Infigio^® (Tablets) Instructions for Use

Marketing Authorization Holder

Nizhpharm JSC (Russia)

Manufactured By

Chemopharm, LLC (Russia)

Or

Nizhpharm JSC (Russia)

ATC Code

G04BX14 (Dapoxetine)

Active Substance

Dapoxetine (Rec.INN registered by WHO)

Dosage Forms

	Infigio®	Film-coated tablets, 30 mg: 3 or 6 pcs.
		Film-coated tablets, 60 mg: 3, 6 or 10 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets of a greenish-blue color, round, biconvex; the core on the cross-section is white or almost white.

Excipients: lactose monohydrate, croscarmellose sodium, microcrystalline cellulose type 101, microcrystalline cellulose PH 102, colloidal silicon dioxide, magnesium stearat.

Coating: hypromellose, lactose monohydrate, macrogol, titanium dioxide, brilliant blue/patent blue dye, quinoline yellow dye.

3 pcs. – contour cell blisters (1) – cardboard packs.
3 pcs. – contour cell blisters (2) – cardboard packs.
6 pcs. – contour cell blisters (1) – cardboard packs.

Film-coated tablets of a greenish-blue color, round, biconvex; the core on the cross-section is white or almost white.

Excipients: lactose monohydrate, croscarmellose sodium, microcrystalline cellulose type 101, microcrystalline cellulose PH 102, colloidal silicon dioxide, magnesium stearat.

Coating: hypromellose, lactose monohydrate, macrogol, titanium dioxide, brilliant blue/patent blue dye, quinoline yellow dye.

3 pcs. – contour cell blisters (1) – cardboard packs.
3 pcs. – contour cell blisters (2) – cardboard packs.
6 pcs. – contour cell blisters (1) – cardboard packs.
10 pcs. – contour cell blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment of premature ejaculation

Pharmacotherapeutic Group

Remedy for premature ejaculation

Pharmacological Action

Agent for the treatment of premature ejaculation, serotonin reuptake inhibitor.

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 impulse activity of the perineal motor neurons. 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.

Pharmacokinetics

After oral administration, Dapoxetine is rapidly absorbed, C_max in blood plasma is reached in 1-2 hours. 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 C_max of the substance in blood plasma is 297 ng/ml (after 1.01 hours) and 498 ng/ml (after 1.27 hours), respectively. Intake of fatty food moderately decreases the C_max of dapoxetine (by 10%) and increases AUC and the time to reach C_max in blood plasma by 12%. However, the extent of dapoxetine absorption does not change. These changes are not clinically significant. More than 99% of dapoxetine binds to plasma proteins in vitro. The active metabolite, desmethyldapoxetine, binds to blood plasma proteins by 98.5%. Dapoxetine is rapidly distributed throughout the body with a mean V_d at steady state of 162 L. With intravenous administration in humans, the mean T_1/2 in the initial, intermediate, and terminal elimination phases is 0.10, 2.19, and 19.3 hours, respectively.

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 examining the metabolism of ¹⁴C-dapoxetine, Dapoxetine after oral administration was actively metabolized mainly via N-oxidation, N-demethylation, naphthyl group hydroxylation, glucuronidation, and sulfation. Evidence of presystemic metabolism in the liver was found after oral administration. The main components circulating in the blood 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.

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 the low plasma concentration of the substance (less than 5% of the maximum) 24 hours after dose administration. With daily intake, accumulation of the substance in the body is minimal. With oral administration, the terminal T_1/2 is approximately 19 hours.

Indications

Treatment of premature ejaculation in men aged 18 to 64 years.

ICD codes

Dosage Regimen

The recommended initial dose for all men is 30 mg; this dose is taken 1-3 hours before the 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 frequency of dose administration is once every 24 hours.

The physician prescribing the drug for the treatment of premature ejaculation should assess the risk and benefit 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 the drug containing Dapoxetine.

Use with caution at a dose of 60 mg in patients with low activity of the CYP2D6 isoenzyme or in patients taking potent inhibitors of CYP2D6.

When dapoxetine is used concomitantly with moderate inhibitors of CYP3A4, the dose of dapoxetine should be reduced to 30 mg.

Adverse Reactions

Psychiatric disorders: common – anxiety, agitation, restlessness, unusual dreams, decreased libido; uncommon – depression, depressed mood, euphoric state, mood swings, nervousness, indifference, apathy, confusion, disorientation, pathological thinking, somatosensory amplification, sleep disorders, initial insomnia, intrasomnic disorder, nightmares, bruxism, loss of libido, anorgasmia.

