Erotex for men

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EROTEX FOR MEN (EROTEX DLIA CHOLOVIKIV)

Composition:

Active substance: sildenafil;

One film-coated tablet contains sildenafil citrate equivalent to 50 mg of sildenafil or

One film-coated tablet contains sildenafil citrate equivalent to 100 mg of sildenafil;

Excipients: lactose monohydrate; microcrystalline cellulose; povidone K 29-32; sodium croscarmellose; magnesium stearate; Opadry Blue 03F20404 (hypromellose, titanium dioxide (E 171), polyethylene glycol 6000, indigo carmine aluminum lake).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg: blue, biconvex, film-coated, oval-shaped tablets with the imprint «SL50» on one side;

100 mg: blue, biconvex, film-coated, oval-shaped tablets with the imprint «SL100» on one side.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Sildenafil is a medicinal product used for the treatment of erectile dysfunction. During sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis.

The physiological mechanism responsible for penile erection involves the release of nitric oxide (NO) into the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, leading to increased levels of cyclic guanosine monophosphate (cGMP), which results in relaxation of smooth muscle in the corpus cavernosum and induces blood inflow.

Sildenafil is a potent, selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for cGMP degradation. Sildenafil acts peripherally on erection. Sildenafil does not exhibit direct relaxing effects on isolated human corpus cavernosum, but it strongly potentiates the relaxing effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs during sexual stimulation, inhibition of PDE5 by sildenafil leads to increased cGMP levels in the corpus cavernosum. Thus, sexual stimulation is required to achieve the pharmacological effect of sildenafil.

Pharmacodynamic Effect

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 in the retina. At maximum recommended doses, the selectivity of sildenafil 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, the selectivity of sildenafil for PDE5 is 4000 times greater than for PDE3 – the cAMP-specific phosphodiesterase isoform involved in regulation of cardiac contractility.

Pharmacokinetics

Absorption

Sildenafil is rapidly absorbed. Maximum plasma concentration (Cmax) is reached within 30–120 minutes (median 60 minutes) after oral administration on an empty stomach. The mean absolute bioavailability after oral administration is 41% (range 25–63%). Within the recommended dose range (25–100 mg), the area under the plasma concentration-time curve (AUC) and Cmax of sildenafil increase proportionally with dose.

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

Distribution

The mean steady-state volume of distribution (Vd) of sildenafil is 105 L, 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 binding of sildenafil (and its major N-desmethyl metabolite) to plasma proteins is 96%, the mean maximum free sildenafil concentration in plasma is 18 ng/mL (38 nmol). The degree of plasma protein binding is independent of total sildenafil concentration.

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 after 90 minutes.

Metabolism

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 selectivity profile of this metabolite for phosphodiesterase type 5 is similar to that of sildenafil, and its activity against PDE5 is approximately 50% of the parent compound. Plasma concentration of this metabolite is about 40% of the plasma concentration of sildenafil. The N-desmethyl metabolite is further metabolized, and its elimination half-life is approximately 4 hours.

Excretion

Total clearance of sildenafil is 41 L/h, resulting in an elimination half-life of 3–5 hours. Following both oral and intravenous administration, excretion of sildenafil metabolites occurs predominantly in feces (approximately 80% of orally administered dose) and to a lesser extent in urine (approximately 13% of orally administered dose).

Pharmacokinetics in Special Patient Populations

Elderly Patients

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

Renal Impairment

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

Clinical characteristics.

Indications.

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

For effective action of the Eroteks for men, sexual stimulation is required.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the NO/cGMP metabolic pathway and potentiates the hypotensive effect of nitrates.
• Concomitant use of PDE5 inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated, as it may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").
• Conditions in which sexual activity is not recommended (e.g., severe cardiovascular disorders such as unstable angina or severe heart failure).
• 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.
• Conditions such as severe hepatic impairment, arterial hypotension (blood pressure below 90/50 mm Hg), recent stroke or myocardial infarction, and known hereditary degenerative retinal diseases such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterases), since the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on sildenafil

In vitro studies

Sildenafil is metabolized primarily 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

Population pharmacokinetic analysis of clinical trial data demonstrated reduced sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increased incidence of adverse events was not observed in these patients, consideration should be given to initiating sildenafil therapy at a dose of 25 mg when administered concomitantly with CYP3A4 inhibitors.

