Superviga 100

INSTRUCTIONS FOR MEDICAL USE | consumption | of the medicinal product SUPERVIGA 25, SUPERVIGA 50, SUPERVIGA 100

Composition:

Active substance: 1 tablet contains sildenafil citrate equivalent to sildenafil 25 mg or 50 mg or 100 mg;

Excipients: microcrystalline cellulose; calcium hydrogen phosphate; aluminum hydroxide; sodium croscarmellose; povidone; magnesium stearate; colloidal anhydrous silicon dioxide; dry mixture "Opadry II white" containing titanium dioxide (E 171), talc, polyethylene glycol (macrogol), polyvinyl alcohol; indigocarmine (E 132); Candurin "Silver Sparkle".

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets ranging from blue to dark blue in color with a pearly sheen, round (dosage 25 mg, 50 mg or 100 mg) or rhomboid (dosage 50 mg or 100 mg) in shape, with a biconvex surface. Mottling is permissible. The trade mark "ZT" may be printed on one side of rhomboid-shaped tablets, and the dosage "50" or "100" on the other side.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Sildenafil is an oral medication indicated for the treatment of erectile dysfunction. During sexual stimulation, the drug restores impaired erectile function by enhancing blood flow to the penis.

The physiological mechanism leading to erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Released NO activates the enzyme guanylate cyclase, which stimulates an increase in the level of cyclic guanosine monophosphate (cGMP), resulting in 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 peripheral in nature. Sildenafil does not exert a direct relaxant effect on isolated human corpus cavernosum, 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, sexual stimulation is required for sildenafil to produce the desired pharmacological effect.

Effect on pharmacodynamics. 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 in the retina. At maximum recommended doses, sildenafil’s selectivity for PDE5 is 80 times greater than for PDE1, and 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—the cAMP-specific phosphodiesterase isoenzyme 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% (range: 25–63%). 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 rate of absorption is reduced, with a mean increase in Tmax to 60 minutes and a mean reduction in Cmax by 29%.

Distribution. The mean steady-state volume of distribution (Vd) is 105 L, indicating extensive distribution of the drug into body tissues. After a single 100 mg oral dose, the mean maximum 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 is about 96%, the mean maximum free plasma concentration of sildenafil reaches approximately 18 ng/mL (38 nmol). The degree of plasma protein binding is independent of total sildenafil concentrations.

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

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 activity against PDE5 is approximately 50% of the parent compound. Plasma concentrations of this metabolite are about 40% of sildenafil plasma concentrations. The N-desmethyl metabolite undergoes further metabolism, with a half-life (T½) of approximately 4 hours.

Elimination. Total clearance of sildenafil is 41 L/h, resulting in a half-life (T½) of 3–5 hours. Following both oral and intravenous administration, excretion of sildenafil metabolites occurs primarily 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 elderly individuals (aged 65 years and older), reduced clearance of sildenafil was observed, resulting in plasma concentrations of sildenafil and its active N-desmethyl metabolite approximately 90% higher than in younger individuals (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 individuals 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 126% and 73%, respectively, compared to individuals of similar age with normal renal function. However, due to high inter-individual variability, these differences were not statistically significant. In individuals 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 individuals with normal renal function. Additionally, AUC and Cmax of the N-desmethyl metabolite increased significantly by 79% and 200%, respectively.

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

Clinical characteristics.

Indications. The drug is recommended for use in men with erectile dysfunction, defined as the inability to achieve or maintain an erection of the penis sufficient for successful sexual intercourse.

For effective action of the drug, sexual stimulation is required.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the drug.
• 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) metabolic pathway and potentiates the hypotensive effect of nitrates.
• Concomitant use of phosphodiesterase-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, regardless of whether this condition is associated with prior use of PDE5 inhibitors or not.
• Presence of 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), since 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. Sildenafil metabolism occurs primarily via cytochrome P450 isoenzyme 3A4 (major pathway) and isoenzyme 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, while inducers may increase it.

Data exist on reduced sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although increased incidence of adverse events has not been observed with concomitant use of sildenafil and CYP3A4 inhibitors, consideration should be given to initiating sildenafil therapy at a dose of 25 mg.

Concomitant administration of the HIV-protease inhibitor ritonavir, a very potent CYP inhibitor, at steady state (500 mg once daily) and sildenafil (single dose 100 mg) resulted in a 300% increase (4-fold) in sildenafil Cmax and a 1000% increase (11-fold) in plasma AUC. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL typical after sildenafil alone, indicating a significant effect of ritonavir on a wide range of CYP 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 a dose providing steady-state concentration (1200 mg three times daily) and sildenafil (single dose 100 mg) resulted in a 140% increase in sildenafil Cmax and a 210% increase in systemic exposure (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 (100 mg single dose) with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in systemic exposure (AUC) of sildenafil. No effect of azithromycin (500 mg daily for 3 days) on AUC, Cmax, Tmax, elimination rate constant, or subsequent T½ of sildenafil or its major circulating metabolite was observed. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg, when administered concomitantly with 50 mg sildenafil, increased plasma concentrations of sildenafil by 56%.

