Dapoxetine-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

G04BX14 (Dapoxetine)

Active Substance

Dapoxetine (Rec.INN registered by WHO)

Dosage Forms

	Dapoxetine-SZ	Film-coated tablets, 30 mg: 4, 6, 8, 10, 12, 20 or 30 pcs.
		Film-coated tablets, 60 mg: 4, 6, 8, 10, 12, 20 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light yellow to yellow in color, round, biconvex; the tablet core on the cross-section is white or almost white.

Excipients: lactose monohydrate, croscarmellose sodium, microcrystalline cellulose 102, colloidal silicon dioxide, magnesium stearate.

Coating composition: hypromellose, polysorbate-80, talc, titanium dioxide (E171), yellow iron oxide (E172).

4 pcs. – contour cell blisters (1) – cardboard packs.
6 pcs. – contour cell blisters (1) – cardboard packs.
6 pcs. – contour cell blisters (2) – cardboard packs.
8 pcs. – contour cell blisters (1) – cardboard packs.
10 pcs. – contour cell blisters (1) – cardboard packs.
10 pcs. – contour cell blisters (2) – cardboard packs.
10 pcs. – contour cell blisters (3) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
20 pcs. – polymer bottles (1) – cardboard packs.

Film-coated tablets from light yellow to yellow in color, round, biconvex; the core on the cross-section is white or almost white.

Excipients: lactose monohydrate, croscarmellose sodium, microcrystalline cellulose 102, colloidal silicon dioxide, magnesium stearate.

Coating composition: hypromellose, polysorbate-80, talc, titanium dioxide (E171), yellow iron oxide (E172).

4 pcs. – contour cell blisters (1) – cardboard packs.
6 pcs. – contour cell blisters (1) – cardboard packs.
6 pcs. – contour cell blisters (2) – cardboard packs.
8 pcs. – contour cell blisters (1) – cardboard packs.
10 pcs. – contour cell blisters (1) – cardboard packs.
10 pcs. – contour cell blisters (2) – cardboard packs.
10 pcs. – contour cell blisters (3) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
20 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment of premature ejaculation

Pharmacotherapeutic Group

Drugs used in urology; other drugs used in urology

Pharmacological Action

Dapoxetine is a potent selective serotonin reuptake inhibitor (SSRI) with a half-maximal inhibitory concentration (IC₅₀) of 1.12 nM, metabolized in the body to the main metabolites – desmethyldapoxetine (IC₅₀<1.0 nM) and didesmethyldapoxetine (IC₅₀=2.0 nM), equally or less active (Dapoxetine-N-oxide (IC₅₀=282 nM)).

The mechanism of action of dapoxetine in premature ejaculation (PE) is associated with inhibition of serotonin reuptake by neurons with subsequent enhancement of the neurotransmitter’s action on pre- and postsynaptic receptors.

In rats, Dapoxetine inhibits the reflex mechanism of ejaculation by acting on the lateral paragigantocellular nucleus at the supraspinal level. Postganglionic sympathetic fibers innervating the seminal vesicles, vas deferens, prostate gland, muscles surrounding the bulbourethral glands, and the bladder neck cause their coordinated contractions necessary for ejaculation to occur. In rats, Dapoxetine alters this reflex mechanism of ejaculation.

Clinical safety and efficacy

The efficacy of dapoxetine in the treatment of PE was established in five double-blind, placebo-controlled clinical trials in which a total of 6081 patients were randomized. Patients were 18 years of age and older, and for 6 months prior to their inclusion in the study, they had experienced PE in the majority of sexual intercourses. PE was defined according to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) diagnostic criteria: short time to ejaculation (intravaginal ejaculatory latency time [IELT; time from vaginal penetration to intravaginal ejaculation] is less than 2 minutes, measured using a stopwatch in four studies), poor control over ejaculation, and significant stress or interpersonal difficulties caused by this condition.

Individuals with other types of sexual dysfunction, including erectile dysfunction (ED), as well as individuals taking other medications for the treatment of PE, were excluded from all studies.

The results of all randomized studies were comparable. Efficacy was demonstrated after 12 weeks of treatment. One study included patients from both EU and non-EU countries, and the treatment duration was 24 weeks. This study randomized 1162 patients: 385 received placebo, 388 received Dapoxetine 30 mg as needed, and 389 received Dapoxetine 60 mg as needed. The mean and median values of the average IELT at the end of the study are presented in Table 1 below, and the cumulative distribution of subjects achieving at least a characteristic level of average IELT at the end of the study is presented in Table 3 below. Other studies and pooled analysis of data at 12 weeks showed similar results.

Table 1. Mean and median IELT at the end of treatment, calculated by the least squares method*

*Baseline value carried forward for patients with missing baseline data.

**The difference was statistically significant (p-value ≤ 0.001).

Table 2. Subjects who achieved at least a characteristic level of mean IELT at the end of the study*

* Baseline value carried forward for patients with missing baseline data.

