Erosil

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EROSIL (EROSIL)

Composition:

Active substance: sildenafil;

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

Excipients: lactose monohydrate; magnesium gluconate; powdered sugar; calcium stearate; lemon flavoring; tartrazine dye (E 102).

Pharmaceutical form. Tablets.

Main physico-chemical properties: yellow or yellow-brownish biconvex tablets with speckles and a score line on one side.

Pharmacotherapeutic group.

Agents used for the treatment of erectile dysfunction. ATC code G04BE03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Sildenafil is an oral medicinal product 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 responsible for 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), leading to relaxation of the smooth muscle 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 the breakdown of cGMP. The effect of sildenafil on erection is peripheral. Sildenafil does not exert a direct relaxing effect on isolated human corpus cavernosum, but it strongly potentiates the relaxing effect of NO on this tissue. During activation of the NO/cGMP metabolic pathway, which occurs under sexual stimulation, sildenafil-induced inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce the desired pharmacological effect, sexual stimulation is required.

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

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. Maximum plasma concentration (Cmax) is 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), the area under the concentration-time curve (AUC) and Cmax of sildenafil increase proportionally with dose.

When sildenafil is taken with food, the extent of absorption is reduced, with a mean delay in Tmax by 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 of sildenafil, the mean Cmax of sildenafil is approximately 440 ng/mL (coefficient of variation 40%). Since protein binding of sildenafil and its major N-desmethyl metabolite to plasma proteins is about 96%, the mean Cmax of free sildenafil reaches approximately 18 ng/mL (38 nmol). The degree of plasma protein binding is independent of total sildenafil concentrations.

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

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-desmethyl metabolite undergoes further metabolism, and its elimination half-life is approximately 4 hours.

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

Pharmacokinetics in special patient populations.

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

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

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

Clinical characteristics.

Indications.

Erosil 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 Erosil to be effective, sexual stimulation is required.

Contraindications.

• Hypersensitivity to sildenafil or to any of the other components of the medicinal product.
• Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form, 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).
• Sudden vision loss in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this condition is associated with prior use of PDE5 inhibitors.
• 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 diseases 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.

Effect of other medicinal products on sildenafil.

In vitro studies. Sildenafil metabolism occurs primarily via the 3A4 isoform (major pathway) and the 2C9 isoform (minor pathway) of cytochrome P450 (CYP). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, while inducers of these isoenzymes may increase sildenafil clearance.

In vivo studies. Data from studies have demonstrated reduced sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increase in the frequency 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 inhibitor of P450, at steady-state concentration (500 mg once daily), and sildenafil (single 100 mg dose) 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, consistent with the significant effect of ritonavir on a broad range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Due to these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended (see section "Special precautions for use"); in any case, the maximum sildenafil dose should not exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a dose providing steady-state concentration (1200 mg three times daily), and sildenafil (single 100 mg dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in AUC. No effect of sildenafil on saquinavir pharmacokinetics was observed. 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 sildenafil AUC. In healthy male volunteers, azithromycin (500 mg daily for 3 days) did not affect AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor), at a dose of 800 mg, when co-administered with sildenafil 50 mg in healthy volunteers, 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.

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

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

In a study involving healthy male volunteers, 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 plasma concentration of sildenafil.

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

Effect of sildenafil on other medicinal products.

In vitro studies. Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 µmol). Since peak plasma concentrations of sildenafil are approximately 1 µmol, the effect of Erosil 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.

In vivo studies. Since it is known that sildenafil affects the NO-cGMP metabolic pathway, it has been established that sildenafil potentiates the hypotensive effect of nitrates; therefore, concomitant use with NO donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat. Additive systemic blood pressure-lowering effects have been reported with concomitant use of PDE5 inhibitors and riociguat. Study data indicate that riociguat enhances the hypotensive effect of PDE5 inhibitors. In patients participating in the study, no positive clinical effect was observed with concomitant use of PDE5 inhibitors and riociguat. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section "Contraindications").

