Primaxetine 30 mg, 6 pills

Film-coated tablets.

1 tablet contains:

active substance:

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

Excipients:

lactose monohydrate,

microcrystalline cellulose,

croscarmellose sodium

silicon dioxide colloidal anhydrous,

magnesium stearate;

excipients for the shell:

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

Pharmacotherapeutic group

A treatment tool for premature ejaculation.

ATX Code: G04BX14

Pharmacological properties

Pharmacodynamics

It is assumed that the mechanism of action of dapoxetine in premature ejaculation is associated with inhibition of serotonin reuptake by neurons, followed by increased 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, urethral muscles and bladder neck, causing them to contract in a coordinated fashion to achieve ejaculation.

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

Pharmacokinetics

Suction

Dapoxetine is rapidly absorbed, and the maximum concentration in blood plasma (Cmax) is achieved 1-2 hours after taking the drug. Absolute bioavailability is 42% (range 15-76%). After a single oral administration 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.

The intake of fatty foods moderately reduces Cmax of dapoxetine (by 10%) and by 12% increases AUC (the area under the concentration-time curve) and the time to reach maximum plasma concentration. However, the degree of absorption of dapoxetine does not change. These changes are not clinically significant. Primaxetine® can be taken without regard to meals.

Distribution

Over 99% of dapoxetine binds to plasma proteins in vitro. An active metabolite - desmethyldoxetine - binds to plasma proteins by 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 excretion 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 (FMO1) kidneys. In a clinical study that examined the metabolism of 14C-dapoxetine, after oral administration, dapoxetine was actively metabolized mainly by the pathways of N-oxidation, N-demethylation, hydroxylation of the naphtho group, glucuronidation and addition of the sulfo group. After oral administration, signs of a 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 found that dapoxetine N-oxide is inactive. Besides, less than 3% of the total number of circulating metabolites of dapoxetine were found to be desmethyl dapoxetine and didemethyl dapoxetine. An in vitro study found that desmethyldoxetine is comparable in activity to dapoxetine, and didemethyldoxetine is about 2 times less active than dapoxetine. Exposure (AUC and Cmax) of unbound desmethyl dapoxetine was 50% and 23% of unbound dapoxetine, respectively.Breeding

Dapoxetine metabolites are excreted mainly in the urine in the form of conjugates. Unchanged active substance in the urine is not detected. 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 taking the dose. With daily use, the accumulation of substances in the body is minimal. When taken orally, the final elimination half-life is approximately 19 hours.

Special patient groups

Race

A single dose of dapoxetine at a dose of 60 mg did not reveal a statistically significant difference in the rates among Europeans, persons of the black race, Hispanics and people of the Asian race. 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 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 average AUC of dapoxetine and the final half-life were higher, respectively, by 12% and 46% in older men compared with men of a younger age.

Impaired renal function

A single dose of 60 mg dapoxetine did not reveal a relationship between creatinine clearance and Cmax or AUC of dapoxetine in patients with weak (creatinine clearance of 50-80 ml / min), moderately expressed (creatinine clearance of 30 to <50 ml / min) and severe ( creatinine clearance <30 ml / min) impaired renal function. 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 impaired renal function are limited. In patients requiring hemodialysis, the pharmacokinetics of dapoxetine has not been studied.

Impaired liver function

In patients with mild hepatic impairment, the pharmacokinetics of dapoxetine and desmethyl dapoxetine did not change. In patients with impaired liver function of moderate severity (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, while AUC was increased by 2 times.

In patients with severe hepatic impairment, Cmax of unbound dapoxetine was not changed, and the AUC of unbound dapoxetine was increased by more than 3 times. AUC of the active fraction was also increased several times.

CYP2D6 Polymorphism

The concentration of dapoxetine in blood plasma after a single dose of Primaxetine® at a dose of 60 mg was higher in patients with low CYP2D6 activity than in patients with high CYP2D6 activity (Cmax by about 31%, AUC by about 36%). Similarly, Cmax of desmethyldoxetine in patients with low CYP2D6 activity was increased by 98%, and AUC by 161%. The average final half-life of dapoxetine is increased by 2.4 hours in patients with low activity of the CYP2D6 isoenzyme compared with patients with high activity of the CYP2D6 isoenzyme. Cmax of the active fraction of dapoxetine is increased by - 46%, and AUC - by 90%. This increase may be accompanied by an increased frequency and severity of dose-related adverse events.

In patients with ultra-high CYP2D6 activity, plasma concentrations of dapoxetine and desmethyl dapoxetine are expected to be reduced.

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

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

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

- Simultaneous administration of monoamine oxidase inhibitors (MAO-I) and administration within 14 days after cessation of their use. Similarly, MAO-I can not be taken within 7 days after stopping the drug Primaxetin®.

- Concomitant use of thioridazine and within 14 days after cessation of its use. Similarly, thioridazine should not be taken within 7 days after stopping the use of Primaxetine®.