The value of IELT prolongation was correlated with the baseline IELT level and varied among individual patients. The clinical significance of the effect of dapoxetine was also demonstrated by analyzing the treatment outcome reported by various patients who showed a therapeutic effect. A patient with a therapeutic effect was defined as a subject who had an increase in ejaculatory control by at least 2 categories and a decrease in the level of stress associated with ejaculation by at least 1 category. A greater percentage of subjects in each of the Dapoxetine groups compared to placebo developed a therapeutic effect at the end of 12 or 24 weeks of the study, which was statistically significant. In the groups of participants taking Dapoxetine at doses of 30 mg (11% – 95% CI [7.24; 14.87]) and 60 mg (16.4% – 95% CI [13.01; 19.75]), there was a greater percentage of patients with a therapeutic effect at 12 weeks compared to the group of participants taking placebo (pooled analysis).

The clinical significance of the effect of treatment with dapoxetine was shown using the therapeutic group for measuring the outcome. Clinical Global Impression of Change (CGIC) assessments, where patients were asked to compare their PE since the start of treatment, with response gradations from “much better” to “much worse”. At the end of the study (24 weeks), 28.4% (Dapoxetine 30 mg) and 35.5% (Dapoxetine 60 mg) of subjects taking Dapoxetine reported that their condition became “better” or “much better”, compared to 14% in the placebo group, and 53.4% and 65.6% of subjects taking Dapoxetine 30 mg and 60 mg, respectively, reported that their condition became at least “a little better”, compared to 28.8% in the placebo group.

Pharmacokinetics

Absorption

Dapoxetine is rapidly absorbed, C_max in plasma is reached 1-2 hours after administration. Absolute bioavailability is 42% (range 15-76%) and exposure (AUC and C_max) increases proportionally to the dose in the range from 30 mg to 60 mg. After multiple oral administration, the AUC of dapoxetine and its active metabolite desmethyldapoxetine increases by approximately 50% compared to the AUC values after a single dose.

Taking a fatty meal moderately reduces the C_max of dapoxetine (by 10%) and increases the AUC and time to reach C_max in plasma by 12%. These changes are not clinically significant. The drug Dapoxetine-SZ can be taken regardless of meals.

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 distributed throughout the body with an average equilibrium V_d of 162 L.

Metabolism

In vitro studies suggest that Dapoxetine is metabolized by many liver and kidney enzymes, especially CYP2D6, CYP3A4, and renal flavin-containing monooxygenase (FMO1). In a clinical study examining the metabolism of ¹⁴C-dapoxetine, Dapoxetine after oral administration was actively metabolized mainly by N-oxidation, N-demethylation, naphthyl group hydroxylation, glucuronidation, and sulfation. After oral administration, signs of presystemic metabolism in the liver were found. The main components circulating in plasma were intact Dapoxetine and Dapoxetine-N-oxide. In vitro studies have found that Dapoxetine-N-oxide is inactive. In addition, desmethyldapoxetine and didesmethyldapoxetine were detected in amounts of less than 3% of the total circulating metabolites of dapoxetine. An in vitro study found that desmethyldapoxetine is comparable in activity to dapoxetine, and didesmethyldapoxetine is approximately 2 times less active than Dapoxetine. The exposure (AUC and C_max) of unbound desmethyldapoxetine was 50% and 23% of unbound dapoxetine, respectively.

Excretion

Dapoxetine metabolites are excreted mainly by the kidneys as conjugates. Dapoxetine unchanged is not detected in urine. After oral administration, the initial (dispositional) T_1/2 of dapoxetine is approximately 1.5 hours, the plasma level is less than 5% of C_max 24 hours after administration, and the terminal T_1/2 is about 19 hours. With daily administration, the terminal T_1/2 is approximately 19 hours.

Pharmacokinetics in special patient groups

The metabolite desmethyldapoxetine enhances the pharmacological effect of dapoxetine, especially if its concentration is increased. Below is a demonstration of the increase in parameters of the active fraction in some patient groups. It represents the sum of the concentrations of free dapoxetine and desmethyldapoxetine. Desmethyldapoxetine and Dapoxetine are equally effective. Preliminary calculations suggest the same distribution of desmethyldapoxetine in the CNS, but it is not known if this is the case.

Race. A single dose of dapoxetine 60 mg did not reveal a statistically significant difference in parameters among Caucasians, Negroids, Hispanics, and Mongoloids. A comparison of the pharmacokinetics of dapoxetine in Caucasians and Japanese showed higher C_max and AUC values in the latter (by 10-20%) due to lower body weight. The higher level of systemic exposure is unlikely to cause a significant difference in clinical effect.

Elderly patients (65 years and older). An analysis of a clinical pharmacology study with a single dose of dapoxetine 60 mg did not reveal a significant difference in pharmacokinetic parameters (C_max, AUC_0-∞, T_max) between healthy elderly men and healthy younger men.

