Dapigra

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DAPIGRA (DAPIGRA)

Composition:

Active substance: dapoxetine;

One film-coated tablet contains dapoxetine hydrochloride equivalent to dapoxetine 30 or 60 mg;

Excipients: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry Grey 20G275000 coating;

Composition of Opadry Grey 20G275000 coating: hypromellose, polyethylene glycol 400, polyethylene glycol 6000, talc, titanium dioxide (E 171), iron oxide black (E 172), iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

30 mg: round film-coated tablets of grey color, with a break line on one side and embossing «30» on the other side;

60 mg: round film-coated tablets of grey color, with a break line on one side and embossing «60» on the other side.

Pharmacotherapeutic group.

Other urological agents. ATC code G04B X14.

Pharmacological Properties

Pharmacodynamics

Dapoxetine is a potent, selective serotonin reuptake inhibitor (SSRI). Ejaculation in humans is primarily regulated by the sympathetic nervous system. Ejaculation is initiated by a spinal reflex center with input from 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 reuptake of serotonin and subsequent enhancement of neurotransmitter effects on pre- and post-synaptic receptors.

Clinical Efficacy and Safety

The efficacy of dapoxetine 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. Premature ejaculation was defined according to DSM-IV diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders): short time to ejaculation (intravaginal ejaculatory latency time [IELT] less than 2 minutes, measured using a stopwatch in four of the studies), poor control over ejaculation, and significant distress or interpersonal difficulties related to this condition.

Patients with other forms of sexual dysfunction, including erectile dysfunction, as well as those using other medicinal products for the treatment of premature ejaculation, 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 this study, 1,162 patients were randomized: 385 patients received placebo, 388 patients received dapoxetine 30 mg as needed, and 游戏副本 389 patients received dapoxetine 60 mg as needed. Mean and median IELT values at the end of the study, calculated by the least squares method, are presented in Table 1. 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 pooled analyses at week 12 yielded similar results.

Table 1

Mean and median IELT values at the end of the study, calculated by the least squares method*

Mean IELT	Placebo, min	Dapoxetine 30 mg, min	Dapoxetine 60 mg, min
Median	1.05	1.72	1.91
Difference compared to placebo [95 % CI]		0.6 ** [0.37; 0.72]	0.9 ** [0.66; 1.06]
Least squares mean	1.7	2.9	3.3
Difference compared to placebo [95 % CI]		1.2 ** [0.59; 1.72]	1.6 ** [1.02; 2.16]

* Baseline (pre-treatment) value extrapolated to patients for whom baseline data were not available.

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

Table 2

Patients achieving at least a specified level of mean IELT at the end of the study*

IELT (minutes)	Placebo %	Dapoxetine 30 mg, %	Dapoxetine 60 mg, %
≥1.0	51.6	68.8	77.6
≥2.0	23.2	44.4	47.9
≥3.0	14.3	26.0	37.4
≥4.0	10.4	18.4	27.6
≥5.0	7.6	14.3	19.6
≥6.0	5.0	11.7	14.4
≥7.0	3.9	9.1	9.8
≥8.0	2.9	6.5	8.3

* Baseline value extrapolated to patients lacking baseline data.

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

A patient with therapeutic response was defined as one who had at least a 2-category improvement in ejaculatory control plus at least a 1-category reduction in ejaculation-related distress. Statistically significantly more patients in each dapoxetine treatment group achieved therapeutic response compared to the placebo group at the end of the study (week 12 or 24). A higher percentage of patients with therapeutic response was observed in the dapoxetine 30 mg group (11.1–95% CI [7.24; 14.87]) and the dapoxetine 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 dapoxetine 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 dapoxetine 30 mg and 60 mg, respectively, reported that their condition was at least somewhat improved 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 concentration-time curve) increased proportionally with dose. Following multiple dosing, AUC values for dapoxetine and its active metabolite desmethyldapoxetine increased by approximately 50% compared to AUC values after a single dose. Administration with a high-fat meal slightly reduced Cmax (by 10%) and slightly increased AUC of dapoxetine (by 12%), as well as slightly prolonged the time to reach Cmax. These changes were not clinically significant. Dapigra can be taken independently 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-labeled dapoxetine, extensive metabolism occurs, forming numerous metabolites primarily via the following biotransformation pathways: N-oxidation, N-demethylation, naphthyl hydroxylation, glucuronidation, and sulfation. Evidence suggests 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 indicate that dapoxetine N-oxide is inactive. Additional metabolites, including desmethyldapoxetine and didesmethyldapoxetine, constitute less than 3% of total drug-related substances in plasma. In vitro binding studies show that desmethyldapoxetine has similar potency to dapoxetine, while didesmethyldapoxetine has approximately 50% of the activity of dapoxetine. The concentration of free desmethyldapoxetine (AUC and Cmax) is 50% and 23%, respectively, of the concentration of free dapoxetine.

