Visarsin® q-tab®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Vizarsin® Q-Tab® (Vizarsin® Q-Tab®)

Composition:

Active substance: sildenafil;

1 tablet contains 25 mg or 50 mg or 100 mg of sildenafil;

Excipients: hydroxypropylcellulose, crospovidone, calcium silicate, magnesium stearate, neohesperidin dihydrochalcone, aspartame (E 951), mannitol (E 421), spearmint flavor, peppermint flavor (contains sorbitol (E 420)1 or sucrose2).

1for 25 mg dose

2for 50 mg and 100 mg doses

Medicinal form: Orodispersible tablets.

Main physicochemical properties: round, slightly biconvex tablets, white to almost white in color, with possible dark specks.

Pharmacotherapeutic group: Medicinal products used in erectile dysfunction. Sildenafil. ATC code G04BE03.

Pharmacological Properties.

Pharmacodynamics.

Sildenafil is an oral therapeutic agent used for the treatment of erectile dysfunction in men. Under natural conditions, particularly during sexual stimulation, it restores impaired erection by enhancing blood flow to the penis.

The physiological mechanism of penile erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO activates the enzyme guanylate cyclase, leading to increased levels of cyclic guanosine monophosphate (cGMP), relaxation of smooth muscles in the corpus cavernosum, and enhanced blood inflow.

Sildenafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE-5) specific to cGMP in the corpus cavernosum, where PDE-5 is responsible for cGMP breakdown. Sildenafil exerts a peripheral effect on erection. It does not have a direct relaxing effect on isolated human corpus cavernosum tissue but significantly enhances the relaxing effect of NO on this tissue.

When the NO/cGMP pathway is activated during sexual stimulation, inhibition of PDE-5 by sildenafil leads to increased cGMP levels in the corpus cavernosum. Therefore, sexual stimulation is necessary for sildenafil to exert its targeted positive pharmacological effect.

In vitro studies have shown that sildenafil is selective for PDE-5, which is involved in the erectile process. Its inhibitory effect is stronger on PDE-5 than on other known phosphodiesterases. It shows 10-fold selectivity over PDE-6, which is involved in retinal phototransduction. At maximally recommended doses, it demonstrates 80-fold selectivity over PDE-1 and more than 700-fold selectivity over PDE-2, 3, 4, 7, 8, 9, 10, and 11. In particular, sildenafil has more than 4000-fold selectivity for PDE-5 over PDE-3, a cGMP-specific phosphodiesterase isoform involved in regulating cardiac contraction.

Pharmacokinetics.

Absorption.

Sildenafil is rapidly absorbed. Maximum observed concentrations are reached within 30–120 minutes (on average, 60 minutes) after oral administration on an empty stomach. The mean absolute bioavailability after oral administration is 41% (range 25–63%). After oral administration, AUC and Cmax increase proportionally with dose within the recommended dosage range (25–100 mg).

When sildenafil is taken with food, the rate of absorption is reduced, with a mean delay in tmax of 60 minutes and a mean reduction in Cmax by 29%.

Distribution.

The mean steady-state volume of distribution (Vd) for sildenafil is 105 L, indicating extensive tissue distribution. After a single 100 mg oral dose, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (coefficient of variation 40%). Since sildenafil (and its major metabolite N-desmethyl in systemic circulation) is 96% bound to plasma proteins, this results in a mean maximum free sildenafil concentration in plasma of 18 ng/mL (38 nmol). Protein binding is independent of total drug concentration.

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

Metabolism.

Sildenafil is primarily metabolized by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major metabolite in systemic circulation is formed via N-demethylation of sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and exhibits approximately 50% of the in vitro potency of the parent drug for PDE-5. Plasma concentrations of this metabolite are approximately 40% of those observed for sildenafil. The N-desmethyl metabolite is further metabolized with a terminal half-life of approximately 4 hours.

Elimination.

The total systemic clearance of sildenafil is 41 L/h, with a terminal half-life of 3–5 hours. After oral or intravenous administration, sildenafil is excreted as metabolites, 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

Geriatric Patients

Healthy elderly volunteers (aged 65 years and older) had reduced sildenafil clearance, resulting in higher plasma concentrations of sildenafil and its N-desmethyl metabolite (approximately 90% higher) 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 concentrations was approximately 40%.

