Intagra® ic

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INTAGRA® IC (INTAGRA IC)

Composition:

Active substance: sildenafil citrate;

One tablet contains sildenafil citrate (calculated as sildenafil) 25 mg (0.025 g), 50 mg (0.05 g), or 100 mg (0.1 g);

Excipients: lactose monohydrate, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, potato starch, sodium croscarmellose, sodium bicarbonate, gelatin, colloidal anhydrous silicon dioxide, talc, magnesium stearate, hypromellose (hydroxypropylmethylcellulose), polyethylene glycol (macrogol), titanium dioxide (E 171), acesulfame potassium, candurin (for 25 mg tablets – potassium aluminosilicate (E 555), iron oxide red (E 172); for 50 mg tablets – potassium aluminosilicate (E 555), titanium dioxide (E 171); for 100 mg tablets – potassium aluminosilicate (E 555), titanium dioxide (E 171), iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets, bronze-colored (0.025 g dosage), silver-colored (0.05 g dosage), or golden-colored (0.1 g dosage).

Pharmacotherapeutic group.

Agents used in erectile dysfunction. Sildenafil. ATC code G04BE03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Sildenafil is an oral medication intended for the treatment of erectile dysfunction. In the presence of sexual stimulation, the drug restores impaired erectile function by enhancing blood flow to the penis.

The physiological mechanism causing erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Released nitric oxide activates the enzyme guanylate cyclase, which stimulates an increase in the level of cyclic guanosine monophosphate (cGMP), leading in turn to relaxation of the smooth musculature of the corpus cavernosum and promoting blood inflow.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for cGMP degradation. The effects of sildenafil on erection are peripherally mediated. Sildenafil does not exert a direct relaxing effect on isolated human corpus cavernosum tissue, but strongly potentiates the relaxing effect of NO on this tissue. When the NO/cGMP metabolic pathway is activated during sexual stimulation, sildenafil's inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce the desired pharmacological effect, sexual stimulation is required.

Effect on pharmacodynamics.

In vitro studies have demonstrated that sildenafil is selective for PDE5, which actively participates in the erectile process. The effect of sildenafil on PDE5 is more potent than on other known phosphodiesterases. This effect is 10-fold more potent than its effect on PDE6, which is involved in phototransduction processes in the retina. At maximum recommended doses, sildenafil's selectivity for PDE5 is 80 times greater than for PDE1, 700 times greater than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. Specifically, sildenafil's selectivity for PDE5 is 4000 times greater than for PDE3—an isoform of cAMP-specific phosphodiesterase involved in regulating cardiac contractility.

Pharmacokinetics.

Absorption.

Sildenafil is rapidly absorbed. Maximum plasma concentrations are reached within 30–120 minutes (median 60 minutes) after oral administration on an empty stomach. The mean absolute bioavailability after oral administration is 41% (ranging from 25% to 63%). Within the recommended dose range (25–100 mg), AUC and Cmax values of sildenafil increase proportionally with dose.

When sildenafil is taken with food, the extent of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%.

Distribution.

The mean volume of distribution at steady state (Vd) is 105 liters, indicating extensive distribution of the drug into body tissues. After a single 100 mg oral dose of sildenafil, the mean peak total plasma concentration of sildenafil is approximately 440 ng/mL (coefficient of variation 40%). Since binding of sildenafil and its major N-desmethyl metabolite to plasma proteins reaches 96%, the mean peak free plasma concentration of sildenafil is approximately 18 ng/mL (38 nmol). The degree of protein binding is independent of total sildenafil concentrations.

In healthy volunteers who received a single 100 mg dose of sildenafil, less than 0.0002% (mean 188 ng) of the administered dose was detected in semen 90 minutes after dosing.

Biotransformation.

Sildenafil is metabolized primarily by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite is formed via N-demethylation of sildenafil. The metabolite's selectivity for PDE5 is comparable to that of sildenafil, and its in vitro activity against PDE5 is approximately 50% of the parent compound. Plasma concentrations of this metabolite are approximately 40% of sildenafil plasma concentrations. The N-desmethyl metabolite undergoes further metabolism, and its elimination half-life is approximately 4 hours.