Elimination. Dapoxetine metabolites are primarily excreted in urine as conjugates. The unchanged active substance is 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 Cmax within 24 hours after intake, while the terminal elimination half-life is approximately 19 hours, similar to that of desmethyldapoxetine.

Pharmacokinetics in special patient populations.

The metabolite desmethyldapoxetine contributes to the pharmacological effect of dapoxetine, particularly when its influence is increased. Below are increases in active fraction parameters in certain patient groups. This represents the combined free effect of dapoxetine and desmethyldapoxetine. Desmethyldapoxetine has the same potency as dapoxetine. Preliminary calculations suggest uniform distribution of desmethyldapoxetine in the CNS, but it is unknown whether this will be the case.

Race. Clinical pharmacology analysis of a single 60 mg dose of dapoxetine showed no statistically significant differences among patients of different races.

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

Geriatric patients (aged 65 years and older).

Pharmacokinetic analysis of a single 60 mg dose of dapoxetine 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 dose of dapoxetine 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.

Patients with hepatic impairment.

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

In patients with severe hepatic impairment, free Cmax of dapoxetine is reduced by 42%, but free AUC is increased by approximately 223%. Cmax and A游戏副本 of the active fraction show similar changes.

CYP2D6 polymorphism.

A clinical pharmacology study of a single 60 mg dose of dapoxetine showed that plasma concentrations were higher in CYP2D6 poor metabolizers than in extensive metabolizers (approximately 31% higher Cmax, 36% higher AUCinf for dapoxetine; 98% higher Cmax, 161% higher AUCinf for desmethyldapoxetine). The active fraction of dapoxetine may be increased by approximately 46% for Cmax and 90% for AUC. This increase may lead to higher incidence and severity of dose-dependent adverse effects, such as dose-dependent side effects. The safety of dapoxetine 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 in adult men aged 18 to 64 years.

Dapigra is recommended to be prescribed only to patients who meet the following criteria:
• intravaginal ejaculatory latency time (IELT) is less than 2 minutes;
• persistent or recurrent ejaculation following minimal sexual stimulation before, during, or shortly after penetration, occurring earlier than desired by the patient;
• significant distress or interpersonal difficulties resulting from premature ejaculation;
• insufficient control over the timing of ejaculation;
• onset of premature ejaculation in most sexual attempts over the past 6 months.

Dapigra should be taken on-demand with the intention of treating premature ejaculation prior to anticipated sexual intercourse. The drug must not be prescribed for delaying ejaculation in men who have not been diagnosed with premature ejaculation.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the drug.
• 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), or within 14 days of discontinuation of MAOIs. Dapigra must be discontinued at least 7 days before initiating MAOI therapy.
• Concomitant use of thioridazine or within 14 days after discontinuation of thioridazine. Dapigra must be discontinued at least 7 days before initiating thioridazine therapy.
• Concomitant use of SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), 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 agents. These medicinal products/herbal preparations should not be taken within 7 days after discontinuation of Dapigra.
• 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 types of interactions").
• Moderate or severe hepatic impairment.

Interaction with other medicinal products and other types of interactions.

Pharmacodynamic interactions.

Potential interaction with MAOIs.

Serious reactions, sometimes fatal, have been reported when SSRIs are used concomitantly with MAOIs, including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes including agitation progressing to delirium and coma. Such reactions have also been reported in patients who recently discontinued SSRIs and started MAOIs. Isolated cases with symptoms resembling neuroleptic malignant syndrome have been observed. Animal studies on the combined use of SSRIs and MAOIs suggest a synergistic effect, increasing blood pressure and causing excitation. Therefore, Dapigra must not be used in combination with MAOIs or within 14 days after their discontinuation. MAOIs must not be initiated within 7 days after discontinuation of Dapigra.

