Vivivra

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIVAYRA

Composition:

Active substance: sildenafil citrate;

One chewable tablet contains sildenafil 50 mg in the form of sildenafil citrate 70.24 mg or

One chewable tablet contains sildenafil 100 mg in the form of sildenafil citrate 140.48 mg;

Excipients: potassium polacrilin; magnesium stearate; colloidal anhydrous silicon dioxide; aspartame (E 951); sodium croscarmellose; peppermint flavor; lactose monohydrate; povidone K-30.

Pharmaceutical form. Chewable tablets.

Main physicochemical properties: white, triangular, biconvex tablets with the imprint «50» or «100» on one side.

Pharmacotherapeutic group. Agents used in erectile dysfunction. Sildenafil. ATC code G04BE03.

Pharmacological Properties.

Pharmacodynamics.

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 NO activates the enzyme guanylate cyclase, which stimulates an increase in cyclic guanosine monophosphate (cGMP) levels, 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 degradation. The effects of sildenafil on erection are peripheral in nature. Sildenafil does not exert direct relaxant effects on isolated human corpus cavernosum tissue, but it potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP metabolic pathway is activated during sexual stimulation, sildenafil's inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Therefore, for the desired pharmacological effect to occur after sildenafil administration, sexual stimulation is required.

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 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, sildenafil's selectivity for PDE5 is 80 times greater than for PDE1, 700 times greater than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. In particular, sildenafil's selectivity for PDE5 is 4000 times greater than for PDE3—an isoform of cAMP-specific phosphodiesterase involved in regulating cardiac contractility.

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. Maximum plasma concentrations are 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 plasma concentration-time curve (AUC) and maximum concentration (Cmax) of sildenafil increase proportionally with dose.

When sildenafil is taken with food, the extent of absorption is reduced, with a mean delay in time to reach maximum concentration (Tmax) of 60 minutes and a mean reduction in Cmax of 29%.

Distribution. The mean steady-state volume of distribution (Vd) is 105 liters, indicating extensive distribution of the drug into body tissues. After a single 100 mg oral dose of sildenafil, the mean peak total plasma concentration of sildenafil is approximately 440 ng/mL (coefficient of variation 40%). Since binding of sildenafil and its major N-desmethyl metabolite to plasma proteins is about 96%, the mean peak plasma concentration 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 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.

Metabolism. 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 concentrations of this metabolite are about 40% of sildenafil plasma concentrations. The N-desmethyl metabolite undergoes further metabolism, and its elimination half-life is approximately 4 hours.

Excretion. The 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, leading to 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 126% and 73%, respectively, compared to age-matched volunteers with normal renal function. 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, 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.

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

For effective action of the medication, sexual stimulation is required.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medication.
• Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the NO/cGMP metabolic pathway and may potentiate 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).
• Loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this condition is associated with prior use of PDE5 inhibitors or not.
• Presence of the following conditions: severe hepatic impairment, arterial hypotension (blood pressure below 90/50 mm Hg), recent stroke or myocardial infarction, and hereditary degenerative retinal disorders such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterases) — because the safety of sildenafil has not been studied in such conditions.

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on sildenafil

In vitro studies

Metabolism of sildenafil 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

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 increased frequency of adverse events was not observed when sildenafil was used concomitantly with CYP3A4 inhibitors, consideration should be given to using an initial dose of sildenafil of 25 mg.

Concomitant administration of the HIV protease inhibitor ritonavir, a very potent inhibitor of P450, at steady-state concentration (500 mg twice daily) and sildenafil (single dose of 100 mg) resulted in a 300% increase (4-fold) in Cmax of sildenafil and a 1000% increase (11-fold) in plasma AUC of sildenafil. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL typical after administration of sildenafil alone, indicating a 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 achieving steady-state concentration (1200 mg three times daily) and sildenafil (single dose of 100 mg) resulted in a 140% increase in Cmax of sildenafil and a 210% increase in AUC of sildenafil. No effect of sildenafil on the pharmacokinetics of saquinavir was observed (see section "Dosage and administration"). More potent CYP3A4 inhibitors, such as ketoconazole and itraconazole, are expected to have a more pronounced effect.

