Prilidge® 30 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRILIGY® 30 mg / PRILIGY® 60 mg (PRILIGY® 30 mg / PRILIGY® 60 mg)

Composition:

Active substance: dapoxetine;

One film-coated tablet contains 33.6 mg or 67.2 mg of dapoxetine hydrochloride, equivalent to 30 mg or 60 mg of dapoxetine, respectively;

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

Coating:

• 30 mg film-coated tablets: Powder Grey 4 (lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, iron oxide black (E 172), iron oxide yellow (E 172));
• 60 mg film-coated tablets: Powder Grey 3 (lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, iron oxide black (E 172), iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

• 30 mg film-coated tablets: grey, round, convex film-coated tablets with an imprint "30" inside a triangle on one side and a plain reverse side;
• 60 mg film-coated tablets: grey, round, convex film-coated tablets with an imprint "60" inside a triangle on one side and a plain reverse side.

Pharmacotherapeutic group. Other urological preparations.

ATC code G04B X14.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Dapoxetine is a potent, selective serotonin reuptake inhibitor (SSRI) with an IC50 of 1.12 nM, while its primary metabolites—desmethyldapoxetine (IC50 < 1.0 nM) and didesmethyldapoxetine (IC50 = 2.0 nM)—are equipotent or less potent (dapoxetine-N-oxide, IC50 = 282 nM).

Ejaculation in humans is primarily regulated by the sympathetic nervous system. Ejaculation is initiated by a spinal reflex center involving the brainstem, which is primarily influenced by several brain nuclei (medial preoptic and paraventricular nuclei). The mechanism of action of dapoxetine in premature ejaculation is likely related to inhibition of neuronal serotonin reuptake, resulting in enhanced neurotransmitter effects on pre- and postsynaptic receptors.

Clinical efficacy and safety

The efficacy of Priligy® in the treatment of premature ejaculation was established in five randomized, double-blind, placebo-controlled clinical trials involving a total of 6,081 patients. Patient age was at least 18 years. In the 6 months prior to enrollment, the majority of sexual acts in these individuals were characterized by premature ejaculation, defined according to 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] less than two minutes, measured using a stopwatch in four studies), poor control over ejaculation, and significant distress or interpersonal difficulties related to this condition.

Individuals with other types of sexual dysfunction, including erectile dysfunction, as well as those using other medicinal products for the treatment of PE, were excluded from all studies.
Results from all randomized trials were consistent. Efficacy was observed after 12 weeks of treatment. One study included patients from both EU and non-EU countries and lasted 24 weeks. In study 1162, 385 patients received placebo, 388 received Priligy® 30 mg as needed, and 389 received Priligy® 60 mg as needed. Mean and median IELT (Intravaginal Ejaculatory Latency Time – intravaginal ejaculatory latency time) at the end of the study are presented in Table 1, and the overall distribution of patients achieving at least a certain level of mean IELT at the end of the study is presented in Table 2. Other studies and the pooled analysis at week 12 yielded similar results.

Table 1. Mean and median IELT values at the end of the study, calculated using the least squares method*

* Baseline value extrapolated to patients for whom baseline data were not available.

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

Table 2. Patients achieving at least the defined level of mean IELT at the end of the study*

*Baseline value imputed for patients with missing baseline data.

The magnitude of IELT prolongation was related to baseline IELT and varied among individual patients: the clinical significance of treatment efficacy with Priligy® was demonstrated in the presented efficacy outcomes and analysis of data from patients with therapeutic effect.

A patient with therapeutic effect was defined as one who had at least a 2-category improvement in control of ejaculation plus at least a 1-category reduction in distress related to ejaculation. Statistically significantly more patients had a therapeutic effect in each of the Priligy® treatment groups compared to the placebo group at the end of the study: week 12 or 24. A higher percentage of patients with therapeutic effect was observed in the Priligy® 30 mg group (11.1%, 95% CI [7.24; 14.87]) and the Priligy® 60 mg group (16.4%, 95% CI [13.01; 19.75]) compared to the placebo group at week 12 (pooled analysis).

The clinical significance of the effect of Priligy® treatment is illustrated by the results of the Patient Global Impression of Change (PGIC) assessment, in which patients were asked to compare their premature ejaculation at the end of the study with the beginning using a response scale ranging from "much better" to "much worse." At the end of the study (week 24), 28.4% (30 mg group) and 35.5% (60 mg group) of patients reported that their condition had become better or much better compared to 14% in the placebo group. Additionally, 53.4% and 65.6% of patients receiving Priligy® 30 mg and 60 mg, respectively, reported that their condition was at least somewhat better compared to 28.8% in the placebo group.

