrome

There is evidence that abrupt discontinuation of SSRIs, which have been used for a long time to treat chronic depressive disorders, leads to the following symptoms: decreased 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 evaluate the effect of dapoxetine withdrawal after 62 days of taking 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 use, only minor withdrawal symptoms were found in the form of mild to moderate insomnia and dizziness. Similar results were obtained in another double-blind clinical trial with a one-week period for evaluating the effects of withdrawal after 24 weeks of using the drug at a dose of 30 mg or 60 mg as needed.

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

When taking dapoxetine, cases of dizziness, impaired attention, fainting, blurred vision, drowsiness are described. The patient should be warned to avoid situations where injury may occur, including driving a car and operating dangerous machinery.

Form of production

Round biconvex tablets, covered with a film-coated gray color. On a cross-section, the core is white or almost white in color.

Active ingredient

Dapoxetine

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

Men, Adults by doctor’s prescription