Potential interaction with thioridazine.

Thioridazine prolongs the QTc interval, which is associated with the occurrence of severe ventricular arrhythmias. Drugs such as Dapigra, which inhibit the CYP2D6 isoenzyme, are likely to inhibit thioridazine metabolism. The resulting increased thioridazine levels are expected to cause more pronounced QTc prolongation. Dapigra must not be used in combination with thioridazine or within 14 days after its discontinuation. Thioridazine must not be initiated within 7 days after discontinuation of Dapigra.

Medicinal products/herbal preparations with serotonergic activity.
As with SSRIs, concomitant use with medicinal products/herbal preparations having serotonergic mechanisms of action (including MAOIs, L-tryptophan, triptans, tramadol, linezolid, SSRIs, SNRIs, lithium, and St. John’s wort (Hypericum perforatum)) may increase the risk of serotonin-related effects. Dapigra must not be used in combination with other SSRIs, MAOIs, or other medicinal products/herbal preparations with serotonergic activity, or within 14 days after their discontinuation. Similarly, these medicinal products/herbal preparations must not be taken within 7 days after discontinuation of Dapigra.

Medicinal products acting on the CNS.

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

Pharmacokinetic interactions.

Effect of other medicinal products on dapoxetine pharmacokinetics.

In vitro studies using human liver, kidney, and intestinal microsomes have shown that dapoxetine is primarily metabolized by CYP2D6, CYP3A4, and 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) increases Cmax and AUCinf of dapoxetine (single 60 mg dose) by 35% and 99%, respectively. Regarding the distribution of both free dapoxetine and desmethyldapoxetine, Cmax of the active moiety may increase by approximately 25%, and 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 Dapigra and strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, and atazanavir is contraindicated.

Moderate CYP3A4 inhibitors.

Concomitant use of dapoxetine and moderate CYP3A4 inhibitors (e.g., erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem) may also lead to a marked increase in exposure to dapoxetine and desmethyldapoxetine, particularly in poor metabolizers of CYP2D6. When used concomitantly with any of these agents, the maximum dose of dapoxetine should be limited to 30 mg.

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 used concomitantly with a strong CYP3A4 inhibitor. Caution should be exercised when co-administering dapoxetine 60 mg 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 distribution of both free dapoxetine and desmethyldapoxetine, Cmax of the active moiety may increase by approximately 50%, and AUC of the active moiety may double when strong CYP2D6 inhibitors are co-administered. This increase in Cmax and AUC of the active moiety is similar to that expected in poor metabolizers of CYP2D6 and may lead to an increased frequency and severity of dose-dependent adverse reactions.

PDE5 inhibitors.

Patients taking PDE5 inhibitors should not take Dapigra due to the potential for reduced orthostatic tolerance. 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 Dapigra and PDE5 inhibitors may cause orthostatic hypotension. The efficacy and safety of dapoxetine in patients with premature ejaculation and erectile dysfunction who are concurrently taking Dapigra and PDE5 inhibitors have not been established.

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

Tamsulosin.
Concomitant administration of a single or multiple dose of 30 mg or 60 mg of the drug in patients receiving tamsulosin at a daily dose of 0.4 mg did not alter the pharmacokinetics of tamsulosin. Concomitant use of dapoxetine and tamsulosin did not cause changes in orthostatic profile or orthostatic effects compared to tamsulosin alone or in combination with dapoxetine 30 or 60 mg. However, caution should be exercised when prescribing Dapigra to patients taking alpha-adrenergic antagonists due to the potential for reduced orthostatic tolerance.

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 similar increases in plasma concentrations of other drugs metabolized by CYP2D6. This is unlikely to be of clinical significance.

Medicinal products metabolized by CYP3A4.

Repeated administration of dapoxetine (60 mg/day for 6 days) resulted in approximately a 20% decrease in AUCinf of midazolam (single 8 mg dose) (range from 60% decrease to 18% increase). This effect on midazolam is likely not clinically significant for most patients. However, increased CYP3A activity may be clinically relevant in some patients who are concomitantly taking a drug primarily metabolized by CYP3A and having 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.
There are no data on the effect of chronic warfarin use with dapoxetine; therefore, caution is recommended when using dapoxetine in patients on chronic warfarin therapy. 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.

