Дуагра - долгая и стойкая Любовь 🥰

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT

DUAGRA Trade name DUAGRA

International non-proprietary name None

Dosage form Film-coated tablets

Composition Each film-coated tablet contains: Active substances: Sildenafil citrate USP eq. Sildenafil 100 mg Dapoxetine hydrochloride eq. Dapoxetine 60 mg Excipients: lactose, calcium hydrogen phosphate, microcrystalline cellulose, corn starch, Povidone (K-30), isopropyl alcohol, purified talc, magnesium stearate, sodium starch glycolate, crospovidone (type A) Coating composition: Super Coat, purified talc, titanium dioxide, isopropyl alcohol, dichloromethane, Colour brilliant blue (Lake)

Pharmacotherapeutic group Drugs for the treatment of urological diseases. Other drugs for the treatment of urological diseases, including antispasmodics. Other drugs for the treatment of urological diseases. Drugs for the treatment of erectile dysfunction. Combinations. ATC code G04BE30

Pharmacological properties Pharmacodynamics Sildenafil is an oral therapy for erectile dysfunction. In a natural setting, i.e., with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. Dapoxetine is a short-acting drug for the treatment of premature ejaculation in men.

Mechanism of action The physiological mechanism responsible for penile erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which leads to an increase in the level of cyclic guanosine monophosphate (cGMP), causing relaxation of the smooth muscles in the corpus cavernosum and allowing blood flow. Dapoxetine is a potent selective serotonin reuptake inhibitor (SSRI) with an IC50 of 1.12 nM, while its main human metabolites, desmethyldapoxetine (IC50 <1.0 nM) and didesmethyldapoxetine (IC50 = 2.0 nM) are equivalent or less effective (dapoxetine-N-oxide) (IC50 = 282 nM). It is assumed that the mechanism of action of dapoxetine in premature ejaculation is associated with the inhibition of serotonin reuptake by neurons and the subsequent enhancement of the neurotransmitter's action on pre- and postsynaptic receptors.

Pharmacokinetics Sildenafil Absorption: Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30–120 minutes (average 60 minutes) when taken orally in a fasting state. The mean absolute oral bioavailability is 41% (range 25-63%). After oral administration of Sildenafil, AUC and Cmax increase in proportion to the dose within the recommended dose range (25-100 mg). When Sildenafil is taken with food, the rate of absorption decreases with an average delay in tmax of 60 minutes and an average decrease in Cmax of 29%. Distribution: The mean steady-state volume of distribution (Vd) for sildenafil is 105 L, indicating distribution into tissues. After a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (CV 40%). Since sildenafil (and its main circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in a mean maximum free plasma concentration for sildenafil of 18 ng/mL (38 nM). Protein binding is independent of total drug concentration. In healthy volunteers receiving sildenafil (single 100 mg dose), less than 0.0002% (average 188 ng) of the administered dose was present in the ejaculate 90 minutes after dosing. Biotransformation: Sildenafil is broken down primarily by liver microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The main circulating metabolite is the result of N-demethylation of sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those observed for sildenafil. The N-desmethyl metabolite is further metabolized with a terminal half-life of about 4 hours. Elimination: The total clearance of sildenafil is 41 L/h with a terminal half-life of 3-5 hours. After oral or intravenous administration, sildenafil is excreted as metabolites primarily in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).

Dapoxetine hydrochloride Absorption: Dapoxetine is rapidly absorbed with maximum plasma concentrations (Cmax) occurring approximately 1-2 hours after taking the tablet. Absolute bioavailability is 42% (range 15–76%), and a proportional increase in dose (AUC and Cmax) is observed at a dose of 30–60 mg. After multiple doses, AUC values for both dapoxetine and the active metabolite desmethyldapoxetine (DED) increase by approximately 50% compared to single-dose AUC values. A high-fat meal slightly decreased Cmax (by 10%) and moderately increased AUC (by 12%) of dapoxetine and slightly delayed the time to reach peak dapoxetine concentrations. These changes are not clinically significant. Dapoxetine can be taken with or without food. Distribution: More than 99% of dapoxetine is bound in vitro to human serum proteins. The active metabolite desmethyldapoxetine (DED) is 98.5% protein-bound. Dapoxetine has a mean steady-state volume of distribution of 162 L. Biotransformation: In vitro studies show that dapoxetine is cleared by several enzyme systems in the liver and kidneys, primarily CYP2D6, CYP3A4, and flavin monooxygenase (FMO1). After oral administration of 14C-dapoxetine, dapoxetine was extensively metabolized into several metabolites, mainly through the following biotransformation pathways: N-oxidation, N-demethylation, naphthyl hydroxylation, glucuronidation, and sulfation. There was evidence of presystemic first-pass metabolism after oral administration. Intact dapoxetine and dapoxetine-N-oxide were the main circulating components in plasma. In vitro binding and transport studies show that dapoxetine-N-oxide is inactive. Additional metabolites, including desmethyl-dapoxetine and didesmethyl-dapoxetine, account for less than 3% of the total circulating drug-related substances. In vitro binding studies show that DED is equipotent to dapoxetine, and didesmethyldapoxetine has approximately 50% of the activity of dapoxetine (see section 5.1). Unbound exposures (AUC and Cmax) of DED are approximately 50% and 23%, respectively, of the unbound exposure of dapoxetine. Elimination: Dapoxetine metabolites are mainly excreted in the urine as conjugates. No unchanged active substance was detected in the urine. After oral administration, dapoxetine has an initial half-life (disposition) of approximately 1.5 hours, with plasma levels less than 5% of peak concentrations 24 hours after dosing and a terminal half-life of approximately 19 hours. The terminal half-life of DED is approximately 19 hours.

