KOMBOGLIZA HR

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SUPERVIGA 25, SUPERVIGA 50, SUPERVIGA 100

Composition

active substance: 1 tablet contains sildenafil citrate in terms of sildenafil 25 mg or 50 mg, or 100 mg; excipients: microcrystalline cellulose; calcium hydrophosphate; aluminum hydroxide; sodium croscarmellose; povidone; magnesium stearate; colloidal silicon dioxide anhydrous; dry mixture "Opadry II white", which contains titanium dioxide (E 171), talc, polyethylene glycol (macrogol), polyvinyl alcohol; indigocarmine (E 132); Candurin "Silver Shine".

Pharmaceutical Form

Coated tablets.

Main Physical and Chemical Properties

Coated tablets, from blue to blue with a pearlescent sheen, round (25 mg, 50 mg or 100 mg) or rhomboid (50 mg or 100 mg) shape, with a biconvex surface. Mottling is allowed. On the surface of rhomboid-shaped tablets, it is allowed to apply the company's trademark "ZT" or on one side and the dosage "50" or "100" - on the other.

Pharmacotherapeutic Group

Drugs used for erectile dysfunction. Sildenafil. ATC code G04B E03.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Sildenafil is an oral medication for the treatment of erectile dysfunction. During sexual arousal, the drug restores reduced erectile function by enhancing blood flow to the penis.

The physiological mechanism that causes an erection involves the release of nitric oxide (NO) in the cavernous bodies during sexual arousal. The released nitric oxide activates the enzyme guanylate cyclase, which stimulates an increase in the level of cyclic guanosine monophosphate (cGMP), which, in turn, causes relaxation of the smooth muscle of the cavernous bodies, contributing to blood flow.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase 5 (PDE5) in the cavernous bodies, where PDE5 is responsible for the breakdown of cGMP. The effects of sildenafil on erection are peripheral. Sildenafil does not have a direct relaxing effect on isolated human cavernous bodies, but it potently enhances the relaxing effect of NO on this tissue. When the metabolic pathway of NO/cGMP is activated, which occurs during sexual stimulation, the inhibition of PDE5 by sildenafil leads to an increase in the level of cGMP in the cavernous bodies. Thus, for sildenafil to have the desired pharmacological effect, sexual arousal is necessary.

Effect on Pharmacodynamics

Sildenafil is selective for PDE5, which plays an active role in the process of erection. The effect of sildenafil on PDE5 is more potent than on other known phosphodiesterases. This effect is 10 times more potent than the effect on PDE6, which is involved in the processes of phototransformation in the retina. When using the maximum recommended doses, the selectivity of sildenafil for PDE5 is 80 times higher than its selectivity for PDE1, 700 times higher than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. In particular, the selectivity of sildenafil for PDE5 is 4000 times higher than its selectivity for PDE3 - a cAMP-specific isoform of phosphodiesterase involved in the regulation of heart rate.

Pharmacokinetics

Absorption

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

When taking sildenafil during meals, the degree of absorption decreases with a mean prolongation of Tmax to 60 minutes and a mean decrease in Cmax by 29%.

Distribution

The mean equilibrium volume of distribution (Vd) is 105 liters, which indicates the distribution of the drug in the body tissues. After a single oral administration of sildenafil at a dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/ml (the coefficient of variation is 40%). Since the binding of sildenafil and its main N-desmethyl metabolite to plasma proteins is 96%, the mean maximum plasma concentration of free sildenafil reaches 18 ng/ml (38 nmol). The degree of binding to plasma proteins does not depend on the total concentrations of sildenafil.

In individuals who took sildenafil once at a dose of 100 mg, after 90 minutes, less than 0.0002% (on average, 188 ng) of the applied dose was determined in the ejaculate.

Metabolism

The metabolism of sildenafil is carried out mainly with the participation of microsomal liver isoenzymes CYP3A4 (main pathway) and CYP2C9 (secondary pathway). The main circulating metabolite is formed by N-demethylation of sildenafil. The selectivity of the metabolite for PDE5 is comparable to the selectivity of sildenafil, and the activity of the metabolite for PDE5 is approximately 50% of the activity of the original substance. The plasma concentrations of this metabolite are approximately 40% of the concentration of sildenafil in the blood plasma. The N-demethylated metabolite undergoes further metabolism, and the T1/2 is approximately 4 hours.

