Vander

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VANDER® (WONDER®)

Composition:

Active substance: dapoxetine;

One tablet contains dapoxetine hydrochloride equivalent to 30 mg or 60 mg of dapoxetine;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate, Opadry 03K575000 grey coating: hypromellose, titanium dioxide (E 171), triacetin, black iron oxide (E 172), yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, smooth tablets on both sides, film-coated, grey in color.

Pharmacotherapeutic group

Agents used in urology. Other urological agents.

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 main metabolites, desmethyldapoxetine (DMD) (IC50 < 1.0 nM) and didesmethyldapoxetine (IC50 = 2.0 nM), are equivalent 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 (PE) is likely related to inhibition of neuronal serotonin reuptake and subsequent enhancement of neurotransmitter effects on presynaptic and postsynaptic receptors.

Pharmacokinetics

Absorption

Dapoxetine is rapidly absorbed and reaches peak plasma concentration (Cmax) approximately 1–2 hours after tablet intake. The absolute bioavailability of dapoxetine is approximately 42% (ranging from 15 to 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.

After repeated administration, AUC values for dapoxetine and the active metabolite desmethyldapoxetine increase by approximately 50% compared to AUC values after single-dose administration.

Consumption of a high-fat meal slightly reduced Cmax of dapoxetine (by 10%) and moderately increased AUC (by 12%), as well as slightly prolonged the time to reach peak plasma concentration. These changes were not clinically significant. VANDER® may be taken independently of food intake.

Distribution

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

Biotransformation

Based on in vitro studies, dapoxetine is metabolized by multiple hepatic and renal enzyme systems (primarily CYP2D6, CYP3A4) and flavin-containing monooxygenase (FMO1). After oral administration of 14C-dapoxetine, the drug is extensively metabolized, forming numerous metabolites via pathways including N-oxidation, N-demethylation, naphthyl hydroxylation, glucuronidation, and sulfation. Evidence indicates 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, account for less than 3% of the total drug-related substances in plasma. In vitro binding studies indicate that DMD and dapoxetine have similar potency, while the activity of didesmethyldapoxetine is approximately 50% that of dapoxetine (see section "Pharmacodynamics"). The concentration of free DMD (AUC and Cmax) is 50% and 23% of free dapoxetine concentration, respectively.

Elimination

Dapoxetine metabolites are primarily excreted in urine as conjugates. The unchanged active substance is not detected in urine.

After oral administration of dapoxetine, the initial half-life in plasma is approximately 1.5 hours, while the terminal half-life is 19 hours. After 24 hours, the drug concentration in plasma is about 5% of the peak concentration following administration. The terminal half-life of DMD is approximately 19 hours.

Pharmacokinetics in special patient populations

The metabolite DMD contributes to the pharmacological effect of VANDER®, particularly when its effect is increased. Below is an increase in active fraction parameters in certain patient groups. This results from the combined free effects of dapoxetine and DMD. DMD has the same potency as dapoxetine. Preliminary modeling predicts uniform distribution of DMD in the CNS, but it is unknown whether this will be the case.

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 Caucasians revealed higher plasma levels of dapoxetine in Japanese subjects (10–20% higher) (area under the curve and peak concentration) due to lower body weight. No clinically significant effect is expected from slightly higher concentrations.

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 (see section "Dosage and administration").

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 has 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) are reduced by 30% and 5%, respectively. In patients with moderate hepatic impairment, free Cmax of dapoxetine is virtually unchanged (3% reduction), and free AUC increases by 66%. Free Cmax and AUC of the active fraction are virtually 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 "Dosage and administration").

CYP2D6 polymorphism

A clinical pharmacology study of a single 60 mg dose of dapoxetine 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 VANDER® 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 "Dosage and administration"). The safety of VANDER® in CYP2D6 poor metabolizers is of particular concern when co-administered with other drugs that may inhibit dapoxetine metabolism, such as moderate and strong CYP3A4 inhibitors (see sections "Contraindications" and "Dosage and administration").

Clinical Characteristics

Indications

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

The medicinal product Vandre® 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;
  • marked distress or interpersonal difficulties resulting from PE;
• insufficient control over the timing of ejaculation;
• history of PE during most attempts at sexual intercourse over the past 6 months.