Administration of sildenafil (single dose of 100 mg) and erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in AUC of sildenafil. In healthy male volunteers, azithromycin (500 mg daily for 3 days) had no effect on 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 administered concomitantly with sildenafil 50 mg in healthy volunteers, increased plasma concentrations of sildenafil by 56%.

Grapefruit juice is a weak inhibitor of CYP3A4 in the intestinal wall and may cause a moderate increase in 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), 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 such potent CYP3A4 inducers as rifampicin may lead to a more pronounced decrease in plasma concentrations of sildenafil.

Nicorandil is a hybrid calcium channel activator and nitrate. The nitrate component implies the possibility of serious interaction with sildenafil.

Effects 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 of sildenafil with non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.

In vivo studies

Since it is known that sildenafil affects the NO/cGMP metabolism, it has been established that sildenafil potentiates the hypotensive effect of nitrates; therefore, concomitant use of sildenafil with nitric oxide donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat. Preclinical studies have demonstrated an additive systemic effect of 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 from the concomitant use of PDE5 inhibitors with riociguat. Concomitant use of riociguat with PDE5 inhibitors (including sildenafil) is contraindicated (see section "Contraindications").

Concomitant use of sildenafil and α-adrenoreceptor blockers may lead to the development of symptomatic hypotension in some susceptible patients. Such a reaction most commonly occurred within 4 hours after administration of sildenafil (see sections "Special precautions for use" and "Dosage and administration"). In three specific drug interaction studies, the α-adrenoreceptor 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 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. Concomitant use of sildenafil and doxazosin in patients whose condition had been stabilized on doxazosin was occasionally associated with reports of symptomatic orthostatic hypotension. These reports described episodes of dizziness and pre-syncope, but no syncope.

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

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

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol 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 concomitantly using 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 a specific interaction study, concomitant administration of sildenafil (100 mg) and amlodipine to 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 reductions in blood pressure were comparable to those observed with sildenafil alone in healthy volunteers.

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 significantly greater blood pressure reduction compared to sacubitril/valsartan alone. Therefore, caution should be exercised when initiating sildenafil in patients receiving treatment 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 prior to starting any treatment for erectile dysfunction. Sildenafil has vasodilatory effects, resulting in mild and transient reduction in blood pressure. Before prescribing sildenafil, physicians should carefully consider whether this effect might adversely affect patients with certain underlying diseases, especially when combined with sexual activity. Patients particularly 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 regulation of blood pressure.

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

During the post-marketing period, serious adverse cardiovascular events have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, which temporally coincided with sildenafil use. Most patients had underlying cardiovascular risk factors. Many of these adverse events occurred during or immediately after sexual intercourse, and only a few occurred shortly after taking the drug 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 (angulation, cavernous fibrosis, or Peyronie’s disease) and in patients with conditions predisposing to priapism (sickle cell anaemia, multiple myeloma, or leukaemia).

After the drug was introduced to the market, 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 medications for erectile dysfunction

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 medications for erectile dysfunction, have not been studied. Therefore, the use of such combinations is not recommended.

Effect on vision

Cases of visual disturbances and non-arteritic anterior ischemic optic neuropathy have been reported in connection with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be warned that if sudden vision loss occurs, the drug should be discontinued immediately and medical advice sought (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 taking sildenafil. Therefore, hemodynamic parameters should be stable in patients receiving α-adrenoreceptor blockers before initiating sildenafil therapy. Consideration should be given to starting treatment with a 25 mg dose of sildenafil (see section "Dosage and administration"). In addition, patients should be informed about 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 effects of sodium nitroprusside. There is no information on the safety of sildenafil use in patients with coagulation disorders or acute peptic ulcer. Therefore, sildenafil may be used in these patient groups only after careful assessment of the benefit-risk ratio.

Hearing loss

Physicians should advise patients to discontinue PDE5 inhibitors, including Vivanza, 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 the use of PDE5 inhibitors, including Vivanza. 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

Vivanza exerts systemic vasodilatory effects and may further reduce blood pressure in patients taking antihypertensive medications. In a dedicated drug interaction study, concomitant oral administration of amlodipine (5 mg or 10 mg) and Vivanza (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 diseases

Use of Vivanza does not protect against sexually transmitted diseases. Patients should be advised on necessary preventive measures to protect against sexually transmitted infections, including human immunodeficiency virus.

