Longraid

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

Composition:

Active substance: dapoxetine hydrochloride;

One film-coated tablet contains 33.58 mg or 67.16 mg of dapoxetine hydrochloride, equivalent to 30 mg or 60 mg of dapoxetine;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; colloidal anhydrous silicon dioxide; magnesium stearate; Opadry II Grey 85G575003 (polyvinyl alcohol, talc, titanium dioxide (E 171), polyethylene glycol, lecithin, black iron oxide (E 172), yellow iron oxide (E 172), red iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

30 mg tablets: round, grey-colored, biconvex film-coated tablets, smooth on both sides;

60 mg tablets: round, grey-colored, biconvex film-coated tablets, smooth on both sides.

Pharmacotherapeutic group.

Agents used in urology. Other agents used in urology.

ATC code G04B X14.

Pharmacological Properties

Pharmacodynamics.

Mechanism of action

Dapoxetine is a potent, selective serotonin reuptake inhibitor (SSRI) with an IC50 value of 1.12 nmol. Its primary metabolites, desmethyldapoxetine (IC50 < 1.0 nmol) and didesmethyldapoxetine (IC50 = 2.0 nmol), are equivalent or less potent (dapoxetine-N-oxide (IC50 = 282 nmol)).

Ejaculation in males is primarily regulated by the sympathetic nervous system. The stimulus triggering ejaculation is generated in the spinal reflex center, which is controlled by several brain nuclei, including the medial preoptic and paraventricular nuclei, via the brainstem.

The mechanism of action of dapoxetine in premature ejaculation is related to inhibition of neuronal serotonin reuptake, resulting in enhanced neurotransmitter action on pre- and postsynaptic receptors.

In animals, dapoxetine inhibits the ejaculation reflex by acting at the supraspinal level within the lateral paragigantocellular nucleus (LPGN). Postganglionic sympathetic fibers stimulate the seminal vesicles, vas deferens, prostate, bulbourethral glands, and bladder neck, causing them to contract in a coordinated manner to achieve ejaculation. Dapoxetine modulates this ejaculatory reflex in animals.

Pharmacokinetics.

Absorption. Dapoxetine is rapidly absorbed, reaching peak plasma concentration (Cmax) approximately 1–2 hours after tablet intake. Absolute bioavailability is 42% (range 15–76%), and dose-proportional increases in exposure (AUC and Cmax) were observed between doses of 30 and 60 mg.

Following multiple dosing, AUC values for both dapoxetine and its active metabolite desmethyldapoxetine (DED) increase by approximately 50% compared to AUC after a single dose. Consumption of a high-fat meal moderately reduced Cmax (by 10%) and moderately increased AUC (by 12%) of dapoxetine, as well as slightly delayed the time to peak concentrations. These changes are not clinically significant. Longrayd may be taken regardless of food intake.

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

Metabolism. In vitro studies indicate that dapoxetine is metabolized by multiple enzyme systems in the liver and kidneys, primarily by CYP2D6, CYP3A4, and flavin-containing monooxygenase (FMO1). After oral administration of 14C-dapoxetine, dapoxetine was extensively transformed into numerous metabolites via major biotransformation pathways: N-oxidation, N-demethylation, naphthyl hydroxylation, glucuronidation, and sulfation. Evidence of presystemic metabolism was observed after oral administration.

Dapoxetine and dapoxetine-N-oxide were the main circulating components in plasma. In vitro binding and transport studies demonstrate that dapoxetine-N-oxide is inactive. Additional metabolites, including desmethyldapoxetine and didesmethyldapoxetine, account for less than 3% of the total drug-related substances circulating in plasma. In vitro binding studies indicate that DED has potency equivalent to dapoxetine, while the potency of didesmethyldapoxetine is approximately 50% that of dapoxetine. Exposures (AUC and Cmax) of unbound DED are approximately 50% and 23%, respectively, of unbound dapoxetine exposure.