Elimination.

Total clearance of sildenafil is 41 L/h, resulting in an elimination half-life of 3–5 hours. Following both oral and intravenous administration, sildenafil is excreted primarily as metabolites in feces (approximately 80% of the orally administered dose) and to a lesser extent in urine (approximately 13% of the orally administered dose).

Pharmacokinetics in special patient populations.

Elderly patients.

In healthy elderly volunteers (aged 65 years and older), reduced clearance of sildenafil was observed, resulting in approximately 90% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite compared to younger healthy volunteers (aged 18–45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

Renal impairment.

In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil remained unchanged after a single 50 mg oral dose. Mean AUC and Cmax of the N-desmethyl metabolite increased by up to 126% and 73%, respectively, compared to age-matched volunteers with normal renal function. However, due to high inter-individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax by 100% and 88%, respectively, compared to age-matched volunteers with normal renal function. Additionally, AUC and Cmax of the N-desmethyl metabolite increased significantly by 200% and 79%, respectively.

Hepatic impairment.

In volunteers with mild to moderate hepatic impairment (Child-Pugh classes A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with normal liver function. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

INTAGRA® IS is recommended for use in men with erectile dysfunction, defined as the inability to achieve or maintain an erection sufficient for successful sexual performance.

For INTAGRA® IS to be effective, sexual stimulation is required.

Contraindications.

Hypersensitivity to the active substance or to any of the other components of the medicinal product.

Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway and may potentiate the hypotensive effect of nitrates.

Concomitant use of phosphodiesterase type 5 (PDE5) inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated, as it may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").

Conditions in which sexual activity is not recommended (e.g., severe cardiovascular disorders such as unstable angina or severe heart failure).

Unilateral vision loss due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this condition is related to previous use of PDE5 inhibitors.

Conditions such as severe hepatic impairment, arterial hypotension (blood pressure below 90/50 mm Hg), recent stroke or myocardial infarction, and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterases), as the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on sildenafil.

In vitro studies.

Sildenafil is metabolized primarily by cytochrome P450 isoenzyme 3A4 (major pathway) and to a lesser extent by isoenzyme 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, while inducers may increase its clearance.

In vivo studies.

Population pharmacokinetic analysis of clinical trial data demonstrated reduced sildenafil clearance when co-administered with CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, cimetidine). Although an increased incidence of adverse events has not been observed with concomitant use of sildenafil and CYP3A4 inhibitors, consideration should be given to initiating treatment with a sildenafil dose of 25 mg.

Concomitant administration of the HIV-protease inhibitor ritonavir, a very potent inhibitor of P450, at steady-state concentrations (500 mg twice daily), and sildenafil (single 100 mg dose) resulted in a 300% increase (4-fold) in sildenafil maximum concentration (Cmax) and a 1000% increase (11-fold) in systemic exposure (AUC). After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL when sildenafil was administered alone, indicating a significant effect of ritonavir on a wide range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Due to these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended (see section "Special precautions for use"); in any case, the maximum sildenafil dose should not exceed 25 mg within 48 hours.

Concomitant administration of the HIV-protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady-state concentrations (1200 mg three times daily), and sildenafil (single 100 mg dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in AUC. No effect of sildenafil on saquinavir pharmacokinetics was observed (see section "Dosage and administration"). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have a more pronounced effect.

Administration of sildenafil (single 100 mg dose) with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in sildenafil AUC. In healthy male volunteers, azithromycin (500 mg daily for 3 days) did not affect AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg, when administered concomitantly with 50 mg sildenafil in healthy volunteers, increased plasma concentrations of sildenafil by 56%.

Grapefruit juice is a weak inhibitor of intestinal CYP3A4 and may cause a moderate increase in plasma levels of sildenafil.

Single administration of antacids (magnesium hydroxide/aluminum hydroxide) did not affect sildenafil bioavailability.