From the CNS: very common – dizziness, headache; common – drowsiness, impaired concentration, tremor, paresthesia; uncommon – syncope, including vasovagal syncope, postural dizziness, akathisia, taste perversion, hypersomnia, lethargy, sedated state, depressed level of consciousness; rare – exertional dizziness, sudden onset of sleep.

From the organ of vision: common – blurred vision; uncommon – mydriasis, eye pain, visual impairment.

From the ear and labyrinth disorders: common – tinnitus; uncommon – vertigo.

From the cardiovascular system: common – flushing; uncommon – sinus arrest, sinus bradycardia, tachycardia, decreased BP, systolic hypertension; rare – hot flushes.

From the respiratory system: common – nasal congestion, yawning.

From the digestive system: common – diarrhea, vomiting, constipation, abdominal pain, dyspepsia, flatulence, stomach discomfort, abdominal distension, dry mouth.

From the skin and subcutaneous tissues: common – hyperhidrosis; uncommon – pruritus, cold sweat.

From the reproductive system: common – erectile dysfunction; uncommon – absence of ejaculation, orgasm disorder, including male anorgasmia, male genital paresthesia.

General reactions: common – weakness, irritability; uncommon – asthenia, feeling hot, feeling of anxiety, malaise, feeling of drunkenness.

Changes in laboratory parameters: common – increased BP; uncommon – increased heart rate, increased diastolic BP, increased orthostatic BP.

Contraindications

Severe heart disease (e.g., heart failure NYHA class II-IV, cardiac conduction disorders (AV block 2-3 degree 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 discontinuation of dapoxetine; concomitant use of thioridazine and within 14 days after its discontinuation; similarly, thioridazine should not be taken within 7 days after discontinuation of dapoxetine; concomitant use of serotonin reuptake inhibitors (selective serotonin reuptake inhibitors – SSRIs), serotonin and norepinephrine reuptake inhibitors and tricyclic antidepressants and other drugs with serotonergic activity (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 discontinuation of dapoxetine; concomitant use with potent inhibitors of CYP3A4, including ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, atazanavir; moderate and severe liver dysfunction; severe renal impairment; history of established or suspected orthostatic hypotension, history of mania/hypomania or bipolar disorder; children and adolescents under 18 years of age; hypersensitivity to dapoxetine.

Use in Pregnancy and Lactation

Dapoxetine is not intended for use in women.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

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.

Patients should be advised not to take Dapoxetine together with narcotic drugs. Concomitant use of dapoxetine with drugs possessing serotonergic activity, for example, ketamine, methylenedioxymethamphetamine (MDMA) and lysergic acid diethylamide (LSD), may lead to potentially serious reactions, including but not limited to arrhythmia, hyperthermia, and serotonin syndrome. Taking dapoxetine together with sedatives, for example, opiates or benzodiazepines, may enhance drowsiness and dizziness.

The combination of dapoxetine with alcohol may enhance the effect of the latter on the CNS and the neurocardiogenic side effects of alcohol, for example, syncope, which increases the risk of accidental injury. During the use of dapoxetine, it is recommended to refrain from alcohol consumption.

Possible prodromal symptoms, for example, nausea, dizziness, lightheadedness, palpitations, asthenia, confusion, and sweating, were also usually observed within the first 3 hours after taking dapoxetine and often preceded syncope. Patients should be informed that during treatment with dapoxetine, syncope with or without prodromal symptoms may occur at any time. The physician should inform the patient about the importance of adequate hydration and about recognizing prodromal signs and symptoms to reduce the risk of serious injury from falling due to loss of consciousness.

In patients with organic diseases of the heart and blood vessels (e.g., cardiac outflow obstruction, valvular disease, carotid artery stenosis, coronary artery atherosclerosis), the risk of adverse cardiovascular consequences of cardiac and other syncope is increased. However, there is currently insufficient data to determine whether this risk extends to vasovagal syncope in patients with cardiovascular diseases.

The physician should inform the patient in advance that if possible prodromal symptoms appear, for example, lightheadedness immediately upon standing up, they should immediately lie down so that the head is lower than the body, or sit down with the head lowered 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.

Use with caution in patients taking vasodilator drugs (e.g., alpha-blockers, nitrates, PDE5 inhibitors) due to the possible reduced tolerance of such patients to the orthostatic effect of dapoxetine.

When taking dapoxetine concomitantly with moderate inhibitors of CYP3A4 (erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem), the drug dose should be reduced to 30 mg, caution should be exercised.