The medicinal product Vandre® should be taken on an as-needed basis only, prior to anticipated sexual activity. The drug 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 of the medicinal product.
• 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), or within 14 days after discontinuation of MAOIs. Treatment with Vandre® must be discontinued at least 7 days before starting therapy with MAOIs (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of thioridazine or within 14 days after discontinuation of thioridazine. Treatment with Vandre® must be discontinued at least 7 days before starting therapy with thioridazine (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)) or within 14 days after discontinuation of these medicinal products/herbal preparations. These medicinal products/herbal preparations should not be used within 7 days after discontinuation of Vandre® (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 MAO inhibitors

Serious reactions, sometimes fatal, have been reported when SSRIs are administered concomitantly with MAOIs. These include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations in 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 MAOI therapy. Isolated cases with symptoms resembling neuroleptic malignant syndrome have been observed. Animal studies on the combined use of SSRIs and MAOIs suggest a possible synergistic effect leading to increased blood pressure and excitation. Therefore, Vandre® is contraindicated for concomitant use with MAOIs or within 14 days after their discontinuation. MAOIs are contraindicated within 7 days after discontinuation of Vandre® (see section "Contraindications").

Potential interaction with thioridazine

Thioridazine administration causes QTc interval prolongation, which is associated with the occurrence of severe ventricular arrhythmias. Medicinal products containing dapoxetine and inhibiting the CYP2D6 isoenzyme are likely to inhibit thioridazine metabolism. The expected increase in thioridazine levels due to this interaction may lead to more pronounced QTc prolongation. Vandre® must not be used concomitantly with thioridazine or within 14 days after its discontinuation. Thioridazine is contraindicated within 7 days after discontinuation of Vandre® (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 preparations (Hypericum perforatum)) may increase the risk of serotonergic effects. Vandre® is contraindicated for concomitant use with other SSRIs, MAOIs, or other medicinal products/herbal preparations with serotonergic mechanisms of action, or within 14 days after their discontinuation.

These medicinal products and herbal preparations are contraindicated within 7 days after discontinuation of Vandre® (see section "Contraindications").

Medicinal products acting on the CNS

Systematic evaluation of concomitant administration of dapoxetine with CNS-acting medicinal products (such as antiepileptic agents, antidepressants, antipsychotics, anxiolytics, sedative-hypnotics) in patients with PE has not been performed. Therefore, caution is recommended if concomitant administration of dapoxetine and these medicinal products is necessary.

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) increases Cmax and AUCinf of dapoxetine (single 60 mg dose) by 35% and 99%, respectively. Regarding the distribution of both free dapoxetine and DED, the Cmax of the active fraction may increase by approximately 25%, and the AUC of the active fraction may double with concomitant use of strong CYP3A4 inhibitors.

The increase in Cmax and AUC of the active fraction may be significantly greater in patients with impaired functional CYP2D6 enzyme activity, particularly in patients with slow CYP2D6-mediated metabolism, or when used concomitantly with strong CYP2D6 inhibitors.

Therefore, concomitant use of dapoxetine and 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; therefore, its consumption should be avoided within 24 hours before taking Vandre® (see section "Contraindications").

Moderate CYP3A4 inhibitors

Concomitant use of dapoxetine and moderate CYP3A4 inhibitors (such as erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem) may also lead to a marked increase in dapoxetine and DED exposure, especially in patients with slow CYP2D6-mediated metabolism. When used concomitantly with any of these agents, the maximum dapoxetine dose should be limited to 30 mg (see sections "Special precautions for use" and "Method of administration and dosage").

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 is advised when using dapoxetine 60 mg concomitantly 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 DED, Cmax of the active fraction may increase by approximately 50%, and AUC of the active fraction may double with concomitant use of strong CYP2D6 inhibitors. This increase in Cmax and AUC of the active fraction is similar to that expected in patients with slow CYP2D6-mediated metabolism and may lead to an increased frequency and severity of dose-dependent adverse reactions (see section "Special precautions for use").

PDE5 inhibitors

Patients taking PDE5 inhibitors should not take dapoxetine due to the potential for reduced orthostatic tolerance (see section "Special precautions for use"). Pharmacokinetic assessment of dapoxetine (60 mg) in combination with tadalafil (20 mg) and sildenafil (100 mg) was performed 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 dapoxetine and PDE5 inhibitors may cause orthostatic hypotension (see section "Special precautions for use"). The efficacy and safety of dapoxetine in patients with PE and erectile dysfunction who are concomitantly taking dapoxetine 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 result in changes in orthostatic profile or orthostatic effects when comparing tamsulosin alone versus tamsulosin combined with dapoxetine 30 mg or 60 mg. However, caution should be exercised when prescribing dapoxetine to patients taking alpha-adrenergic antagonists due to the potential for reduced orthostatic tolerance (see section "Special precautions for use").

