Symptoms: in clinical studies, cases of overdose are not described. Taking the drug Extensil® at a dose of up to 240 mg (2 doses of 120 mg with an interval of 3 hours) , it did not cause unexpected adverse events. In general, symptoms of an SSRI overdose include serotonergic reactions, including drowsiness, gastrointestinal disorders (nausea, vomiting), tachycardia, tremor, agitation, and dizziness.
Treatment: if necessary, perform standard maintenance therapy. Due to the significant binding of the drug to plasma proteins and the large Vd dapoxetine hydrochloride forced diuresis, dialysis, hemoperfusion, and blood transfusion are unlikely to be effective. The specific antidote is unknown.
hypersensitivity to dapoxetine hydrochloride or any other component of the drug,
severe heart diseases, including heart failure of class II-IV according to NYHA, cardiac conduction disorders (atrioventricular conduction block of degree 2-3 or sinus weakness syndrome) in the absence of a permanent pacemaker, severe ischemic heart disease or valvular apparatus damage,
simultaneous administration of MAO inhibitors and administration within 14 days after discontinuation of their use (similarly, MAO inhibitors should not be taken within 7 days after discontinuation of Extensil®),
simultaneous administration of thioridazine and within 14 days after discontinuation of its use (similarly, thioridazine can not be taken within 7 days after discontinuation of the drug Extensil®),
simultaneous administration of SSRIs, SSRIs and tricyclic antidepressants and other drugs with serotonergic action (including L-tryptophan, tryptans, tramadol, linezolid, lithium, St. John's wort preparations (Hypericum perforatum), and within 14 days after discontinuation of these drugs (similarly, these drugs cannot be taken for 7 days after discontinuation of Extensil®),
concomitant administration with active CYP3A4 inhibitors (including ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, atazanavir),
moderate to severe hepatic impairment,
severe renal impairment,
lactase deficiency, lactose intolerance, glucose-galactose malabsorption,
a history of established or suspected orthostatic hypotension,
a history of mania / hypomania or bipolar disorder,
age up to 18 years.
With caution: mild or moderate renal impairment, concomitant use with potent inhibitors of the CYP2D6 isoenzyme and moderate inhibitors of CYP3A4 in patients with genotypically low activity of the CYP2D6 isoenzyme and patients with high activity of the CYP2D6 isoenzyme (in combination with moderate inhibitors of the CYP3A4 isoenzyme), concomitant use with drugs that affect platelet aggregation, and with anticoagulants due to the risk of bleeding.
MAO inhibitors
In patients treated simultaneously with SSRIs and MAO inhibitor, serious, sometimes fatal reactions have been described, including.tsch. hyperthermia, rigidity, myoclonus, instability of the autonomic system with possible rapid fluctuations in vital signs, as well as changes in the mental state, in t.tsch. severe arousal, progressing to delirium and coma. These reactions have also been observed in patients who have recently stopped taking SSRIs and started treatment with MAO inhibitors. In some cases, the symptoms resembled a malignant neuroleptic syndrome. Data on the combined use of SSRIs and MAO inhibitors in animals suggest that these drugs can synergistically increase blood pressure and cause behavioral arousal. Therefore, the drug Extensil® It should not be taken simultaneously with MAO inhibitors and within 14 days after discontinuation of their use. Similarly MAO inhibitors should not be taken for 7 days after discontinuation of Extensil®.
Thioridazine
Thioridazine prolongs the QTc interval, which is accompanied by ventricular arrhythmia. Drugs similar to Extensil® Those that inhibit the CYP2D6 enzyme appear to inhibit the metabolism of thioridazine. The resulting increase in the level of thioridazine is expected to increase the prolongation of the QTc interval. Extensil preparation® do not take at the same time with thioridazine and within 14 days after discontinuation of its use. Similarly, thioridazine should not be taken for 7 days after discontinuation of Extensil®.
Drugs that have a serotonergic effect
As in the case of SSRIs, taking the drug Extensil® simultaneously with serotonergic drugs (including MAO inhibitors, L-tryptophan, tryptans, tramadol, linezolid, SSRIs, SSRIs, lithium and St. John's wort preparations (Hypericum perforatum) may increase the frequency of serotonergic side effects. Extensil preparation® Do not take concomitantly with other SSRIs, MAO inhibitors, or other serotonergic drugs and for 14 days after discontinuation of these drugs. Similarly these medications should not be taken for 7 days after discontinuation of Extensil®.
Drugs that act on the central nervous system
Taking the drug Extensil® concomitantly with drugs acting on the central nervous system, in patients with premature ejaculation has not been studied. It is recommended to exercise caution if you need to take these drugs simultaneously.