Pharmacokinetics.

Absorption. Dapoxetine is rapidly absorbed and reaches peak plasma concentration (Cmax) approximately 1–2 hours after tablet intake. Absolute bioavailability is 42% (range 15–76%), and within the dose range of 30 mg to 60 mg, Cmax and AUC (area under the curve) increase proportionally with dose. After repeated administration, AUC values for dapoxetine and its active metabolite desmethyldapoxetine increase by approximately 50% compared to AUC values after single-dose administration. Administration with a fatty meal slightly reduced Cmax (by 10%) and slightly increased AUC of dapoxetine (by 12%), as well as slightly prolonged the time to reach peak concentration. These changes were not clinically significant. Priligy® can be taken regardless of food intake.

Distribution. More than 99% of dapoxetine is bound to human serum proteins in vitro. The active metabolite desmethyldapoxetine is 98.5% protein-bound. The mean volume of distribution at steady state for dapoxetine is 162 L.

Biotransformation. In vitro studies indicate that dapoxetine is metabolized by multiple enzyme systems in liver and kidney tissues (primarily CYP2D6, CYP3A4) and flavin-containing monooxygenase (FMO1). After oral administration of 14C-dapoxetine, the drug is extensively metabolized, forming numerous metabolites, primarily via the following biotransformation pathways: N-oxidation, N-demethylation, naphthyl hydroxylation, glucuronidation, and sulfation. Evidence suggests the presence of a presystemic first-pass effect after oral administration.

Most circulating substances in plasma are intact dapoxetine and dapoxetine-N-oxide. In vitro binding and transport studies have shown that dapoxetine-N-oxide is inactive. Additional metabolites, including desmethyldapoxetine and didesmethyldapoxetine, accounted for less than 3% of total drug-related substances in plasma. In vitro binding studies indicate that desmethyldapoxetine and dapoxetine have similar potency, while didesmethyldapoxetine has approximately 50% of the activity of dapoxetine (see section "Pharmacodynamics"). The concentration of free desmethyldapoxetine (AUC and Cmax) is 50% and 23% of the free dapoxetine concentration, respectively.

Elimination. Dapoxetine metabolites are primarily excreted in urine as conjugates. The unchanged active substance was not detected in urine. After oral administration, the initial elimination half-life of dapoxetine (pharmacokinetics) is approximately 1.5 hours; plasma levels fall below 5% of peak concentration within 24 hours after intake, and the terminal elimination half-life is approximately 19 hours. The terminal elimination half-life of desmethyldapoxetine is approximately 19 hours.

Pharmacokinetics in special patient populations.

The metabolite desmethyldapoxetine contributes to the pharmacological effect of Priligy®, particularly when the effect of desmethyldapoxetine is increased. Below are increases in active fraction levels in certain patient groups. This reflects the combined free effects of dapoxetine and desmethyldapoxetine. Desmethyldapoxetine has the same potency as dapoxetine. Preliminary modeling predicts uniform distribution of desmethyldapoxetine in the CNS, but it is unknown whether this will occur.

Race.

Analysis of clinical pharmacology studies after single 60 mg dapoxetine dose showed no statistically significant differences between Latino, Caucasian, African, and Asian populations. Clinical studies comparing dapoxetine pharmacokinetics in Japanese and Caucasian subjects found higher plasma levels of dapoxetine (10–20% higher) in Japanese subjects (AUC and peak concentration) due to lower body weight. No clinically significant effect is expected from this slightly higher concentration.

Elderly patients (aged 65 years and older).

Pharmacokinetic analysis of single 60 mg dapoxetine dose studies showed no significant differences in pharmacokinetic parameters (Cmax, AUCinf, Tmax) between healthy elderly and healthy young men. Efficacy and safety have not been established in this patient group.

Patients with renal impairment.

A clinical pharmacology study of a single 60 mg dapoxetine dose was conducted in patients with mild (creatinine clearance 50–80 mL/min), moderate (creatinine clearance 30 to <50 mL/min), and severe renal impairment (creatinine clearance <30 mL/min), as well as in patients with normal renal function (creatinine clearance >80 mL/min). No trend toward increased dapoxetine AUC with decreasing renal function was observed. AUC in patients with severe renal impairment was approximately twice that in patients with normal renal function, although data in patients with severe renal impairment are limited. Pharmacokinetics of dapoxetine have not been evaluated in patients requiring hemodialysis (see sections "Dosage and administration" and "Special precautions").

Patients with hepatic impairment.