Renal impairment. A clinical pharmacology study of a single dose of dapoxetine 60 mg was conducted in patients with mild (CrCl from 50 to 80 ml/min), moderate (CrCl from 30 to < 50 ml/min), and severe (CrCl < 30 ml/min) renal impairment, as well as in subjects with normal renal function (CrCl > 80 ml/min). No clear trend towards an increase in dapoxetine AUC with renal impairment was found. In subjects with severe renal impairment, the AUC was approximately 2 times higher than in subjects with normal renal function, although data in patients with severe renal impairment are limited. The pharmacokinetics of dapoxetine have not been evaluated in patients on renal dialysis.

Hepatic impairment . In patients with mild hepatic impairment, the C_max of unbound dapoxetine decreased by 28%, and the AUC did not change. The C_max and AUC of the active fraction (the sum of the unbound fractions of dapoxetine and desmethyldapoxetine) decreased by 30% and 5%, respectively. In patients with moderate hepatic impairment, the C_max of unbound dapoxetine usually does not change (decreases within 3%), and the AUC increases by 66%. The C_max of the unbound active fraction of dapoxetine was unchanged, and the AUC was doubled. In patients with severe hepatic impairment, the C_max of unbound dapoxetine was reduced by 42%, and the AUC of unbound dapoxetine was increased by approximately 223%. The C_max and AUC of the active fraction changed in a similar manner.

CYP2D6 polymorphism . In a clinical pharmacology study of a single dose of dapoxetine 60 mg, the plasma concentration was higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (approximately C_max – by 31%, AUC_0-∞ of dapoxetine – by 36%, C_max – by 98%, AUC_0-∞ of desmethyldapoxetine – by 161%). The Cmax of the active fraction of the drug Dapoxetine-SZ may be increased by approximately 46%, and the AUC – by approximately 90%. This increase may increase the frequency and severity of dose-dependent adverse reactions. When taking the drug Dapoxetine-SZ in patients with low CYP2D6 activity, special attention should be paid to safety when co-administering other drugs that may inhibit the biotransformation of dapoxetine, such as moderate and strong CYP3A4 inhibitors.

Indications

The drug Dapoxetine-SZ is indicated for the treatment of premature ejaculation in men aged 18 to 64 years.

The drug Dapoxetine-SZ should be used only in patients who meet all of the following criteria:

• Intravaginal ejaculatory latency time (IELT) <2 min;
• Persistently or recurrently occurring ejaculation after minimal sexual stimulation before, during, or shortly after penetration, and occurring earlier than desired by the patient;
• Significant personal distress or interpersonal difficulties due to premature ejaculation;
• Poor control of ejaculation;
• Occurrence of premature ejaculation in the majority of attempts at sexual intercourse over the past 6 months.

The drug Dapoxetine-SZ should be used only in an as-needed regimen before anticipated sexual activity. The drug Dapoxetine-SZ should not be used to delay ejaculation in men without a confirmed diagnosis of premature ejaculation.

ICD codes

Dosage Regimen

Orally. The tablet should be swallowed whole with at least one full glass of water. The drug Dapoxetine-SZ can be taken regardless of meals.

Adult men from 18 to 64 years

The recommended initial dose for all patients is 30 mg; this dose is taken 1-3 hours before the anticipated sexual intercourse. Treatment with the drug Dapoxetine-SZ should not be started with a dose of 60 mg.

The drug Dapoxetine-SZ is not intended for continuous daily use. It should be taken only in case of anticipated sexual intercourse. The drug Dapoxetine-SZ should not be taken more frequently than every 24 hours.

If the effect is insufficient and the 30 mg dose is well tolerated (the patient does not report moderate or severe adverse reactions or phenomena that may precede syncope), the dose can be increased to the maximum recommended – 60 mg, taken as needed 1-3 hours before sexual activity. The frequency and severity of adverse reactions are higher when taking the drug at a dose of 60 mg.

If the patient experienced orthostatic reactions when taking the initial dose, the dose should not be increased to 60 mg (see section “Special Instructions”).

After the first 4 weeks of therapy (or at least after taking 6 doses of the drug), the physician should conduct a thorough assessment of the benefit-risk ratio of Dapoxetine-SZ in each specific case to decide on the advisability of continuing treatment with this drug.

Data on the efficacy and safety of dapoxetine use for more than 24 weeks are limited. The clinical need for continuing therapy and the benefit/risk ratio of Dapoxetine-SZ should be assessed at least every 6 months.

Special Patient Groups

Elderly patients (≥ 65 years)

The efficacy and safety of Dapoxetine-SZ in patients ≥ 65 years have not been established.

Patients with renal impairment

Caution should be exercised when administering the drug to patients with mild to moderate renal impairment. Dapoxetine-SZ is contraindicated in patients with severe renal failure.

