Sildenafil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SILDENAFIL

Composition:

Active substance: sildenafil;

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

Excipients: microcrystalline cellulose; calcium hydrogen phosphate; aluminium hydroxide; sodium croscarmellose; povidone; magnesium stearate; colloidal anhydrous silicon dioxide; Opadry II white dry blend 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, blue to light blue in color with a pearly sheen, round-shaped, with a biconvex surface. Mottling is permissible.

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. During sexual stimulation, the drug restores impaired erectile function by enhancing blood flow to the penis.

The physiological mechanism responsible for 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, thereby promoting blood inflow.

Sildenafil is a potent, selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for cGMP degradation. The effect of sildenafil on erection is peripheral. Sildenafil does not exert a direct relaxing effect on isolated human corpus cavernosum tissue, but it potently enhances the relaxing effect of NO on this tissue. During activation of the NO/cGMP metabolic pathway, which occurs 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. Sildenafil is selective for PDE5, which actively participates in the process of erection. The effect of sildenafil on PDE5 is more potent than its effect on other known phosphodiesterases—specifically, 10 times 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 its selectivity for PDE1, 700 times greater than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. In particular, sildenafil's selectivity for PDE5 is 4000 times greater than its selectivity for PDE3—the cAMP-specific isoenzyme of phosphodiesterase involved in the regulation of cardiac contractility.

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. Maximum plasma concentration is reached within 30–120 minutes (with a median of 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 to 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 to 60 minutes and a mean reduction in Cmax by 29%.

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

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 concentration of this metabolite is about 40% of the plasma concentration of sildenafil. The N-demethylated 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 T½ of approximately 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 corresponding concentrations 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 values in age-matched individuals without renal impairment. However, due to high 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 without renal impairment. Additionally, AUC and Cmax of the N-desmethyl metabolite were significantly increased by 200% and 79%, respectively.

Hepatic impairment. In individuals with mild to moderate hepatic cirrhosis (Child-Pugh classes A and B), sildenafil clearance was reduced, resulting in increased AUC (by 84%) and Cmax (by 47%) compared to age-matched individuals without hepatic dysfunction. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

The medicinal product is recommended for use in men with erectile dysfunction, defined as the inability to achieve or maintain a penile erection sufficient for successful sexual intercourse.

For effective action of the medicinal product, sexual stimulation is required.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, since sildenafil is known to affect the nitric oxide/cyclic guanosine monophosphate (cGMP) metabolic pathway and potentiates the hypotensive effect of nitrates.
• Concomitant use of 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 associated with prior use of PDE5 inhibitors or not.
• 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 is primarily mediated by cytochrome P450 isoform 3A4 (major pathway) and isoform 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, while inducers of these isoenzymes may increase sildenafil clearance.

Data indicate reduced sildenafil clearance when administered concomitantly with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increased incidence of adverse effects 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 CYP inhibitor, at steady-state concentration (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 of sildenafil. After 24 hours, plasma sildenafil levels 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 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) of sildenafil. 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 dose 100 mg) together with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in systemic exposure to sildenafil (AUC). 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 sildenafil 50 mg, increased plasma concentration of sildenafil by 56%.

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

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

The pharmacokinetics of sildenafil were not altered when administered concomitantly 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-adrenergic receptor 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% decrease in AUC and a 55.4% decrease in Cmax of sildenafil, respectively. Therefore, concomitant use of potent CYP3A4 inducers such as rifampicin may result in a more pronounced reduction in plasma concentration of sildenafil.

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

Effects of sildenafil on other medicinal products. Sildenafil is a weak inhibitor of cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 μmol). Since peak plasma concentration of sildenafil is 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 between sildenafil and non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.

Since it is known that sildenafil affects the nitric oxide/cyclic guanosine monophosphate (cGMP) metabolism, it has been established that sildenafil potentiates 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 effect of 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 studies, 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 and α-adrenergic receptor blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most commonly occurred within 4 hours after sildenafil administration (see section "Dosage and administration" and "Special precautions for use"). When sildenafil (25 mg, 50 mg, and 100 mg) was administered concomitantly with the α-adrenergic receptor blocker doxazosin (4 mg and 8 mg) to patients with benign prostatic hyperplasia whose condition had been stabilized with doxazosin, mean additional reductions in supine blood pressure were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, respectively, and mean reductions in standing blood pressure were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. When sildenafil and doxazosin were used concomitantly in patients whose condition had been stabilized with 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 administered concomitantly 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 a mean maximum blood ethanol concentration of 80 mg/dL.

