Priligy^® (Tablets) Instructions for Use

Marketing Authorization Holder

Berlin-Chemie, AG (Germany)

Manufactured By

Menarini-Von Heyden, GmbH (Germany)

ATC Code

G04BX14 (Dapoxetine)

Active Substance

Dapoxetine (Rec.INN registered by WHO)

Dosage Forms

	Priligy®	Film-coated tablets, 30 mg: 3 or 6 pcs.
		Film-coated tablets, 60 mg: 3 or 6 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets grey in color, round, biconvex, with the embossed inscription “30” inside a triangle on one side and smooth on the other side; the tablet core is white or almost white in cross-section.

Excipients: dried mixture “MicroceLac 100” (75:25, lactose monohydrate : microcrystalline cellulose), croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.

Film coating composition grey coating powder, mixture 4 (lactose monohydrate, hypromellose 2910 (15 cP), titanium dioxide (E171), triacetin, iron oxide black (E172), iron oxide yellow (E172)).

3 pcs. – blisters (1) – cardboard envelope packs with a booklet.
6 pcs. – blisters (1) – cardboard envelope packs with a booklet.

Film-coated tablets grey in color, round, biconvex, with the embossed inscription “60” inside a triangle on one side and smooth on the other side; the tablet core is white or almost white in cross-section.

Excipients: dried mixture “MicroceLac 100” (75:25, lactose monohydrate : microcrystalline cellulose), croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.

Film coating composition grey coating powder, mixture 3 (lactose monohydrate, hypromellose 2910 (15 cP), titanium dioxide (E171), triacetin, iron oxide black (E172), iron oxide yellow (E172)).

3 pcs. – blisters (1) – cardboard envelope packs with a booklet.
6 pcs. – blisters (1) – cardboard envelope packs with a booklet.

Clinical-Pharmacological Group

Drug for the treatment of premature ejaculation

Pharmacotherapeutic Group

Drugs used in urology; other drugs used in urology

Pharmacological Action

It is assumed that the mechanism of action of dapoxetine in premature ejaculation is associated with inhibition of serotonin reuptake by neurons with subsequent enhancement of the neurotransmitter’s action on pre- and postsynaptic receptors. The mechanism of ejaculation is regulated mainly by the sympathetic nervous system. Postganglionic sympathetic nerve fibers innervate the seminal vesicles, vas deferens, prostate gland, urethral muscles, and bladder neck, causing their coordinated contraction to achieve ejaculation. Dapoxetine affects the ejaculation reflex by increasing the latent period and reducing the duration of reflex motor neuron impulses in the perineal ganglia. The stimulus triggering ejaculation is generated in the spinal reflex center, which is controlled through the brainstem by several brain nuclei, including the pleoptic and paraventricular nuclei.

Pharmacokinetics

Absorption

Dapoxetine is rapidly absorbed, and the maximum plasma concentration (C_max) is reached 1-2 hours after taking the drug. The absolute bioavailability is 42% (range 15-76%). After a single oral dose of dapoxetine on an empty stomach at doses of 30 mg and 60 mg, the maximum plasma concentration of the substance is 297 ng/ml (after 1.01 h) and 498 ng/ml (after 1.27 h), respectively. Taking a fatty meal moderately reduces the C_max of dapoxetine (by 10%) and increases the AUC (area under the concentration-time curve) by 12% and the time to reach maximum plasma concentration. However, the extent of dapoxetine absorption does not change. These changes are not clinically significant. Priligy^® can be taken with or without food.

Distribution

More than 99% of dapoxetine binds to plasma proteins in vitro. The active metabolite, desmethyldapoxetine, is 98.5% bound to plasma proteins. Dapoxetine is rapidly distributed throughout the body with a mean steady-state volume of distribution of 162 L.

After intravenous administration in humans, the mean half-life in the initial, intermediate, and terminal elimination phases is 0.10, 2.19, and 19.3 hours, respectively.

Metabolism

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

Elimination

Dapoxetine metabolites are excreted mainly in the urine as conjugates. The unchanged active substance is not detected in the urine. Dapoxetine is rapidly eliminated, as evidenced by low plasma concentrations (less than 5% of the maximum) 24 hours after taking the dose. With daily administration, accumulation of the substance in the body is minimal. After oral administration, the terminal half-life is approximately 19 hours.