Although specific interaction studies with all medicinal products have not been conducted, population pharmacokinetic analysis data indicate that the pharmacokinetics of sildenafil were not altered when co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-blockers, or CYP450 metabolism inducers (e.g., rifampicin, barbiturates).

In a study involving healthy male volunteers, concomitant administration of the endothelin antagonist bosentan (a moderate CYP3A4 inducer, CYP2C9 inducer, and possibly CYP2C19 inducer) at steady state (125 mg twice daily) and sildenafil at steady state (80 mg three times daily) resulted in a 62.6% and 55.4% reduction in AUC and Cmax of sildenafil, respectively. Therefore, concomitant use of potent CYP3A4 inducers such as rifampicin may lead to a more pronounced decrease in plasma sildenafil concentrations.

Nicorandil is a hybrid compound combining a potassium channel opener and a nitrate donor. The nitrate component implies a potential for serious interaction with sildenafil.

Effects of sildenafil on other medicinal products.

In vitro studies.

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 µmol). Since peak plasma concentrations of sildenafil are approximately 1 µmol, clinically significant effects of INTAGRA® IS on the clearance of substrates of these isoenzymes at recommended doses are unlikely.

There are no data on the interaction between sildenafil and non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.

In vivo studies.

Since sildenafil affects the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, it is known to potentiate the hypotensive effect of nitrates. Therefore, concomitant use of sildenafil with nitric oxide donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat. Preclinical studies have demonstrated an additive systemic blood pressure-lowering effect when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. In patients participating in the study, no positive clinical effect was observed from the concomitant use of PDE5 inhibitors and riociguat. Concomitant use of riociguat with PDE5 inhibitors (including sildenafil) is contraindicated (see section "Contraindications").

Concomitant use of sildenafil and alpha-adrenoreceptor blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most commonly occurred within 4 hours after sildenafil administration (see sections "Dosage and administration" and "Special precautions for use"). In three drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were administered concomitantly to patients with benign prostatic hyperplasia whose condition was stabilized on doxazosin. In these populations, mean additional reductions in supine blood pressure were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean reductions in standing blood pressure were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Cases of symptomatic orthostatic hypotension were occasionally reported with concomitant use of sildenafil and doxazosin in patients whose condition was stabilized on doxazosin. These reports described dizziness and pre-syncope, but no syncope.

No significant interactions were observed with concomitant administration of sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), both metabolized by CYP2C9.

Sildenafil (50 mg) did not prolong bleeding time induced by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers at moderate maximum blood ethanol levels of 80 mg/dL.

No differences in adverse effect profile were observed in patients taking sildenafil compared to placebo when used concomitantly with antihypertensive drug classes such as diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, vasodilators and centrally acting antihypertensives, adrenergic neuron blockers, calcium channel blockers, and alpha-adrenoreceptor blockers.

In a specific interaction study, concomitant administration of sildenafil (100 mg) and amlodipine in patients with arterial hypertension resulted in an additional 8 mm Hg reduction in supine systolic blood pressure and a 7 mm Hg reduction in diastolic blood pressure. These additional reductions were comparable in magnitude to those observed with sildenafil alone in healthy volunteers.

Sildenafil 100 mg did not affect the pharmacokinetic parameters of the HIV-protease inhibitors saquinavir and ritonavir, which are CYP3A4 substrates.

In healthy male volunteers, administration of sildenafil at steady state (80 mg three times daily) increased AUC and Cmax of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.

Administration of a single dose of sildenafil to patients with arterial hypertension on stable therapy with sacubitril/valsartan, whose pharmacokinetic parameters had reached steady state, was associated with a significantly greater reduction in blood pressure compared to sacubitril/valsartan alone. Therefore, caution is advised when initiating sildenafil treatment in patients receiving sacubitril/valsartan therapy.

Special precautions for use.

Before initiating therapy, a medical history should be obtained and a physical examination performed to diagnose erectile dysfunction and determine its possible causes.

Cardiovascular risk factors.