Indications for use

• treatment of erectile dysfunction in men, characterized by the inability to achieve and maintain a penile erection sufficient for satisfactory sexual intercourse
• intravaginal ejaculatory latency time (IELT) is less than two minutes
• persistent or recurrent ejaculation after minimal sexual stimulation before, during, or shortly after penetration, and occurring earlier than the patient desires
• marked distress or interpersonal difficulty as a consequence of PE
• poor control over ejaculation

Method of administration and dosage Take 1 tablet one to three hours before sexual activity with at least one full glass of water. Do not take more than 1 tablet within 24 hours. Use in adults: The recommended dose is 50 mg for sildenafil and 30 mg for dapoxetine, and it can be taken as needed - approximately one hour before sexual activity. Based on efficacy and tolerability, the dose may be increased to 100 mg of sildenafil and 60 mg of dapoxetine. The maximum recommended dose is 100 mg for sildenafil and 60 mg for dapoxetine. The maximum recommended dosing frequency is once daily. Method of administration Take orally with a glass of water. It should be taken 1-2 hours before sexual activity. Take once daily as needed 1-3 hours before sexual activity. Do not take more than once a day.

Drug interactions Nitrates Concomitant use of sildenafil citrate with nitrates in any form is contraindicated. Peritoneal and other potent CYP3A inhibitors Concomitant use of sildenafil citrate with peritoneal or other potent CYP3A inhibitors is not recommended. Alpha-blockers Use caution when prescribing alpha-blockers concurrently with sildenafil citrate due to the additive hypotensive effect. Amlodipine When sildenafil citrate 100 mg was administered concurrently with amlodipine, 5 mg or 10 mg orally, to hypertensive patients, the mean additional reduction in supine blood pressure was 8 mm Hg systolic and 7 mm Hg diastolic. Potential for interaction with monoamine oxidase inhibitors (MAOIs) Dapoxetine should not be used in combination with MAOIs, or within 14 days of discontinuing MAOI treatment. Similarly, MAOIs should not be administered within 7 days of discontinuing dapoxetine. Potential for interaction with thioridazine Thioridazine should not be administered within 14 days of discontinuing dapoxetine. Medicinal/herbal products with serotonergic effects Dapoxetine should not be used concurrently with other SSRIs, MAOIs, or other medicinal/herbal products, or within 14 days of discontinuing treatment with these medicinal/herbal products. Similarly, these medicinal products should not be administered within 7 days of discontinuing dapoxetine treatment. Medicinal products acting on the CNS Caution should be exercised if concurrent use of dapoxetine with such medicinal products is required. Effect of concurrently administered medicinal products on dapoxetine hydrochloride In vitro studies in hepatic, renal, and intestinal microsomes show that dapoxetine is metabolized primarily by CYP2D6, CYP3A4, and flavin monooxygenase 1 (FMO1). Thus, inhibitors of these enzymes may reduce the clearance of dapoxetine. CYP3A4 inhibitors Concomitant use of dapoxetine and potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, and atazanavir, is contraindicated. CYP2D6 inhibitors Caution should be exercised when increasing the dose to 60 mg in patients taking potent CYP2D6 inhibitors or when increasing the dose to 60 mg in patients who are poor CYP2D6 metabolizers.