Fertility

No effects on sperm morphology or motility were observed in healthy volunteers after a 100 mg dose.

Vivanza contains lactose. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicine. Aspartame (E 951) in the formulation is a phenylalanine derivative and may be harmful to patients with phenylketonuria.

Use during pregnancy or breastfeeding.

The drug 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 or operating machinery.

Method of administration and dosage

The medication is taken orally.

The tablet should be completely chewed and then swallowed.

Adults

Vivayra should be taken as needed, approximately 1 hour before sexual activity. The recommended dose is 50 mg. Since taking the medication with food may delay absorption and slow down its effect (see section "Pharmacokinetics"), it is recommended to take the medication on an empty stomach.

Depending on efficacy and tolerability, the dose may be increased to 100 mg or reduced to 25 mg*. The maximum recommended dose is 100 mg.

The maximum recommended frequency of administration is once daily.

Elderly patients

Dose adjustment is not required for elderly patients (aged 65 years and older).

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 described 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 up to 100 mg, if needed.

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 up to 100 mg, if needed.

Patients taking other medicinal products

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

Due to the risk of postural hypotension, in patients taking α-adrenoreceptor blockers, it is important to ensure that their condition is stable before initiating sildenafil therapy. A starting dose of 25 mg* should also be considered (see sections "Interaction with other medicinal products and other types of interactions" and "Special warnings and precautions for use").

* Administer in the appropriate dosage form.

Children

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

Overdose

During clinical trials involving adult volunteers, adverse reactions following single doses of sildenafil up to 800 mg were similar to those observed at lower doses but occurred more frequently and were more severe. Administration of sildenafil at a dose of 200 mg did not 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 needed. Hemodialysis is unlikely to accelerate sildenafil clearance significantly 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 were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia, and blurred vision. Information on adverse reactions from post-marketing surveillance has been collected over a period of more than 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.

All clinically significant adverse reactions observed during clinical trials more frequently than with placebo 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), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data). The frequency of clinically significant adverse reactions reported during post-marketing surveillance is categorized as not known. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations

Uncommon: rhinitis.

Immune system disorders

Uncommon: hypersensitivity reactions.

Nervous system disorders

Very common: headache.

Common: dizziness.

Uncommon: somnolence, hypoesthesia.

Rare: stroke, syncope, transient ischaemic attack, seizures, seizure recurrence.

Eye disorders

Common: colour vision disturbance*, visual disturbances, blurred vision.

Uncommon: lacrimation disorders**, eye pain, photophobia, photopsia, eye hyperaemia, visual brightness, 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 light sources in the visual field, eye oedema, eye swelling, eye disorders, conjunctival hyperaemia, eye irritation, abnormal eye sensations, eyelid oedema, scleral discolouration.

Ear and labyrinth disorders

Uncommon: dizziness, vertigo, tinnitus.

Rare: deafness.

Cardiac disorders

Common: facial flushing, hot flushes.

Uncommon: tachycardia, palpitations, hypertension, hypotension.

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

Respiratory, thoracic and mediastinal disorders

Common: nasal congestion.

Uncommon: epistaxis, nasal sinus congestion.

Rare: throat tightness, nasal mucosal oedema, 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.

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

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

Cardiac 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, increased cough.

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

Specific sensations: 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. The following adverse reactions have been identified after marketing authorization. As these reactions 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 were reported due to their severity, frequency of reporting, lack of clear alternative cause, 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 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 drug use, 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 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 disorders: anxiety, transient global amnesia.

Specific sensations

Hearing. After marketing authorization, 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 could have contributed to hearing-related adverse reactions were reported. In many cases, follow-up medical information is lacking. It is not possible to determine whether these events are directly related to sildenafil use, underlying risk factors for hearing loss, a combination of these, 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 marketing authorization, 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 of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization 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 reporting requirements.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

1 or 4 tablets in a blister. One blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Belupo, lijekovi i kozmetika d.d.

Manufacturer's address and place of business.

Danice 5, 48000 Koprivnica, Croatia.