Igra®

INSTRUCTIONS for medical use of the medicinal product iGra® (iGra®)

Composition:

Active substance: sildenafil;

One chewable tablet contains sildenafil citrate equivalent to sildenafil 50 mg or 100 mg;

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

Pharmaceutical form. Chewable tablets.

Main physico-chemical characteristics:

white triangular, biconvex tablets with "50" embossed on one side;

white triangular, biconvex tablets with "100" embossed on one side.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Sildenafil is an oral medication intended for the treatment of erectile dysfunction. During sexual stimulation, the drug restores impaired erectile function by enhancing blood flow to the penis.

The physiological mechanism leading to erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Released NO activates the enzyme guanylate cyclase, which stimulates an increase in the level of cyclic guanosine monophosphate (cGMP), 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 effect of sildenafil on erection is peripheral. Sildenafil does not exert a direct relaxing effect on isolated human corpus cavernosum tissue, but it strongly potentiates the relaxing effect of NO on this tissue. During activation of the NO/cGMP metabolic pathway, which occurs during sexual stimulation, sildenafil's inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce the desired pharmacological effect, sexual stimulation is required.

Effect on pharmacodynamics. In vitro studies have shown that sildenafil is selective for PDE5, which actively participates in the erectile process. The effect of sildenafil on PDE5 is more potent than its effect on other known phosphodiesterases. This effect is 10 times more potent than its effect on PDE6, which is involved in phototransduction processes in the retina. At maximum recommended doses, sildenafil's selectivity for PDE5 is 80 times greater than its selectivity for PDE1, 700 times greater than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. In particular, sildenafil's selectivity for PDE5 is 4000 times greater than its selectivity for PDE3 – the cAMP-specific isoenzyme of phosphodiesterase involved in the 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 from 25% to 63%). Within the recommended dose range (25 to 100 mg), AUC and Cmax values of sildenafil increase proportionally with dose.

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

Distribution. The mean volume of distribution at steady state (Vd) is 105 liters, indicating extensive tissue distribution. After a single 100 mg oral dose of sildenafil, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (coefficient of variation 40%). Since the binding of sildenafil and its major N-desmethyl metabolite to plasma proteins is about 96%, the mean maximum free plasma concentration of 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 after 90 minutes.

Biotransformation. Sildenafil metabolism is primarily mediated by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite is formed via N-demethylation of sildenafil. The metabolite's selectivity for PDE5 is comparable to that of sildenafil, and its activity against PDE5 is approximately 50% of the parent compound. Plasma concentration of this metabolite is about 40% of the plasma concentration of sildenafil. The N-desmethyl metabolite undergoes further metabolism, and its elimination half-life is approximately 4 hours.

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

Pharmacokinetics in Special Patient Populations

Elderly patients. In healthy elderly volunteers (aged 65 years and older), reduced clearance of sildenafil was observed, resulting in plasma concentrations of sildenafil and its active N-desmethyl metabolite approximately 90% higher than in 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 values in age-matched volunteers with normal renal function. However, due to high individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax by 100% and 88%, respectively, compared to age-matched volunteers with normal renal function. Additionally, AUC and Cmax of the N-desmethyl metabolite increased significantly by 200% and 79%, respectively.

Hepatic impairment. In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh classes A and B), sildenafil clearance was reduced, 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 medicinal product iGRA® is recommended for use in men with erectile dysfunction, defined as the inability to achieve or maintain an erection sufficient for successful sexual intercourse.

For effective action of iGRA® medication, sexual stimulation is required.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the drug.
• Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway and 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 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 disorders such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterases), since the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on sildenafil

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

In vivo studies. Population pharmacokinetic analysis of clinical trial data demonstrated reduced sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although increased frequency of adverse events was not observed during concomitant use of sildenafil and CYP3A4 inhibitors, consideration should be given to initiating treatment with a sildenafil dose of 25 mg.

Concomitant administration of the HIV protease inhibitor ritonavir, a very potent CYP450 inhibitor, at steady-state concentration (500 mg once daily) and sildenafil (single dose of 100 mg) resulted in a 300% increase (4-fold) in sildenafil Cmax and a 1000% increase (11-fold) in plasma AUC. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL typically observed with sildenafil alone, consistent with the significant effect of ritonavir on a broad range of CYP450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Due to these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended (see section "Special precautions for use"); in any case, the maximum sildenafil dose should not exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a dose providing steady-state concentration (1200 mg three times daily) and sildenafil (single dose of 100 mg) resulted in a 140% increase in sildenafil Cmax and a 210% increase in systemic exposure (AUC) of sildenafil. No effect of sildenafil on the pharmacokinetics of saquinavir was observed (see section "Method of administration and dosage"). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have a more pronounced effect.

Administration of sildenafil (100 mg single dose) with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in sildenafil AUC. In healthy male volunteers, azithromycin (500 mg daily for 3 days) did not affect AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg, when co-administered with sildenafil 50 mg in healthy volunteers, increased plasma concentration of sildenafil by 56%.

Grapefruit juice is a weak inhibitor of CYP3A4 in the intestinal wall and may cause a moderate increase in plasma levels of sildenafil.

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

Although specific interaction studies with all medicinal products have not been conducted, population pharmacokinetic analysis data indicate that sildenafil pharmacokinetics were not altered when co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitor group (such as 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 blockers, or CYP450 metabolism inducers (such as rifampicin, barbiturates).