In patients with mild hepatic impairment, free Cmax of dapoxetine is reduced by 28%, while free AUC remains unchanged. Free Cmax and AUC of the active fraction (sum of free dapoxetine and desmethyldapoxetine exposure) are reduced by 30% and 5%, respectively. In patients with moderate hepatic impairment, free Cmax of dapoxetine is practically unchanged (3% reduction), and free AUC increases by 66%. Free Cmax and AUC of the active fraction are practically unchanged and doubled, respectively.

In patients with severe hepatic impairment, free Cmax of dapoxetine is reduced by 42%, but free AUC is increased by approximately 223%. Cmax and AUC of the active fraction show similar changes (see sections "Contraindications" and "Special precautions").

CYP2D6 polymorphism.

A clinical pharmacology study of a single 60 mg dapoxetine dose showed that plasma concentrations in CYP2D6 poor metabolizers were higher than in extensive metabolizers (approximately 31% higher for Cmax, 36% higher for AUCinf of dapoxetine, 98% higher for Cmax, and 161% higher for AUCinf of desmethyldapoxetine). The active fraction of Priligy® may be increased by approximately 46% for Cmax and approximately 90% for AUC. This increase may lead to higher incidence and more severe dose-dependent adverse effects (see section "Contraindications"). The safety of Priligy® use in CYP2D6 poor metabolizers is of particular concern when co-administered with other medicinal products that may inhibit dapoxetine metabolism, such as moderate and strong CYP3A4 inhibitors.

Clinical characteristics.

Indications.

Treatment of premature ejaculation (PE) in adult men aged 18 to 64 years.

Priligy® is recommended to be prescribed only to patients who meet the following criteria:

• intravaginal ejaculatory latency time (IELT) is less than two minutes;
  persistent or recurrent ejaculation after minimal sexual stimulation occurring before, during, or shortly after vaginal penetration, which happens earlier than desired by the patient;
• marked distress or interpersonal difficulties resulting from PE;
• insufficient control over the timing of ejaculation;
• onset of premature ejaculation in most attempts at sexual intercourse over the past 6 months.

Priligy® should be taken on an as-needed basis only, prior to anticipated sexual activity. Priligy® must not be prescribed for delaying ejaculation in men who have not been diagnosed with PE.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Severe cardiac conditions, such as heart failure (NYHA class II–IV).
• Conduction disorders, such as AV block or sick sinus syndrome.
• Severe ischemic heart disease.
• Severe valvular heart disease.
• History of syncope.
• History of mania or severe depression.
• Concomitant use of monoamine oxidase inhibitors (MAOIs) and within 14 days after discontinuation of MAOIs. Priligy® treatment must be discontinued at least 7 days before starting therapy with MAOIs.
• Concomitant use of thioridazine and within 14 days after discontinuation of thioridazine. Priligy® treatment must be discontinued at least 7 days before starting thioridazine therapy (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of serotonin reuptake inhibitors (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants [TCAs]) or other medicinal products/herbal preparations with serotonergic activity [such as L-tryptophan, triptans, tramadol, linezolid, lithium, St. John’s wort (Hypericum perforatum)] and within 14 days after discontinuation of these medicinal products/herbal preparations. The aforementioned medicinal products/herbal preparations must not be used within 7 days after stopping Priligy® (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, atazanavir, etc. (see section "Interaction with other medicinal products and other forms of interaction").
• Moderate or severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Potential interaction with monoamine oxidase inhibitors.

Serious reactions, sometimes fatal, including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations in vital signs, and mental status changes including agitation progressing to delirium and coma, have been reported when SSRIs are co-administered with MAOIs. Such reactions have also been reported in patients who have recently discontinued SSRIs and started MAOI therapy. Isolated cases with symptoms resembling neuroleptic malignant syndrome have also been reported. Data from animal studies on the combined use of SSRIs and MAOIs suggest a possible synergistic effect, increasing blood pressure and causing excitation. Therefore, Priligy® is contraindicated for use in combination with MAOIs or within 14 days after their discontinuation. MAOIs are contraindicated within 7 days after stopping Priligy® (see section "Contraindications").

Potential interaction with thioridazine.

Thioridazine causes QTc interval prolongation, which is associated with the occurrence of severe ventricular arrhythmias. Medicinal products such as Priligy®, which inhibit the CYP2D6 isoenzyme, are likely to inhibit thioridazine metabolism. The resulting increased thioridazine levels are expected to lead to more pronounced QTc interval prolongation. Priligy® must not be used in combination with thioridazine or within 14 days after its discontinuation. Thioridazine is contraindicated within 7 days after stopping Priligy® (see section "Contraindications").