Pharmacokinetics in special patient categories

Race

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

Elderly patients (65 years and older)

A single dose of dapoxetine 60 mg did not reveal significant differences in pharmacokinetic parameters (C_max, AUC_0-∞, T_max) between healthy elderly men and younger men. The mean AUC_0-∞ of dapoxetine and the terminal half-life were higher by 12% and 46%, respectively, in elderly men compared to younger men.

Renal impairment

A single dose of dapoxetine 60 mg did not reveal a dependence between creatinine clearance and C_max or AUC_0-∞ of dapoxetine in patients with mild (CrCl 50-80 ml/min), moderate (CrCl from 30 to <50 ml/min), and severe (CrCl <30 ml/min) renal impairment. The AUC of dapoxetine in patients with severe renal impairment was approximately 2 times higher than in patients with normal renal function. Data on the use of the drug in patients with severe renal impairment are limited. The pharmacokinetics of dapoxetine have not been studied in patients requiring hemodialysis.

Hepatic impairment

In patients with mild hepatic impairment, the pharmacokinetics of dapoxetine and desmethyldapoxetine were unchanged. In patients with moderate hepatic impairment (Child-Pugh class B), the C_max and AUC of unbound dapoxetine were increased by 55% and 120%, respectively. The C_max of the unbound active fraction of dapoxetine was unchanged, and the AUC was doubled.

In patients with severe hepatic impairment, the C_max of unbound dapoxetine was unchanged, and the AUC of unbound dapoxetine was increased more than 3-fold. The AUC of the active fraction was also increased several times.

CYP2D6 polymorphism

The plasma concentration of dapoxetine after a single dose of Priligy^® 60 mg was higher in patients with low CYP2D6 activity than in patients with high CYP2D6 activity (C_max by approximately 31%, AUC_0-∞ by approximately 36%). Similarly, the C_max of desmethyldapoxetine in patients with low CYP2D6 activity was increased by 98%, and the AUC_0-∞ by 161%. The mean terminal half-life of dapoxetine was increased by 2.4 hours in patients with low CYP2D6 isoenzyme activity compared to patients with high CYP2D6 isoenzyme activity. The C_max of the active fraction of dapoxetine was increased by approximately 46%, and the AUC by approximately 90%. This increase may be accompanied by an increased frequency and severity of dose-dependent adverse events. The safety of using Priligy^® in patients with low CYP2D6 activity may be questionable when taking other drugs that can inhibit the metabolism of dapoxetine, in particular, potent and moderate CYP3A4 inhibitors.

In patients with ultra-high CYP2D6 activity, plasma concentrations of dapoxetine and desmethyldapoxetine are expected to be reduced.

Indications

• For the treatment of premature ejaculation in men aged 18 to 64 years.

ICD codes

Dosage Regimen

For oral administration. The tablet should be swallowed whole with at least one full glass of water. Priligy^® can be taken with or without food.

Adult men from 18 to 64 years

The recommended starting dose for all men is 30 mg; this dose is taken 1-3 hours before anticipated sexual intercourse. If the effect is insufficient and the 30 mg dose is well tolerated, it can be increased to 60 mg. The maximum recommended dosing frequency is once every 24 hours.

The physician prescribing Priligy^® for the treatment of premature ejaculation should assess the risks and benefits of using the drug after the first 4 weeks of treatment or after taking 6 doses and should determine the risk-benefit ratio to decide on the advisability of further treatment with Priligy^®.

Patients with renal impairment

For patients with mild or moderate renal impairment, dose adjustment is not required, but caution is recommended. Priligy^® is not recommended for patients with severe renal impairment.

Patients with hepatic impairment

For patients with mild hepatic impairment, dose adjustment is not required. Priligy^® is contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh classes B and C).

Patients with low CYP2D6 activity, concomitant use with potent CYP2D6 inhibitors

Caution should be exercised when increasing the dose of Priligy^® to 60 mg in individuals with low CYP2D6 activity or in patients concomitantly taking Priligy^® with potent CYP2D6 inhibitors.

Patients taking potent or moderate CYP3A4 inhibitors

Concomitant use with potent CYP3A4 inhibitors is contraindicated. When Priligy^® is used concomitantly with moderate CYP3A4 inhibitors, the dose of the drug should be reduced to 30 mg.

Adverse Reactions

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

Undesirable adverse reactions observed during clinical studies are listed in the table below.