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

If symptoms of mania/hypomania or bipolar disorder appear, the use of dapoxetine should be discontinued.

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

If the patient has signs and symptoms of depression before starting dapoxetine, an examination should be performed to rule out the presence of an undiagnosed depressive disorder. Dapoxetine 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 dapoxetine. Dapoxetine is not intended for the treatment of mental disorders (e.g., schizophrenia or depression), and it should not be taken by men with these diseases, as an exacerbation of depressive symptoms cannot be ruled out. Any worrisome thoughts or feelings should be reported to the doctor immediately, and if signs and symptoms of depression appear during treatment, Dapoxetine should be discontinued.

Caution is recommended when taking dapoxetine concomitantly with drugs that affect platelet function (e.g., atypical antipsychotics, phenothiazines, acetylsalicylic acid and other NSAIDs, anticoagulants), as well as in patients with a history of bleeding or coagulation disorders.

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

Effect on the ability to drive vehicles and operate machinery

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

Drug Interactions

Serious, sometimes fatal reactions have been described in patients receiving SSRIs and an MAO inhibitor concomitantly, including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations in vital signs, as well as changes in mental status, including severe 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 on the combined use of SSRIs and MAO inhibitors in animals suggest that these drugs may synergistically increase blood pressure and cause behavioral agitation. Therefore, Dapoxetine should not be taken concomitantly with MAO inhibitors and within 14 days after their discontinuation. Similarly, MAO inhibitors should not be taken within 7 days after discontinuation of dapoxetine.

Thioridazine prolongs the QT_c interval, which is accompanied by ventricular arrhythmia. Drugs that inhibit the CYP2D6 isoenzyme, Dapoxetine, appear to inhibit the metabolism of thioridazine. The resulting increase in thioridazine levels is expected to enhance the QT_c interval prolongation. Dapoxetine should not be taken concomitantly with thioridazine and within 14 days after its discontinuation. Similarly, thioridazine should not be taken within 7 days after discontinuation of dapoxetine.

As with SSRIs, the concomitant use of dapoxetine with serotonergic drugs (including MAO inhibitors, L-tryptophan, triptans, tramadol, linezolid, SSRIs, serotonin and norepinephrine reuptake inhibitors, lithium, and St. John’s Wort preparations) may increase the incidence of serotonergic adverse effects. Dapoxetine should not be taken concomitantly with other SSRIs, MAO inhibitors, and other serotonergic drugs, and for 14 days after discontinuation of these drugs. Similarly, these drugs should not be taken for 7 days after discontinuation of dapoxetine.

Caution is recommended when it is necessary to use dapoxetine concomitantly with drugs affecting CNS activity.

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.

Administration of ketoconazole at a dose of 200 mg twice daily for 7 days increased the C_max and AUC of dapoxetine (60 mg single dose) by 35% and 99%, respectively. Taking into account 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 the concomitant use of potent CYP2D6 inhibitors.

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

Administration of fluoxetine at a dose of 60 mg/day for 7 days increased the C_max and AUC of dapoxetine (60 mg single dose) by 50% and 88%, respectively. Taking into account 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 increased incidence and severity of dose-dependent adverse reactions. Therefore, caution is recommended when increasing the dapoxetine dose to 60 mg in patients receiving potent CYP2D6 inhibitors and in patients with low CYP2D6 activity.

Dapoxetine should be used with caution in patients taking PDE5 inhibitors due to their possibly reduced tolerance to orthostatic hypotension.

Dapoxetine should be used with caution in patients taking alpha-adrenergic blockers due to their possibly reduced tolerance to orthostatic hypotension.

Repeated administration of dapoxetine (60 mg/day for 6 days) increased the C_max and AUC 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.

Repeated administration of dapoxetine (60 mg/day for 6 days) decreased the AUC of midazolam (8 mg single dose) by approximately 20% (range from -60% to +18%). The clinical significance of this phenomenon in most patients is likely to be small. However, increased CYP3A activity may be clinically significant in some patients concomitantly taking drugs metabolized primarily by CYP3A and having a narrow therapeutic index.

Caution is recommended when using dapoxetine in patients chronically taking warfarin.

Concomitant use of ethanol and dapoxetine increases the frequency and severity of adverse reactions such as dizziness, drowsiness, slowed reflexes, and impaired judgment. The combination of alcohol with dapoxetine may also enhance neurocardiogenic adverse effects, particularly the frequency of syncope, which increases the risk of accidental injury. Therefore, patients should be advised to refrain from alcohol consumption during treatment with drugs containing Dapoxetine.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.