Medicinal products/herbal preparations with serotonergic effects.
As with SSRIs, concomitant use of medicinal products/herbal preparations with serotonergic mechanisms of action (including MAOIs, L-tryptophan, triptans, tramadol, linezolid, SSRIs, SNRIs [serotonin-norepinephrine reuptake inhibitors], lithium, and St. John’s wort [Hypericum perforatum]) may increase the frequency of serotonergic effects. Priligy® is contraindicated for use in combination with other SSRIs, MAOIs, and other medicinal products/herbal preparations with serotonergic mechanisms of action, and within 14 days after their discontinuation. The aforementioned medicinal products/herbal preparations are contraindicated within 7 days after stopping Priligy® (see section "Contraindications").

Medicinal products acting on the CNS.

Systematic evaluation of the concomitant use of Priligy® with CNS-acting medicinal products (such as antiepileptic drugs, antidepressants, antipsychotics, anxiolytics, sedative hypnotics) in patients with premature ejaculation has not been performed. Therefore, caution is recommended when co-prescribing Priligy® with the aforementioned medicinal products.

Pharmacokinetic interactions.

Effect of other concomitantly administered medicinal products on dapoxetine pharmacokinetics.

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

CYP3A4 inhibitors.

Strong CYP3A4 inhibitors. Administration of ketoconazole (200 mg twice daily for 7 days) increased the Cmax and AUCinf of dapoxetine (single 60 mg dose) by 35% and 99%, respectively. Regarding the contribution of both free dapoxetine and desmethyldapoxetine, the Cmax of the active moiety may increase by approximately 25%, and the AUC of the active moiety may double when strong CYP3A4 inhibitors are co-administered.

The increase in Cmax and AUC of the active moiety may be significantly greater in patients with impaired functional CYP2D6 enzyme activity, particularly in poor metabolizers of CYP2D6, or when used concomitantly with strong CYP2D6 inhibitors.

Therefore, concomitant use of Priligy® and strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, and atazanavir, is contraindicated. Grapefruit juice is also a strong CYP3A4 inhibitor; therefore, its consumption should be avoided within 24 hours before taking Priligy® (see section "Contraindications").

Moderate CYP3A4 inhibitors.

Concomitant use of Priligy® and moderate CYP3A4 inhibitors (such as erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem) may also lead to a pronounced increase in dapoxetine and desmethyldapoxetine exposure, particularly in poor CYP2D6 metabolizers. When co-administered with any of these agents, the maximum dapoxetine dose should be limited to 30 mg (see sections "Dosage and administration" and "Special precautions").

This applies to all patients except those identified as extensive metabolizers of CYP2D6 based on genotyping or phenotyping. For patients who are extensive metabolizers of CYP2D6, a maximum dapoxetine dose of 30 mg is recommended when co-administered with a strong CYP3A4 inhibitor. Caution is advised when co-administering 60 mg dapoxetine with a moderate CYP3A4 inhibitor.

Strong CYP2D6 inhibitors.

Cmax and AUCinf of dapoxetine (single 60 mg dose) increase by 50% and 88%, respectively, in the presence of fluoxetine (60 mg/day for 7 days). Regarding the contribution of both free dapoxetine and desmethyldapoxetine, the Cmax of the active moiety may increase by approximately 50%, and the AUC of the active moiety may double when co-administered with strong CYP2D6 inhibitors. This increase in Cmax and AUC of the active moiety is similar to that expected in poor CYP2D6 metabolizers and may lead to an increased frequency and severity of dose-dependent adverse reactions (see section "Special precautions").

Phosphodiesterase-5 (PDE5) inhibitors.

Patients taking phosphodiesterase-5 (PDE5) inhibitors should not take Priligy® due to the potential for reduced orthostatic tolerance (see section "Special precautions"). The pharmacokinetics of dapoxetine (60 mg) in combination with tadalafil (20 mg) and sildenafil (100 mg) were evaluated in a crossover study with single-dose administration. Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil caused minor changes in dapoxetine pharmacokinetics (22% increase in AUCinf and 4% increase in Cmax), which are unlikely to be clinically significant.

Concomitant use of Priligy® and PDE5 inhibitors may cause orthostatic hypotension (see section "Special precautions"). The efficacy and safety of Priligy® in patients with premature ejaculation and erectile dysfunction who are concurrently taking Priligy® and PDE5 inhibitors have not been established.

Effect of dapoxetine on the pharmacokinetics of concomitantly administered medicinal products.