Elimination

The total clearance of sildenafil is 41 l/h, which leads to a T1/2 of 3-5 hours. Both after oral and intravenous administration, the excretion of sildenafil in the form of metabolites is carried out mainly with feces (approximately 80% of the oral dose) and to a lesser extent with urine (approximately 13% of the oral dose).

Pharmacokinetics in Special Patient Groups

Elderly Patients

In elderly patients (aged 65 years and older), a decrease in sildenafil clearance was noted, which led to an increase in plasma concentrations of sildenafil and its active N-desmethylated metabolite by approximately 90% compared to the corresponding concentrations in younger patients (18-45 years). Due to age-related differences in plasma protein binding, the corresponding increase in plasma free sildenafil concentration was approximately 40%.

Renal Insufficiency

In patients with mild and moderate renal impairment (creatinine clearance 30-80 ml/min), the pharmacokinetics of sildenafil remained unchanged after its single oral administration at a dose of 50 mg. The mean AUC and Cmax of the N-desmethylated metabolite increased by 126% and 73%, respectively, compared to those in patients of the same age without renal impairment. However, due to high individual variability, these differences were not statistically significant. In patients with severe renal impairment (creatinine clearance below 30 ml/min), the clearance of sildenafil decreased, leading to mean increases in AUC and Cmax by 100% and 88%, respectively, compared to patients of the same age without renal impairment. Additionally, the values of AUC and Cmax of the N-desmethylated metabolite significantly increased by 79% and 200%, respectively.

Hepatic Insufficiency

In patients with liver cirrhosis of mild and moderate severity (Child-Pugh classes A and B), the clearance of sildenafil decreased, leading to an increase in AUC (84%) and Cmax (47%) compared to patients of the same age without liver function impairment. The pharmacokinetics of sildenafil in patients with severe liver function impairment has not been studied.

Clinical Characteristics

Indications

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

For the effective action of the drug, sexual arousal is necessary.

Contraindications

• Increased sensitivity 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 it is known that sildenafil affects the pathways of nitric oxide metabolism/cyclic guanosine monophosphate (cGMP) and potentiates the hypotensive effect of nitrates.
• Concomitant use of PDE5 inhibitors (including sildenafil) with guanylate cyclase stimulants, such as riociguat, is contraindicated, as it may lead to symptomatic hypotension (see section "Interactions 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 heart failure of severe degree).
• Loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this pathology is associated with previous use of PDE5 inhibitors or not.
• Patient with severe liver dysfunction, arterial hypotension (blood pressure below 90/50 mmHg), 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 phosphodiesterase), as the safety of sildenafil has not been studied in these patient subgroups.

Interactions with Other Medicinal Products and Other Forms of Interaction

Effects of other medicinal products on sildenafil. The metabolism of sildenafil occurs mainly with the participation of isoenzyme 3A4 (main pathway) and isoenzyme 2C9 (secondary pathway) of cytochrome P450 (CYP). Therefore, inhibitors of these isoenzymes can decrease the clearance of sildenafil, and inducers of these isoenzymes can increase the clearance of sildenafil.

There are data on a decrease in sildenafil clearance when it is used concomitantly with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increase in the frequency of adverse events was not observed when sildenafil was used concomitantly with CYP3A4 inhibitors, it is recommended to consider the possibility of using an initial dose of sildenafil of 25 mg.

Concomitant use of the HIV protease inhibitor ritonavir, a very potent inhibitor of CYP, in a state of equilibrium (500 mg once daily) and sildenafil (single dose of 100 mg) led to an increase in Cmax of sildenafil by 300% (4 times) and an increase in the plasma AUC of sildenafil by 1000% (11 times). After 24 hours, plasma levels of sildenafil were still approximately 200 ng/ml compared to a level of approximately 5 ng/ml, characteristic of the use of sildenafil alone, which corresponds to a significant effect of ritonavir on a wide range of CYP substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Given these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended (see section "Special warnings and precautions for use"); in any case, the maximum dose of sildenafil should not exceed 25 mg within 48 hours.