Renal Impairment

In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil were not altered after a single 50 mg oral dose. Mean AUC and Cmax of the N-desmethyl metabolite increased by 126% and 73%, respectively, compared to age-matched healthy volunteers without renal impairment. However, due to high inter-individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance < 30 mL/min), sildenafil clearance was reduced, leading to mean increases in AUC and Cmax by 100% and 88%, respectively, compared to age-matched healthy volunteers. Additionally, AUC and Cmax values of the N-desmethyl metabolite were significantly increased by 79% and 200%, 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 (by 84%) and Cmax (by 47%) compared to age-matched volunteers without hepatic dysfunction. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

Vizarsin® Q-Tab® is recommended for use in men with erectile dysfunction, defined as the inability to achieve or maintain a penile erection sufficient for successful sexual performance.

For Vizarsin® Q-Tab® to be effective, 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 (NO) donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the NO/cyclic guanosine monophosphate (cGMP) pathway and to potentiate the hypotensive effect of nitrates (see section "Pharmacodynamics").
• 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 where 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 previous use of PDE5 inhibitors (see section "Special precautions for use").
• 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), 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 metabolism is primarily mediated by cytochrome P450 (CYP) isoenzymes 3A4 (major pathway) and 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, while inducers of these isoenzymes may increase sildenafil clearance.

In vivo studies

Clinical studies have shown reduced sildenafil clearance when co-administered with CYP3A4 inhibitors (ketoconazole, erythromycin, cimetidine).

Although an increased incidence of adverse effects has not been observed when sildenafil is 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 CYP3A4, at steady state (500 mg twice 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, indicating a significant effect of ritonavir on a broad range of CYP3A4 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 steady state (1200 mg three times daily) with sildenafil (single 100 mg dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. 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, would have a more pronounced effect.

Administration of a single 100 mg dose of sildenafil 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). In healthy male volunteers, azithromycin (500 mg daily for 3 days) did not affect the 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 50 mg sildenafil in healthy volunteers, increased plasma concentrations of sildenafil by 56%.

Grapefruit juice is a weak inhibitor of intestinal CYP3A4 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 with 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 inhibitor group (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 CYP450 metabolism inducers (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% reduction in AUC and a 55.4% reduction in Cmax of sildenafil. Therefore, concomitant use of potent CYP3A4 inducers such as rifampicin may lead to a more pronounced decrease in plasma concentrations of sildenafil.

Nicorandil is a hybrid of a potassium channel activator and a nitrate. Due to its nitrate component, it has 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 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 the NO/cyclic guanosine monophosphate (cGMP) pathway, it has been established that sildenafil potentiates the hypotensive effect of nitrates; therefore, its concomitant use with NO donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat. Preclinical studies have demonstrated an additive systemic effect on lowering blood pressure when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. In patients 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. This reaction 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 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. Symptomatic orthostatic hypotension has occasionally been reported when sildenafil was used concomitantly with doxazosin in patients whose condition was stabilized on doxazosin. These reports described episodes of dizziness and presyncope, but not syncope.

No significant interactions were observed when sildenafil (50 mg) was administered concomitantly with tolbutamide (250 mg) or warfarin (40 mg), both of which are 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 mean peak blood ethanol levels of 80 mg/dL.

In patients taking sildenafil, no differences in the adverse effect profile were observed compared to placebo when concomitantly using antihypertensive drug classes such as diuretics, β-adrenergic receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, vasodilators and centrally acting antihypertensives, 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 and a 7 mm Hg reduction in diastolic blood pressure. These additional reductions in blood pressure were comparable in magnitude to those observed with sildenafil alone in healthy volunteers (see section "Pharmacological properties").

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.

Sildenafil 100 mg did not affect the pharmacokinetic parameters of HIV protease inhibitors saquinavir and ritonavir, both 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.

Special precautions for use.

A thorough medical history and physical examination are required to diagnose erectile dysfunction, determine possible causes of the disease, and prescribe appropriate treatment.

Cardiovascular risk factors. Before initiating any treatment for erectile dysfunction, the cardiovascular status of patients should be carefully evaluated, since there is a certain cardiovascular risk associated with sexual activity. Sildenafil has vasodilatory properties, leading to mild and transient reduction in blood pressure. Before prescribing sildenafil, physicians should carefully consider the risk of adverse vasodilatory effects in patients with certain comorbidities during sexual activity. Increased sensitivity to vasodilators is observed in patients with left ventricular outflow tract obstruction (e.g., aortic stenosis; obstructive hypertrophic cardiomyopathy) or in patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic nervous system dysfunction in blood pressure regulation.