Special instructions Sexual activity poses a cardiac risk in patients with cardiovascular disease. Sildenafil citrate should generally not be used in men for whom sexual activity is inadvisable due to their cardiovascular status. Before prescribing sildenafil, the physician should carefully consider whether such vasodilatory effects could adversely affect patients, especially in combination with sexual activity. Caution is advised when administering phosphodiesterase type 5 (PDE5) inhibitors concurrently with alpha-blockers. PDE5 inhibitors, including Viagra (sildenafil citrate), and alpha-adrenergic blocking agents are both vasodilators that have blood pressure-lowering effects. When used in combination, an additive effect on BP can be expected. In some patients, concurrent use of both drugs can significantly lower BP and lead to symptomatic hypotension. Sildenafil citrate has a systemic vasodilatory effect and may enhance the blood pressure-lowering effect of other antihypertensive drugs. Sildenafil citrate should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) or in patients with conditions that may predispose to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). The safety and efficacy of combinations of Viagra (sildenafil citrate) with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended. Ethanol Combining alcohol with dapoxetine may increase alcohol-related cognitive effects and may also increase the frequency of adverse effects on the electrocardiogram, such as syncope, thereby increasing the risk of accidental injury; therefore, patients are advised to avoid alcohol consumption while taking dapoxetine. Syncope Dapoxetine should be administered with caution to patients taking medicinal products with vasodilatory properties (such as alpha-adrenergic receptor antagonists, nitrates, PDE5 inhibitors) due to possible reduced orthostatic tolerance. Moderate CYP3A4 inhibitors Caution is recommended for patients taking moderate CYP3A4 inhibitors, and the dose is limited to 30 mg. Potent CYP2D6 inhibitors Caution is recommended if increasing the dose to 60 mg in patients taking potent CYP2D6 inhibitors or if increasing the dose to 60 mg in patients who are poor CYP2D6 metabolizers, as this may increase exposure levels, which may lead to a higher frequency and severity of dose-dependent adverse reactions. Suicide/suicidal thoughts Antidepressants, including SSRIs, compared to placebo, increase the risk of suicidal thoughts and suicide in short-term studies in children and adolescents with major depressive disorders and other psychiatric disorders. Mania Dapoxetine should not be used in patients with a history of mania/hypomania or bipolar disorder, and it should be discontinued in any patient who develops symptoms of these disorders. Seizures: due to the potential of SSRIs to lower the seizure threshold, dapoxetine should be discontinued in any patient who develops seizures and avoided in patients with unstable epilepsy. Patients with controlled epilepsy should be carefully monitored. Use in children and adolescents under 18 years: dapoxetine is not intended for children under 18 years of age. Depression and psychiatric disorders Men with signs and symptoms of depression should be screened before starting dapoxetine to rule out depressive disorders. Concurrent treatment with dapoxetine and antidepressants, including SSRIs and SNRIs, is contraindicated. Physicians should advise patients to report any distressing thoughts or feelings at any time, and if symptoms of depression develop during treatment, dapoxetine treatment should be discontinued. Renal impairment Dapoxetine is not recommended for patients with severe renal impairment, and caution is recommended for patients with mild or moderate renal impairment. Lactose intolerance Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug. CYP3A4 inhibitors CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, and atazanavir are contraindicated. Moderate CYP3A4 inhibitors Caution should be exercised when prescribing dapoxetine 60 mg concurrently with a moderate CYP3A4 inhibitor. PDE5 inhibitors Dapoxetine should be administered with caution to patients using PDE5 inhibitors due to possible reduced orthostatic tolerance. Alpha-blockers Dapoxetine should be administered with caution to patients using alpha-adrenergic receptor antagonists due to possible reduced orthostatic tolerance. Warfarin There are no data evaluating the effect of chronic warfarin use with dapoxetine; therefore, caution should be exercised when prescribing dapoxetine to patients taking warfarin chronically. Pregnancy and lactation Contraindicated for pregnant women and during lactation. Animal studies do not demonstrate direct or indirect negative effects on fertility, pregnancy, or embryo-fetal development. It is not known whether the substance is excreted in breast milk.

Overdose No cases of overdose have been reported. In case of overdose, standard supportive measures should be taken as necessary. Due to high protein binding and a large volume of distribution, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be effective. No specific antidote is known.

Side effects Common

• headache, dizziness
• chromatopsia (mild and transient, mainly changes in color perception), visual impairment
• nasal congestion
• dyspepsia
• flushing

Rare

• myocardial infarction, atrial fibrillation
• acute cerebrovascular accident, syncope
• deafness
• epistaxis
• hypertension, hypotension
• hypersensitivity reactions
• seizures, recurrent seizures

Very rare

• tachycardia
• somnolence, decreased sensitivity
• conjunctival disorders and other eye diseases
• tinnitus
• nausea, vomiting, dry mouth
• skin rash
• muscle pain
• chest pain, fatigue

Not known

• ventricular arrhythmia, unstable angina, sudden death
• transient ischemic attack, seizure, recurrent seizure
• non-arteritic anterior ischemic optic neuropathy, retinal vascular occlusion
• priapism, prolonged erection

Contraindications

• hypersensitivity to the active substance or components of the drug
• patients for whom sexual activity is not recommended (e.g., in cases of unstable angina or severe heart failure)
• patients who have lost vision in one eye due to non-arteritic anterior ischemic optic neuropathy
• severe hepatic impairment
• patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption
• use in combination with nitrates or nitric oxide donors
• not intended for use by women
• children and adolescents under 18 years of age

Use with caution in:

• anatomical deformation of the penis (including angulation, cavernosal fibrosis, or Peyronie's disease)
• conditions predisposing to priapism (such as sickle cell anemia, multiple myeloma, leukemia, thrombocythemia)
• bleeding disorders
• active peptic ulcer disease
• hereditary retinitis pigmentosa
• heart failure
• unstable angina, myocardial infarction, stroke, or life-threatening arrhythmias within the last 6 months
• arterial hypertension (blood pressure (BP) > 170/100 mm Hg) or hypotension (BP < 90/50 mm Hg)

Storage conditions Store at a temperature not exceeding 30ºC in a dry place. Keep out of reach of children.

Dosage form and packaging Film-coated tablets Packaging: blister pack of 1 x 4 tablets

Shelf life 36 months.

Pharmacy dispensing terms By prescription.