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

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

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

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

In patients taking sildenafil, no differences in adverse effect profile were observed compared to placebo when co-administered with classes of antihypertensive drugs such as diuretics, β-adrenoreceptor blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive agents (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and α-adrenoreceptor blockers. In an interaction study with concomitant administration of sildenafil (100 mg) and amlodipine in 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. These additional blood pressure reductions were comparable in magnitude to those observed with sildenafil alone in healthy volunteers (see section "Pharmacological properties").

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

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

Adding a single dose of sildenafil to sacubitril/valsartan at steady state in patients with arterial hypertension was associated with a significantly greater reduction in blood pressure compared to monotherapy with sacubitril/valsartan. Therefore, caution should be exercised when initiating sildenafil in patients treated with 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 starting any treatment for erectile dysfunction. Sildenafil has vasodilatory effects, manifested by mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians should carefully consider whether this effect might adversely affect patients with underlying cardiovascular conditions, particularly when combined with sexual activity. Patients who are more sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) and patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic regulation of blood pressure.

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

Serious cardiovascular adverse events, 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. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many of these adverse events occurred during or immediately after sexual intercourse, and only a few occurred shortly after Erosil 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 contributed to their occurrence.

Priapism. Medicinal products for the treatment of erectile dysfunction, including sildenafil, should be administered with caution to patients with anatomical deformation of the penis (such as angulation, cavernous fibrosis, or Peyronie's disease) or to patients with conditions predisposing to priapism (e.g., 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 potency.

Concomitant use with other PDE5 inhibitors or other erectile dysfunction treatments. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other medicinal products for the treatment of pulmonary arterial hypertension containing sildenafil (e.g., Revatio), or with other erectile dysfunction treatments, have not been studied. Therefore, such combinations are not recommended.

Effect on vision. Isolated reports of visual defects associated with the use of sildenafil and other PDE5 inhibitors have been reported (see section "Adverse reactions"). Spontaneous reports and data from observational studies have described cases of non-arteritic anterior ischemic optic neuropathy, a rare condition, associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised that if they experience sudden vision loss, they should discontinue Erosil 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. 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, patients should have their condition stabilized with α-adrenoreceptor blockers before initiating sildenafil therapy. Consideration should also be given to starting with a dose of 25 mg. Additionally, patients should be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Effect on bleeding. In vitro studies on human platelets have shown that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside. There is no information on the safety of sildenafil use in patients with bleeding disorders or active peptic ulcer. Therefore, sildenafil may be used in such patients only after careful assessment of the benefit-risk ratio.

Erosil contains lactose and therefore should not be administered to men with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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

Hearing loss. Physicians should advise patients to discontinue use of PDE5 inhibitors, including Erosil, and seek immediate medical help if they experience 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 Erosil. It is not possible to determine whether these events are directly related to PDE5 inhibitor use or to other factors.

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

Sexually transmitted diseases. Use of Erosil does not protect against sexually transmitted diseases. Consideration should be given to informing patients about necessary preventive measures to protect against sexually transmitted diseases, including human immunodeficiency virus.

Use during pregnancy or breastfeeding.

Erosil is not intended for use in women.

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

The medication is administered orally.

Adults. The recommended dose of Erosil 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 frequency of administration is once daily. When Erosil is taken with food, the 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 of 30–80 mL/min), the recommended dose is the same as stated above for 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. If patients are concurrently using CYP3A4 inhibitors (except ritonavir, which is not recommended to be used concomitantly with sildenafil—see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use"), a starting dose of 25 mg should be considered.

To minimize the potential risk of postural hypotension in patients taking α-adrenoblockers, their condition should be stabilized on α-adrenoblockers prior to initiating sildenafil therapy. A starting dose of 25 mg should also be considered (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Children.

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

Overdose.

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

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

Adverse Reactions

The most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia, and blurred vision.

Adverse reactions are listed below by System Organ Class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Infections and infestations: uncommon – rhinitis.

Immune system disorders: uncommon – hypersensitivity.