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 is approximately 1.5 hours; plasma levels fall to less than 5% of peak concentration within 24 hours after dose intake, and the terminal elimination half-life is approximately 19 hours. The terminal elimination half-life of DED is approximately 19 hours.

Pharmacokinetics in special patient populations

The metabolite DED contributes to the pharmacological effect of Longrayd, especially when DED exposure is increased. Below are parameters of active component exposure in certain patient groups. This is the sum of exposure of unbound dapoxetine and DED. DED has potency equivalent to dapoxetine. This assessment assumes equal distribution of DED in the CNS, although in practice it is unknown whether this is truly the case.

Racial origin

Results from clinical pharmacology studies of a single 60 mg dose of dapoxetine showed no statistically significant differences among patients of different races.

Elderly patients (aged 65 years and older)

Results from a clinical pharmacology study of a single 60 mg dose of dapoxetine showed no substantial differences in pharmacokinetic parameters (Cmax, AUCinf, Tmax) between healthy elderly and healthy young males. The efficacy and safety of the drug in this patient group have not been established.

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 clear trend of increasing dapoxetine AUC with decreasing renal function was observed. The AUC of dapoxetine in patients with severe renal impairment was approximately twice as high as in individuals with normal renal function, although data in patients with severe renal impairment are limited. The pharmacokinetics of dapoxetine have not been evaluated in patients requiring hemodialysis.

Hepatic impairment

In patients with mild hepatic impairment, Cmax of unbound dapoxetine was reduced by 28%, while AUC of unbound dapoxetine remained unchanged. Cmax and AUC of the unbound active component (sum of unbound dapoxetine and desmethyldapoxetine exposure) decreased by 30% and 5%, respectively. In patients with moderate hepatic impairment, Cmax of unbound dapoxetine was essentially unchanged (3% decrease), while AUC of unbound dapoxetine increased by 66%. Cmax of the unbound active fraction was mainly unchanged, while AUC doubled. In patients with severe hepatic impairment, Cmax of unbound dapoxetine decreased by 42%, but AUC of unbound dapoxetine increased by approximately 223%. Cmax and AUC of the active fraction showed similar changes.

CYP2D6 polymorphism

In a clinical pharmacology study of a single 60 mg dose of dapoxetine, plasma concentrations were higher in CYP2D6 poor metabolizers than in extensive metabolizers (approximately 31% higher Cmax and 36% higher AUCinf of dapoxetine, and 98% higher Cmax and 161% higher AUCinf of desmethyldapoxetine). Cmax of the active substance of Longrayd may increase by approximately 46%, and AUC by approximately 90%. This increase may lead to increased frequency and severity of dose-dependent adverse effects. The safety of Longrayd 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.

Longrayd, film-coated tablets, should be prescribed only to patients meeting the following criteria:

• intravaginal ejaculatory latency time (IELT) of less than two minutes;
• persistent or recurrent ejaculation with minimal sexual stimulation occurring before, during, or immediately after penetration, earlier than desired by the patient;
• marked psychological distress or interpersonal difficulties due to PE;
• poor control over ejaculation;
• premature ejaculation in most sexual attempts in the history over the past 6 months.

Longrayd, film-coated tablets, should be used only as needed before anticipated sexual intercourse. Longrayd, film-coated tablets, should not be prescribed to delay ejaculation in men not diagnosed with PE.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Cardiac disorders 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 use within 14 days after discontinuation of MAOI therapy. Similarly, MAOIs should not be used within 7 days after discontinuation of Longrayd.
• Concomitant use of thioridazine or use within 14 days after discontinuation of thioridazine therapy. Similarly, thioridazine should not be used within 7 days after discontinuation of Longrayd.
• Concomitant use of serotonin reuptake inhibitors [selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs)] or other medicinal products/herbal products with serotonergic effect [e.g., L-tryptophan, triptans, tramadol, linezolid, lithium, St. John’s wort (Hypericum perforatum)] or use within 14 days after discontinuation of these medicinal products/herbal products. These medicinal products/herbal products should not be taken within 7 days after discontinuation of Longrayd.
• Concomitant treatment with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, atazanavir, etc.
• Moderate or severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Potential for interaction with monoamine oxidase inhibitors

Serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes including extreme agitation progressing to delirium and coma have been reported in patients receiving SSRIs in combination with a monoamine oxidase inhibitor (MAOI). Such reactions have also been reported in patients who recently discontinued SSRI treatment and started MAOI therapy. Some cases presented features typical of neuroleptic malignant syndrome. Animal study data on the effect of combined use of SSRIs and MAOIs suggest that these medicinal products may have a synergistic effect leading to increased blood pressure and behavioral excitation. Therefore, Longrayd, film-coated tablets, should not be used in combination with MAOIs or within 14 days after discontinuation of MAOI therapy.

Similarly, MAOIs should not be used within 7 days after discontinuation of Longrayd.

Potential for interaction with thioridazine

Thioridazine alone prolongs the QTc interval, which is associated with serious ventricular arrhythmias. Medicinal products such as Longrayd, which inhibit the CYP2D6 isoenzyme, inhibit thioridazine metabolism and increased thioridazine levels are expected to further prolong the QTc interval. Longrayd, film-coated tablets, should not be used in combination with thioridazine or within 14 days after discontinuation of thioridazine therapy. Similarly, thioridazine should not be taken within 7 days after discontinuation of Longrayd.

Medicinal products/herbal products with serotonergic effect

As with other SSRIs, concomitant use with serotonergic medicinal products/herbal products (including MAOIs, L-tryptophan, triptans, tramadol, linezolid, SSRIs, SNRIs, lithium, St. John’s wort (Hypericum perforatum)) may increase the frequency of serotonergic adverse effects. Longrayd, film-coated tablets, should not be used in combination with other SSRIs, MAOIs, or other serotonergic medicinal products/herbal products or within 14 days after discontinuation of these medicinal products/herbal products. Similarly, such medicinal products/herbal products should not be taken within 7 days after discontinuation of Longrayd.

Medicinal products actively affecting the CNS

The use of Longrayd in combination with medicinal products actively affecting the CNS (e.g., antiepileptic agents, antidepressants, neuroleptics, anxiolytics, sedative-hypnotics) has not been systematically evaluated in patients with premature ejaculation. Therefore, Longrayd should be used with caution when concomitant use with such medicinal products is necessary.

Effect of concomitant medicinal products on dapoxetine pharmacokinetics

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

CYP3A4 inhibitors

Strong CYP3A4 inhibitors. Administration of ketoconazole (200 mg twice daily for 7 days) increased Cmax and AUCinf of dapoxetine (60 mg single dose) by 35% and 99%, respectively. Considering the effect on both unbound dapoxetine and desmethyldapoxetine, Cmax of the active substance may increase by approximately 25%, and AUC of the active substance may double when a strong CYP3A4 inhibitor is taken.

Elevated Cmax and AUC levels of the active substance may increase further in patients who lack functional CYP2D6 enzyme, i.e., in CYP2D6 poor metabolizers, or when used in combination with strong CYP2D6 inhibitors.

Therefore, concomitant use of Longrayd and strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, and atazanavir is contraindicated.

Moderate CYP3A4 inhibitors. Concomitant treatment with moderate CYP3A4 inhibitors (e.g., erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem) may also lead to significant increases in systemic exposure to dapoxetine and desmethyldapoxetine, especially in CYP2D6 poor metabolizers. The maximum dapoxetine dose should be 30 mg when dapoxetine is combined with any of these medicinal products.

These measures apply to all patients unless it has been established that the patient is a CYP2D6 rapid metabolizer by genotype or phenotype. For patients confirmed as rapid CYP2D6 metabolizers, the recommended maximum dose is 30 mg when dapoxetine is combined with a strong CYP3A4 inhibitor, and dapoxetine 60 mg should be used cautiously when taken concomitantly with a moderate CYP3A4 inhibitor.

