Sildex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SILDEX (SILDEX)

Composition:

Active substance:
sildenafil;

One tablet contains 70.24 mg of sildenafil citrate, equivalent to 50 mg of sildenafil, or

One tablet contains 140.48 mg of sildenafil citrate, equivalent to 100 mg of sildenafil;

Excipients:
potassium polacrilin; potassium hydroxide or hydrochloric acid; magnesium stearate; colloidal silicon dioxide, anhydrous; aspartame (E 951); sodium croscarmellose; mint flavoring; lactose monohydrate; povidone K-30.

Pharmaceutical form.
Chewable tablets.

Main physicochemical properties:
White, triangular-shaped, biconvex tablets with "50" or "100" embossed on one side.

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), resulting in 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 cGMP breakdown. The effect of sildenafil on erection is peripheral. Sildenafil does not exert a direct relaxing effect on isolated human corpus cavernosum tissue, but it strongly potentiates the relaxing effect of NO on this tissue. During activation of the NO/cGMP metabolic pathway, which occurs during sexual stimulation, inhibition of PDE5 by sildenafil leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce the desired pharmacological effect, sexual stimulation is required.

Effect on pharmacodynamics. *In vitro* studies have demonstrated that sildenafil is selective for PDE5, which actively participates in the erectile process. The effect of sildenafil on PDE5 is more potent than its effect on other known phosphodiesterases. This effect is 10 times 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 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, the selectivity of sildenafil for PDE5 is 4000 times greater than its selectivity for PDE3—an isoform of cAMP-specific PDE involved in the regulation of cardiac contractility.

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. Maximum plasma concentration 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), 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 volume of distribution at steady state (Vd) is 105 liters, indicating distribution of the drug into body tissues. 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 the binding of sildenafil and its major N-desmethyl metabolite to plasma proteins is 96%, the mean maximum plasma concentration of free sildenafil reaches 18 ng/mL (38 nmol). The extent of protein binding is independent of total sildenafil concentrations.

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

Biotransformation. Sildenafil metabolism is primarily mediated 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 approximately 40% of the plasma concentration of sildenafil. The N-desmethyl metabolite undergoes further metabolism, and its elimination half-life is approximately 4 hours. Elimination. Total clearance of sildenafil is 41 L/h, resulting in an elimination half-life of 3–5 hours. After 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 healthy elderly volunteers (aged 65 years and older), reduced clearance of sildenafil was observed, resulting in approximately 90% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite compared to younger healthy volunteers (aged 18–45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%. Renal impairment. In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil remained unchanged after a single 50 mg oral dose. Mean AUC and Cmax of the N-desmethyl metabolite increased by up to 126% and 73%, respectively, compared to age-matched volunteers without renal impairment. However, due to high individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance below 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 without renal impairment. Additionally, AUC and Cmax of the N-desmethyl metabolite increased significantly by 200% and 79%, respectively. Hepatic impairment. In volunteers with mild to moderate hepatic cirrhosis (Child–Pugh classes A and B), sildenafil clearance was reduced, resulting in increased 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.

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

For effective action of Cildex, sexual stimulation is required.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the drug.
• Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the nitric oxide/cyclic guanosine monophosphate (cGMP) 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 loss of vision due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this condition is related to 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), as 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 is metabolized primarily by cytochrome P450 (CYP) 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. In vivo studies. Population pharmacokinetic analysis of clinical trial data demonstrated reduced clearance of sildenafil when co-administered 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, 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 dose of 100 mg) resulted in a 300% increase (4-fold) in sildenafil Cmax and a 1000% increase (11-fold) in plasma AUC. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL when sildenafil was administered 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 dose of sildenafil 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 of 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 the pharmacokinetics of saquinavir was observed (see section "Dosage and administration"). It is expected that more potent CYP3A4 inhibitors, such as ketoconazole and itraconazole, will 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 a 182% increase in systemic exposure of 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.

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

Although specific interaction studies between sildenafil and all medicinal products have not been conducted, population pharmacokinetic analysis data indicate that the pharmacokinetics of sildenafil were not altered when co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (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-adrenergic receptor 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 isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 µmol). Since peak plasma concentrations of sildenafil are approximately 1 µmol, the effect of the drug on the clearance of substrates of these isoenzymes is unlikely.