Concomitant use of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a dose that provides equilibrium (1200 mg three times a day) and sildenafil (single dose of 100 mg) led to an increase in Cmax of sildenafil by 140% and an increase in the systemic exposure (AUC) of sildenafil by 210%. No effect of sildenafil on the pharmacokinetics of saquinavir was found (see section "Posology and method of administration"). It is expected that more potent CYP3A4 inhibitors, such as ketoconazole and itraconazole, will have a more pronounced effect.

When using sildenafil (100 mg) and erythromycin, a moderate CYP3A4 inhibitor, in a state of equilibrium (500 mg twice daily for 5 days), an increase in systemic exposure to sildenafil by 182% (AUC) was observed. No effect of azithromycin (500 mg daily for 3 days) on AUC, Cmax, Tmax, elimination rate constant, and subsequent T1/2 of sildenafil or its main circulating metabolite was observed. Cimetidine (an inhibitor of cytochrome P450 and a non-specific inhibitor of CYP3A4) at a dose of 800 mg, when used concomitantly with sildenafil at a dose of 50 mg, led to an increase in plasma concentrations of sildenafil by 56%.

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

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

The pharmacokinetics of sildenafil was not changed when it was used concomitantly with drugs belonging to the group of CYP2C9 inhibitors (such as tolbutamide, warfarin, phenytoin), the group of CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), the group of thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, ACE inhibitors, calcium antagonists, beta-adrenergic blockers, or inducers of CYP metabolism (such as rifampicin, barbiturates).

Concomitant use of the endothelin antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19) in a state of equilibrium (125 mg twice daily) and sildenafil in a state of equilibrium (80 mg three times daily) led to a decrease in AUC and Cmax of sildenafil by 62.6% and 55.4%, respectively. Therefore, concomitant use of such potent CYP3A4 inducers as rifampicin may lead to a more pronounced decrease in sildenafil plasma concentrations.

Nicorandil is a hybrid of a calcium channel activator and a nitrate. The nitrate component may cause a serious interaction with sildenafil.

Effects of Sildenafil on Other Medicinal Products

Sildenafil is a weak inhibitor of isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 of cytochrome P450 (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 the interaction of sildenafil with non-specific phosphodiesterase inhibitors, such as theophylline and dipyridamole.

Since it is known that sildenafil affects the metabolism of nitric oxide/cyclic guanosine monophosphate (cGMP), it has been established that sildenafil potentiates the hypotensive effect of nitrates, and therefore, its 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 of lowering blood pressure when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. In patients who participated in the study, no positive clinical effect was observed from the 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 (50 mg) and the alpha-adrenergic blocker doxazosin (4 mg and 8 mg) in patients with benign prostatic hyperplasia, whose condition was stabilized when using doxazosin, led to a mean additional decrease in blood pressure in the supine position by 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, and a mean decrease in blood pressure in the standing position by 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively. When concomitantly using sildenafil and doxazosin in patients whose condition was stabilized when using doxazosin, symptomatic orthostatic hypotension was sometimes reported, namely, cases of dizziness and a state before fainting, but without syncope.

No significant interactions were observed when sildenafil (50 mg) was used concomitantly with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP2C9.

Sildenafil (50 mg) did not lead to an increase in bleeding time caused by the use of acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol at average maximum blood ethanol levels of 80 mg/dl.

In patients who used sildenafil, no differences in the profile of adverse reactions were observed when used concomitantly with such classes of antihypertensive drugs as diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and central action), adrenergic neuron blockers, calcium channel blockers, and alpha-adrenergic blockers. When sildenafil (100 mg) was used concomitantly with amlodipine in patients with arterial hypertension, an additional decrease in systolic blood pressure in the supine position by 8 mmHg was observed. The corresponding decrease in diastolic blood pressure was 7 mmHg. These additional decreases in blood pressure were comparable to those observed when using sildenafil alone.