Tamsulosin.
Concomitant administration of single or multiple doses of dapoxetine 30 mg or 60 mg in patients taking tamsulosin at a daily dose of 0.4 mg did not alter the pharmacokinetics of tamsulosin. Concomitant use of dapoxetine and tamsulosin did not alter the orthostatic profile or orthostatic effects compared to tamsulosin alone or tamsulosin combined with dapoxetine 30 or 60 mg. However, caution should be exercised when prescribing Priligy® to patients taking alpha-adrenergic receptor antagonists due to the potential for reduced orthostatic tolerance (see section "Special precautions").

Medicinal products metabolized by CYP2D6.

Repeated administration of dapoxetine (60 mg/day for 6 days) followed by a single 50 mg dose of desipramine resulted in an 11% and 19% increase in mean Cmax and AUCinf of desipramine, respectively, compared to desipramine alone. Dapoxetine may cause a similar increase in plasma concentrations of other drugs metabolized by CYP2D6. This is unlikely to be of significant clinical importance.

Medicinal products metabolized by CYP3A4.

Repeated administration of dapoxetine (60 mg/day for 6 days) resulted in approximately a 20% reduction in AUCinf of midazolam (single 8 mg dose) (range from -60% to +18%). This effect on midazolam is unlikely to be of significant clinical importance for most patients. However, increased CYP3A activity may be clinically relevant in some patients concurrently taking a medicinal product primarily metabolized by CYP3A with a narrow therapeutic index.

Medicinal products metabolized by CYP2C19.

Repeated administration of dapoxetine (60 mg/day for 6 days) did not inhibit metabolism following a single 40 mg dose of omeprazole. Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C19 substrates.

Medicinal products metabolized by CYP2C9.

Repeated administration of dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics of a single 5 mg dose of glyburide. Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C9 substrates.

Warfarin and medicinal products affecting blood coagulation and/or platelet function.
Data on the evaluation of the effect of chronic warfarin use with dapoxetine are lacking; therefore, caution is recommended when using dapoxetine in patients chronically taking warfarin. In a pharmacokinetic study, dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics (PT or INR) of a single 25 mg dose of warfarin.

Bleeding has been reported with the use of SSRIs (see section "Special precautions").

Alcohol.
Concomitant administration of a single dose of ethanol (0.5 g/kg, approximately 2 drinks on average) did not affect the pharmacokinetics of dapoxetine (single 60 mg dose); however, dapoxetine in combination with ethanol enhances drowsiness and significantly impairs alertness. Pharmacodynamic assessments of cognitive impairment (digit symbol substitution test, digit vigilance test) also revealed an additive effect when dapoxetine and ethanol are used together. Concomitant use of alcohol and dapoxetine increases the likelihood or severity of adverse reactions such as dizziness, drowsiness, slowed reflexes, or impaired judgment. The combination of alcohol and dapoxetine may intensify alcohol-related effects and may increase the risk of neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised not to consume alcohol during treatment with Priligy® (see section "Special precautions").

Special precautions for use.

General recommendations.

Priligy® should be prescribed only to men with premature ejaculation (see section "Indications"). Priligy® should not be prescribed to men who have not been diagnosed with premature ejaculation. The safety of use has not been established, and there are no data on the effect on ejaculation delay in men who do not have premature ejaculation.

Other forms of sexual disorders.

Prior to initiating treatment, patients with other forms of sexual disorders, including erectile dysfunction, should be thoroughly evaluated by a physician. Priligy® should not be used in men with erectile dysfunction who are taking PDE-5 inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Orthostatic hypotension (hypotension).

A thorough medical examination by a physician, including history of orthostatic events, is required prior to starting treatment. Perform an orthostatic test before initiating therapy (arterial pressure and pulse rate in the supine and standing positions). Priligy® should be avoided in cases of documented history or suspected orthostatic reaction.

Orthostatic hypotension has been reported in clinical trials. Physicians should advise patients in advance that if prodromal symptoms such as dizziness occur shortly after standing up, they should immediately lie down with the head lower than the rest of the body, or sit and place the head between the knees, and remain in this position until symptoms resolve. Patients should avoid rapid rising after prolonged lying or sitting.

Suicidal thoughts/behaviour.

Antidepressants, including SSRIs, have been shown to increase the risk of suicidal thoughts and suicidal behaviour in children and adolescents with major depressive and other psychiatric disorders compared to placebo in short-term studies. Short-term studies do not indicate an increased risk of suicidality with antidepressant use compared to placebo in adults aged 24 years and older. In clinical trials of Priligy® for the treatment of premature ejaculation, there was no clear evidence of increased suicidality during treatment based on assessment of potential adverse events according to the Columbia Classification Algorithm of Suicide Assessment (C-CASA), Montgomery–Åsberg Depression Rating Scale, or Beck Depression Inventory-II.

Syncope.