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

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

The pharmacokinetics of sildenafil were not altered when co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, β-adrenoreceptor antagonists, or CYP metabolism inducers (such as rifampicin, barbiturates).

Concomitant administration of the endothelin antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19) 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 sildenafil plasma concentration.

Nicorandil is a hybrid of a calcium channel activator and a nitrate. The nitrate component implies a potential for serious interaction with sildenafil.

Effects of sildenafil on other medicinal products. 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, the effect of the drug on the clearance of substrates of these isoenzymes is unlikely.

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

Since sildenafil is known to affect nitric oxide/cyclic guanosine monophosphate (cGMP) metabolism, it has been established that sildenafil potentiates the hypotensive effect of nitrates; therefore, concomitant use with nitric oxide donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat. Preclinical studies have demonstrated an additive systemic effect on blood pressure reduction 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 concomitant use of PDE5 inhibitors with riociguat. Concomitant use of riociguat with PDE5 inhibitors (including sildenafil) is contraindicated (see section "Contraindications").

Concomitant use of sildenafil and α-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"). When the α-adrenoreceptor 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 stabilized on doxazosin, 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. When sildenafil was used concomitantly with doxazosin in patients stabilized on doxazosin, symptomatic orthostatic hypotension, including dizziness and pre-syncope, was occasionally reported, but without syncope.

No significant interactions were observed when sildenafil (50 mg) was co-administered with 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 at moderate maximum blood ethanol levels of 80 mg/dL.

In patients taking sildenafil, no differences in adverse effect profile were observed when concomitantly using antihypertensive drug classes such as diuretics, β-adrenoreceptor blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and α-adrenoreceptor blockers. 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 in blood pressure were comparable in magnitude to those observed with sildenafil alone.

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

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.

Adding a single dose of sildenafil to sacubitril/valsartan at steady state in patients with hypertension was associated with significantly greater blood pressure reduction compared to sacubitril/valsartan alone. Therefore, initiation of sildenafil should be approached with caution in patients receiving sacubitril/valsartan.

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 evaluate the cardiovascular status of patients before initiating any treatment for erectile dysfunction. Sildenafil has vasodilatory effects, manifested by mild and transient reduction in blood pressure. Before prescribing sildenafil, physicians should carefully consider whether such an effect might adversely affect patients with underlying medical conditions, particularly when combined with sexual activity. Patients who may be particularly 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.

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

Serious cardiovascular adverse reactions, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, have been reported in temporal association with sildenafil use. In most, but not all patients, cardiovascular risk factors were present. Many of these adverse reactions 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 other factors contribute to their occurrence.

Priapism. Medications for the treatment of erectile dysfunction, including sildenafil, 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 (such as sickle cell anaemia, multiple myeloma, or leukaemia).

Cases of prolonged erection and priapism have been reported. If an erection lasts longer than 4 hours, patients should seek immediate medical help. Without prompt treatment, priapism may lead to penile tissue damage and permanent loss of potency.

Concomitant use with other PDE5 inhibitors or other medications for erectile dysfunction. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or with other medications for pulmonary arterial hypertension containing sildenafil, or with other medications for erectile dysfunction have not been studied. Therefore, the use of such combinations is 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 have also been received and published regarding 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 that in case of sudden visual impairment, they should discontinue the use of the drug and seek immediate medical attention (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. Patients receiving α-adrenoreceptor blockers should use sildenafil with caution, 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 receiving α-adrenoreceptor blockers, their condition should be stabilized with α-blockers before initiating sildenafil therapy. Additionally, consideration should be given to starting with a dose of 25 mg (see section "Dosage and administration"). Patients should also be informed about the appropriate actions to take if symptoms of orthostatic hypotension occur.

Effect on bleeding. In vitro, sildenafil potentiates the antiplatelet effects of sodium nitroprusside. There is no information on the safety of sildenafil use in patients with bleeding disorders or acute peptic ulcer. Therefore, the use of sildenafil in these patient groups should only be considered after careful assessment of the benefit-risk ratio.

After administration of a 100 mg dose, no effect on sperm morphology or motility was observed.

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 the use of PDE5 inhibitors, including sildenafil. It is not possible to determine whether these events are directly related to the use of PDE5 inhibitors 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. When administered concomitantly, oral amlodipine (5 mg or 10 mg) and sildenafil (100 mg) resulted in a mean additional reduction in systolic pressure of 8 mm Hg and diastolic pressure of 7 mm Hg.

Sexually transmitted infections. The use of the drug does not protect against sexually transmitted infections. Consideration should be given to advising patients on the necessary protective measures to prevent sexually transmitted infections, including human immunodeficiency virus.

Use during pregnancy or breastfeeding. The drug is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery. Studies on the effect of the drug on the ability to drive vehicles or operate machinery have not been conducted. Since dizziness and visual disturbances have been reported during sildenafil use, patients should determine their individual response to the drug before driving or operating machinery.

Dosage and Administration

The medication should be administered orally.