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

The use of sildenafil in a state of equilibrium (80 mg three times daily) led to an increase in AUC and Cmax of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.

Adding a single dose of sildenafil to sacubitril/valsartan in a state of equilibrium in patients with hypertension was associated with a significantly greater decrease in blood pressure compared to the use of sacubitril/valsartan alone. Therefore, it is recommended to use sildenafil with caution in patients who are taking sacubitril/valsartan.

Special Warnings and Precautions for Use

Before starting therapy, it is necessary to collect the patient's medical history and conduct a physical examination to diagnose erectile dysfunction and determine its possible causes.

Cardiovascular Risk Factors

Since sexual activity is associated with a certain risk to the heart, before starting any treatment for erectile dysfunction, the doctor must assess the patient's cardiovascular system. Sildenafil has a vasodilating effect, which is manifested by a slight and short-term decrease in blood pressure. Before prescribing sildenafil, the doctor must carefully weigh whether this effect can have an adverse effect on patients with certain underlying diseases, especially in combination with sexual activity. Patients with increased sensitivity to vasodilators include patients with obstruction of the left ventricular outflow tract (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with a rare syndrome of multisystem atrophy, one of the manifestations of which is severe impairment of blood pressure regulation by the autonomic nervous system.

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

There have been reports of severe cardiovascular reactions, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, arterial hypertension, and arterial hypotension, which coincided in time with the use of sildenafil. In most patients, but not all, there were factors of cardiovascular risk. Many of these reactions occurred during or immediately after sexual intercourse, and several occurred shortly after using sildenafil without sexual activity. Therefore, it is impossible to determine whether the development of these reactions is directly related to the factors of risk, or to other factors.

Priapism

Drugs for the treatment of erectile dysfunction, including sildenafil, should be prescribed with caution to patients with anatomical deformities of the penis (such as angulation, cavernous fibrosis, or Peyronie's disease) or patients with conditions that contribute to the development of priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

There have been reports of prolonged erections and priapism. If an erection lasts more than 4 hours, patients should immediately seek medical attention. In the absence of immediate treatment, priapism can lead to tissue damage and permanent loss of potency.

Concomitant Use with Other PDE5 Inhibitors or Other Drugs for Erectile Dysfunction

The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other drugs for the treatment of pulmonary arterial hypertension that contain sildenafil, or with other drugs 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 received in association with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). There have been reports of non-arteritic anterior ischemic optic neuropathy, a rare condition, which have been associated in time with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be warned that in the event of sudden visual impairment, the use of the drug should be discontinued and immediate medical attention should be sought (see section "Contraindications").

Concomitant Use with Ritonavir

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

Concomitant Use with Alpha-Adrenergic Blockers

Patients who are using alpha-adrenergic blockers should use sildenafil with caution, as this combination may lead to symptomatic hypotension in some susceptible patients. Symptomatic hypotension usually occurs within 4 hours after using sildenafil. To minimize the possible development of postural hypotension in patients using alpha-adrenergic blockers, their condition should be stabilized using alpha-adrenergic blockers before starting sildenafil. It is also recommended to consider the possibility of using an initial dose of 25 mg (see section "Posology and method of administration" and "Interactions with other medicinal products and other forms of interaction"). Additionally, patients should be informed about how to act in case of symptoms of orthostatic hypotension.

Effect on Bleeding

In vitro, sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside. There is no information on the safety of using sildenafil in patients with bleeding disorders or acute peptic ulcer. Therefore, the use of sildenafil in this group of patients is possible only after a careful assessment of the risk-benefit ratio.

After using a dose of 100 mg, no effect on the morphology or motility of spermatozoa was observed.

Hearing Loss

Doctors should advise patients to stop using PDE5 inhibitors, including sildenafil, and seek medical attention immediately in cases of sudden decrease or loss of hearing. These phenomena, which may also be accompanied by tinnitus and dizziness, have been reported in association with the use of PDE5 inhibitors, including sildenafil. It is impossible to determine whether these phenomena are directly related to the use of PDE5 inhibitors or to other factors.