Description of selected adverse effects

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

The frequency of syncope and prodromal symptoms was dose-dependent, as demonstrated in patients receiving higher doses of the drug.

Effects upon drug withdrawal

Upon abrupt discontinuation of long-term use of selective serotonin reuptake inhibitors for the treatment of chronic depressive disorders, the following symptoms have been noted: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. Safety study results showed a higher frequency of withdrawal symptoms in the form of mild to moderate insomnia and dizziness after drug discontinuation following 62 days of use.

Contraindications

• Hypersensitivity to dapoxetine hydrochloride or any excipient of the drug.
• Significant heart disease (e.g., heart failure NYHA class II-IV, conduction disorders (2nd-3rd degree AV block or sick sinus syndrome) in the absence of a permanent pacemaker, significant coronary artery disease or valvular disease);
• Concomitant use of MAO inhibitors and use within 14 days after their discontinuation. Similarly, MAO inhibitors should not be taken within 7 days after discontinuing Priligy^®;
• Concomitant use of thioridazine and within 14 days after its discontinuation. Similarly, thioridazine should not be taken within 7 days after discontinuing Priligy^®;
• Concomitant use of serotonin reuptake inhibitors (selective serotonin reuptake inhibitors – SSRIs, serotonin and norepinephrine reuptake inhibitors, and tricyclic antidepressants) and other drugs with serotonergic effects (e.g., L-tryptophan, triptans, tramadol, linezolid, lithium, St. John’s wort (Hypericum perforatum) preparations) and within 14 days after discontinuation of these drugs. Similarly, these drugs should not be taken within 7 days after discontinuing Priligy^®;
• Concomitant use with potent CYP3A4 inhibitors, e.g., ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, atazanavir, etc.;
• Moderate and severe hepatic impairment;
• Severe renal impairment;
• Children and adolescents under 18 years of age;
• Lactose intolerance.

In case of a history of established or suspected orthostatic hypotension, as well as a history of mania/hypomania or bipolar disorder, treatment with the drug should be avoided.

With caution

• Mild or moderate renal impairment;
• Concomitant use with potent inhibitors of the CYP2D6 isoenzyme and moderate inhibitors of CYP3A4 in patients with genotypically low activity of the CYP2D6 isoenzyme and patients with high activity of the CYP2D6 isoenzyme (in combination with moderate inhibitors of the CYP3A4 isoenzyme);
• Concomitant use with drugs that affect platelet aggregation and with anticoagulants due to the risk of bleeding.

Use in Pregnancy and Lactation

Priligy^® is not intended for use in women.

Pregnancy

Based on limited data from clinical studies, there is no reason to assume that a man’s intake of dapoxetine could affect his partner’s pregnancy. Well-controlled studies of dapoxetine use in pregnant women have not been conducted.

Lactation

It is not known whether Dapoxetine and its metabolites are excreted in human milk.

Use in Hepatic Impairment

No dose adjustment is required for patients with mild hepatic impairment. Priligy^® is contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh classes B and C).

Use in Renal Impairment

No dose adjustment is required for patients with mild or moderate renal impairment, but caution is recommended. Priligy^® is not recommended for patients with severe renal impairment.

Pediatric Use

Priligy^® should not be taken by patients under 18 years of age.

Geriatric Use

A single dose of dapoxetine 60 mg did not reveal significant differences in pharmacokinetic parameters (C_max, AUC_0-∞, T_max) between healthy elderly men (over 65 years) and younger men. The mean AUC_0-∞ values of dapoxetine and the terminal half-life were higher by 12% and 46%, respectively, in elderly men compared to younger men.

Special Precautions

General

Priligy^® is intended only for men with premature ejaculation. The safety of the drug in men without premature ejaculation has not been established, and there are no data on delayed ejaculation.

Use with drugs of abuse

Patients should be advised not to take Priligy^® concomitantly with drugs of abuse. Concomitant use of Priligy^® with drugs having serotonergic activity, such as ketamine, methylenedioxymethamphetamine (MDMA), and lysergic acid diethylamide (LSD), may lead to potentially serious reactions, including but not limited to arrhythmia, hyperthermia, and serotonin syndrome. Concomitant use of Priligy^® with sedative drugs, such as opiates or benzodiazepines, may enhance drowsiness and dizziness.

Ethanol

Combining Priligy^® with alcohol may enhance the effect of the latter on the central nervous system and the neurocardiogenic adverse effects of alcohol, such as syncope, which increases the risk of accidental injury. Therefore, patients should be advised to refrain from alcohol consumption while taking Priligy^®.