Concomitant administration of the HIV protease inhibitor ritonavir, a potent inhibitor of P450, at steady-state concentration (500 mg once daily) with sildenafil (single 100 mg dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil AUC in plasma. After 24 hours, the plasma concentration of sildenafil was approximately 200 ng/mL, compared to 5 ng/mL when sildenafil was administered alone. This reflects the significant effect of ritonavir on a large number of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Based on these pharmacokinetic results, concomitant administration of sildenafil with ritonavir is not recommended (see section "Special precautions for use"), and the maximum sildenafil dose should in no case 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) with sildenafil (single 100 mg dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil does not affect the pharmacokinetics of saquinavir (see section "Dosage and administration"). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to 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 sildenafil AUC. Healthy male volunteers showed no evidence of azithromycin (500 mg daily for 3 days) affecting AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, increased plasma concentrations of sildenafil by 56% when co-administered with sildenafil (50 mg) in healthy volunteers.

Grapefruit juice, a weak inhibitor of CYP3A4, affects intestinal wall metabolism and may cause a moderate increase in plasma sildenafil concentrations.

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

Although specific interaction studies have not been conducted for all medicinal products, population pharmacokinetic analysis showed no effect on sildenafil pharmacokinetics from concomitant therapy with CYP2C9 inhibitors (such as 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-blockers, or CYP450 metabolism inducers (e.g., rifampicin, barbiturates). In a study conducted in 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) with 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. Thus, concomitant use of strong CYP3A4 inducers such as rifampicin leads to a greater decrease in plasma sildenafil concentrations.

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 µM). Considering peak plasma concentrations of sildenafil of approximately 1 µM after administration of recommended doses, Eroteks for men is unlikely to alter the clearance of substrates of these isoenzymes.

Data on interaction between sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole are lacking.

In vivo studies

Consistent with known effects on the NO/cGMP metabolic pathway, sildenafil has demonstrated potentiation of the hypotensive effect of nitrates; therefore, concomitant administration of sildenafil with nitric oxide donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat. Preclinical studies demonstrated an additive systemic blood pressure-lowering effect when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. No positive clinical effect was observed in patients participating in the study when PDE5 inhibitors were used concomitantly with riociguat. Concomitant use of riociguat with PDE5 inhibitors (including sildenafil) is contraindicated (see section "Contraindications").

Concomitant use of sildenafil with α-blockers may cause symptomatic hypotension in a small number of sensitive individuals, most likely within 4 hours after sildenafil administration (see sections "Special precautions for use" and "Dosage and administration"). In three specific drug interaction studies, the α-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign prostatic hyperplasia who were receiving doxazosin to stabilize their condition. In these patients, mean additional reductions in supine blood pressure were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean additional reductions in standing blood pressure were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. When sildenafil and doxazosin were administered together to patients stabilized on doxazosin, rare reports of symptomatic postural hypotension, dizziness, and pre-syncope occurred, but no syncope.

No significant interactions were observed when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized via CYP2C9.

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

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

In patients taking sildenafil, no differences in adverse effect profile were observed compared to placebo when co-administered with classes of antihypertensive drugs such as diuretics, β-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive agents (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and α-adrenergic receptor blockers. In a specific interaction study where sildenafil (100 mg) was administered together with amlodipine to patients with hypertension, an additional mean reduction in supine systolic blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg was observed. These additional reductions in blood pressure were similar to those observed with sildenafil monotherapy 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 significantly greater blood pressure reduction compared to sacubitril/valsartan alone. Therefore, initiation of sildenafil therapy should be approached with caution in patients receiving sacubitril/valsartan.

Sildenafil (100 mg) did not affect the steady-state pharmacokinetics of the HIV protease inhibitors saquinavir and ritonavir, both of which are CYP3A4 substrates.

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

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 degree of cardiovascular risk, physicians should assess the cardiovascular status of patients prior to initiating any treatment for erectile dysfunction. Sildenafil has vasodilatory effects, resulting in mild and transient decreases in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians should carefully consider whether such an effect could adversely affect patients with underlying cardiovascular conditions, particularly when combined with sexual activity. Patients who may be more sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) and patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic regulation of blood pressure.

Erox for Men potentiates the hypotensive effect of nitrates (see section "Contraindications").