Patients with hepatic impairment

Dapoxetine-SZ is contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh class B and C).

Patients with low CYP2D6 activity and patients concomitantly taking potent CYP2D6 inhibitors

Caution should be exercised when increasing the dose of Dapoxetine-SZ to 60 mg in patients with low CYP2D6 activity or in patients taking Dapoxetine-SZ concomitantly with potent CYP2D6 inhibitors. Caution is recommended when increasing the dose to 60 mg in patients diagnosed with CYP2D6 poor metabolizer status and in patients concomitantly taking potent CYP2D6 inhibitors.

Patients receiving potent CYP3A4 inhibitors or moderate CYP3A4 inhibitors

Concomitant use of dapoxetine with potent CYP3A4 inhibitors is contraindicated. Patients concomitantly taking moderate CYP3A4 inhibitors should exercise caution and not exceed a dose of 30 mg.

Children

Dapoxetine-SZ is contraindicated in children and adolescents under 18 years of age.

Adverse Reactions

Syncope and orthostatic hypotension were reported in clinical studies.

In Phase 3 clinical studies, the following adverse reactions were reported, which were frequent and dose-dependent: nausea (11.0% and 22.2% for 30 mg and 60 mg dapoxetine, respectively), dizziness (5.8% and 10.9%), headache (5.6% and 8.8%), diarrhea (3.5% and 6.9%), insomnia (2.1% and 3.9%), fatigue (2.0% and 4.1%). The most common reactions leading to treatment discontinuation were nausea (in 2.2% of patients) and dizziness (1.2% of patients).

The safety of dapoxetine was evaluated in 4224 patients with PE who participated in 5 double-blind, placebo-controlled clinical studies. Of the 4224 patients, 1616 patients took Dapoxetine 30 mg as needed, and 2608 took 60 mg either as needed or once daily.

Adverse reactions observed during clinical studies of dapoxetine are categorized by system organ class with the frequency of their occurrence according to WHO recommendations: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000).

Adverse reactions reported during a 9-month long-term extended open-label study were similar to those reported in double-blind studies. No additional adverse reactions were reported.

Description of selected adverse reactions

Syncope with loss of consciousness, with bradycardia or sinus arrest was observed in patients during Holter monitoring and was recorded in clinical studies. These adverse reactions were considered related to the use of dapoxetine. Most cases occurred within the first 3 hours after taking dapoxetine, after the first dose, or were associated with medical procedures (blood sampling, changes in body position, blood pressure measurement). Prodromal symptoms often preceded syncope.

The occurrence of syncope and possibly prodromal symptoms appears to be dose-dependent, as demonstrated by a higher frequency of their occurrence among patients taking Dapoxetine in Phase 3 clinical studies at doses exceeding the recommended ones.

Reports of orthostatic hypotension occurred during clinical studies. The incidence of syncope characterized by loss of consciousness in the dapoxetine clinical development program varied depending on the study population and ranged from 0.06% (30 mg) to 0.23% (60 mg) in subjects included in Phase 3 placebo-controlled clinical studies, and up to 0.64% (all doses combined) for Phase 1 studies involving healthy volunteers without PE.

Other special patient groups

Caution should be exercised when increasing the dose to 60 mg in patients taking potent CYP2D6 inhibitors, or when increasing the dose to 60 mg in patients with the CYP2D6 poor metabolizer genotype.

Effects of drug withdrawal

Upon abrupt discontinuation of SSRIs used long-term for the treatment of chronic depressive disorders, the following symptoms have been noted: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.

Safety study results showed a higher frequency of withdrawal symptoms in the form of mild to moderate insomnia and dizziness after drug discontinuation following 62 days of use.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to dapoxetine and/or to any excipient included in the drug composition;
• Significant cardiac pathology, such as:
  • Heart failure (NYHA class II-IV);
  • Conduction disorders such as atrioventricular block (AV block) or sick sinus syndrome;
  • Significant coronary artery disease;
  • Significant valvular heart disease;
  • History of syncope;
• History of mania or severe depression;
• Concomitant use of MAO inhibitors, or if less than 14 days have passed since their discontinuation. Similarly, MAO inhibitors should not be taken within 7 days after discontinuation of Dapoxetine-SZ;
• Concomitant use of thioridazine, or within 14 days after discontinuation of thioridazine. Accordingly, thioridazine should not be taken within 7 days after discontinuation of Dapoxetine-SZ;
• Concomitant use of serotonin reuptake inhibitors (SSRIs, SNRIs, tricyclic antidepressants) or other medicinal products/herbal preparations with serotonergic activity (e.g., L-tryptophan, triptans, tramadol, linezolid, lithium, St. John’s wort (Hypericum perforatum)), or within 14 days after discontinuation of these medicinal products/herbal preparations. Accordingly, these medicinal products/herbal preparations should not be taken within 7 days after discontinuation of Dapoxetine-SZ;
• Concomitant use of potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, atazanavir, etc.;
• Moderate and severe hepatic impairment;
• Severe renal impairment;
• Age under 18 years.