Syncope

The frequency of syncope in clinical studies of Priligy^® depended on the patient category and ranged from 0.06% (for the 30 mg dose) to 0.23% (for the 60 mg dose) to 0.64% (for both doses combined) in a study involving healthy volunteers.

Patients taking Priligy^®, compared to patients taking placebo, more frequently experienced prodromal symptoms, including nausea, dizziness/lightheadedness, and sweating. With the Priligy^® 30 mg dose, the frequency of nausea was 11.0%, dizziness 5.8%, and hyperhidrosis 0.8%. With the Priligy^® 60 mg dose, these figures were 21.2%, 11.7%, and 1.5%, respectively. The frequency of syncope and possible prodromal symptoms was dose-dependent, as evidenced by higher rates in patients receiving doses higher than the maximum recommended daily dose of 60 mg. Cases of syncope observed in clinical studies were considered to be of vasovagal origin. Most of these cases occurred within the first 3 hours after taking the first dose or were associated with study procedures in a clinical setting (e.g., blood sampling, sudden standing, blood pressure measurement). Possible prodromal symptoms, such as nausea, dizziness, lightheadedness, palpitations, asthenia, confusion, and sweating, were also usually observed within the first 3 hours after taking the drug and often preceded syncope. Patients should be informed that during treatment with Priligy^®, syncope with or without prodromal symptoms may occur at any time. The physician should inform the patient about the importance of adequate hydration and recognizing prodromal signs and symptoms to reduce the risk of serious injury from falls due to loss of consciousness. If possible prodromal symptoms occur, the patient should immediately lie down so that the head is lower than the body, or sit with the head between the knees, and should remain in this position until the symptoms disappear. If syncope or other CNS effects occur, the patient should be warned to avoid potentially hazardous situations, including driving and operating dangerous machinery.

Combining Priligy^® with alcohol may enhance neurocardiogenic adverse effects, including syncope, which increases the risk of accidental injury; therefore, patients should be advised to refrain from alcohol consumption during treatment with Priligy^®.

Patients at risk of cardiovascular diseases

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

Orthostatic hypotension

Cases of orthostatic hypotension have been described in clinical studies. The physician should inform the patient in advance that if possible prodromal symptoms occur, such as lightheadedness immediately after standing up, they should immediately lie down so that the head is lower than the body, or sit with the head between the knees, and remain in this position until the symptoms disappear. In addition, the patient should be informed about the need to avoid sudden rising after prolonged lying or sitting. Furthermore, Priligy^® should be prescribed with caution to patients taking vasodilators (e.g., alpha-adrenergic blockers, nitrates, PDE5 inhibitors) due to the possible reduced tolerance of such patients to the orthostatic effect of the drug.

Moderate CYP3A4 inhibitors

When Priligy^® is taken concomitantly with moderate CYP3A4 inhibitors (erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem), the dose of Priligy^® should be reduced to 30 mg, and caution should be exercised.

Potent CYP2D6 inhibitors

Caution is recommended when increasing the dose of Priligy^® to 60 mg in patients receiving potent CYP2D6 inhibitors and in patients with low CYP2D6 activity, as this may increase systemic exposure to the drug with a corresponding increase in the frequency and severity of dose-dependent adverse events.

Suicide/suicidal thoughts

In short-term studies, antidepressants, including SSRIs, compared to placebo, increased the risk of suicide and suicidal thoughts in children and adolescents with generalized depression and other mental disorders. This effect was not observed in adults over 24 years of age. In clinical studies of Priligy^® for the treatment of premature ejaculation, no clear data on the association of suicidal thoughts with treatment were obtained.

Mania

Priligy^® should not be taken by patients with a history of mania/hypomania or bipolar disorder; if symptoms of these conditions appear, the drug should be discontinued.

Seizures

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

Use in children and adolescents under 18 years

Priligy^® should not be taken by patients under 18 years of age.

Concomitant depression and mental disorders

If a patient has signs and symptoms of depression before starting Priligy^®, an examination should be performed to rule out an undiagnosed depressive disorder. Priligy^® should not be taken concomitantly with antidepressants, including SSRIs and serotonin and norepinephrine reuptake inhibitors. It is not recommended to discontinue treatment for depression or anxiety to start treatment with Priligy^®. Priligy^® is not intended for the treatment of mental disorders (e.g., schizophrenia or depression) and should not be taken by men with these conditions, as an exacerbation of depressive symptoms cannot be ruled out. Any worrisome thoughts or feelings should be reported to a physician immediately, and if signs and symptoms of depression appear during treatment, Priligy^® should be discontinued.