Patients should be warned to avoid situations that could lead to injury, including driving or operating dangerous machinery, as syncope or prodromal symptoms such as dizziness or presyncope may occur (see section "Adverse reactions").

Prodromal symptoms such as nausea, dizziness/presyncope, and sweating have been reported and occur more frequently in patients taking Priligy® compared to placebo.

In clinical trials, episodes of syncope were characterized by loss of consciousness associated with bradycardia or cessation of sinus node activity. These events occurred in patients monitored with Holter ECG and are considered vasovagal in etiology. Most cases occurred within the first 3 hours after the first dose or were associated with clinical procedures (e.g., blood sampling, orthostatic procedures, blood pressure measurements). Possible prodromal symptoms such as nausea, dizziness, presyncope, palpitations, weakness, confusion, and sweating usually appeared within the first 3 hours after dosing and often preceded syncope. Patients should be informed about the possibility of syncope at any time, with or without prodromal symptoms, during treatment with Priligy®. Physicians should advise patients on the importance of maintaining adequate hydration and recognizing prodromal signs and symptoms to reduce the risk of serious injury due to falls associated with loss of consciousness. If a patient experiences prodromal symptoms, they should immediately lie down with the head lower than the rest of the body or sit and place the head between the knees and remain in this position until symptoms resolve. Patients should avoid situations, including driving or operating dangerous machinery, as syncope or other CNS effects may occur (see section "Ability to affect reaction speed when driving or operating machinery").

Patients with cardiovascular risk factors.

Patients with cardiovascular diseases were excluded from phase 3 clinical trials. The risk of adverse cardiovascular outcomes of syncope (cardiac syncope and syncope from other causes) is increased in patients with underlying structural cardiovascular diseases (such as documented outflow obstruction, cardiac valve defects, carotid stenosis, and ischemic heart disease). There is insufficient data to determine whether this increased risk of vasovagal syncope extends to patients with cardiovascular diseases.

Use with recreational drugs.

Patients should not be advised to use Priligy® in combination with recreational drugs.

Recreational drugs (substances) with serotonergic activity, such as ketamine, methylenedioxymethamphetamine, and diethylamide of lysergic acid, may lead to potentially serious reactions when used with Priligy®. These reactions include, among others, arrhythmia, hyperthermia, and serotonin syndrome. The use of Priligy® with recreational drugs having sedative properties, such as narcotics and benzodiazepines, may increase somnolence and dizziness.

Alcohol.

Patients should be advised not to use Priligy® in combination with alcohol.

The combination of alcohol and dapoxetine may enhance alcohol-related neurocognitive effects and may also lead to an increased risk of neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised not to consume alcohol during treatment with Priligy® (see sections "Interaction with other medicinal products and other forms of interaction" and "Ability to affect reaction speed when driving or operating machinery").

Medicinal products with vasodilatory properties.

Priligy® should be prescribed with caution to patients taking medicinal products with vasodilatory properties (e.g., alpha-adrenergic antagonists and nitrates) due to possible reduced orthostatic tolerance (see section "Interaction with other medicinal products and other forms of interaction").

Moderate CYP3A4 inhibitors.

Patients should exercise caution when using moderate CYP3A4 inhibitors with a limited dose of up to 30 mg (see sections "Method of administration and dosage" and "Interaction with other medicinal products and other forms of interaction").

Strong CYP2D6 inhibitors.

Patients should exercise caution when increasing the dose to 60 mg when using strong CYP2D6 inhibitors or when increasing the dose to 60 mg in patients known to have a low CYP2D6 metabolizer genotype, as this may increase exposure, potentially leading to a higher frequency and severity of dose-dependent adverse reactions.

Manic syndrome.

Priligy® should not be prescribed to patients with a history of manic syndrome/hypomania or bipolar affective disorder. Treatment should be discontinued if symptoms of these disorders occur.

Seizure.

Due to the properties of SSRIs to lower the seizure threshold, Priligy® should be discontinued in any patient experiencing a seizure. Priligy® should be avoided in patients with unstable epilepsy. Patients with controlled epilepsy should be closely monitored during treatment with Priligy®.

Depression and/or psychiatric disorders.

Men with primary signs and symptoms of depression should be evaluated prior to initiating Priligy® treatment to exclude undiagnosed depressive disorders. Combined treatment with Priligy® and antidepressants, including SSRIs and SNRIs, is contraindicated (see section "Contraindications"). It is not recommended to discontinue ongoing treatment for depression or anxiety in order to initiate Priligy® for the treatment of PE. Priligy® is not recommended for the treatment of psychiatric disorders and should not be used in men with disorders such as schizophrenia or individuals with hypochondriasis, as worsening of depression-related symptoms cannot be excluded. This may result from the underlying psychiatric disorder or as a consequence of drug therapy. Physicians should encourage patients to report any troubling thoughts or feelings at any time. If signs and symptoms of depression occur during treatment, Priligy® should be discontinued.