- Concomitant use of serotonin reuptake inhibitors (SSRI selective selective serotonin reuptake inhibitors), serotonin and norepinephrine reuptake inhibitors and tricyclic antidepressants and other drugs with serotonergic effects (for example, L-tryptophan, tryptanium, linderol, tradolzoledolide (Hypericum perforatum) and within 14 days after discontinuation of these drugs.Likewise, these drugs can not be taken within 7 days after discontinuation of the drug Primaxetin®.

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

- Moderately severe and severe liver dysfunction.

- Severe renal impairment.

- Children and adolescents under the age of 18.

- 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 Primaxetine® should be avoided.

Carefully

- mild or moderate renal impairment;

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

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

In clinical studies, the following side effects were recorded, which were often observed and were dose-dependent: nausea (11.0% and 22.2% when taking 30 mg and 60 mg of 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 %). The most common symptoms requiring discontinuation of treatment were nausea (in 2.2% of patients) and dizziness (1.2%).

Adverse adverse reactions observed during clinical trials are listed below:

Mental disorders

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

Infrequently: depression, depressive mood, a state of euphoria, mood changes, nervousness, indifference, apathy, confusion, disorientation, pathological thinking, somatosensory amplification, sleep disturbances, initial insomnia, intrasomic disorder, nightmares, bruxism, loss of libido, anorg, libido.

Disorders from the central nervous system

Very often: dizziness, headache.

Often: drowsiness, impaired concentration, tremor, paresthesia.

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

Rarely: dizziness during physical exertion, sudden falling asleep.

Violations of the organ of vision

Often: blurred vision.

Infrequently: mydriasis, pain in the eye, visual impairment.

Hearing impairment and labyrinthine disorders

Often: ringing in the ears.

Infrequently: vertigo.

Disorders of the cardiovascular system

Often: hot flashes.

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

Rarely: hot flashes.

Respiratory system disorders

Often: nasal congestion, yawning.

Gastrointestinal Disorders

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

Disorders of the skin and subcutaneous tissue

Often: hyperhidrosis.

Infrequently: itching, cold sweat.

Reproductive system disorders

Often: erectile dysfunction.

Infrequently: lack of ejaculation, violation of orgasm, including anorgasmia in men, paresthesia of the genitals of men.

General state

Often: weakness, irritability.

Infrequently: asthenia, a feeling of heat, a feeling of anxiety, a feeling of malaise, a feeling of intoxication.

Laboratory changes

Often: high blood pressure.

Infrequently: an increase in heart rate, an increase in diastolic blood pressure, an increase in orthostatic blood pressure.

Description of individual side effects

Fainting with loss of consciousness, with bradycardia or sinus node arrest was observed in patients under Holter monitoring and were reported in clinical trials. 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 associated with medical procedures (blood sampling, changes in body position, measurement of blood pressure). Prodromal symptoms often preceded syncope.

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

Effects of drug withdrawal

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

Interactions with Monoamine Oxidase Inhibitors

Serious, sometimes fatal reactions, including hyperthermia, rigidity, myoclonus, instability of the autonomic system with possible rapid fluctuation of vital signs, and also a change in mental state, are described in patients who received both SSRIs and a monoamine oxidase inhibitor (MAO-I) including intense arousal, 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 malignant antipsychotic syndrome. Data on the combined use of SSRIs and MAOI 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 within 14 days after stopping their use. Similarly, MAO-I can not be taken within 7 days after stopping the drug Primaxetin®.

Interactions with Thioridazine

Thioridazine prolongs the QTc interval, which is accompanied by ventricular arrhythmia. Primaxetine® drugs that inhibit the CYP2D6 enzyme appear to inhibit the metabolism of thioridazine. It is expected that the resulting increase in thioridazine levels will enhance the lengthening of the QTc interval. The drug Primaxetine® cannot be taken simultaneously with thioridazine and within 14 days after stopping it. Similarly, thioridazine should not be taken within 7 days after stopping the use of Primaxetine®.

Drugs with serotonergic action

As with SSRIs, taking Primaxetine® simultaneously with serotonergic drugs (including MAO-I, L-tryptophan, triptans, tramadol,

linezolid, SSRIs, serotonin and norepinephrine uptake inhibitors, lithium, and St. John's wort (Hypericum perforatum) drugs can increase the incidence of serotonergic side effects. The drug Primaxetine® cannot be taken simultaneously with other SSRIs, MAO-I and other serotonergic drugs and within 14 days after stopping these drugs. Similarly, these drugs should not be taken within 7 days after stopping the use of Primaxetine®.

Drugs acting on CHC

The administration of Primaxetine® along with the drugs acting on the central nervous system has not been studied in patients with premature ejaculation. Caution is advised if you need to take these drugs at the same time.