Medicinal products metabolized by CYP2D6

Multiple-dose 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 likely not clinically significant.

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 likely not clinically significant for most patients. However, increased CYP3A activity may be clinically relevant in some patients who are concomitantly taking a medicinal product primarily metabolized by CYP3A and having a narrow therapeutic index.

Medicinal products metabolized by CYP2C19

Multiple-dose 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

Multiple-dose 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 evaluation of the effect of regular concomitant use of warfarin and dapoxetine; therefore, caution is recommended when administering dapoxetine to patients on chronic warfarin therapy (see section "Special precautions for use"). In a pharmacokinetic study, dapoxetine administration (60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics of warfarin (prothrombin time [PT] or international normalized ratio [INR]) following a single 25 mg dose.

Bleeding events have been reported with SSRI use (see section "Special precautions for use").

Alcohol (ethanol)

Concomitant administration of a single 0.5 g/kg dose of ethanol (approximately 2 drinks) did not affect the pharmacokinetics of dapoxetine (single 60 mg dose). However, dapoxetine in combination with ethanol increases drowsiness and significantly impairs alertness. Pharmacodynamic measurements of cognitive impairment (digit symbol substitution test, digit vigilance test) also revealed an additive effect with concomitant use of dapoxetine and ethanol. Concomitant use of alcohol and dapoxetine increases the likelihood or severity of adverse reactions such as dizziness, somnolence, slowed reflexes, or impaired judgment. The combination of alcohol and dapoxetine may exacerbate alcohol-related effects and may increase the risk of neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury. Given the above, patients should be advised not to consume alcohol during treatment with Vandre® (see sections "Special precautions for use" and "Ability to affect reaction speed when driving or operating machinery").

Special precautions for use

General recommendations

The medicinal product VANDER® should be prescribed only to men with PE (see section "Indications"). The drug should not be prescribed to men in whom PE has not been diagnosed. There are no data on safety or effect on ejaculatory delay in men who do not have PE.

Other forms of sexual dysfunction

Prior to initiating treatment, patients with other forms of sexual dysfunction, including erectile dysfunction (ED), should be thoroughly evaluated by a physician. The medicinal product VANDER® should not be used in men with ED who are taking PDE5 inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Orthostatic hypotension (hypotension)

Prior to initiating treatment with VANDER®, a thorough medical evaluation by a physician, including a history of orthostatic hypotension, is required. An orthostatic test (blood pressure and pulse rate in supine and standing positions) should also be performed before starting treatment with dapoxetine. Dapoxetine should be avoided in patients with a history of orthostatic hypotension or suspected risk of its occurrence.

Orthostatic hypotension has been reported in clinical trials. Physicians should advise patients in advance that if prodromal symptoms of orthostatic hypotension (dizziness upon changing from a horizontal to a vertical position) occur, they should immediately change body position (lie down with the head lower than the rest of the body, or sit with the head between the knees) and wait until symptoms resolve. Patients should avoid rapid rising after prolonged lying or sitting.

Suicide / suicidal thoughts

Data indicate that antidepressants, including SSRIs, may increase the risk of suicidal thoughts and suicidal behavior in children and adolescents with major depressive disorder and other psychiatric disorders.

Short-term use of antidepressants has not been associated with an increased risk of suicidal tendencies in adults aged 24 years and older. Treatment with dapoxetine for PE has not been associated with increased suicidal tendencies as assessed by appropriate scales (C-CASA (Columbia Classification Algorithm of Suicide Assessment), Montgomery-Åsberg Depression Rating Scale, and Beck Depression Inventory-II).

Syncope (fainting)

Patients should be warned to avoid situations that may lead to injury, including driving or operating dangerous machinery, as syncope or pre-syncopal symptoms (nausea, dizziness / pre-syncope, and excessive sweating) may occur during dapoxetine therapy (see section "Adverse reactions").