Bleeding.

There are reports of impaired hemostasis with the use of SSRIs. Priligy® should be used with caution, particularly when used concomitantly with medicinal products affecting platelet function (such as atypical antipsychotics and phenothiazines, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, antiplatelet agents), or with anticoagulants (e.g., warfarin), and in patients with a history of bleeding or coagulation disorders (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacokinetics").

Renal impairment.

Priligy® is not recommended for use in patients with severe renal impairment and should be used with caution in patients with mild to moderate renal impairment (see sections "Methods of administration and dosage", "Pharmacokinetics").

Drug withdrawal syndrome.

Abrupt discontinuation of chronic SSRI treatment for chronic depressive disorders has been reported to cause symptoms such as dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.

A double-blind clinical study in patients with PE designed to evaluate drug withdrawal syndrome after daily administration for 62 days or as-needed dosing of 60 mg Priligy® showed mild withdrawal symptoms, with a higher frequency of insomnia and dizziness in patients who switched to placebo after daily treatment (see section "Pharmacodynamics").

Ocular disorders.

The use of Priligy® has been associated with adverse effects on the eyes, such as mydriasis and eye pain. Priligy® should be used with caution in patients with elevated intraocular pressure or at risk of developing angle-closure glaucoma.

Lactose intolerance.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicine.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Priligy® is not intended for use in women.

Animal studies do not indicate direct or indirect harmful effects on fertility, pregnancy, or embryonic/fetal development.

It is unknown whether dapoxetine or its metabolites are excreted in human breast milk.

Ability to affect reaction speed when driving or operating machinery.

Priligy® has a minor or moderate influence on the ability to drive or operate machinery. In clinical trials, patients taking dapoxetine reported dizziness, attention disturbance, syncope, blurred vision, and somnolence. Therefore, patients should be warned to avoid injury-prone situations, including driving and operating dangerous machinery.

The combination of alcohol with dapoxetine may enhance neurocognitive effects associated with alcohol. Neurocardiogenic adverse reactions such as syncope may also be intensified, thereby increasing the risk of accidental injury. Therefore, patients should be advised to avoid alcohol consumption during Priligy® treatment (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction").

Method of Administration and Dosage.

Dosage.

Adult males aged 18 to 64 years.

The recommended initial dose for patients aged 18 to 64 years is 30 mg, taken 1–3 hours before anticipated sexual activity. Treatment with Priligy® should not be initiated with a 60 mg dose.

Priligy® is not intended for continuous daily use. Priligy® should be taken only when sexual activity is anticipated. The medication should not be taken more frequently than once every 24 hours.

If the individual response to the 30 mg dose is inadequate and the patient has not experienced moderate or severe adverse reactions or prodromal symptoms suggesting possible syncope, the dose may be increased to the maximum recommended dose of 60 mg, taken as needed approximately 1–3 hours before sexual activity. The frequency and severity of adverse reactions increase with the 60 mg dose.
If orthostatic reactions occur after taking the initial dose, dose escalation to 60 mg is not recommended (see section "Special Warnings and Precautions for Use").

A careful benefit-risk assessment of Priligy® treatment is required after the first four weeks of therapy (or at least after six doses) to determine whether continued treatment with Priligy® is appropriate.

Data on the efficacy and safety of Priligy® beyond 24 weeks are limited. The clinical need for continued treatment and the benefit-risk ratio of Priligy® therapy should be reviewed at least every six months.

Elderly patients (over 65 years of age).

The efficacy and safety of Priligy® have not been established in patients aged 65 years and older (see section "Pharmacokinetics").

Renal impairment.

Caution should be exercised when administering Priligy® to patients with mild or moderate renal impairment. Priligy® is not recommended in patients with severe renal impairment (see sections "Pharmacokinetics", "Special Warnings and Precautions for Use").

Hepatic impairment.

Priligy® is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh classification, class B and C).

Known poor metabolizers of CYP2D6 or patients receiving strong CYP2D6 inhibitors.

Dose increase to 60 mg should be used with caution in patients who are known poor metabolizers of CYP2D6 or who are concurrently taking strong CYP2D6 inhibitors (see sections "Pharmacokinetics", "Interaction with Other Medicinal Products and Other Forms of Interaction", "Special Warnings and Precautions for Use").