Strong CYP2D6 inhibitors

Cmax and AUCinf of dapoxetine (60 mg single dose) increased by 50% and 88%, respectively, when fluoxetine (60 mg/day for 7 days) was administered concomitantly. Considering the effect on both unbound dapoxetine and desmethyldapoxetine, Cmax of the active substance may increase by approximately 50%, and AUC of the active substance may double when a strong CYP2D6 inhibitor is taken. Such increased Cmax and AUC levels of the active substance are similar to those expected in CYP2D6 poor metabolizers and may lead to a higher number and increased severity of dose-dependent adverse effects.

PDE5 inhibitors

Longrayd, film-coated tablets, should not be used in patients taking PDE5 inhibitors due to possible reduction in orthostatic tolerance. The pharmacokinetics of dapoxetine (60 mg) in combination with tadalafil (20 mg) and sildenafil (100 mg) were evaluated in a single-dose crossover study. Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil caused minor changes in dapoxetine pharmacokinetics (increase in AUCinf by 22% and Cmax by 4%), which are not clinically significant.

Concomitant use of Longrayd with PDE5 inhibitors may lead to orthostatic hypotension.

The efficacy and safety of Longrayd in patients with premature ejaculation and erectile dysfunction receiving concomitant treatment with Longrayd and PDE5 inhibitors have not been established.

Effect of dapoxetine on the pharmacokinetics of concomitantly administered medicinal products

Tamsulosin

Concomitant administration of single or repeated doses of 30 mg or 60 mg dapoxetine in patients receiving daily tamsulosin doses did not result in changes in tamsulosin pharmacokinetics.

Adding dapoxetine to tamsulosin did not alter the orthostatic profile. No difference in orthostatic effects was observed between tamsulosin combined with 30 mg or 60 mg dapoxetine and tamsulosin alone; however, Longrayd, film-coated tablets, should be prescribed with caution to patients taking alpha-adrenergic receptor antagonists due to possible reduction in orthostatic tolerance.

Medicinal products metabolized by CYP2D6

Multiple doses of dapoxetine (60 mg/day for 6 days) followed by a single 50 mg dose of desipramine increased mean Cmax and AUCinf of desipramine by approximately 11% and 19%, respectively, compared to desipramine alone. Dapoxetine may cause a similar increase in plasma concentrations of other drugs metabolized by CYP2D6. The clinical significance is likely negligible.

Medicinal products metabolized by CYP3A4

Multiple doses of dapoxetine (60 mg/day for 6 days) reduced AUCinf of midazolam (8 mg single dose) by approximately 20% (range from -60% to +18%). The clinical significance of the effect on midazolam is likely negligible for most patients. Increased CYP3A activity may be clinically significant in some individuals who are concomitantly taking a medicinal product primarily metabolized by CYP3A and having a narrow therapeutic window.

Medicinal products metabolized by CYP2C19

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

Medicinal products metabolized by CYP2C9

Multiple doses 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 with known effects on coagulation and/or platelet function

Data on the effect of chronic warfarin use with dapoxetine are lacking; therefore, dapoxetine should be used with caution in patients taking warfarin chronically. In a pharmacokinetic study, dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics (prothrombin time or international normalized ratio) of warfarin after a single 25 mg dose. There have been reports of abnormal bleeding with SSRIs.

Alcohol (ethanol)

Concomitant administration of a single dose of ethanol 0.5 g/kg did not affect the pharmacokinetics of dapoxetine (60 mg single dose); however, dapoxetine in combination with ethanol enhanced drowsiness and significantly reduced attention levels as assessed by patients. Pharmacodynamic measures of cognitive impairment (digit span test, digit symbol substitution test) also demonstrated an additive effect from concomitant use of dapoxetine with ethanol. Concomitant use of alcohol and dapoxetine increases the likelihood and severity of adverse reactions such as dizziness, drowsiness, slowed reactions, or altered judgment. Combining alcohol with dapoxetine may enhance alcohol-related effects and may also lead to neurocardiogenic adverse reactions such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol consumption during treatment with Longrayd.