Bleeding

Cases of bleeding have been reported with the use of SSRIs. Caution is recommended when taking Priligy^® concomitantly with drugs that affect platelet function (e.g., atypical antipsychotics, phenothiazines, acetylsalicylic acid, NSAIDs, anticoagulants), as well as in patients with a history of bleeding or coagulation disorders.

Renal impairment

Priligy^® is not recommended for patients with severe renal impairment; caution should be exercised in patients with moderate and mild renal impairment.

Discontinuation syndrome

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

In a clinical study conducted to assess the discontinuation effect of Priligy^® after 62 days of use at a dose of 60 mg (daily or as needed) in patients with premature ejaculation, no signs of discontinuation syndrome were identified. After switching patients to placebo following daily use of Priligy^®, only minor withdrawal symptoms in the form of mild or moderate insomnia and dizziness were detected. Similar results were obtained in another double-blind controlled clinical study with a one-week assessment of withdrawal effects after 24 weeks of use of the drug at a dose of 30 mg or 60 mg as needed.

Effect on ability to drive and use machines

Cases of dizziness, impaired attention, syncope, blurred vision, and drowsiness have been reported with dapoxetine use. The patient should be warned to avoid situations where injury is possible, including driving and operating dangerous machinery.

Overdose

No cases of overdose have been reported in clinical studies.

Taking Priligy^® at a dose of up to 240 mg (2 doses of 120 mg with a 3-hour interval) did not cause unexpected adverse events. In general, symptoms of SSRI overdose include serotonergic reactions, including drowsiness, gastrointestinal disorders (nausea, vomiting), tachycardia, tremor, agitation, and dizziness.

In case of overdose, standard supportive therapy should be administered if necessary. Due to the significant plasma protein binding and large volume of distribution of dapoxetine hydrochloride, forced diuresis, dialysis, hemoperfusion, and blood transfusion are unlikely to be effective. A specific antidote is unknown.

Drug Interactions

Interaction with MAO inhibitors

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

Interaction with thioridazine

Thioridazine prolongs the QTc interval, which is associated with ventricular arrhythmia. Drugs like Priligy^®, which inhibit the CYP2D6 enzyme, appear to inhibit the metabolism of thioridazine. The resulting increase in thioridazine levels is expected to enhance the QTc interval prolongation. Priligy^® should not be taken concomitantly with thioridazine and for 14 days after discontinuing its use. Similarly, thioridazine should not be taken for 7 days after discontinuing Priligy^®.

Serotonergic drugs

As with SSRIs, taking Priligy^® concomitantly with serotonergic drugs (including MAO inhibitors, L-tryptophan, triptans, tramadol, linezolid, SSRIs, serotonin and norepinephrine reuptake inhibitors, lithium, and St. John’s wort (Hypericum perforatum) preparations) may increase the frequency of serotonergic adverse effects. Priligy^® should not be taken concomitantly with other SSRIs, MAO inhibitors, and other serotonergic drugs and for 14 days after discontinuing these drugs. Similarly, these drugs should not be taken for 7 days after discontinuing Priligy^®.

Drugs acting on the CNS

The concomitant use of Priligy^® with drugs acting on the CNS has not been studied in patients with premature ejaculation. Caution is recommended if concomitant use of these drugs is necessary.

Effect of other drugs on Dapoxetine hydrochloride

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

CYP3A4 inhibitors

Potent CYP3A4 inhibitors

Administration of ketoconazole 200 mg twice daily for 7 days increased the C_max and AUC_0-∞ of dapoxetine (60 mg single dose) by 35% and 99%, respectively. Considering the unbound fraction of dapoxetine and desmethyldapoxetine, the C_max of the active fraction (sum of unbound dapoxetine and desmethyldapoxetine) in the presence of potent CYP3A4 inhibitors may increase by approximately 25%, and the AUC may double. This increase in C_max and AUC of the active fraction may be significantly more pronounced in the subpopulation of patients lacking functionally active CYP2D6 enzyme, as well as with concomitant use of potent CYP2D6 inhibitors.