With caution

• In patients with mild or moderate renal failure;
• Concomitant use with potent inhibitors of the CYP2D6 isoenzyme and moderate CYP3A4 inhibitors in patients with genotypically low activity of the CYP2D6 isoenzyme and patients with high activity of the CYP2D6 isoenzyme (in combination with moderate CYP3A4 inhibitors);
• Concomitant use with drugs that affect platelet aggregation and with anticoagulants due to the risk of bleeding, as well as in patients with a history of bleeding or coagulation disorders.

Use in Pregnancy and Lactation

Dapoxetine-SZ is not intended for use in women.

Animal studies have not revealed any direct or indirect negative effects on fertility, pregnancy, or embryonic/fetal development.

It is unknown whether Dapoxetine and its metabolites pass into breast milk.

Use in Hepatic Impairment

The use of the drug is contraindicated in moderate and severe hepatic impairment.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment.

For patients with mild or moderate renal impairment, dose adjustment is not required, but caution is recommended.

Pediatric Use

The use of dapoxetine in patients under 18 years of age is contraindicated, as there are no clinical data on the efficacy and safety of dapoxetine use in this patient population.

Geriatric Use

The use of dapoxetine in patients over 65 years of age is contraindicated, as there are no clinical data on the efficacy and safety of dapoxetine use in this patient population.

Special Precautions

General recommendations

Dapoxetine is intended only for men with PE who meet all the criteria listed in the “Indications” and “Pharmacological Properties” sections. Dapoxetine should not be used by men who have not been diagnosed with PE. The safety of dapoxetine use in men without PE has not been established, and there are no data on delayed ejaculation.

Other types of sexual dysfunction

Before starting treatment, patients with other types of sexual disorders, including ED, should undergo a thorough medical examination. Dapoxetine should not be used in men with ED who are taking PDE5 inhibitors.

Orthostatic hypotension

Before starting therapy, the physician should conduct a thorough medical examination, including taking a history of orthostatic events, and perform an orthostatic test (measuring BP and heart rate in sitting and standing positions). If there is a history of confirmed or suspected orthostatic reactions, therapy with dapoxetine should be avoided.

Cases of orthostatic hypotension have been described in clinical studies. The physician should inform the patient in advance that if possible prodromal symptoms occur, such as dizziness immediately upon standing up, they should immediately lie down so that the head is lower than the body or sit down with the head lowered between the knees, and remain in this position until the symptoms disappear. The physician prescribing Dapoxetine should inform the patient of the need to avoid standing up abruptly after prolonged lying or sitting.

Suicide/suicidal thoughts

In short-term studies, antidepressants, including SSRIs, compared to placebo, increased the risk of suicidal thoughts and behavior in children and adolescents with major depressive disorder and other psychiatric disorders. In short-term studies, no increased risk of suicidality with antidepressants compared to placebo was detected in adults over 24 years of age. In clinical studies of dapoxetine for the treatment of PE, no clear data on the emergence of suicidal thoughts during treatment, assessed by the Columbia Classification Algorithm for Suicide Assessment (C-CASA), the Montgomery-Asberg Depression Rating Scale, or the Beck Depression Inventory, were identified.

Syncope

Patients should avoid potentially hazardous situations, in particular, driving vehicles or operating machinery, in case of syncope or its prodromal symptoms, such as dizziness or lightheadedness (see section “Adverse Reactions”). Patients treated with Dapoxetine, compared to patients receiving placebo, more frequently experienced prodromal symptoms, including nausea, dizziness/lightheadedness, and increased sweating.

Cases of syncope observed in clinical studies, characterized as loss of consciousness, with bradycardia or sinus arrest in patients during Holter monitoring, were attributed to vasovagal origin, and most of them occurred within the first 3 hours after administration, after the first dose, or were associated with clinical medical examinations (blood sampling, changes in body position, blood pressure measurement). Possible prodromal symptoms, such as nausea, dizziness, lightheadedness, palpitations, asthenia, confusion, and increased sweating, were also typically observed within the first 3 hours after taking dapoxetine and often preceded syncope. Patients should be informed that during treatment with dapoxetine, syncope with or without prodromal symptoms may develop at any time. The physician should inform the patient about the importance of adequate hydration and recognizing prodromal signs and symptoms to reduce the risk of serious injury from a possible fall due to loss of consciousness. If possible prodromal symptoms occur, the patient should immediately lie down so that the head is lower than the body, or sit down with the head lowered between the knees, and remain in this position until the symptoms disappear. In case of syncope or other CNS adverse reactions, the patient should be warned to avoid potentially hazardous situations, including driving cars and other machinery.