Special precautions for use.

General recommendations

The medicine Longryde is intended only for men with premature ejaculation. Longryde, film-coated tablets, should not be prescribed to men who have not been diagnosed with premature ejaculation. The safety of use has not been established, and there is no data on ejaculation delay in men without premature ejaculation.

Other forms of sexual dysfunction

Prior to initiating treatment, patients with other forms of sexual dysfunction, including erectile dysfunction, should be carefully evaluated by a physician. Longryde should not be used in men with erectile dysfunction (ED) who are taking PDE5 inhibitors.

Orthostatic hypotension

Before initiating therapy, the physician should perform a thorough medical evaluation, including a history of orthostatic symptoms. An orthostatic test should be performed prior to starting therapy (blood pressure and pulse rate in supine and standing positions). If confirmed or suspected orthostatic reactions are present, treatment with Longryde should be avoided. Cases of orthostatic hypotension have been reported in clinical trials. The physician should warn the patient in advance that if prodromal symptoms such as dizziness upon standing occur, the patient should lie down with the head lower than the body or sit with the head between the knees until symptoms resolve. The physician should also inform the patient not to stand up abruptly 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 involving children and adolescents with major depressive disorder and other psychiatric disorders. Short-term studies did not demonstrate an increased risk of suicidality with antidepressant use compared to placebo in adults aged 24 years and older. In clinical trials of Longryde for the treatment of premature ejaculation, a clear link between treatment and suicidality was not established when assessing potential suicide-related adverse effects using the Columbia Suicide Severity Rating Scale (C-CASA), the Montgomery–Åsberg Depression Rating Scale, or the Beck Depression Inventory-II.

Syncope

Patients should be advised to avoid situations that may lead to injury, including driving or operating dangerous machinery, if they experience syncope or prodromal symptoms such as dizziness or loss of consciousness. Prodromal symptoms such as nausea, faintness/dizziness, and increased sweating have been reported more frequently in patients treated with Longryde compared to placebo.

In clinical trials, episodes of syncope characterized by loss of consciousness, sometimes associated with bradycardia or sinus arrest, were observed in patients wearing Holter monitors. These cases were considered vasovagal in etiology, most occurring within the first 3 hours after dose intake, following the first dose, or associated with procedures performed during the study (such as blood sampling, orthostatic tests, and blood pressure measurements). Possible prodromal symptoms, including nausea, faintness, dizziness, tachycardia, asthenia, confusion, and increased sweating, were mainly observed within the first 3 hours after dosing and often preceded syncope. Patients should be warned that syncope may occur at any time during treatment with Longryde, with or without prodromal symptoms. Physicians should inform patients about the importance of maintaining adequate hydration and recognizing prodromal symptoms to reduce the likelihood of serious injury due to falls following loss of consciousness. If prodromal symptoms occur, patients should immediately lie down with the head lower than the body or sit with the head between the knees until symptoms resolve. Caution should be exercised, and situations that may lead to injury, including driving or operating dangerous machinery, should be avoided in case of syncope or other CNS-related reactions.

Patients with cardiovascular risk factors

Patients with cardiovascular diseases were excluded from phase 3 clinical trials. The risk of cardiovascular adverse reactions related to syncope (due to a sudden drop in cardiac output or other causes) is increased in patients with underlying structural cardiovascular disease (such as confirmed outflow obstruction, valvular heart disease, carotid stenosis, and ischemic heart disease). There is insufficient data to determine whether this increased risk extends to vasovagal syncope in patients with underlying cardiovascular disease.

Concomitant use with recreational drugs

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

Recreational drugs with serotonergic activity, such as ketamine, methylenedioxymethamphetamine (MDMA), and diethylamide of lysergic acid (LSD), may lead to potentially serious reactions when combined with Longryde. Such reactions include arrhythmia, hyperthermia, and serotonin syndrome. This list is not exhaustive. The use of Longryde with recreational drugs having sedative properties, such as opioids and benzodiazepines, may enhance somnolence and dizziness.