Vizarsin® Q-Tab® enhances the hypotensive effect of nitrates (see section "Contraindications").

Since the introduction of sildenafil into widespread clinical use, serious cardiovascular events have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, arterial hypertension, and arterial hypotension. Most, but not all, of these patients had pre-existing cardiovascular risk factors. The majority of such cases occurred during or immediately after sexual activity, while a small number occurred shortly after taking sildenafil without sexual activity. It is not possible to establish a direct causal relationship between these events and the use of sildenafil, sexual activity, underlying cardiovascular diseases, a combination of these factors, or other factors.

Priapism. Medicinal products indicated for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernous fibrosis, or Peyronie’s disease) or in patients with conditions predisposing to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia).

After the drug was marketed, cases of prolonged erection and priapism were reported. If an erection lasts more 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 treatments. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other medications for pulmonary arterial hypertension containing sildenafil, or with other treatments for erectile dysfunction, have not been studied; therefore, such combinations are not recommended.

Effect on vision. Spontaneous reports of visual disturbances associated with the use of sildenafil and other PDE5 inhibitors have been received (see section "Adverse reactions"). Spontaneous reports and data from observational studies have indicated cases of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition, associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised to discontinue sildenafil and seek immediate medical advice in case of sudden visual disturbance (see section "Contraindications").

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

α-Adrenoreceptor blockers. Sildenafil should be used with caution in patients who are concurrently using α-adrenoblockers, as in some cases this may lead to symptomatic hypotension in susceptible individuals. Symptomatic hypotension usually occurs within 4 hours after sildenafil administration. To minimize the risk of postural hypotension, blood pressure should be stabilized with α-blockers before initiating sildenafil therapy. Additionally, consideration should be given to starting with an initial dose of 25 mg (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 studies on human platelets indicate that sildenafil enhances the anti-aggregatory effect of sodium nitroprusside. There is no safety data available regarding the use of sildenafil in patients with bleeding tendencies or with active peptic ulcer; therefore, sildenafil should be prescribed to these patients only after careful assessment of benefit versus risk.

Administration of a 100 mg dose to healthy volunteers showed no effect on sperm morphology or motility (see section "Pharmacodynamics").

Hearing loss. Physicians should advise patients to discontinue use of PDE5 inhibitors, including Vizarsin® Q-Tab®, and seek immediate medical help in case of sudden decrease or loss of hearing. These events, which may also be accompanied by tinnitus and dizziness, have been temporally associated with the use of PDE5 inhibitors, 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. Vizarsin® Q-Tab® 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 in systolic blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg.

Sexually transmitted infections. The use of Vizarsin® Q-Tab® does not protect against sexually transmitted infections. Consideration should be given to advising patients on necessary protective measures to prevent sexually transmitted infections, including human immunodeficiency virus (HIV).

Vizarsin® Q-Tab® contains aspartame (E 951), a source of phenylalanine. The product may be harmful to men with phenylketonuria.

Vizarsin® Q-Tab®, orally disintegrating tablets containing 25 mg, contain sorbitol (E 420). Men with rare hereditary fructose intolerance should not take this medicine.

Vizarsin® Q-Tab®, orally disintegrating tablets containing 50 mg and 100 mg, contain sucrose. The medicinal product should not be used by patients with hereditary conditions associated with fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Vizarsin® Q-Tab® is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery.

Vizarsin® Q-Tab® may have a minor influence on the ability to drive or operate machinery.

Since dizziness and visual disturbances have been reported during clinical trials with sildenafil, patients should determine their individual response to Vizarsin® Q-Tab® before driving or operating machinery.

Method of Administration and Dosage

The medication is intended for oral use in adult males.

The tablet should be placed on the tongue, where it rapidly disperses in saliva, after which it can be easily swallowed. The tablet may be taken with or without liquid. It is difficult to remove the dispersible tablet from the mouth intact. Since the tablet is fragile, it should be taken immediately after removing from the blister pack.

Dispersible tablets may serve as an alternative to Vizarsin® film-coated tablets for patients who experience difficulty swallowing film-coated tablets. If a 100 mg dose is required, the second tablet should be taken only after complete dispersion of the first tablet.