Priligy^® should not be taken concomitantly with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, and atazanavir.

Moderate CYP3A4 inhibitors

Concomitant use of moderate CYP3A4 inhibitors, such as erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, or diltiazem, may significantly increase systemic exposure to dapoxetine and desmethyldapoxetine, especially in patients with low CYP2D6 activity. The maximum dose of Priligy^® taken concomitantly with these drugs should be limited to 30 mg and taken with caution.

Potent CYP2D6 inhibitors

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

Interaction with drugs metabolized by CYP1A and CYP2B6 isoenzymes

Based on comparative data of C_max of dapoxetine at a dose of 60 mg and the dapoxetine concentration at 50% inhibition (IC₅₀) of the CYP1A2 isoenzyme in vitro, it is concluded that no effect of dapoxetine on the concentration of concomitantly administered drugs metabolized by this isoenzyme is expected. The effect of dapoxetine on the CYP2B6 isoenzyme has not been studied.

PDE5 inhibitors

The pharmacokinetics of dapoxetine taken at a dose of 60 mg concomitantly with tadalafil (20 mg) or sildenafil (100 mg) were studied. Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil slightly increased the AUC_0-∞ and C_max of dapoxetine (by 22% and 4%, respectively), which is considered clinically insignificant. Priligy^® should be prescribed with caution to patients taking PDE5 inhibitors due to the possible reduced tolerance of these patients to orthostatic hypotension.

Effect of dapoxetine hydrochloride on concomitantly administered drugs

Tamsulosin

Single and multiple doses of Priligy^® 30 mg and 60 mg in patients receiving daily tamsulosin did not lead to changes in the pharmacokinetics of the latter. The frequency of orthostatic hypotension also did not change, being the same with tamsulosin alone and in combination with Priligy^® 30 mg or 60 mg. Priligy^® should be prescribed with caution to patients taking alpha-adrenergic blockers due to the possible reduced tolerance of these patients to orthostatic hypotension.

Drugs metabolized by CYP2D6

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

Drugs Metabolized by CYP3A

Repeated administration of Priligy^® (60 mg/day for 6 days) reduced the AUC_0-∞ of midazolam (8 mg single dose) by approximately 20% (range from -60% to +18%). The clinical significance of this phenomenon is likely to be small in the majority of patients. However, increased CYP3A activity may be of clinical importance in some patients who are concurrently taking drugs that are primarily metabolized by CYP3A and have a narrow therapeutic window.

Drugs Metabolized by CYP2C19

Repeated administration of Priligy^® (60 mg/day for 6 days) did not affect the pharmacokinetics of omeprazole (40 mg single dose). Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C19 substrates.

Drugs Metabolized by CYP2C9

Repeated administration of Priligy^® (60 mg/day for 6 days) did not affect the pharmacokinetics and pharmacodynamics of glibenclamide (5 mg single dose). Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C9 substrates.

PDE5 Inhibitors

According to study results, Dapoxetine (60 mg) did not affect the pharmacokinetics of tadalafil (20 mg) and sildenafil (100 mg).

Warfarin

There are no data on the effects of long-term warfarin use concomitantly with Priligy^®. Caution is recommended when prescribing Priligy^® to patients taking warfarin long-term. In a pharmacokinetic study, repeated administration of dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics and pharmacodynamics (PT and INR) of warfarin (25 mg single dose).

Ethanol

A single dose of ethanol (0.5 g/kg, or approximately 2 drinks) did not affect the pharmacokinetics of dapoxetine (60 mg single dose) and vice versa.

Concomitant administration of Priligy^® and ethanol increased drowsiness and significantly reduced alertness as assessed by the patient.

Administration of ethanol alone and Priligy^® alone did not significantly alter cognitive function measures (reaction time in the Digit Recognition Test and the Digit Symbol Substitution Test) compared to placebo; however, the combination of ethanol and Priligy^® statistically significantly altered these measures compared to ethanol alone.

Concomitant use of ethanol and Priligy^® increases the frequency and severity of adverse reactions such as dizziness, drowsiness, slowed reflexes, and impaired judgment.

The combination of alcohol and Priligy^® may also enhance neurocardiogenic adverse effects, particularly the frequency of syncope, which increases the risk of accidental injury.

Therefore, patients should be advised to avoid alcohol consumption while being treated with Priligy^®.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

Dispensing Status

By prescription.

Important Safety Information

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