Ethanol

Patients should be advised not to take Longryde with alcohol. Combining alcohol with dapoxetine may exacerbate alcohol-related neurocognitive effects and may also enhance neurocardiogenic adverse reactions such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol consumption during treatment with Longryde.

Medicinal products with vasodilatory properties

Longryde, film-coated tablets, should be prescribed with caution to patients taking medicinal products with vasodilatory properties (such as alpha-adrenergic receptor antagonists and nitrates) due to the potential for reduced orthostatic tolerance.

Moderate CYP3A4 inhibitors

Patients taking moderate CYP3A4 inhibitors should be advised to exercise caution when taking dapoxetine concomitantly. The dose of dapoxetine should be reduced to 30 mg.

Potent CYP2D6 inhibitors

Caution should be exercised when increasing the dose to 60 mg in patients taking potent CYP2D6 inhibitors and in patients who are poor CYP2D6 metabolizers, as this may lead to increased systemic exposure, resulting in a higher number and severity of dose-dependent adverse reactions.

Mania

Longryde, film-coated tablets, should not be prescribed to patients with a history of mania/hypomania or bipolar disorder. Treatment should be discontinued if symptoms of such disorders occur.

Seizures

Due to the potential of SSRIs to lower the seizure threshold, treatment with Longryde should be discontinued if seizures develop, and the drug should be avoided in patients with unstable epilepsy. Patients with controlled epilepsy should remain under close supervision.

Children

Longryde, film-coated tablets, should not be used in patients under 18 years of age.

Depression and/or psychiatric disorders

Men with symptoms of depression should be evaluated before initiating treatment with Longryde to rule out undiagnosed depressive disorders. Concomitant use of Longryde and antidepressants, including SSRIs and SNRIs, is contraindicated. It is not recommended to discontinue treatment for depression or anxiety in order to initiate Longryde for the treatment of PE. Longryde, film-coated tablets, is not indicated for psychiatric disorders and should not be used in men with such conditions as schizophrenia or those suffering from comorbid depression, as worsening of depressive symptoms cannot be excluded. This may result from the underlying psychiatric disorder or from drug therapy. Physicians should encourage patients to report any distressing thoughts or feelings at any time. If symptoms of depression develop during treatment, Longryde should be discontinued.

Bleeding

There have been reports of abnormal bleeding with SSRIs. Patients taking Longryde should be advised to exercise caution, particularly when used concomitantly with medicinal products that may affect platelet function (such as atypical antipsychotics and phenothiazines, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs [NSAIDs], antiplatelet agents), anticoagulants (e.g., warfarin), or in patients with a history of bleeding or coagulation disorders.

Renal impairment

Longryde, film-coated tablets, is not recommended for use in patients with severe renal impairment, and caution should be exercised when used in patients with mild to moderate renal impairment.

Withdrawal syndrome

Abrupt discontinuation of SSRIs used chronically for the treatment of 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.

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.

Eye disorders

The use of Longryde has been associated with ocular reactions such as mydriasis and eye pain. Longryde, film-coated tablets, should be used with caution in patients with elevated intraocular pressure or at risk of angle-closure glaucoma.

Lactose intolerance

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

Use during pregnancy or breastfeeding.

The medicinal product is used by men.

Ability to affect reaction speed when driving or operating machinery.

Cases of dizziness, attention disturbance, syncope, visual impairment, and somnolence have been reported in patients receiving dapoxetine. Therefore, patients should be warned to avoid situations with a risk of injury, including driving or operating dangerous machinery. Combining alcohol with dapoxetine may exacerbate alcohol-related neurocognitive effects and may also lead to neurocardiogenic adverse reactions such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol consumption during treatment with Longryde.

Method of administration and dosage.