Adults. The recommended dose is 50 mg, taken as needed approximately 1 hour before sexual activity. 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. The efficacy of Vizarsin® Q-Tab® may be delayed when taken with food compared to administration on an empty stomach.

Elderly patients. No dosage adjustment is 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), no dosage adjustment is necessary. Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min), treatment should be initiated with a 25 mg dose. Depending on efficacy and tolerability, the dose may be gradually increased to 50 mg and then to 100 mg, if needed.

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

Patients taking other medicinal products. If patients are concurrently using CYP3A4 inhibitors (see section "Interaction with other medicinal products and other forms of interactions"), consideration should be given to initiating treatment with a 25 mg dose (except for ritonavir, which is not recommended to be used concomitantly with sildenafil; see section "Special precautions for use").

To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, the patient's condition should be stabilized with α-adrenoreceptor blockers before initiating sildenafil therapy. Additionally, consideration should be given to initiating treatment with a 25 mg dose (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interactions").

Children.

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

Overdose.

In clinical studies involving healthy volunteers, administration of single doses of sildenafil up to 800 mg resulted in adverse reactions similar to those observed with 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 an increased incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In the event of overdose, standard supportive measures should be implemented as 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 safety profile of sildenafil is based on data from 74 double-blind, placebo-controlled clinical trials (9,570 patients). The most commonly reported adverse reactions in clinical studies among patients taking sildenafil were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, visual disturbances, cyanopsia, and blurred vision. Information on adverse reactions from post-marketing surveillance of sildenafil use has been collected for over 10 years.

Since not all adverse reactions were reported to the marketing authorization holder and not all were included in the safety database, the frequency of such reactions cannot be reliably determined.

Listed below are all clinically significant adverse reactions that occurred in clinical trials at a frequency higher than with placebo, categorized by system organ class and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000).

Also included is the frequency of clinically significant adverse reactions reported from post-marketing experience as "unknown".

Within each frequency grouping, adverse effects are listed in order of decreasing incidence.

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, brightness of vision, conjunctivitis.

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 in visual field, eye swelling, eye swelling, eye disorders, conjunctival hyperaemia, eye irritation, abnormal sensations in eyes, eyelid oedema, scleral discoloration.

Ear and labyrinth disorders

Uncommon: vertigo, 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, flushing.

Uncommon: hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders

Common: nasal congestion.

Uncommon: epistaxis, nasal sinus congestion.

Rare: throat tightness, nasal mucosal oedema, dryness in nose.

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 studies.

** 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 in controlled clinical trials; causal relationship not established. Reports included events with a probable relationship to drug use. Events not listed were mild and reports too imprecise to be meaningful.

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

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

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

Blood and lymphatic system disorders: anaemia, leucopenia.

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

Musculoskeletal system: arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

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

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

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

Specific sensations: sudden decrease or loss of hearing, ear pain, eye haemorrhage, cataract, dry eyes.

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

Post-marketing experience. The adverse reactions listed below were identified after the drug was marketed. Because these reactions are reported voluntarily from a population of uncertain 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 seriousness, 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 were temporally associated 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 drug use, sexual activity, pre-existing risk factors, a combination of these factors, or other factors.

Blood and lymphatic system: vaso-occlusive crisis. In a small, prematurely terminated study of Revatio (sildenafil) 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 using sildenafil for the treatment of erectile dysfunction is unknown.

Nervous system: anxiety, transient global amnesia.

Specific sensations.

Hearing. 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 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, pre-existing risk factors for hearing loss, a combination of these factors, or other factors.

Vision: temporary vision loss, eye redness, eye burning, increased intraocular pressure, retinal oedema, retinal vascular disease or haemorrhage, vitreous detachment.

Rare cases of non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision including permanent vision loss, temporally associated with PDE5 inhibitors, including sildenafil, have been reported post-marketing. Many, but not all, patients had pre-existing 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, pre-existing anatomical or vascular risk factors, a combination of these factors, or other factors.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

For 25 mg dosage: 2 years.

For 50 mg and 100 mg dosages: 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture. Keep out of reach of children.

Packaging.

1 tablet in a blister; 1 or 2 blisters in a cardboard box.

4 tablets in a blister; 1, 2, or 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.