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

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

Riociguat. Preclinical studies demonstrated additive systemic blood pressure-lowering effects when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. In patients participating in the study, no positive clinical effect was observed 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-adrenergic receptor blockers may lead to symptomatic hypotension in some susceptible patients. Such reactions most commonly occurred within 4 hours after sildenafil administration (see sections "Dosage and administration" and "Special precautions for use"). In three drug interaction studies, the α-adrenergic receptor blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were administered concomitantly in patients with benign prostatic hyperplasia whose condition had been stabilized on doxazosin. In these populations, mean additional reductions in blood pressure in the supine position were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean reductions in blood pressure in the standing position were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Cases of symptomatic orthostatic hypotension have been reported with concomitant use of sildenafil and doxazosin in patients whose condition had been stabilized on doxazosin. These reports included episodes of dizziness and pre-syncope, but no syncope.

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

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

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

In patients taking sildenafil, there were no differences in the adverse effect profile compared to placebo when co-administered with antihypertensive drug classes such as diuretics, β-adrenergic receptor blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and α-adrenergic receptor blockers. In a specific interaction study, concomitant administration of sildenafil (100 mg) and amlodipine in patients with arterial hypertension resulted in an additional 8 mm Hg reduction in supine systolic blood pressure. 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 at a dose of 100 mg did not affect the pharmacokinetic parameters of HIV protease inhibitors saquinavir and ritonavir, which are substrates of CYP3A4.

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 sacubitril/valsartan alone. Therefore, sildenafil should be initiated with caution in patients receiving sacubitril/valsartan.

Special precautions for use.

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

Cardiovascular risk factors.
Since sexual activity carries a certain risk to the cardiovascular system, physicians should assess the cardiovascular status of patients before starting any treatment for erectile dysfunction. Sildenafil has vasodilatory effects, which manifest as mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians should carefully consider whether such an effect could adversely affect patients with underlying medical 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 manifestation of which is severe autonomic nervous system regulation of blood pressure.

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

Serious cardiovascular adverse reactions, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, have been reported temporally associated with sildenafil use. In most, but not all, patients, there were pre-existing cardiovascular risk factors. Many of these adverse reactions occurred during or immediately after sexual intercourse, and only a few occurred shortly after sildenafil administration without sexual activity. Therefore, it is not possible to determine whether the development of such adverse reactions is directly related to risk factors or whether other factors contributed to their occurrence.

Priapism.
Medications for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients with conditions that may predispose to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia).

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

Concomitant use with other PDE5 inhibitors or other erectile dysfunction medications.
The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other medications for pulmonary arterial hypertension containing sildenafil (e.g., Revatio), 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 reported in association with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports and findings from observational studies have also reported cases of non-arteritic anterior ischaemic 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, sildenafil use should be discontinued and they should 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 in patients taking α-adrenoreceptor blockers, their condition should be stabilized with α-blocker therapy before initiating sildenafil. Consideration should also be given to using an initial dose of 25 mg (see section "Dosage and administration"). 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 demonstrated that 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 may be used in such patients only after careful assessment of the benefit-risk ratio.

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 Sildex, and seek immediate medical attention in case of sudden decrease or loss of hearing. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with PDE5 inhibitor use, including this product. 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.
The drug exerts systemic vasodilatory effects and may further reduce blood pressure in patients taking antihypertensive medications. In a specific drug interaction study, concomitant oral administration of amlodipine (5 mg or 10 mg) and sildenafil (100 mg) resulted in an average additional reduction of systolic pressure by 8 mm Hg and diastolic pressure by 7 mm Hg.

Sexually transmitted diseases.
Sildenafil does not protect against sexually transmitted diseases. Consideration should be given to advising patients on necessary preventive measures to protect against sexually transmitted diseases, including human immunodeficiency virus.

Sildex tablets contain lactose. Men diagnosed with intolerance to certain sugars should consult their physician before taking this medicinal product.

Sildex tablets also contain aspartame, a phenylalanine derivative; therefore, they should not be used in patients with phenylketonuria.

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

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

Dosage and Administration

The medication should be taken orally. The tablets should be chewed before swallowing. The medication can be taken with or without water.