Since sexual activity carries a certain cardiovascular risk, physicians should assess the cardiovascular status of patients before initiating any treatment for erectile dysfunction. Sildenafil exerts a vasodilatory effect, manifested as mild and transient reduction in blood pressure. Before prescribing sildenafil, physicians should carefully consider whether this effect could adversely affect patients with underlying cardiovascular conditions, particularly when combined with sexual activity. Patients who may be more sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic regulation of blood pressure.

Sildenafil potentiates the hypotensive effect of nitrates (see section "Contraindications").

In the post-marketing period, serious adverse cardiovascular events have been reported, including myocardial infarction, unstable angina, sudden cardiovascular events with fatal outcome, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, arterial hypertension, and arterial hypotension, which temporally coincided with sildenafil use. In most, but not all, patients, risk factors for cardiovascular disease were present. Many of these adverse events occurred during or immediately after sexual intercourse, and only a few occurred shortly after sildenafil administration without sexual activity. Therefore, it is not possible to determine whether the development of such adverse reactions is directly related to risk factors or whether their occurrence is influenced by other factors.

Priapism.

Medications for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical penile deformities (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients with conditions predisposing to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Since the market introduction of sildenafil, cases of prolonged erection and priapism have been reported. If an erection lasts longer than 4 hours, patients should seek immediate medical assistance. Without prompt treatment, priapism may lead to penile tissue damage and permanent loss of potency.

Concomitant use with other PDE5 inhibitors or other erectile dysfunction medications.

The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other medications for the treatment of pulmonary arterial hypertension containing sildenafil, or with other erectile dysfunction medications, have not been studied. Therefore, such combinations are not recommended.

Effect on vision.

Spontaneous reports of visual disturbances have been associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports and data from observational studies have indicated cases of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition, associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised to discontinue sildenafil and seek immediate medical advice in case of sudden visual impairment (see section "Contraindications").

Concomitant use with ritonavir.

Concomitant use of sildenafil and ritonavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with α-adrenoreceptor blockers.

Sildenafil should be used with caution in patients taking α-adrenoreceptor blockers, as this combination may lead to symptomatic hypotension in some susceptible individuals. Symptomatic hypotension usually occurs within 4 hours after sildenafil administration. To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized on α-blocker therapy before initiating sildenafil. Additionally, consideration should be given to starting with an initial dose of 25 mg (see section "Dosage and administration"). Patients should also be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Effect on bleeding.

Studies on human platelets have demonstrated in vitro that sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside. There is no information available on the safety of sildenafil use in patients with bleeding disorders or active peptic ulcer. Therefore, sildenafil use in these patient groups should only be considered after careful assessment of the benefit-risk ratio.

The product contains lactose and therefore should not be used in men with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

After administration of a 100 mg dose to healthy volunteers, no effect on sperm morphology or motility was observed (see section "Pharmacological properties. Pharmacodynamics").

Hearing loss.

Physicians should advise patients to discontinue PDE5 inhibitors, including sildenafil, and seek immediate medical help in case of sudden decrease or loss of hearing. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with PDE5 inhibitors, including sildenafil. It is not possible to determine whether these events are directly related to PDE5 inhibitor use or to other factors.

Concomitant use with antihypertensive agents.

Sildenafil exerts systemic vasodilatory effects and may further reduce blood pressure in patients taking antihypertensive medications. In a specific drug interaction study, concomitant oral administration of amlodipine (5 mg or 10 mg) and sildenafil (100 mg) resulted in an average additional reduction in systolic blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg.

Sexually transmitted diseases.

Use of the medication INTAGRA® IS does not protect against sexually transmitted diseases. Consideration should be given to instructing patients about necessary preventive measures to protect against sexually transmitted diseases, including human immunodeficiency virus.

Use during pregnancy or breastfeeding.

INTAGRA® IS is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product INTAGRA® IS may have a minor influence on the ability to drive or operate machinery. Since dizziness and visual disturbances have been reported during clinical trials with sildenafil, patients should determine their individual response to INTAGRA® IS before driving a vehicle or operating machinery.