Concomitant Use with Hypotensive Drugs

Sildenafil has a systemic vasodilating effect and may further lower blood pressure in patients using hypotensive drugs. When using amlodipine (5 mg or 10 mg) and sildenafil (100 mg) orally, a mean additional decrease in systolic blood pressure by 8 mmHg and diastolic by 7 mmHg was observed.

Sexually Transmitted Diseases

The use of the drug does not protect against sexually transmitted diseases. It is recommended to consider the possibility of instructing patients on the necessary precautions to protect against sexually transmitted diseases, including HIV.

Use During Pregnancy or Breastfeeding

The drug is not intended for use in women.

Ability to Affect the Speed of Reaction When Driving or Operating Other Mechanisms

Studies on the effect of the drug on the ability to drive vehicles and work with other mechanisms have not been conducted. Since dizziness and visual disturbances have been reported when using sildenafil, before driving a vehicle or working with mechanisms, patients should determine their individual reaction to the use of the drug.

Posology and Method of Administration

The drug should be taken orally.

Adults

The recommended dose of the drug is 50 mg and is used as needed, approximately 1 hour before sexual activity. Depending on the effectiveness and tolerability of the drug, the dose can be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The frequency of administration of the maximum recommended dose of the drug is 1 time per day. When using the drug during meals, the effect of the drug may occur later than when using it on an empty stomach.

Elderly Patients

No need for dose adjustment in elderly patients (≥ 65 years).

Patients with Renal Impairment

Patients with mild and moderate renal impairment (creatinine clearance 30-80 ml/min) should use the recommended dose of the drug as described above in the "Adults" subsection.

Since the clearance of sildenafil is decreased in patients with severe renal impairment (creatinine clearance < 30 ml/min), it is recommended to consider the possibility of using a dose of 25 mg. Depending on the effectiveness and tolerability of the drug, the dose can be gradually increased to 50 mg and 100 mg if necessary.

Patients with Hepatic Impairment

Since the clearance of sildenafil is decreased in patients with liver dysfunction (e.g., cirrhosis), it is recommended to consider the possibility of using a dose of 25 mg. Depending on the effectiveness and tolerability of the drug, the dose can be gradually increased to 50 mg and 100 mg if necessary.

Patients Using Other Medicinal Products

If patients are concomitantly using CYP3A4 inhibitors (see section "Interactions with other medicinal products and other forms of interaction"), it is recommended to consider the possibility of using an initial dose of 25 mg (except for ritonavir, whose concomitant use with sildenafil is not recommended, see section "Special warnings and precautions for use").

To minimize the possible development of postural hypotension in patients using alpha-adrenergic blockers, their condition should be stabilized using alpha-adrenergic blockers before starting sildenafil. It is also recommended to consider the possibility of using an initial dose of 25 mg (see section "Special warnings and precautions for use" and "Interactions with other medicinal products and other forms of interaction").

Children

The drug is not indicated for use in persons under 18 years of age.

Overdose

During the use of a single dose of sildenafil up to 800 mg, adverse reactions were similar to those observed when using sildenafil at lower doses, but they were more frequent and more severe. The use of sildenafil at a dose of 200 mg did not lead to an increase in efficacy, but it caused an increase in the number of cases of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In case of overdose, if necessary, standard supportive measures should be used. Acceleration of sildenafil clearance during hemodialysis is unlikely due to the high degree of binding of the drug to plasma proteins and the absence of sildenafil elimination with urine.