Patients at risk of cardiovascular diseases

Patients with cardiovascular diseases did not participate in clinical studies of dapoxetine. Patients with organic diseases of the heart and blood vessels (e.g., cardiac outflow obstruction, valvular heart disease, carotid artery stenosis, coronary artery atherosclerosis) are at increased risk of adverse cardiovascular consequences of syncope (of cardiac and other origin). However, there are currently insufficient data to determine whether this risk extends to vasovagal syncope in patients with cardiovascular diseases.

Use with drugs of abuse

Patients should not take Dapoxetine together with drugs of abuse. Concomitant use of dapoxetine with drugs of abuse that have serotonergic activity, such as ketamine, methylenedioxymethamphetamine (MDMA), and lysergic acid diethylamide (LSD), may lead to potentially serious reactions, including but not limited to arrhythmia, hyperthermia, and serotonin syndrome. The use of dapoxetine concomitantly with sedatives, such as opiates or benzodiazepines, may enhance drowsiness and dizziness.

Use with ethanol

Patients should be advised not to take Dapoxetine together with alcohol. Concomitant use of dapoxetine with alcohol may enhance its effects on the CNS and may also enhance such neurocardiogenic adverse reactions as syncope, thereby increasing the risk of accidental injury. Therefore, patients should be advised to refrain from drinking alcohol while taking dapoxetine.

Medicinal products with vasodilating properties

Dapoxetine should be used with caution in patients taking medicinal products with vasodilating properties (such as alpha-blockers and nitrates) due to a possible decrease in orthostatic tolerance.

Moderate CYP3A4 inhibitors

Caution should be exercised when prescribing dapoxetine to patients taking moderate CYP3A4 inhibitors; the dose should not exceed 30 mg.

Potent CYP2D6 inhibitors

Caution is recommended when increasing the dose of dapoxetine to 60 mg in patients receiving potent CYP2D6 inhibitors, or when increasing the dose to 60 mg in patients with the CYP2D6 poor metabolizer genotype, as this may increase systemic exposure to dapoxetine with a corresponding increase in the frequency and severity of dose-dependent adverse reactions.

Mania

Dapoxetine should not be taken by patients with a history of mania/hypomania or bipolar disorder; if symptoms of these conditions appear, dapoxetine should be discontinued.

Seizures

Due to the ability of SSRIs to lower the seizure threshold, dapoxetine should be avoided in patients with unstable epilepsy; if seizures occur, the drug should be discontinued. Patients with controlled epilepsy require careful monitoring.

Comorbid depression and/or psychiatric disorders

Before starting therapy with dapoxetine, men with signs and symptoms of depression should be examined to rule out undiagnosed depressive disorders. Concomitant use of dapoxetine and antidepressants, including SSRIs and SNRIs, is contraindicated. Discontinuing treatment for existing depression or anxiety in order to start taking dapoxetine for PE therapy is not recommended. Dapoxetine is not indicated for psychiatric disorders and should not be used in men with conditions such as schizophrenia, or in patients with comorbid depression, as worsening of symptoms related to depression cannot be ruled out. This may be a consequence of the underlying mental disorder or a consequence of taking the medicinal product. The physician should recommend that patients report any depressive thoughts or feelings at any time, and if depressive phenomena and symptoms develop during treatment, dapoxetine should be discontinued.

Bleeding

Cases of bleeding have been described with the use of SSRIs. Caution is recommended when using dapoxetine concomitantly with drugs that affect platelet function (e.g., atypical antipsychotics, phenothiazines, acetylsalicylic acid, NSAIDs, anticoagulants (e.g., warfarin)), as well as in patients with a history of bleeding or impaired blood clotting.

Renal Impairment

Dapoxetine is not recommended for patients with severe renal impairment; patients with moderate or mild renal impairment should exercise caution.

Discontinuation Syndrome

There is evidence that abrupt discontinuation of SSRIs, used long-term for the treatment of chronic depressive disorders, leads to the following symptoms: low mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia such as electric shock sensations), anxiety, confusion, headache, drowsiness, emotional lability, insomnia, hypomania.

In a double-blind clinical trial in individuals with PE, conducted to assess discontinuation syndrome after taking dapoxetine 60 mg daily or as needed for 62 days, individuals switched to placebo after daily dapoxetine administration experienced moderate symptoms, including a slight increase in the frequency of insomnia and dizziness.

Ophthalmic Disorders

Adverse reactions such as mydriasis and eye pain have been observed during the use of dapoxetine. Dapoxetine should be used with caution in patients with increased intraocular pressure or at risk of angle-closure glaucoma.

Excipients

The drug Dapoxetine-SZ contains lactose monohydrate. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Effect on the Ability to Drive and Operate Machinery

Dapoxetine has a minor to moderate influence on the ability to drive and operate machinery. During clinical trials, individuals receiving Dapoxetine reported cases of dizziness, impaired attention, syncope, blurred vision, and drowsiness. The patient should be warned to avoid situations where injury is possible, including driving vehicles and operating machinery. Concurrent use of alcohol and dapoxetine may enhance alcohol-related neurocognitive effects and may also increase the risk of neurocardiogenic adverse reactions, such as syncope, which in turn increases the risk of injury. Thus, patients should be advised to avoid concurrent alcohol consumption while using the drug Dapoxetine-SZ.