Dosage and Administration

The medication should be taken orally.

Adults.

The recommended dose of INTAGRA® IS is 50 mg, taken as needed approximately 1 hour before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once per day. When INTAGRA® IS is taken with food, the onset of action may be delayed compared to administration on an empty stomach.

Elderly Patients.

Dose adjustment in elderly patients (≥ 65 years of age) is not required.

Patients with Renal Impairment.

For patients with mild to moderate renal impairment (creatinine clearance of 30–80 mL/min), the recommended dose is the same as stated above in the section «Adults».

In patients with severe renal impairment (creatinine clearance < 30 mL/min), sildenafil clearance is reduced; therefore, a starting dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be gradually increased to 50 mg and then to 100 mg if necessary.

Patients with Hepatic Impairment.

Since sildenafil clearance is reduced in patients with hepatic impairment (e.g., cirrhosis), a starting dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be gradually increased to 50 mg and then to 100 mg if necessary.

Patients Taking Other Medications.

If patients are concurrently taking CYP3A4 inhibitors (see section «Interaction with Other Medicinal Products and Other Forms of Interaction»), a starting dose of 25 mg should be considered (except for ritonavir, which is not recommended to be used concomitantly with sildenafil; see section «Special Warnings and Precautions for Use»).

To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized on α-blocker therapy before initiating sildenafil. Additionally, consideration should be given to starting with a dose of 25 mg (see sections «Special Warnings and Precautions for Use» and «Interaction with Other Medicinal Products and Other Forms of Interaction»).

Children.

The medication is not indicated for use in individuals under 18 years of age.

Overdose.

In clinical studies involving healthy volunteers, administration of single doses of sildenafil up to 800 mg resulted in adverse reactions similar to those observed at lower doses, but occurring more frequently and with greater severity. Administration of sildenafil at a dose of 200 mg did not increase efficacy but led to a higher incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

Treatment. In case of overdose, standard supportive measures should be implemented as necessary. Enhanced clearance of sildenafil by hemodialysis is unlikely due to the high degree of plasma protein binding and the absence of urinary elimination of sildenafil.

Adverse Reactions.

In double-blind, placebo-controlled clinical trials, the most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, visual disturbances, cyanopsia, and blurred vision.

All clinically significant adverse reactions observed during clinical trials more frequently than with placebo are listed below according to the "System Organ Class" and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Additionally, the frequency of clinically significant adverse reactions reported during post-marketing experience with sildenafil is considered unknown. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations: uncommon – rhinitis.

Immune system disorders: uncommon – hypersensitivity.

Nervous system disorders: very common – headache; common – dizziness; uncommon – somnolence, hypoesthesia; rare – stroke, transient ischemic attack, seizures*, seizure recurrence*, syncope.

Eye disorders: common – color vision disturbances (chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia), visual disturbances, blurred vision; uncommon – lacrimation disorders (dry eyes, abnormal lacrimation, increased lacrimation), eye pain, photophobia, photopsia, eye hyperemia, visual brightness, conjunctivitis; rare – non-arteritic anterior ischemic optic neuropathy*, retinal vessel occlusion*, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, halos around light sources in the visual field, eye edema, eye swelling, eye disorders, conjunctival hyperemia, eye irritation, abnormal eye sensations, eyelid edema, scleral discoloration.

Ear and labyrinth disorders: uncommon – vertigo, tinnitus; rare – deafness.

Cardiac disorders: uncommon – tachycardia, palpitations (increased heart rate); rare – fatal cardiovascular event*, myocardial infarction, ventricular arrhythmia*, atrial fibrillation, unstable angina.

Vascular disorders: common – flushing; uncommon – hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders: common – nasal congestion; uncommon – epistaxis, nasal sinus congestion; rare – throat tightness, nasal mucosal edema, nasal dryness.

Gastrointestinal disorders: common – nausea, dyspepsia; uncommon – gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth; rare – oral hypoesthesia.

Skin and subcutaneous tissue disorders: uncommon – rash; rare – Stevens-Johnson syndrome*, toxic epidermal necrolysis*.