Ethanol.
Concomitant administration of ethanol at a single dose of 0.5 g/kg 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 demonstrated an additive effect with concomitant use of dapoxetine and ethanol. Concurrent 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 these 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 dapoxetine.

Special precautions for use.

General recommendations.

Dapigra should be prescribed only to men with premature ejaculation (see section "Indications"). The drug should not be prescribed to men who have not been diagnosed with premature ejaculation. Safety has not been established, and there are no data on the effect on delaying ejaculation 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 physicians. Dapigra should not be used in men with erectile dysfunction who are taking PDE5 inhibitors (phosphodiesterase-5 inhibitors).

Orthostatic hypotension (hypotension).

A thorough medical examination, including history of orthostatic episodes, should be performed by a physician prior to initiating treatment. An orthostatic test (blood pressure and pulse rate in supine and standing positions) should be performed before starting therapy. Dapigra should be avoided in patients with 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 their head lower than the rest of the body, or sit with their head between their knees until symptoms resolve. Patients should avoid rapid standing after prolonged lying or sitting.

Suicide/suicidal thoughts.

Antidepressants, including SSRIs, have been associated with an increased risk of suicidal thoughts and suicidal behavior compared to placebo in short-term studies in children and adolescents with major depressive disorder and other psychiatric disorders. Short-term studies do not indicate an increased risk of suicidal tendencies in adults aged 24 years and older treated with antidepressants compared to placebo. In clinical trials of dapoxetine for the treatment of premature ejaculation, there was no clear evidence of increased suicidal tendencies during treatment based on assessment of potential adverse effects using the Columbia Classification Algorithm of Suicide Assessment (C-CASA), Montgomery-Åsberg Depression Rating Scale, or Beck Depression Inventory-II.

Syncope.

Patients should be advised to avoid situations that may lead to injury, including driving or operating hazardous machinery, as syncope or prodromal symptoms such as dizziness or presyncope may occur.

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

In clinical trials, episodes of syncope were characterized by loss of consciousness associated with bradycardia or sinus node pause. These events occurred in patients undergoing Holter ECG monitoring and were 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 increased sweating usually occurred 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 Dapigra use. Physicians should advise patients on the importance of maintaining adequate hydration and recognizing prodromal symptoms to reduce the risk of serious injury from falls due to loss of consciousness. If a patient experiences prodromal symptoms, they should immediately lie down with their head lower than the rest of the body or sit with their head between their knees until symptoms subside.

Patients with cardiovascular risk factors.

Patients with cardiovascular diseases were excluded from phase 3 clinical trials. The risk of adverse cardiovascular outcomes from syncope (cardiac syncope and syncope from other causes) is increased in patients with underlying structural cardiovascular diseases (e.g., documented outflow obstruction, valvular heart disease, 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 Dapigra in combination with recreational drugs.

Recreational drugs (substances) with serotonergic activity, such as ketamine, methylenedioxymethamphetamine (MDMA), and diethylamide of lysergic acid (LSD), may lead to potentially serious reactions when used with Dapigra. These reactions include, but are not limited to, arrhythmia, hyperthermia, and serotonin syndrome. The use of Dapigra with recreational drugs having sedative properties, such as narcotics and benzodiazepines, may increase somnolence and dizziness.

Alcohol consumption together with dapoxetine may enhance alcohol-related neurocognitive effects and may also lead to increased neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients are not advised to consume alcohol during treatment with Dapigra.

Dapigra should be prescribed with caution to patients taking medications with vasodilatory properties (e.g., alpha-adrenergic receptor antagonists and nitrates) due to possible reduced orthostatic tolerance.

Manic syndrome.

Dapigra 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 in any patient, Dapigra should be discontinued if a seizure occurs. Dapigra should be avoided in patients with unstable epilepsy. Patients with controlled epilepsy should be closely monitored during Dapigra treatment.

Depression and/or psychiatric disorders.