The effect of other drugs on dapoxetine
Studies using human liver, kidney, and intestinal microsomes in vitro Dapoxetine has been shown to be primarily metabolized by CYP2D6, CYP3A4, and FMO1. Therefore, inhibitors of these enzymes can reduce the clearance of dapoxetine.
CYP3A4 inhibitors
Active CYP3A4 inhibitors. Taking ketoconazole at a dose of 200 mg 2 times a day for 7 days increased Cmax and the AUC of dapoxetine (60 mg once) by 35 and 99%, respectively. Taking into account the proportion of unbound dapoxetine and desmethyldapoxetine, Cmax The active fraction (the sum of unbound dapoxetine and desmethyldapoxetine) in the presence of active CYP3A4 inhibitors can increase by about 25%, and the AUC can double. This is an increase of Cmax and the AUC of the active fraction can be significantly more pronounced in a subpopulation of patients without a functionally active CYP2D6 enzyme, as well as when taking active CYP2D6 inhibitors simultaneously.
Extensil preparation® Do not take concomitantly with active CYP3A4 inhibitors, including ketoconazole, intraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir and atazanavir.
Moderately active CYP3A4 inhibitors. Concomitant administration of moderately active CYP3A4 inhibitors, including erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, or diltiazem, may significantly increase the level of systemic exposure to dapoxetine and desmethyldapoxetine, especially in patients with low CYP2D6 activity. The maximum dose of Extensil® If taken simultaneously with these medications, it should be limited to 30 mg and taken with caution.
Active CYP2D6 inhibitors
Taking fluoxetine at a dose of 60 mg / day for 7 days increased Cmax and the AUC of dapoxetine (60 mg once) by 50 and 88%, respectively. Taking into account the proportion of unbound dapoxetine and desmethyldapoxetine, Cmax 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 is an increase of Cmax and the 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, it is recommended to exercise caution when increasing the dose of Extensil® up to 60 mg in patients receiving active CYP2D6 inhibitors and patients with low CYP2D6 activity.
Drugs that are metabolized by CYP1A and CYP2 isoenzymesB6
Based on comparative data Cmax dapoxetine when taking a dose of 60 mg and IC50 isoenzyme SUR1A2 in vitro it is concluded that the effect of dapoxetine on the concentration of concomitantly prescribed drugs metabolized by this isoenzyme is not expected. The effect of dapoxetine on the CYP2B6 isoenzyme has not been studied.
PDE-5 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 dapoxetine (22% and 4%, respectively), which is considered clinically insignificant. Extensil preparation® Caution should be used in patients taking PDE-5 inhibitors, due to the possible reduced tolerance of these patients to orthostatic hypotension.
The effect of dapoxetine on concomitant medications
Tamsulosin. Single and multiple use of Extensil® at doses of 30 and 60 mg in patients receiving tamsulosin daily, it did not lead to a change in the pharmacokinetics of the latter. At the same time, the frequency of orthostatic hypotension did not change, which was the same when taking only tamsulosin and the combination of tamsulosin with Extensil® 30 or 60 mg. Extensil preparation® it should be prescribed with caution to patients taking alpha-blockers, because of the possible reduced tolerance of these patients to orthostatic hypotension.
Drugs metabolized by CYP2D6
Multiple use of Extensil® (60 mg/day for 6 days) increased Cmax and the AUC of desipramine (50 mg once) by 11 and 19%, respectively, compared to taking desipramine alone. Dapoxetine may similarly increase plasma concentrations of other drugs metabolized by CYP2D6. The clinical significance of this is probably low.
Drugs metabolized by CYP3A
Multiple use of Extensil® (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 probably low. However, an increase in CYP3A activity may have clinical significance in some patients who are simultaneously taking drugs that are mainly metabolized by CYP3A and have a narrow therapeutic window.
Drugs metabolized by CYP2C19
Multiple use of Extensil® (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
Multiple use of Extensil® (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.
PDE-5 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
Data on the effects of long-term administration of warfarin simultaneously with the drug Extensil® no. Caution is recommended when prescribing Extensil® patients who take warfarin for a long time. In the study of pharmacokinetics, 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 approximately 2 doses) did not affect the pharmacokinetics of dapoxetine (60 mg once) and vice versa. Simultaneous administration of Extensil® and ethanol increased drowsiness and significantly reduced the level of wakefulness when evaluated by the patient. Taking only ethanol and only the drug Extensil® it did not significantly change the cognitive function indicators (the reaction rate in the digit recognition test and the digit character replacement test) compared to placebo, but the combination of ethanol with Extensil® statistically significant changes in these indicators compared only with ethanol.
Simultaneous use of ethanol and Extensil® increases the frequency and severity of adverse reactions such as dizziness, drowsiness, slow reflexes, and changes in judgment. Combination of alcohol with Extensil® it can also increase neurocardiogenic 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 treatment with Extensil®.