Overdose

No cases of overdose have been reported.

Symptoms intake of dapoxetine at a dose of up to 240 mg (2 doses of 120 mg with a 3-hour interval) did not cause unexpected adverse reactions. 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 supportive therapy should be administered if necessary. Due to the significant plasma protein binding and large volume of distribution of dapoxetine, forced diuresis, dialysis, hemoperfusion, and blood transfusion are unlikely to be effective. No specific antidote is known.

Drug Interactions

Pharmacodynamic Interactions

Interaction with MAO Inhibitors

Serious adverse reactions, sometimes fatal, including hyperthermia, rigidity, myoclonus, autonomic nervous system disorders with possible rapid fluctuations in vital signs, and changes in mental status, including severe agitation progressing to delirium and coma, have been reported in patients receiving SSRIs concurrently with an MAO inhibitor. These reactions have also been observed in patients who recently discontinued an SSRI and started treatment with an MAO inhibitor. In some cases, the symptoms resembled neuroleptic malignant syndrome. Data from animal studies on the combined use of SSRIs and MAO inhibitors suggest that these drugs may synergistically increase blood pressure and cause behavioral agitation. Therefore, Dapoxetine must not be taken concurrently with MAO inhibitors and for 14 days after discontinuing their use. Similarly, MAO inhibitors must not be taken for 7 days after discontinuing dapoxetine.

Interaction with Thioridazine

Thioridazine prolongs the QTc interval, which is associated with ventricular arrhythmia. Drugs like dapoxetine, which inhibit the CYP2D6 isoenzyme, appear to inhibit the metabolism of thioridazine. The resulting increase in thioridazine levels is expected to enhance the QTc interval prolongation. Dapoxetine must not be taken concurrently with thioridazine and for 14 days after discontinuing its use. Similarly, thioridazine must not be taken for 7 days after discontinuing dapoxetine.

Drugs/Herbal Preparations with Serotonergic Effects

As with the concurrent use of other SSRIs, the use of dapoxetine concurrently with serotonergic drugs (including MAO inhibitors, L-tryptophan, triptans, tramadol, linezolid, SSRIs, serotonin and norepinephrine reuptake inhibitors, lithium, and preparations of St. John’s wort [Hypericum perforatum]) may increase the frequency of serotonergic adverse reactions. Dapoxetine must not be taken concurrently with other SSRIs, MAO inhibitors, and other serotonergic drugs and for 14 days after discontinuing these drugs. Similarly, these drugs must not be taken for 7 days after discontinuing dapoxetine.

Drugs Acting on the CNS

The use of dapoxetine concurrently with drugs acting on the CNS (e.g., antiepileptic drugs, antidepressants, antipsychotics, anxiolytics, sedative-hypnotic drugs) in patients with premature ejaculation has not been studied. Therefore, caution is recommended if concomitant use of these drugs is necessary.

Pharmacokinetic Interactions

Effect of Concomitant Drugs on the Pharmacokinetics of Dapoxetine

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

CYP3A4 Inhibitors

Strong CYP3A4 Inhibitors. Administration of ketoconazole 200 mg twice daily for 7 days increased the C_max and AUC_0-∞ of dapoxetine (60 mg single dose) by 35% and 99%, respectively. Considering the unbound fractions of dapoxetine and desmethyldapoxetine, the C_max of the active fraction (sum of unbound dapoxetine and desmethyldapoxetine) in the presence of strong CYP3A4 inhibitors may increase by approximately 25%, and the AUC may double. This increase in C_max and AUC of the active fraction may be significantly more pronounced in the subpopulation of patients lacking functionally active CYP2D6 enzyme, e.g., CYP2D6 poor metabolizers, as well as with the concurrent use of strong CYP2D6 inhibitors. Thus, the use of dapoxetine concurrently with strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, and atazanavir, is contraindicated. Grapefruit juice is also a potent inhibitor of CYP3A4, so its consumption should be avoided within 24 hours preceding dapoxetine intake.

Moderate CYP3A4 Inhibitors. Concomitant use with moderate CYP3A4 inhibitors, such as erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, or diltiazem, may significantly increase the systemic exposure to dapoxetine and desmethyldapoxetine, especially in patients with low CYP2D6 activity. These two measures apply to all patients except those genotyped or phenotyped as CYP2D6 extensive metabolizers. For patients who are CYP2D6 extensive metabolizers, a maximum dose of 30 mg is recommended when dapoxetine is used concomitantly with a strong CYP3A4 inhibitor. They should exercise caution when using dapoxetine 60 mg concomitantly with a moderate CYP3A4 inhibitor.