Men with prominent signs and symptoms of depression should be evaluated before starting treatment to exclude undiagnosed depressive disorders. Concomitant treatment with Dapigra and antidepressants, including SSRIs and SNRIs, is contraindicated. Discontinuation of ongoing treatment for depression or anxiety is not recommended in order to initiate Dapigra for the treatment of premature ejaculation. The drug is not recommended for the treatment of psychiatric disorders and should not be used in men with disorders such as schizophrenia or those suffering from hypochondriasis, as worsening of depression-related symptoms cannot be excluded. This may be due to the underlying psychiatric disorder or as a consequence of drug therapy. Physicians should encourage patients to report any distressing thoughts or feelings at any time. If signs and symptoms of depression occur during treatment, the drug should be discontinued.

Bleeding.

There are reports of impaired hemostasis with the use of SSRIs. The drug should be used with caution, especially when used concomitantly with medications affecting platelet function (e.g., atypical antipsychotics and phenothiazines, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, antiplatelet agents), or with anticoagulants (e.g., warfarin), and also in patients with a history of bleeding or coagulation disorders.

Renal impairment.

Dapigra is not recommended for use in patients with severe renal impairment. Caution is advised when administering the drug to patients with mild to moderate renal impairment.

Drug discontinuation syndrome.

Abrupt discontinuation of chronic SSRI treatment for chronic depressive disorders may lead to 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 premature ejaculation, designed to evaluate drug discontinuation syndrome after daily administration for 62 days or as-needed dosing of 60 mg dapoxetine, showed mild withdrawal symptoms with a higher incidence of insomnia and dizziness in patients who switched to placebo after daily treatment.

Ocular disorders.

Dapoxetine use has been associated with ocular adverse effects such as mydriasis and eye pain. There is a risk of developing angle-closure glaucoma.

Lactose intolerance.

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

Use during pregnancy or breastfeeding.

The medicinal product is used in men.

Ability to affect reaction speed when driving or operating machinery.

The drug has a minor or moderate effect on the ability to drive or operate machinery. In clinical trials, dizziness, attention disturbance, syncope, blurred vision, and somnolence were reported in subjects taking dapoxetine. Therefore, patients should be warned to avoid hazardous situations, including driving and operating machinery.

Method of Administration and Dosage

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

Dapigra is intended for on-demand use only and should be taken only when sexual activity is anticipated. The medication must 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 a possible risk of syncope, the dose may be increased to the maximum recommended dose of 60 mg, taken as needed approximately 1 to 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. The maximum recommended dose should not be exceeded.

A careful assessment of the benefits versus potential risks is required after the first 4 weeks of treatment (or after at least 6 doses) to determine whether continued treatment with the drug is appropriate.

Data on the efficacy and safety of dapoxetine use beyond 24 weeks are limited. The clinical necessity of continuing treatment and the benefit-risk balance of therapy should be reviewed at least every 6 months.

Elderly patients (aged 65 years and older).

The efficacy and safety of the drug have not been established in patients aged 65 years and older.

Renal impairment.

Caution should be exercised when administering the drug to patients with mild or moderate renal impairment. The drug is not recommended for patients with severe renal impairment.

Hepatic impairment.

The drug is contraindicated in patients with moderate or severe hepatic impairment.

Patients identified as CYP2D6 poor metabolizers or patients receiving strong CYP2D6 inhibitors.

Dose escalation to 60 mg should be performed with caution in patients who are known CYP2D6 poor metabolizers or in patients receiving concomitant strong CYP2D6 inhibitors.

Patients taking moderate or strong CYP3A4 inhibitors.

Concomitant use of strong CYP3A4 inhibitors is contraindicated. For patients receiving moderate CYP3A4 inhibitors, caution is required and the dose should not exceed 30 mg.

Method of administration.

The drug is intended for oral administration. To avoid a bitter taste, tablets should be swallowed whole without chewing. Tablets should be taken with sufficient water. Dapigra can be taken independently of food intake.

Children.

The use of Dapigra in children is contraindicated due to lack of clinical experience.

Overdose.

No cases of overdose have been reported.

In clinical pharmacology studies, no unexpected adverse reactions were observed with dapoxetine doses up to 240 mg per day (two 120 mg doses administered 3 hours apart). In general, symptoms of SSRI overdose include serotonin-mediated adverse reactions such as drowsiness, gastrointestinal disturbances, nausea and vomiting, tachycardia, tremor, agitation, and dizziness.