In clinical studies, the following side effects were reported, which were often observed and were dose-dependent (when taking 30 and 60 mg of dapoxetine, respectively): nausea (11 and 22.2%), 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 and 4.1%). The most frequent events that required discontinuation of treatment were nausea (in 2.2% of patients) and dizziness (1.2%).
Adverse side effects observed in clinical trials are listed below.
Mental disorders: often-anxiety, agitation, anxiety, unusual dreams, decreased libido, infrequently-depression, depressive mood, euphoria, mood changes, nervousness, indifference, apathy, confusion, disorientation, pathological thinking, somatosensory amplification, sleep disorders, initial insomnia, intrasomnic disorder, nightmares, bruxism, loss of libido, anorgasmia.
From the central nervous system: very often-dizziness, headache, often-drowsiness, impaired concentration, tremor, paresthesia, infrequently-fainting, including vasovagal, postural dizziness, akathisia, perversion of taste, hypersomnia, lethargy, sedation, depression of consciousness, rarely-dizziness during physical exertion, sudden falling asleep.
On the part of the visual organ: often - blurred vision, infrequently-mydriasis, pain in the eye, visual impairment.
On the part of the organ of hearing and labyrinth disorders: often-tinnitus, rarely-vertigo.
From the CCC side: often-flushes of blood, infrequently-cessation of activity of the sinus node, sinus bradycardia, tachycardia, decreased blood pressure, systolic hypertension, rarely-flushes of heat.
From the respiratory system: often-nasal congestion, yawning.
From the gastrointestinal tract: often — diarrhea, vomiting, constipation, abdominal pain, dyspepsia, flatulence, stomach discomfort, bloating, dry mouth.
From the skin and subcutaneous tissues: often-hyperhidrosis, infrequently-itching, cold sweat.
On the part of the reproductive system: often-erectile dysfunction, infrequently-lack of ejaculation, violation of orgasm, including anorgasmia in men, paresthesia of the genitals of men.
General condition: often-weakness, irritability, infrequently-asthenia, a feeling of heat, a feeling of anxiety, a feeling of malaise, a feeling of intoxication.
Changes in laboratory parameters: often-an increase in blood pressure, infrequently-an increase in heart rate, an increase in dBP, an increase in sAD.
Description of individual side effects
Syncope with loss of consciousness, bradycardia, or sinus node arrest has been observed in patients with Holter monitoring and has been reported in clinical studies. These adverse events are regarded as associated with the use of the drug. Most cases were observed within the first 3 hours after taking the drug, taking the first dose, or 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 was dose-dependent, as demonstrated in patients receiving higher doses of the drug.
Effects of drug withdrawal
With the sudden withdrawal of long-term SSRIs for the treatment of chronic depressive disorders, the following symptoms were noted: dysphoric state, irritability, agitation, dizziness, sensory disturbances (including paresthesia), anxiety, confusion, headache, lethargy, emotional lability, insomnia and hypomania. The results of the safety study showed a higher frequency of withdrawal symptoms in the form of insomnia and mild to moderate dizziness after discontinuation of the drug after 62 days of use.
Treatment of premature ejaculation in men from 18 to 64 years old.
It is assumed that the mechanism of action of dapoxetine in premature ejaculation is associated with the inhibition of serotonin reuptake by neurons, followed by an increase in the action of the neurotransmitter on pre - and postsynaptic receptors.
The mechanism of ejaculation is mainly regulated by the sympathetic nervous system. The stimulus that triggers ejaculation is generated in the spinal reflex center, which, through the brainstem, is controlled by several nuclei of the brain, in t.tsch. preoptic and paraventricular. Postganglionic sympathetic nerve fibers innervate the seminal vesicles, vas deferens, prostate, urethral and bladder neck muscles, causing them to contract in a coordinated manner to achieve ejaculation. Dapoxetine affects the ejaculation reflex, increasing the latent period and reducing the duration of reflex impulses of the perineal ganglion motor neurons
Suction. Dapoxetine is rapidly absorbed, and Cmax in the blood plasma, it is reached in 1-2 hours after taking the drug. The absolute bioavailability is 42% (range 15-76%). After a single oral intake of dapoxetine on an empty stomach at doses of 30 and 60 mg Cmax substances in the blood plasma are 297 ng / ml (after 1.01 h) and 498 ng/ml (after 1.27 h), respectively.
Eating fatty foods modestly reduces Cmax dapoxetine (by 10%) and increases the AUC and Tmax in the blood plasma by 12%. However, the degree of absorption of dapoxetine does not change. These changes are not clinically significant. Extensil preparation® it can be taken regardless of the meal.