In 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 the use of Erox for Men. In most patients, cardiovascular risk factors were present. Many of these adverse reactions occurred during or immediately after sexual intercourse, and only a few occurred shortly after taking Erox for Men without sexual activity. Therefore, it is not possible to determine whether the occurrence of such adverse reactions is directly related to risk factors or whether their development is caused by other factors.

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

Post-marketing reports have included cases of prolonged erection and priapism. 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 erectile function.

Concomitant use with other PDE5 inhibitors or other erectile dysfunction treatments. The safety and efficacy of concomitant administration of sildenafil with other PDE5 inhibitors or other medications for pulmonary arterial hypertension containing sildenafil (e.g., Revatio), or with other erectile dysfunction treatments, have not been studied. Therefore, the use of such combinations is 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"). Cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, have been reported spontaneously and in a surveillance study as temporally associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised that if they experience sudden vision loss, they should discontinue use of Erox for Men and seek immediate medical attention (see section "Contraindications").

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

Concomitant use with α-adrenoreceptor blockers. Sildenafil should be used with caution in patients taking α-adrenoreceptor blockers, as this combination may lead to symptomatic hypotension in some susceptible individuals. Symptomatic hypotension usually occurs within 4 hours after sildenafil administration. To minimize the potential for postural hypotension in patients on α-adrenoreceptor blockers, their condition should first be stabilized with α-blocker therapy before initiating sildenafil. 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 with human platelets have shown that sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside. There is no information available on the safety of sildenafil use in patients with bleeding disorders or acute peptic ulcer. Therefore, sildenafil may be used in such patients only after careful evaluation of the benefit-risk ratio.

The film coating of the tablets contains lactose. Erox for Men should not be used in men with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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

Hearing loss. Patients should be advised to discontinue use of PDE5 inhibitors, including Erox for Men, and seek immediate medical help if they experience sudden decrease or loss of hearing. Such events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with PDE5 inhibitor use, including Erox for Men. It is not possible to determine whether these events are related to PDE5 inhibitor use or to other factors.

Concomitant use with antihypertensive agents. Erox for Men 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 Erox for Men (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 Erox for Men does not protect against sexually transmitted diseases. Patients should be informed of this and instructed on necessary preventive measures to protect against sexually transmitted infections, including human immunodeficiency virus (HIV).

Use during pregnancy or breastfeeding.

Erox for Men is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery.

Erox for Men 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 Erox for Men before driving a vehicle or operating machinery.

Method of Administration and Dosage

The drug is administered orally.

Adults. The recommended dose is 50 mg, taken as needed approximately one hour before sexual activity. Based 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. If Eroxet for Men is taken with food, the onset of action may be delayed compared to administration on an empty stomach.

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

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."

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 necessary.

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

Administration to patients taking other medicinal products. Except for ritonavir, for which concomitant administration with sildenafil is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use"), for patients receiving concomitant treatment with CYP3A4 inhibitors, a starting dose of 25 mg* should be considered.

To minimize the potential for postural hypotension in patients being treated with α-blockers, patients should be stabilized on α-blockers prior to initiating sildenafil therapy. Additionally, initial therapy with sildenafil should be considered at a dose of 25 mg* (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

*Administer at the appropriate dosage strength.

Children.

Eroxet for Men is not indicated for use in children (under 18 years of age).

Overdose.

In volunteers who received single doses up to 800 mg, adverse reactions were similar to those observed at lower doses, but the frequency and severity of adverse reactions were increased. Doses of 200 mg did not increase efficacy, while the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances) increased.

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

Adverse reactions.

The safety profile of sildenafil is based on data obtained from 9,570 patients in 74 double-blind, placebo-controlled clinical studies. In clinical trials, the most commonly reported adverse reactions in patients taking sildenafil were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia, and blurred vision.

Adverse reactions reported during post-marketing surveillance were collected over a period of >10 years. Since not all adverse reactions were reported and not all adverse reactions were included in the safety database, the frequency of these reactions cannot be precisely determined.

The table below lists all medically significant adverse reactions observed during clinical trials and occurring more frequently than with placebo, by system organ class and frequency of occurrence (very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1,000)). Within each frequency group, adverse reactions are listed in order of decreasing severity.