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

Adverse Reactions

Syncope and orthostatic hypotension were reported during clinical trials.

The most commonly observed dose-dependent adverse reactions in phase 3 clinical trials were 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 dapoxetine) and dizziness (1.2% of patients receiving dapoxetine).

The safety of dapoxetine was evaluated in 4,224 patients with premature ejaculation who participated in five double-blind, placebo-controlled clinical studies. Of the 4,224 patients, 1,616 received on-demand dapoxetine 30 mg, and 2,608 received on-demand dapoxetine 60 mg or once daily. The frequency of adverse effects is presented below according to the following categories: very common (> 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000).

Psychiatric disorders:
Common – anxiety, agitation, restlessness, insomnia, unusual dreams, decreased libido;
Uncommon – depression, depressed mood, euphoric mood, mood lability, increased irritability, apathy, confusion, disorientation, thought disorder, hypervigilance, sleep disturbance, difficulty falling asleep, middle insomnia, nightmares, bruxism, loss of libido, anorgasmia.

Nervous system disorders:
Very common – headache, dizziness;
Common – somnolence, attention disturbance, tremor, paraesthesia;
Uncommon – syncope, vasovagal syncope, postural dizziness, akathisia, dysgeusia, hypersomnia, lethargy, sedation, decreased level of consciousness;
Rare – dizziness during physical exertion, sudden sleep onset.

Eye disorders:
Common – blurred vision;
Uncommon – mydriasis, eye pain, visual disturbance.

Ear and labyrinth disorders:
Common – tinnitus;
Uncommon – vertigo.

Cardiac disorders:
Uncommon – sinoatrial block, sinus bradycardia, tachycardia;
Common – flushing;
Uncommon – arterial hypotension, systolic hypertension.

Respiratory, thoracic and mediastinal disorders:
Common – nasal sinus congestion, yawning.

Gastrointestinal disorders:
Very common – nausea;
Common – diarrhea, vomiting, constipation, abdominal pain, epigastric pain, dyspeptic symptoms, flatulence, stomach discomfort, abdominal distension, dry mouth;
Rare – imperative need to defecate.

Skin and subcutaneous tissue disorders:
Common – increased sweating;
Uncommon – pruritus, cold sweat.

Reproductive system and breast disorders:
Common – erectile dysfunction;
Uncommon – ejaculation failure, male orgasmic disorder, male genital paraesthesia.

General disorders and administration site conditions:
Common – fatigue, irritability;
Uncommon – weakness, feeling of warmth, feeling of anxiety, unusual sensations, feeling of intoxication.

Investigations:
Common – increased blood pressure;
Uncommon – increased heart rate, increased diastolic blood pressure, increased orthostatic blood pressure.

Description of selected adverse reactions.

Syncope associated with bradycardia or sinus node arrest related to drug intake has been observed in patients undergoing Holter monitoring in clinical studies. Most events occurred within the first 3 hours after drug intake, following the first dose, or were associated with clinical study procedures (such as blood sampling and orthostatic procedures, blood pressure measurements). Syncope was often preceded by prodromal symptoms.

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 studies. The incidence of syncope, defined as loss of consciousness in the dapoxetine clinical study program, varies depending on the study population, ranging from 0.06% (30 mg) to 0.23% (60 mg) in patients included in phase 3 placebo-controlled trials, up to 0.64% (all doses combined) in phase 1 studies involving healthy volunteers.

Other special populations

Caution should be exercised when increasing the dose to 60 mg in patients taking strong CYP2D6 inhibitors or in patients identified as CYP2D6 poor metabolizers.

Drug withdrawal syndrome.

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

Safety study results showed an increased incidence of mild or moderate insomnia and dizziness in patients who switched to placebo after 62 days of daily drug intake.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

3 tablets in a blister. 1 or 2 blisters in a cardboard pack.

Prescription category. Prescription only.

Manufacturer.

Nobel Ilac Sanai ve Ticaret A.S.

Manufacturer's address and place of business.

Sankaklar District, Eskisehir Yolu Akcakoca Highway No: 299, 81100 Duzce, Turkey.