Patients taking moderate or strong CYP3A4 inhibitors.

Concomitant use of strong CYP3A4 inhibitors is contraindicated. Caution is required in patients who are concurrently taking moderate CYP3A4 inhibitors, and the dose should not exceed 30 mg (see sections "Contraindications", "Interaction with Other Medicinal Products and Other Forms of Interaction", "Special Warnings and Precautions for Use").

Method of administration.

The medication is intended for oral use. To avoid a bitter taste, tablets should be swallowed whole. Tablets should be taken with at least one full glass of water. Priligy® can be taken regardless of food intake (see section "Pharmacokinetics").

Warnings before administration or prescription of the medicinal product.

Before initiating treatment, review information regarding orthostatic hypotension in section "Special Warnings and Precautions for Use".

Children.

Priligy® is contraindicated in children due to lack of clinical experience.

Overdose.

There have been no reports of overdose.

In a clinical pharmacology study of Priligy®, no unexpected adverse reactions were observed at single doses up to 240 mg (two 120 mg doses administered 3 hours apart). In general, symptoms of overdose with SSRIs include serotonin-mediated adverse reactions such as drowsiness, gastrointestinal disturbances (nausea and vomiting), tachycardia, tremor, agitation, and dizziness.

Treatment. In the event of overdose, treatment should be symptomatic and supportive. Due to the high degree of plasma protein binding and large volume of distribution of dapoxetine hydrochloride, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. There is no specific antidote.

Adverse reactions.

General safety profile.

During clinical trials, episodes of syncope and orthostatic hypotension were reported (see section "Special warnings and precautions for use").

In phase 3 clinical trials, the most commonly reported adverse reactions, which were dose-dependent, included nausea (11.0% and 22.2% in the groups receiving on-demand dapoxetine 30 mg and 60 mg, 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%), and fatigue (2.0% and 4.1%). The most common adverse events leading to drug discontinuation were nausea (2.2% of patients receiving Priligy®) and dizziness (1.2% of patients receiving Priligy®).

The safety of Priligy® was evaluated in 4224 patients with premature ejaculation who participated in five double-blind, placebo-controlled clinical studies. Of the 4224 patients, 1616 received Priligy® 30 mg on-demand, and 2608 received Priligy® 60 mg on-demand or once daily.

Table 3 presents the reported adverse reactions.

The frequency of adverse reactions is presented according to the MedRA classification.

Table 3. Adverse reactions by system organ class and frequency

Adverse reactions reported in the 9-month long-term extension study were consistent with those observed in the double-blind studies. No additional adverse reactions were identified.

Description of selected adverse reactions.

Syncope associated with bradycardia or due to cessation of sinus node activity related to the medicinal product has been observed in patients wearing Holter monitors in clinical trials. Most events occurred within the first 3 hours after dosing, following the first dose, or were associated with procedures performed during clinical studies (such as blood draws for analysis and orthostatic procedures, blood pressure measurements). Syncope was often preceded by prodromal symptoms (see section "Special precautions for use").

The occurrence of syncope and possibly prodromal symptoms is dose-dependent, with higher incidence observed in patients receiving doses higher than recommended in phase 3 clinical trials.

Orthostatic hypotension was observed in clinical trials (see section "Special precautions for use"). The frequency of syncope, defined as loss of consciousness in the Priligy® clinical trial program, varies depending on the study population, ranging from 0.06% (30 mg) to 0.23% (60 mg) among patients enrolled in the phase 3 placebo-controlled clinical trial, and up to 0.64% (all doses combined) in phase 1 studies involving healthy volunteers.

Other special populations

Increased dose up to 60 mg should be used with caution in patients taking strong CYP2D6 inhibitors or in patients identified as CYP2D6 poor metabolizers (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", "Dosage and administration", "Special precautions for use").

Drug discontinuation syndrome.

Abrupt discontinuation of chronic SSRI therapy for treatment of chronic depressive disorders has been reported to cause symptoms such as 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 increased incidence of mild or moderate insomnia and dizziness in patients who switched to placebo after 62 days of daily drug administration.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging.

Primary: PVC-PE-PVdC/aluminum push-through blister with child-resistant packaging, containing 3 or 6 film-coated tablets.

Secondary: cardboard box containing 1 blister and the instruction for medical use in Ukrainian.

Prescription status. Prescription only.

Manufacturer.

Menarini-Fon Heyden GmbH.

Manufacturer's address.

Leipziger Strasse 7-13, 01097 Dresden, Germany.

Marketing authorization holder.

Berlin-Chemie AG.

Address of marketing authorization holder.

Glienicker Weg 125, 12489 Berlin, Germany.