In patients taking sildenafil, no differences in adverse effect profile were observed when concomitantly using classes of antihypertensive medicinal products such as diuretics, β-adrenergic receptor blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive agents (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and α-adrenergic receptor blockers. When sildenafil (100 mg) was administered concomitantly with amlodipine to patients with arterial hypertension, an additional reduction in supine systolic blood pressure of 8 mm Hg was observed. The corresponding reduction in diastolic blood pressure was 7 mm Hg. In magnitude, these additional reductions in blood pressure were comparable to those observed with sildenafil alone.

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

Administration of sildenafil at steady state (80 mg three times daily) resulted in a 49.8% increase in AUC and a 42% increase in Cmax of bosentan (125 mg twice daily), respectively.

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 prior to initiating any treatment for erectile dysfunction. Sildenafil has vasodilatory properties that result in mild and transient decreases in blood pressure. Before prescribing sildenafil, physicians should carefully consider whether such an effect might adversely affect patients with underlying cardiovascular conditions, particularly in combination 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 features of which is severe autonomic nervous system dysfunction in blood pressure regulation.

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 hemorrhage, transient ischemic attack, arterial hypertension, and arterial hypotension, have been reported in temporal association with sildenafil use. In most patients, but not all, there were pre-existing cardiovascular risk factors. Many of these adverse reactions occurred during or shortly after sexual intercourse, and only a few occurred shortly after sildenafil use 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 anemia, multiple myeloma, or leukemia).

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 erectile function.

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 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 received in association with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports have also been received regarding non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition, in association with sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised to discontinue the use of the drug and seek immediate medical attention in case of sudden visual loss (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 with α-blocker therapy before initiating sildenafil. Additionally, consideration should be given to starting with a 25 mg dose (see section "Dosage and administration"). Patients should also be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Effect on bleeding. In vitro, sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside. There is no information on the safety of sildenafil use in patients with bleeding disorders or active peptic ulceration. Therefore, sildenafil use 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 attention in case of sudden decrease or loss of hearing. Such events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with PDE5 inhibitor use, 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 has systemic vasodilatory properties and may further reduce blood pressure in patients taking antihypertensive medications. When administered concomitantly, amlodipine (5 mg or 10 mg) and sildenafil (100 mg) orally resulted in an average additional reduction of systolic pressure by 8 mm Hg and diastolic pressure by 7 mm Hg.

Sexually transmitted infections. The use of the drug does not protect against sexually transmitted infections. Patients should be instructed on the necessary preventive measures to protect against sexually transmitted infections, including human immunodeficiency virus (HIV).

Use during pregnancy or breastfeeding.

The drug is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect of the drug on the ability to drive vehicles or operate machinery have been conducted. Since dizziness and visual disturbances have been reported with sildenafil use, patients should determine their individual response to the drug before driving vehicles or operating machinery.

Dosage and Administration

The drug 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 dose should not be taken more than once daily. When the drug 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."

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. In patients with hepatic impairment (e.g., cirrhosis), 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 taking other medicinal products. In patients 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 risk of postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized on α-adrenoreceptor blockers prior to initiating sildenafil therapy. A starting dose of 25 mg should also be considered (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Children

The drug 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 result in increased 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 required. Hemodialysis is unlikely to accelerate sildenafil clearance 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, hypesthesia, 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, abnormal lacrimation, increased lacrimation), eye pain, photophobia, photopsia, ocular 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, appearance of halos (luminous circles) around light sources in the visual field, eye swelling, eyelid edema, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in the eyes, eyelid swelling, scleral discoloration, ocular hemorrhage, cataract, dry eyes, transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal edema, retinal vascular disorders or hemorrhage, vitreous body detachment.

Cases of non-arteritic anterior ischemic optic neuropathy (NAION), leading to visual impairment including permanent vision loss, have been reported in temporal association 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 over 50 years, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are related to the use of PDE5 inhibitors, underlying anatomical or vascular risk factors, a combination of these factors, or 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 hearing-related 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, underlying risk factors for hearing loss, a combination of these factors, or 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, ECG abnormalities, cardiomyopathy.

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

Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral hemorrhage, subarachnoid hemorrhage, 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, underlying risk factors, a combination of these factors, or 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, increased cough.

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 drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Physicians should report any suspected adverse reactions in accordance with applicable regulatory requirements.

Shelf life.

3 years (25 mg dosage) from the date of manufacture for bulk packaging.

5 years (50 mg or 100 mg dosage) from the date of manufacture for bulk packaging.

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

Keep out of reach of children.

Packaging.

Tablets: 1 tablet or 4 tablets (1x4) in blisters, in a box.

Prescription category. Prescription only.

Manufacturer.

Limited Liability Company "Pharmaceutical Company "Vertex".

Manufacturer's location and address of place of business.

33, Astronomichna Street, lit. "V-1", Kharkiv, Kharkiv region, 61085, Ukraine.