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

Longryde is intended for oral administration. The tablet should be swallowed whole to avoid a bitter taste, with at least one full glass of water. Longryde can be taken regardless of food intake.

Longryde is not intended for continuous daily use and should be taken only when sexual activity is planned. Longryde film-coated tablets should not be administered more frequently than once every 24 hours. If the response to the 30 mg dose is inadequate and the patient has not experienced moderate or severe adverse effects or prodromal symptoms indicative 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. When using the 60 mg dose, the frequency and severity of adverse effects are higher. Dose escalation to 60 mg should not be performed in patients who have experienced orthostatic reactions with the initial dose.

The physician should perform a careful individual benefit-risk assessment after the first four weeks of treatment (or at least after 6 doses) to determine whether continued treatment with Longryde is appropriate. Data on the efficacy and safety of Longryde beyond 24 weeks are limited. The clinical necessity of continuing treatment and the benefit-risk balance with Longryde should be reassessed at least every six months.

Elderly patients (aged 65 years and older)

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

Patients with renal impairment

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

Patients with hepatic impairment

Longryde is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Patients known to be CYP2D6 poor metabolizers or patients receiving strong CYP2D6 inhibitors

Caution should be exercised when increasing the dose to 60 mg in patients who are CYP2D6 poor metabolizers or in patients receiving concomitant strong CYP2D6 inhibitors.

Patients receiving moderate or strong CYP3A4 inhibitors

Concomitant use of strong CYP3A4 inhibitors is contraindicated. The dose should be reduced to 30 mg in patients receiving concomitant moderate CYP3A4 inhibitors, and caution should be exercised.

Children

Longryde is contraindicated in children due to lack of clinical experience.

Overdose.

There have been no reports of overdose. No unexpected adverse effects were observed in a clinical pharmacological study of Longryde when daily doses up to 240 mg (two 120 mg doses administered 3 hours apart) were taken. In general, symptoms of overdose with SSRIs include serotonin-mediated adverse reactions such as drowsiness, gastrointestinal disturbances (e.g., nausea and vomiting), tachycardia, tremor, agitation, and dizziness. In case of overdose, standard supportive measures should be implemented as needed. Due to the extensive protein binding and large volume of distribution of dapoxetine hydrochloride, interventions such as forced diuresis, dialysis, hemoperfusion, and blood transfusion are unlikely to be effective. Specific antidotes for Longryde are not known.

Adverse reactions.

Syncope and orthostatic hypotension have been reported.

The most frequently reported dose-dependent adverse effects during the use of the drug were: nausea, dizziness, headache, diarrhea, insomnia, and fatigue. The adverse effects most commonly leading to discontinuation of the drug were nausea and dizziness.

Adverse reactions reported during the 9-month long-term open extension trial were similar to those reported in the double-blind studies, and there were no reports of additional adverse effects.

Description of selected adverse reactions

Syncope associated with bradycardia or sinus node arrest related to drug administration has been reported in patients undergoing Holter monitoring. Most cases occurred within the first 3 hours after dose administration, following the first dose, or were associated with clinical procedures (such as blood draws, orthostatic tests, or blood pressure measurements). Syncope was often preceded by prodromal symptoms.

Cases of syncope and prodromal symptoms are dose-dependent, as a higher incidence has been observed among patients treated with doses higher than recommended.

Cases of orthostatic hypotension have been reported.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 1 tablet or 4 tablets of 30 mg or 60 mg in a blister, 1 blister in a cardboard package.

Prescription status. Prescription only.

Manufacturer. MSN Laboratories Private Limited

Manufacturer's address and location of manufacturing site.

Plot No. 42, Anrich Industrial Estate, Bollaram, Sangareddy District - 502 325, Telangana State, India / Plot No. 42, Anrich Industrial Estate, Bollaram, Sangareddy District - 502 325, Telangana State, India.

Marketing Authorization Holder. LLC "Alter Ego Pharma", Ukraine.

Address of the Marketing Authorization Holder.

35 Umanska St., Kyiv, Ukraine, 03087