Musculoskeletal and connective tissue disorders: uncommon – myalgia, limb pain.

Renal and urinary disorders: uncommon – hematuria.

Reproductive system and breast disorders: rare – penile bleeding, priapism*, hematospermia, prolonged erection.

General disorders and administration site conditions: uncommon – chest pain, increased fatigue, feeling of warmth; rare – irritation.

Investigations: uncommon – increased heart rate.

* Reported only during post-marketing experience with sildenafil.

The following events were observed in < 2% of patients during controlled clinical trials of sildenafil; a causal relationship has not been established. Reports included events with a probable relationship to sildenafil use. Events not listed were mild and reports were too imprecise to be meaningful.

General: facial swelling, photosensitivity reactions, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury.

Cardiovascular system: angina pectoris, AV block, migraine, postural hypotension, myocardial ischemia, cerebral vessel thrombosis, sudden cardiac arrest, ECG abnormalities, cardiomyopathy.

Gastrointestinal tract: glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding, gingivitis.

Blood and lymphatic system: anemia, leukopenia.

Metabolism and nutrition: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

Musculoskeletal system: arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Nervous system: ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.

Respiratory system: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

Skin: urticaria, herpes, pruritus, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Specific sensations: sudden decrease or loss of hearing, ear pain, eye hemorrhage, cataract, dry eyes.

Genitourinary system: cystitis, nocturia, increased frequency of urination, breast enlargement, urinary incontinence, ejaculation disorders, genital swelling, anorgasmia.

Post-marketing experience.

Following the marketing of sildenafil, the adverse reactions listed below have been identified. Since these reactions are reported voluntarily and from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were reported due to their severity, frequency of reporting, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular and cerebrovascular events. Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral hemorrhage, subarachnoid and intracerebral hemorrhage, and pulmonary hemorrhage, which occurred in temporal association with sildenafil use. Most, but not all, patients had pre-existing cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred immediately after sildenafil use without sexual activity. Other events occurred within hours or days after sildenafil use and sexual activity. It is not possible to determine whether these events are directly related to sildenafil use, sexual activity, pre-existing risk factors, a combination of these factors, or other factors.

Blood and lymphatic system: vaso-occlusive crisis. In a small, prematurely terminated study of sildenafil use in patients with pulmonary arterial hypertension secondary to sickle cell anemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo. The clinical significance of this information for patients using sildenafil for the treatment of erectile dysfunction is unknown.

Nervous system: anxiety, transient global amnesia.

Specific sensations.

Hearing. Following the marketing of sildenafil, cases of sudden decrease or loss of hearing temporally associated with sildenafil use have been reported. In some cases, medical conditions and other factors that could have contributed to hearing adverse reactions were reported. In many cases, follow-up medical information is lacking. It is not possible to determine whether these events are directly related to sildenafil use, pre-existing risk factors for hearing loss, a combination of these factors, or other factors.

Vision. Transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal edema, retinal vascular disorders or hemorrhage, vitreous detachment.

Rare cases of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of vision loss including permanent vision loss, have been reported after sildenafil marketing, temporally associated with PDE5 inhibitors, including sildenafil. Many, but not all, patients had pre-existing anatomical or vascular risk factors for NAION, including (but not limited to): low cup-to-disc ratio of the optic nerve (crowded optic disc), age over 50 years, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are directly related to PDE5 inhibitor use, pre-existing anatomical or vascular risk factors, a combination of these factors, or other factors.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk ratio associated with the use of this medicinal product. Physicians should report any suspected adverse reactions in accordance with legal requirements.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

Film-coated tablets, 0.025 g, 0.05 g, and 0.1 g, pack sizes: № 1, № 2 (2 × 1), and № 4 (2 × 2) in blisters within a carton.

Prescription category. Prescription only.

Manufacturer.

"INTERKHIM" Limited Liability Company.

Manufacturer's address and location of business activity.

40-A, 21st km of Starokyivska Road, Odesa, 65025, Ukraine.