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 Vss 162 l. With intravenous administration in humans, the average T1/2 in the initial, intermediate and terminal phases of excretion is 0.1, 2.19 and 19.3 hours, respectively.
Metabolism. Researches in vitro It is suggested that dapoxetine is metabolized by many liver and kidney enzymes, especially CYP2D6, CYP3A4, and flavin-containing monooxygenase (FMO1) of the kidneys. In a clinical study that examined metabolism 14After oral administration, dapoxetine was actively metabolized mainly by N-oxidation, N-demethylation, hydroxylation of the naphtho group, glucuronidation, and addition of the sulfo group. After oral administration, 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 research in vitro Dapoxetine-N-oxide was found to be inactive. In addition, desmethyldapoxetine and didezmethyldapoxetine were found to be less than 3% of the total circulating metabolites of dapoxetine. In the study in vitro It was found that desmethyldapoxetine is comparable in activity to dapoxetine, and didezmethyldapoxetine is about 2 times less active than dapoxetine. Exposure (AUC and Cmax) of unbound desmethyldapoxetine was 50% and 23% of unbound dapoxetine, respectively.
Output. Dapoxetine metabolites are mainly excreted in the urine as conjugates. The unchanged active substance is not detected in the urine. Dapoxetine is rapidly eliminated, 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 intake, the accumulation of the substance in the body is minimal. When taken orally, the final T1/2 it 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 indicators of Europeans, persons of the black race, Latin Americans and persons of the Mongoloid race. A 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 (65 years and older). A single dose of dapoxetine at a dose of 60 mg did not reveal a significant difference in pharmacokinetic parameters (Cmax, AUC, Tmax) in healthy older men and younger men. Average AUC values of dapoxetine and final T1/2 They were 12% and 46% higher, respectively, in older men compared to younger men.
Impaired renal function. A single dose of dapoxetine at a dose of 60 mg did not reveal a relationship between Cl creatinine and Cmax or the AUC of dapoxetine in patients with mild (creatinine Cl 50-80 ml/min), moderate (creatinine Cl 30 to <50 ml/min) and severe (creatinine Cl <30 ml/min) renal impairment. 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 the AUC of unbound dapoxetine increased by 55 and 120%, respectively. Cmax The unbound active fraction of dapoxetine was unchanged, and the AUC was increased by 2 times. In patients with severe hepatic impairment Cmax 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 the blood plasma after a single dose of Extensil® at a dose of 60 mg in patients with low CYP2D6 activity was higher than in patients with high CYP2D6 activity (Cmax - about 31%, AUC-about 36%). Similar to Cmax desmethyldapoxetine in patients with low CYP2D6 activity was increased by 98%, and AUC-by 161%. Average final T1/2 dapoxetine was increased by 2.4 h in patients with low activity of the CYP2D6 isoenzyme compared to patients with high activity of the CYP2D6 isoenzyme. Cmax 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. Safety of the use of the drug Extensil® In patients with low activity of CYP2D6, it may cause doubts when taking other drugs that can inhibit the metabolism of dapoxetine, in particular active and moderately active inhibitors of CYP3A4.
Plasma concentrations of dapoxetine and desmethyldapoxetine are expected to be reduced in patients with ultrahigh CYP2D6 activity.
Extensil
Dapoxetine
Inside, the tablet should be swallowed whole, washed down with at least 1 full glass of water. Extensil preparation® it can be taken regardless of the meal.
Adult males from 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. 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 1 time in 24 hours.
The doctor who prescribes the drug Extensil® for the treatment of premature ejaculation, the patient should evaluate the risk and benefit of using the drug after the first 4 weeks of treatment or after taking 6 doses and determine the risk-benefit ratio to decide whether to continue treatment with Extensil®.
Special patient groups
Impaired renal function. For patients with mild or moderate renal impairment, dose adjustment is not required, but caution is recommended. Extensil preparation® it is not recommended for patients with severe renal impairment.
Impaired liver function. For patients with mild hepatic impairment, dose adjustment is not required. Extensil preparation® It is contraindicated in patients with moderate to severe hepatic impairment (classes B and C according to the Child-Pugh classification).
Low CYP2D6 activity, concomitant administration with active CYP2D6 inhibitors. Caution should be exercised when increasing the dose of Extensil® up to 60 mg in individuals with low CYP2D6 activity or patients, simultaneously with Extensil® taking active CYP2D6 inhibitors.
Taking active or moderately active CYP3A4 inhibitors. Concomitant administration of active CYP3A4 inhibitors is contraindicated. When taking the drug Extensil simultaneously® with moderately active CYP3A4 inhibitors, the dose of the drug should be reduced to 30 mg.