The effect of other drugs on dapoxetine hydrochloride

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

CYP3A4 Inhibitors

Active CYP3A4 Inhibitors

The intake of ketoconazole at a dose of 200 mg 2 times a day for 7 days increased Cmax and AUC of dapoxetine (60 mg once) by 35% and 99%, respectively. Taking into account the fraction of unbound dapoxetine and desmethyldoxetine, Cmax of the active fraction (the sum of unbound dapoxetine and desmethyldoxetine) 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 can be significantly more pronounced in a subpopulation of patients who do not have a functionally active CYP2D6 enzyme, as well as while taking active CYP2D6 inhibitors.

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

Moderately Active CYP3A4 Inhibitors

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

Active inhibitors of CYP2D6

The intake of fluoxetine at a dose of 60 mg / day for 7 days increased Cmax and AUC of dapoxetine (60 mg once) by 50% and 88%, respectively. Taking into account the fraction of unbound dapoxetine and desmethyl dapoxetine, Cmax of the active fraction (the sum of unbound dapoxetine and desmethyl doxetine) 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-dependent adverse reactions. Therefore, caution is advised 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 the comparative data of Cmax of dapoxetine when taking a dose of 60 mg and dapoxetine concentration at 50% inhibition (IC50) of the CYP1A2 isoenzyme in vitro, it was concluded that dapoxetine is not expected to influence the concentration of simultaneously prescribed drugs metabolized by this isoenzyme. The effect of dapoxetine on the CYP2B6 isoenzyme has not been studied.

PDE5 Inhibitors

The pharmacokinetics of dapoxetine taken in a dose of 60 mg at the same time as tadalafil (20 mg) or sildenafil (100 mg) was studied. Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil slightly increased AUC and Cmax of dapoxetine (by 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.

The effect of dapoxetine hydrochloride on concomitantly taken tamsulosin preparations

A single and multiple administration of Primaxetine® in doses of 30 mg and 60 mg by patients receiving tamsulosin daily did not lead to a change in the pharmacokinetics of the latter. 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, did not change either. Primaxetine® should be used with caution in patients taking alpha-adrenergic blockers, due to the possibly reduced tolerance of these patients to orthostatic hypotension. CYP2D6 Metabolized Drugs

Multiple doses of Primaxetine® (60 mg / day for 6 days) increased Cmax and AUC of desipramine (50 mg once) by 11% and 19%, respectively, compared with taking desipramine alone. Dapoxetine can likewise increase the concentration in plasma and other drugs metabolized by CYP2D6. The clinical relevance of this is likely to be small.

CYP3A Metabolized Drugs

Multiple doses of Primaxetine® (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 likely to be small. However, an increase in CYP3A activity may have clinical significance in some patients who are taking drugs metabolized primarily by CYP3A and having a narrow therapeutic window.

Drugs Metabolized by CYP2C19

Repeated administration of Primaxetine® (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.

CYP2C9 Metabolized Drugs

Repeated administration of Primaxetine® (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 results of 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 Primaxetine®. Caution is advised when prescribing Primaxetine® to patients who have been taking warfarin for a long time. In a study of pharmacokinetics, repeated dapoxetine administration (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 administration of Primaxetine® and ethanol increased drowsiness and significantly reduced the level of wakefulness when evaluated by the patient. The intake of ethanol alone and Primaxetin® alone did not significantly change the indicators of cognitive functions (reaction rate in the digit recognition test and in the digit character replacement test) compared with placebo, however, the combination of ethanol with Primaxetine® statistically significantly changed these indicators compared with only ethanol . The simultaneous use of ethanol and the drug Primaxetine® increases the frequency and severity of such undesirable reactions as dizziness, drowsiness, slowing reflexes, change of judgment. The combination of alcohol with Primaxetine® 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 drinking alcohol during the treatment with Primaxetine®.

For oral administration. The tablet should be swallowed whole, washed down with at least one full glass of water. Primaxetine® can be taken without regard to meals.

Adult males 18 to 64 years old

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

The doctor prescribing Primaxetine® 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 must determine the risk-benefit ratio to decide on the feasibility of further treatment with Primaxetine®.

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 severe renal impairment.

Patients with impaired liver function

For patients with mild hepatic impairment, dose adjustment is not required. Primaxetine® is contraindicated in patients with moderate to severe impaired liver function (Child-Pugh classification B and C).

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

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

Patients Receiving Active or Moderately Active CYP3A4 Inhibitors Concurrent administration of active CYP3A4 inhibitors is contraindicated. When taking Primaxetine® with moderately active CYP3A4 inhibitors, the dose should be reduced to 30 mg.

Symptoms

In clinical studies, cases of overdose are not described.

Taking Primaxetine® in a dose of up to 240 mg (2 doses of 120 mg with an interval of 3 hours) did not cause unforeseen adverse events. In general, symptoms of an overdose of SSRIs include serotonergic reactions, including drowsiness, gastrointestinal upsets (nausea, vomiting), tachycardia, tremors, agitation, and dizziness.

Treatment

In case of overdose, if necessary, conduct standard maintenance therapy. Due to the significant binding of the drug to blood 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.