Adverse Reactions

• Infectious and invasive diseases: rhinitis.
• Immune system disorders: hypersensitivity.
• Nervous system disorders: headache, dizziness, somnolence, hypesthesia, stroke, transient ischemic attack, seizures, recurrent seizures, syncope, ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes, anxiety, transient global amnesia.
• Eye disorders: color perception disorders (chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia), visual disturbances, blurred vision, disorders of lacrimation (dry eyes, lacrimation disorders, and increased lacrimation), eye pain, photophobia, photopsia, conjunctival hyperemia, visual brightness, conjunctivitis, occlusion of retinal vessels, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, vitreous floaters, disorders of the iris, mydriasis, appearance of shining circles around the light source (halo) in the field of vision, eyelid edema, eyelid swelling, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in the eyes, eyelid edema, scleral discoloration, eye hemorrhage, cataract, dry eyes, temporary vision loss, eye redness, eye burning, increased intraocular pressure, retinal edema, vascular diseases of the retina, or retinal hemorrhage.
• There have been reports of non-arteritic anterior ischemic optic neuropathy, which is a cause of visual impairment, including permanent vision loss, associated in time with the use of PDE5 inhibitors, including sildenafil. Many of the patients, but not all, had existing anatomical or vascular risk factors for the development of non-arteritic anterior ischemic optic neuropathy, including (but not limited to) such factors as a low cup-to-disc ratio (crowded disc), age 50 years or older, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is impossible to determine whether these phenomena are directly related to the use of PDE5 inhibitors, to the existing anatomical or vascular risk factors, or to a combination of all these factors, or to other factors.
• Ear and labyrinth disorders: tinnitus, hearing loss, ear pain.
• There have been reports of sudden decrease or loss of hearing associated in time with the use of sildenafil. In some cases, medical conditions and other factors that could have played a role in the development of adverse reactions from the hearing organ were reported. In many cases, information on further medical observation is missing. It is impossible to determine whether these phenomena are directly related to the use of sildenafil, to the 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 pectoris, AV block, myocardial ischemia, sudden cardiac arrest, changes in ECG, cardiomyopathy.
• Vascular disorders: flushing, facial flushing, hot flashes, hypertension, hypotension, migraine, postural hypotension, cerebral thrombosis.
• There have been reports of serious cardiovascular, cerebrovascular, and vascular events, including cerebrovascular hemorrhage, subarachnoid, and intracerebral hemorrhage, and pulmonary hemorrhage, associated in time with the use of sildenafil. Most patients, but not all, had existing cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred shortly after using sildenafil without sexual activity. It is impossible to determine whether these events are directly related to the use of sildenafil, to sexual activity, to the existing risk factors, or to a combination of these factors or to other factors.
• Respiratory, thoracic, and mediastinal disorders: nasal congestion, nosebleeds, nasal sinus congestion, feeling of throat constriction, nasal mucosal edema, dryness in the nose, asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, cough exacerbation.
• Gastrointestinal disorders: nausea, dyspepsia, gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth, oral hypesthesia, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, changes in liver function tests, rectal bleeding, gingivitis.
• Skin and subcutaneous tissue disorders: rash, Stevens-Johnson syndrome, Lyell's syndrome, urticaria, herpes, itching, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.
• Musculoskeletal and connective tissue disorders: myalgia, limb pain, arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.
• Urinary system disorders: hematuria, cystitis, nocturia, increased urination frequency, 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.
• There have been reports of the development of vaso-occlusive crises that required hospitalization when using sildenafil in patients with pulmonary arterial hypertension secondary to sickle cell anemia. The clinical significance of this information for patients using the drug for the treatment of erectile dysfunction is unknown.
• Metabolic and nutritional disorders: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.
• General disorders and administration site conditions: chest pain, increased fatigue, feeling of heat, irritation, facial edema, photosensitivity reactions, shock, asthenia, pain, sudden injury, abdominal pain, sudden damage.
• Investigations: increased heart rate.

Reporting of Suspected Adverse Reactions

Reporting of suspected adverse reactions after the registration of a medicinal product is important. It allows for the continuous monitoring of the ratio of benefit and risk associated with the use of this medicinal product. Doctors should report any suspected adverse reactions in accordance with the requirements of the legislation.

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.

Store in a place inaccessible to children.

Packaging

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

Release Category

By prescription.

Manufacturer

Limited Liability Company "Pharmaceutical Company "Zdorov'ya"."

Manufacturer's Location and Address

Ukraine, 61013, Kharkiv region, Kharkiv city, Shevchenko street, 22.