Adults. The recommended dose is 50 mg, taken approximately one hour before sexual activity, as needed. 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 daily. When the medication is taken with food, its onset of action may be delayed compared to administration on an empty stomach.

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

Patients with renal impairment. For patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the recommended dose is the same as stated above under "Adults."

Because sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min), 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. Because 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 medicinal products. If patients are concurrently using CYP3A4 inhibitors (see section "Interactions with Other Medicinal Products and Other Forms of Interactions"), 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 risk of postural hypotension in patients taking α-adrenoreceptor blockers, their condition should first be stabilized on α-adrenoreceptor blockers before initiating sildenafil therapy. Additionally, a starting dose of 25 mg should be considered (see sections "Special Warnings and Precautions for Use" and "Interactions with Other Medicinal Products and Other Forms of Interactions").

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

Overdose. When single doses of sildenafil up to 800 mg were administered, adverse reactions were similar to those observed at lower doses but occurred more frequently and were more severe. 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).

In case of overdose, standard supportive measures should be implemented as needed. 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.

Infections and infestations: rhinitis.

Immune system disorders: hypersensitivity.

Nervous system disorders: headache, dizziness, somnolence, hypoesthesia, stroke, transient ischemic attack, seizures, seizure recurrence, syncope, ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes, anxiety, transient global amnesia.

Eye disorders: color vision disturbances (chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia), visual disturbances, blurred vision, lacrimation disorders (dry eyes, impaired lacrimation, and increased lacrimation), eye pain, photophobia, photopsia, eye hyperemia, visual brightness, conjunctivitis, retinal vessel occlusion, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters in the vitreous body, iris disorders, mydriasis, halos around light sources in the visual field, eye swelling, eye puffiness, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in the eyes, eyelid edema, scleral discoloration, ocular hemorrhage, cataract, dry eyes, transient loss of vision, eye redness, eye burning, increased intraocular pressure, retinal edema, retinal vascular disorders or bleeding, vitreous body detachment.

Cases of non-arteritic anterior ischemic optic neuropathy (NAION), leading to visual impairment including permanent vision loss, have been reported and were temporally associated with the use of PDE5 inhibitors, including sildenafil. Many, but not all, of these patients had underlying anatomical or vascular risk factors for NAION, including (but not limited to): small cup-to-disc ratio (crowded optic disc), age 50 years or older, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are directly related to the use of PDE5 inhibitors, to the underlying anatomical or vascular risk factors, to a combination of these factors, or to other factors.

Ear and labyrinth disorders: tinnitus, deafness, ear pain.

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

Cardiac disorders: tachycardia, palpitations, sudden cardiac death, myocardial infarction, ventricular arrhythmia, atrial fibrillation, unstable angina, angina, AV block, myocardial ischemia, cardiac arrest, ECG abnormalities, cardiomyopathy.

Vascular disorders: flushing, facial flushing, hot flushes, hypertension, hypotension, migraine, postural hypotension, cerebral vessel thrombosis.

Serious cardiovascular, cerebrovascular, and vascular events, including cerebral hemorrhage, subarachnoid hemorrhage, intracerebral hemorrhage, and pulmonary hemorrhage, have been reported and were temporally associated with sildenafil use. Most, but not all, of these 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 the following hours or days after sildenafil use and sexual activity. It is not possible to determine whether these events are directly related to sildenafil use, to sexual activity, to pre-existing risk factors, to a combination of these factors, or to other factors.

Respiratory, thoracic and mediastinal disorders: nasal congestion, epistaxis, nasal sinus congestion, throat tightness, nasal mucosal edema, nasal dryness, asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, cough exacerbation.

Gastrointestinal disorders: nausea, dyspepsia, gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth, oral hypoesthesia, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding, gingivitis.

Skin and subcutaneous tissue disorders: rash, Stevens-Johnson syndrome, Lyell's syndrome, urticaria, herpes, pruritus, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Musculoskeletal and connective tissue disorders: myalgia, limb pain, arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Renal and urinary disorders: hematuria, cystitis, nocturia, increased frequency of urination, urinary incontinence.

Reproductive system and breast disorders: penile bleeding, priapism, hematospermia, prolonged erection, breast enlargement, ejaculation disorders, genital swelling, anorgasmia.

Blood and lymphatic system disorders: anemia, leukopenia.

Vaso-occlusive crises requiring hospitalization have been reported in patients with pulmonary arterial hypertension secondary to sickle cell anemia who were treated with sildenafil. The clinical significance of this information for patients taking the drug for the treatment of erectile dysfunction is unknown.

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

General disorders and administration site conditions: chest pain, increased fatigue, feeling of warmth, irritation, facial swelling, photosensitivity reactions, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury, back pain.

Investigations: increased heart rate.

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with national regulatory requirements.

Shelf life. 3 years (25 mg dosage). 5 years (50 mg or 100 mg dosage).

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

Keep out of the reach of children.

Packaging. Tablets №1, №1x4 in blisters in a box.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenko Street, 22.