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

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

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

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

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

Patients taking other medicinal products.
If patients are concurrently taking CYP3A4 inhibitors (except ritonavir, which is not recommended to be used concomitantly with sildenafil; see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction"), a starting dose of 25* mg should be considered.

To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, such patients 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").

* - use sildenafil preparations at the appropriate dosage strength.

Children.

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

Overdose.

In clinical studies involving healthy volunteers, adverse reactions following single doses of sildenafil up to 800 mg were similar to those observed with 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 the event of overdose, standard supportive measures may be employed if necessary. 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.

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

All clinically significant adverse reactions observed during clinical trials more frequently than with placebo are listed below according to the "System Organ Class" and frequency: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1,000 – < 1/100), and rare (≥ 1/10,000 – < 1/1,000). Within each frequency grouping, adverse reactions are listed in decreasing order of 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 disorders**, visual disturbances, blurred vision.

Uncommon: tear disorders***, eye pain, photophobia, photopsia, eye hyperaemia, brightness of vision, conjunctivitis.

Rare: non-arteritic anterior ischaemic optic neuropathy*, retinal vascular occlusion*, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, halos around lights (halo vision), eye swelling, eye oedema, eye disorders, conjunctival hyperaemia, eye irritation, abnormal sensations in eyes, eyelid oedema, scleral discolouration.

Ear and labyrinth disorders.

Uncommon: dizziness, tinnitus.

Rare: deafness.

Cardiac disorders.

Uncommon: tachycardia, palpitations.

Rare: sudden cardiac death*, myocardial infarction, ventricular arrhythmia*, atrial fibrillation, unstable angina.

Vascular disorders.

Common: facial flushing, hot flushes.

Uncommon: hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders.

Common: nasal congestion.

Uncommon: epistaxis, nasal sinus congestion.

Rare: throat tightness, nasal mucosal swelling, nasal dryness.

Gastrointestinal disorders.

Common: nausea, dyspepsia.

Uncommon: gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth.

Rare: oral hypoesthesia.

Skin and subcutaneous tissue disorders.

Uncommon: rash.

Rare: Stevens-Johnson syndrome*, toxic epidermal necrolysis*.

Musculoskeletal and connective tissue disorders.

Uncommon: myalgia, limb pain.

Renal and urinary disorders.

Uncommon: haematuria.

Reproductive system and breast disorders.

Rare: penile haemorrhage, priapism*, haemospermia, prolonged erection.

General disorders and administration site conditions.

Uncommon: chest pain, increased fatigue, feeling of warmth.

Rare: irritation.

Investigations.

Uncommon: increased heart rate.

* Reported only during post-marketing surveillance after sildenafil release.

** Colour vision disorders: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.

*** Tear disorders: dry eyes, abnormal tear production, and increased lacrimation.

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

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

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

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

Blood and lymphatic system disorders: anaemia, leukopenia.

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

Musculoskeletal system 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 system disorders: asthma, dyspnoea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

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

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

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

Post-marketing experience. After sildenafil became available on the market, the following adverse reactions have been identified. Since these are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events are 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, occurring 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 the drug, sexual activity, underlying risk factors, a combination of these, or other factors.

Blood and lymphatic system disorders: 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 finding for patients taking sildenafil for erectile dysfunction is unknown.

Nervous system disorders: anxiety, transient global amnesia.

Sensory organs.

Hearing. After sildenafil became available on the market, cases of sudden decrease or loss of hearing temporally associated with sildenafil use have been reported. In some cases, medical conditions and other factors that could have contributed to hearing disorders 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, or other factors. Vision. Transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal oedema, retinal vascular disorders or haemorrhage, vitreous detachment.

Rarely, after sildenafil became available on the market, 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 PDE5 inhibitors, including sildenafil. Many, but not all, 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, 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, or other factors.

Reporting suspected adverse reactions. Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk profile of the drug. Healthcare professionals should report any suspected adverse reactions in accordance with national reporting requirements.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at temperatures not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

1 tablet in a blister, 1 blister per carton;

4 tablets in a blister, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant" (packaging from bulk supplied by manufacturer “Genepharm SA”, Greece).

Manufacturer's address and location of operations.

17 Myru Street, Kyiv, 03134, Ukraine.