Strong CYP2D6 Inhibitors

Administration of fluoxetine 60 mg/day for 7 days increased the C_max and AUC_0-∞ of dapoxetine (60 mg single dose) by 50% and 88%, respectively. Considering the unbound fractions of dapoxetine and desmethyldapoxetine, the C_max of the active fraction (sum of unbound dapoxetine and desmethyldapoxetine) in the presence of strong CYP2D6 inhibitors may increase by approximately 50%, and the AUC may double. This increase in C_max and AUC of the active fraction is close to that expected in patients with low CYP2D6 activity and may lead to an increased frequency and severity of dose-dependent adverse reactions. Therefore, caution is recommended when increasing the dapoxetine dose to 60 mg in patients receiving active CYP2D6 inhibitors and in patients with low CYP2D6 activity.

Phosphodiesterase 5 (PDE5) Inhibitors

Patients taking PDE5 inhibitors should not take Dapoxetine due to the potential for reduced orthostatic tolerance.

In a crossover single-dose study, the pharmacokinetics of dapoxetine taken at a 60 mg dose concurrently with tadalafil (20 mg) or sildenafil (100 mg) were investigated. Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil caused minor changes in the pharmacokinetics of dapoxetine: an increase in AUC_0-∞ and C_max (by 22% and 4%, respectively), which is considered clinically insignificant. Dapoxetine should be prescribed with caution to patients taking PDE5 inhibitors due to potentially reduced tolerance to orthostatic hypotension. Concurrent use of dapoxetine with PDE5 inhibitors may lead to orthostatic hypotension. The efficacy and safety of dapoxetine in patients with premature ejaculation and erectile dysfunction concurrently taking Dapoxetine and PDE5 inhibitors have not been studied.

Effect of Dapoxetine on Concomitant Drugs

Tamsulosin

Single and multiple doses of dapoxetine 30 mg and 60 mg in patients receiving daily tamsulosin did not lead to changes in the pharmacokinetics of the latter. Furthermore, the frequency of orthostatic hypotension did not change, being the same with tamsulosin alone and in combination with dapoxetine 30 mg or 60 mg. Dapoxetine should be prescribed with caution to patients taking alpha-adrenergic blockers due to their potentially reduced tolerance to orthostatic hypotension.

Drugs Metabolized by CYP2D6

Multiple doses of dapoxetine (60 mg/day for 6 days) increased the C_max and AUC_0-∞ of desipramine (50 mg single dose) by 11% and 19%, respectively, compared to desipramine alone. Dapoxetine may similarly increase the plasma concentration of other drugs metabolized by CYP2D6. The clinical significance of this is likely to be small.

Drugs Metabolized by CYP3A4

Multiple doses of dapoxetine (60 mg/day for 6 days) decreased the AUC_0-∞ of midazolam (8 mg single dose) by approximately 20% (range from -60% to +18%). The clinical significance of this phenomenon is likely to be small for most patients. However, increased CYP3A activity may be clinically significant in some patients concurrently taking drugs metabolized primarily by CYP3A and having a narrow therapeutic index.

Drugs Metabolized by CYP2C19

Multiple doses of dapoxetine (60 mg/day for 6 days) did not lead to inhibition of the metabolism of omeprazole (40 mg single dose). Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C19 substrates.

Drugs Metabolized by CYP2C9

Multiple doses of dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics and pharmacodynamics of glibenclamide (5 mg single dose). Dapoxetine is presumed not to affect the pharmacokinetics of other CYP2C9 substrates.

Warfarin and Drugs that Inhibit Blood Coagulation and/or Platelet Function

There are no data on the effects of long-term warfarin use concurrently with dapoxetine. Caution is recommended when prescribing dapoxetine to patients taking warfarin long-term. In a pharmacokinetic study, multiple doses of dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics and pharmacodynamics (PT and INR) of warfarin (25 mg single dose). Cases of abnormal bleeding have been reported with the concurrent use of SSRIs.

Ethanol

A single dose of ethanol (0.5 g/kg or approximately 2 drinks) did not affect the pharmacokinetics of dapoxetine (60 mg single dose) and vice versa. However, concurrent intake of dapoxetine and ethanol enhances drowsiness and significantly impairs self-assessed alertness. Pharmacodynamic measurements of cognitive function impairment (Digit Vigilance Test, Digit Symbol Substitution Test) also revealed an additive effect with the concurrent use of dapoxetine and ethanol. Concurrent intake of ethanol and dapoxetine increases the frequency and severity of adverse reactions such as dizziness, drowsiness, slowed reflexes, and impaired judgment. The combination of alcohol and dapoxetine may enhance alcohol-related neurocardiogenic adverse reactions, particularly the frequency of syncope, which increases the risk of accidental injury. Therefore, patients should be advised to abstain from alcohol consumption during treatment with dapoxetine.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.