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

Eye disorders: common – colour vision disturbance**, visual disturbances, blurred vision; uncommon – lacrimation disorders***, eye pain, photophobia, photopsia, eye hyperaemia, visual brightness, conjunctivitis, eye discharge, eye irritation, abnormal eye sensations, eyelid oedema, scleral discolouration; rare – non-arteritic anterior ischaemic optic neuropathy*, retinal vessel occlusion*, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, halos around lights, eye swelling, eye puffiness, eye disorders, conjunctival hyperaemia, eye irritation.

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

Cardiovascular disorders: common – facial flushing, hot flushes; uncommon – tachycardia, palpitations, arterial hypotension/hypertension; rare – sudden cardiac death*, myocardial infarction, ventricular arrhythmia*, atrial fibrillation, unstable angina.

Respiratory system disorders: common – nasal congestion; uncommon – epistaxis, nasal sinus congestion; rare – throat tightness, nasal mucosal oedema, nasal dryness.

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

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

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

Renal and urinary disorders: uncommon – haematuria.

Reproductive system and breast disorders: rare – penile haemorrhage, priapism*, haemospermia, prolonged erection.

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

Investigations: uncommon – increased heart rate.

* Reported only during clinical trials.
** Colour vision disturbance: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.
*** Lacrimation disorders: dry eyes, lacrimation disorder, increased lacrimation.

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

General disorders: facial oedema, photosensitivity reactions, shock, asthenia, pain, sudden collapse, abdominal pain, sudden injury.

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

Gastrointestinal disorders: glossitis, colitis, dysphagia, gastritis, gastroenteritis, oesophagitis, stomatitis, abnormal liver function tests, rectal haemorrhage, gingivitis.

Blood and lymphatic system disorders: anaemia, leukopenia.

Metabolism and nutrition disorders: thirst, oedema, gout, unstable diabetes, hyperglycaemia, peripheral oedema, hyperuricaemia, hypoglycaemia, hypernatraemia.

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

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

Respiratory, thoracic and mediastinal disorders: asthma, dyspnoea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, cough increase.

Skin and subcutaneous tissue disorders: urticaria, herpes, pruritus, increased sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Sensory organ disorders: sudden decrease or loss of hearing, ear pain, eye haemorrhage, cataract, dry eyes.

Renal and urinary disorders: cystitis, nocturia, increased frequency of micturition, galactorrhoea, urinary incontinence, ejaculation disorders, genital swelling, anorgasmia.

Adverse reactions reported from a population of unknown size. These events were reported due to their severity, frequency of reporting, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular and cerebrovascular events. Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral haemorrhage, subarachnoid haemorrhage, intracerebral haemorrhage, and pulmonary haemorrhage, which occurred in temporal association with sildenafil use. Most, but not all, patients had underlying cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred shortly 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 related to sildenafil use, sexual activity, underlying risk factors, a combination of these factors, or other factors.

Blood and lymphatic system: vaso-occlusive crisis.

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

Specific sensations.

Hearing. Cases of sudden decrease or loss of hearing, occurring in temporal association with sildenafil use, have been reported. In some cases, medical conditions and other factors that may have contributed to hearing-related adverse reactions were reported. In many cases, follow-up medical information was not available. 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.

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

Cases of non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision including permanent vision loss, have been reported in temporal association with the use of PDE5 inhibitors, including sildenafil. In many, but not all, patients, anatomical or vascular risk factors for NAION were present, including (but not limited to): small cup-to-disc ratio (crowded optic disc), age over 50 years, hypertension, coronary artery disease, hyperlipidaemia, and smoking. It is not possible to determine whether these events are directly related to PDE5 inhibitor use, underlying anatomical or vascular risk factors, a combination of these factors, or other factors.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions in accordance with national regulatory requirements.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

1, 2, or 4 tablets in a blister; 1 blister pack of No. 1, No. 2, or No. 4; or 2 blister packs of No. 4 in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

ASTRAFARM LLC, Ukraine.

Manufacturer's address and location of business activity.

6 Kyivska St., Vyshneve, Kyiv-Sviatoshyn district, Kyiv region, 08132, Ukraine.