In clinical trials, syncope episodes were characterized by loss of consciousness associated with bradycardia or sinus node arrest. These events occurred in patients wearing Holter ECG monitors and are considered vasovagal in etiology. Most cases of syncope occurred within the first 3 hours after the first dose of dapoxetine or were associated with clinical procedures (e.g., blood sampling, orthostatic testing, blood pressure measurement). Prodromal symptoms such as nausea, dizziness, pre-syncope, palpitations, weakness, confusion, and sweating may occur, usually within the first 3 hours after dosing, and often precede syncope. Patients should be informed about the possibility of syncope (with or without prodromal symptoms) at any time during treatment with VANDER®. Physicians should advise patients on the importance of maintaining adequate hydration and recognizing prodromal signs and symptoms to reduce the risk of serious injuries related to falls due to loss of consciousness. If a patient experiences prodromal symptoms, they should immediately change body position (lie down with the head lower than the rest of the body, or sit with the head between the knees) and wait 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 due to loss of consciousness (cardiac syncope and syncope from various causes) increases in patients with organic cardiovascular diseases (such as documented outflow obstruction, valvular heart disease, carotid stenosis, and ischemic heart disease). There is insufficient data to establish a relationship between the risk of vasovagal syncope and the presence of cardiovascular diseases.

Use with recreational drugs

Patients should be advised not to use dapoxetine in combination with recreational drugs. The use of dapoxetine with serotonergic recreational drugs (such as ketamine, methylenedioxymethamphetamine (MDMA), and diethylamide of lysergic acid (LSD)) may lead to severe serious adverse reactions, such as arrhythmia, hyperthermia, and serotonin syndrome. The use of VANDER® with recreational drugs having sedative properties (such as narcotics and benzodiazepines) may increase somnolence and dizziness.

Alcohol (ethanol)

Patients should be advised not to consume alcohol during treatment with dapoxetine, as the combination may enhance neurocognitive effects and may lead to 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 VANDER® (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

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

Moderate CYP3A4 inhibitors

Dapoxetine should be used with caution in patients receiving moderate CYP3A4 inhibitors, with dose limitation to 30 mg (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Potent CYP2D6 inhibitors

When increasing the dose to 60 mg, caution is recommended in patients taking potent CYP2D6 inhibitors or those with the slow CYP2D6 enzyme genotype, as this may increase drug exposure and lead to increased frequency and severity of dose-dependent adverse effects (see sections "Pharmacological properties", "Interaction with other medicinal products and other forms of interaction", and "Dosage and administration").

Manic syndrome

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

Seizure

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

Depression and/or psychiatric disorders

Men with signs and symptoms of depression should receive medical consultation prior to starting dapoxetine treatment to exclude undiagnosed depressive disorders. Concomitant treatment with dapoxetine and antidepressants, including SSRIs and SNRIs, is contraindicated (see section "Contraindications"). It is not recommended to discontinue treatment of chronic depression or anxiety to initiate dapoxetine for PE. Dapoxetine 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 symptoms related to depression cannot be excluded. This may be due to the underlying psychiatric disorder or as a consequence of dapoxetine therapy. Physicians should warn patients to report any distressing thoughts or feelings at any time. If signs and symptoms of depression occur during treatment, VANDER® should be discontinued.

Bleeding

There have been reports of impaired hemostasis with SSRIs. Dapoxetine 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 anticoagulants (e.g., warfarin), and in patients with a history of bleeding or coagulation disorders (see section "Interaction with other medicinal products and other forms of interaction").

Renal impairment

Dapoxetine is not recommended for use in patients with severe renal impairment. The medicinal product should also be used with caution in patients with mild to moderate renal impairment (see sections "Pharmacological properties" and "Dosage and administration").

Drug discontinuation syndrome

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

In clinical trials of 60 mg dapoxetine in patients with PE, mild withdrawal symptoms were reported, with a slightly higher incidence of insomnia and dizziness in patients switched to placebo after daily dosing.

Ocular disorders

Dapoxetine use has been associated with ocular adverse effects such as mydriasis and eye pain. VANDER® should be used with caution in patients with elevated intraocular pressure or at risk of developing angle-closure glaucoma.

Excipients

The product contains lactose. In case of intolerance to certain sugars, consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding

VANDER is not intended for use in women.

Animal studies do not indicate direct or indirect harmful effects on fertility, pregnancy, or embryonal/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

Dapoxetine has a minor or moderate influence on the ability to drive or operate machinery. Dizziness, attention disturbance, syncope, blurred vision, and somnolence have been reported with dapoxetine use. Therefore, patients should be warned to avoid injury-prone situations, including driving and operating machinery.

Combining 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 VANDER® treatment (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction").

Method of Administration and Dosage

Dosage

Adult men 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 Vandre® may be initiated with a dose of 60 mg.

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

If the individual response to the 30 mg dose is insufficient 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 1–3 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 is required after the first four weeks of treatment (or at least after the first six doses) to determine whether continuing therapy is appropriate.

Data on the efficacy and safety of dapoxetine administered for more than 24 weeks are limited. The clinical necessity of continuing treatment and the benefit-risk balance of dapoxetine therapy should be re-evaluated at least every 6 months.