System–organ–class	Adverse reactions
Infections and infestations	Uncommon: rhinitis.
Immune system disorders	Uncommon: hypersensitivity reactions.
Nervous system disorders	Very common: headache.
	Common: dizziness.
	Uncommon: somnolence, paresthesia.
	Rare: stroke, transient ischemic attack, convulsions*, seizure recurrence*, loss of consciousness, syncope.
Eye disorders	Common: color vision disorders**, visual disturbances, blurred vision.
	Uncommon: lacrimation disorders***, eye pain, photophobia, photopsia, eye hyperemia, visual brightness, conjunctivitis.
	Rare: non-arteritic anterior ischemic optic neuropathy*, retinal vessel occlusion, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, appearance of bright circles around light sources (halos) in the visual field, eye swelling, eye edema, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in eyes, eyelid edema, 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, hot flushes.
	Uncommon: hypertension, hypotension.
Respiratory, thoracic and mediastinal disorders	Common: nasal congestion.
	Uncommon: epistaxis, nasal sinus congestion.
	Rare: throat tightness, nasal mucosal swelling, dry nose.
Gastrointestinal disorders	Common: nausea, dyspepsia.
	Uncommon: gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth.
	Rare: oral paresthesia.
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: hematuria.
Reproductive system and breast disorders	Rare: penile bleeding, priapism*, hematospermia, 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.

** Visual disturbances: chromatopsia, chromopsia, cyanopsia, erythropsia, xanthopsia.

*** Lacrimation disorders: dry eyes, abnormal lacrimation, and increased lacrimation.

The following events were observed in <2% of patients during controlled clinical trials; 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: Facial swelling, photosensitivity reactions, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury.

Cardiovascular system: Angina pectoris, AV block, migraine, postural hypotension, myocardial ischemia, cerebral vascular thrombosis, sudden cardiac arrest, ECG abnormalities, cardiomyopathy.

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

Blood and lymphatic system disorders: Anemia, leukopenia.

Metabolism and nutrition disorders: Thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

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

Nervous system: Ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.

Respiratory system: Asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

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

Special senses: Sudden decrease or loss of hearing, ear pain, ocular hemorrhage, cataract, dry eyes.

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

Post-marketing experience. The following adverse reactions have been identified during post-marketing use of sildenafil. Because 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 seriousness, frequency of reporting, lack of clear alternative association, or a combination of these factors.

Cardiovascular, cerebrovascular, and vascular events. Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebrovascular hemorrhage, subarachnoid hemorrhage, intracerebral hemorrhage, and pulmonary hemorrhage, which occurred in temporal association with sildenafil use. Most patients had pre-existing 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 following sildenafil use and sexual activity. It is not possible to determine whether these events are directly related to sildenafil use, sexual activity, underlying risk factors, a combination of these factors, or other factors.

Blood and lymphatic system: Vaso-occlusive crisis. In a small, prematurely terminated study of sildenafil use in patients with pulmonary arterial hypertension secondary to sickle cell anemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo.

Nervous system: Anxiety, transient global amnesia.

Special senses

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-related adverse reactions were noted. In many cases, information on subsequent medical follow-up 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: transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal edema, retinal vascular disorders or hemorrhage, vitreous detachment.

Rare cases of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent vision loss, have been reported in temporal association with the use of PDE5 inhibitors, including sildenafil. Many patients had pre-existing anatomical or vascular risk factors for NAION, including (but not limited to): a low cup-to-disc ratio (crowded disc), age over 50 years, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are directly related to the use of PDE5 inhibitors, pre-existing anatomical or vascular risk factors, a combination of these factors, 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 should report any suspected adverse reactions in accordance with national legislative requirements.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of the reach of children.

Packaging.

1 or 4 film-coated tablets in a blister; 1 blister per cardboard carton.

Prescription category. Prescription only.

Manufacturer.

Actavis Ltd.

Actavis Ltd.

Manufacturers' addresses.

BLB 015, Bulebel Industrial Estate, Zejtun ZTN 3000, Malta

BLB 016, Bulebel Industrial Estate, Zejtun ZTN 3000, Malta

Marketing authorization holder.

SPERCO INTERNATIONAL LIMITED.

SPERCO INTERNATIONAL LIMITED.

Address of marketing authorization holder.

Spyrou Kyprianou, 57, BYBLOSERVE BUSINESS CENTER, 2nd Floor, 6051, Larnaca, Cyprus.