Elderly patients (aged 65 years and older)

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

Renal impairment

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

Hepatic impairment

Dapoxetine is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B and C) (see sections "Contraindications" and "Pharmacokinetics").

Patients with known poor CYP2D6 metabolizer status or patients receiving strong CYP2D6 inhibitors

Dose escalation to 60 mg should be done cautiously in patients who are known poor metabolizers of the CYP2D6 enzyme or in patients receiving concomitant strong CYP2D6 inhibitors (see sections "Pharmacokinetics", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Special Warnings and Precautions for Use").

Patients taking moderate CYP3A4 inhibitors or strong CYP3A4 inhibitors

Concomitant use of strong CYP3A4 inhibitors is contraindicated. Patients receiving moderate CYP3A4 inhibitors should be cautious and must not exceed a dose of 30 mg (see sections "Contraindications", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "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. Vandre® can be taken regardless of food intake (see section "Pharmacokinetics").

Warnings prior to initiation or prescription of the medicinal product

Prior to initiating treatment, the information regarding orthostatic hypotension in section "Special Warnings and Precautions for Use" should be reviewed.

Children

The medication is not intended for use in children under 18 years of age.

Overdose

Cases of overdose have not been reported.

No unexpected adverse reactions were observed with dapoxetine administered at daily doses up to 240 mg (two 120 mg doses taken 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. In case of overdose, 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. There is no specific antidote.

Adverse Reactions

Adverse reactions by organ system classes and frequency

Organs and organ systems	Very common (> 1/10)	Common (≥ 1/100 to <1/10)	Uncommon (≥ 1/1000 to <1/100)	Rare (≥ 1/10000 to <1/1000)
Psychiatric disorders		anxiety, agitation, restlessness, insomnia, abnormal dreams, decreased libido	depression, depressed mood, euphoric mood, labile mood, nervousness, indifference, apathy, confusion, disorientation, thought disorder, hypervigilance, sleep disorder, difficulty in falling asleep, intrasomniac disturbances, nightmares, bruxism, loss of libido, anorgasmia
Nervous system disorders	headache, dizziness	drowsiness, attention disturbance, tremor, paresthesia	syncope, vasovagal syncope, postural dizziness, akathisia, dysgeusia, hypersomnia, lethargy, sedative effect, decreased level of consciousness	dizziness during physical exertion, sudden sleep onset
Eye disorders		blurred vision	mydriasis (see section "Special precautions"), eye pain, visual disturbance
Ear and labyrinth disorders		tinnitus	vertigo
Cardiac disorders		flushing	sinoatrial node block, sinus bradycardia, tachycardia, hypotension, systolic hypertension
Respiratory, thoracic and mediastinal disorders		nasal sinus edema, yawning
Gastrointestinal disorders	nausea	diarrhea, vomiting, constipation, abdominal pain, epigastric pain, dyspeptic symptoms, flatulence, stomach discomfort, bloating, dry mouth	abdominal discomfort, epigastric discomfort	urgent need for defecation
Skin and subcutaneous tissue disorders		Increased sweating (hyperhidrosis)	itching, cold sweat
Reproductive system and breast disorders		erectile dysfunction	ejaculation failure, male orgasmic disorder, male genital paresthesia
General disorders		fatigue, irritability	weakness, feeling of warmth, feeling of anxiety, unusual sensations, feeling of intoxication
Investigations		increased blood pressure	increased heart rate, increased diastolic blood pressure, increased orthostatic blood pressure

Description of selected adverse reactions

Syncope was observed in clinical trials in patients wearing Holter monitors, associated with bradycardia or sinus node pause related to drug administration. Most episodes occurred within the first 3 hours after dosing, following the first dose or in association with procedures performed during clinical studies (such as blood sampling, orthostatic maneuvers, and blood pressure measurements). Syncope was often preceded by prodromal symptoms (see section "Special precautions").

The occurrence of syncope and possibly prodromal symptoms was dose-dependent, with higher incidence observed in patients receiving doses above the recommended levels during phase 3 clinical trials.

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

Other specific populations

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

Drug withdrawal syndrome

Abrupt discontinuation of chronic SSRI treatment for depressive disorders has been reported to cause symptoms such as dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, including 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 drug registration is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all cases of suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

1 or 4 tablets in a blister; 1 blister per cardboard pack.

Prescription status

Prescription only.

Manufacturer

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of its business activity

SP-289 (A), RIICO Industrial Area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India /
SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.