In a study involving healthy male volunteers, concomitant administration of the endothelin antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19) at steady state (125 mg twice daily) and sildenafil at steady state (80 mg three times daily) resulted in a 62.6% and 55.4% reduction in AUC and Cmax of sildenafil, respectively. Therefore, concomitant use of potent CYP3A4 inducers such as rifampicin may lead to a more pronounced decrease in plasma sildenafil concentrations.

Nicorandil is a hybrid of a potassium channel activator and a nitrate. The nitrate component may result in a serious interaction with sildenafil.

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.

Effect of sildenafil on other medicinal products.

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

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

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

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

Concomitant use of sildenafil and α-adrenergic blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most commonly occurred within 4 hours after sildenafil administration (see sections "Method of administration and dosage" and "Special precautions for use"). In three specific drug interaction studies, the α-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (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 were observed: supine position – 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg; standing position – 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Symptomatic orthostatic hypotension was occasionally reported with concomitant use of sildenafil and doxazosin in patients stabilized on doxazosin. These reports described episodes of dizziness and pre-syncope, but no syncope.

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

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

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

In patients taking sildenafil, no differences in adverse effect profile were observed compared to placebo when co-administered with antihypertensive drug classes such as diuretics, β-adrenergic blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive agents (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and α-adrenergic blockers. In a specific interaction study with concomitant administration of sildenafil (100 mg) and amlodipine in patients with arterial hypertension, an additional reduction in supine systolic blood pressure of 8 mm Hg was observed, with a corresponding diastolic reduction of 7 mm Hg. In magnitude, these additional blood pressure reductions were comparable to those observed with sildenafil alone in healthy volunteers (see section "Pharmacological properties").

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

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

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 evaluate the cardiovascular status of patients prior to initiating any treatment for erectile dysfunction. Sildenafil has vasodilatory effects, resulting in mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians should carefully consider whether such an effect could adversely affect patients with underlying cardiovascular conditions, particularly when combined with sexual activity. Patients who may be 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 of the manifestations of which is severe autonomic regulation of blood pressure.

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

During the post-marketing period, serious cardiovascular adverse events have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, arterial hypertension, and arterial hypotension, which temporally coincided with the use of iGRA®. In most, but not all, patients, cardiovascular risk factors were present. Many of these adverse events occurred during or immediately after sexual intercourse, and only a few occurred shortly after taking iGRA® without sexual activity. Therefore, it is not possible to determine whether the development of such adverse reactions is directly related to risk factors or whether other factors contributed to their occurrence.

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

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 erectile function.

Concomitant use with other PDE5 inhibitors or other erectile dysfunction therapies. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or with other pulmonary arterial hypertension treatments containing sildenafil (e.g., Revatio), or with other erectile dysfunction therapies 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 findings from a surveillance study have also described cases of non-arteritic anterior ischemic optic neuropathy, a rare condition, associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised that if sudden visual impairment occurs, use of iGRA® 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 typically occurs within 4 hours after taking sildenafil. To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized with α-blocker therapy before initiating sildenafil. Consideration should also be given to starting with a 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. Studies on human platelets have demonstrated that sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside in vitro. There is no information available on the safety of sildenafil use in patients with bleeding disorders or active peptic ulcer. Therefore, the use of sildenafil in such patients should only be considered after careful benefit-risk assessment.

Hearing loss. Physicians should advise patients to discontinue use of PDE5 inhibitors, including iGRA®, and seek immediate medical help if sudden decrease or loss of hearing occurs. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE5 inhibitors, including iGRA®. It is not possible to determine whether these events are directly related to the use of PDE5 inhibitors or to other factors.

Concomitant use with antihypertensive agents. iGRA® 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 pressure of 8 mm Hg and diastolic pressure of 7 mm Hg.

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

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

The medicinal product contains aspartame, a phenylalanine derivative, which may be harmful for patients with phenylketonuria. If intolerance to certain sugars is known, patients should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

iGRA® is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery.

Sildenafil may have a minor influence on the ability to drive or operate machinery. Since dizziness and visual disturbances have been observed during clinical trials of the medicinal product, patients should be aware of their individual response to the drug before driving a car, operating hazardous machinery, or performing hazardous tasks.

Administration and Dosage

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

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

Patients with renal impairment. For patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the recommended dose is the same as that 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, if necessary, to 50 mg and up to 100 mg.

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, if necessary, to 50 mg and up to 100 mg.

Patients taking other medicinal products. If patients are concurrently using CYP3A4 inhibitors (except ritonavir, the co-administration of which with sildenafil is not recommended; see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"), a starting dose of 25 mg* should be considered.

To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, such patients should be stabilized on α-adrenoreceptor blockers prior to initiating sildenafil therapy. A starting dose of 25 mg* should also be considered (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

*Use the medicinal product at the appropriate dosage.

Children.

The medicine iGRA® is not indicated for use in individuals under 18 years of age.

Overdose.

In clinical studies involving healthy volunteers, single doses of the medicine up to 800 mg were associated with adverse reactions similar to those observed with lower doses of sildenafil, but with increased frequency and severity. Administration of sildenafil at a dose of 200 mg did not result in increased efficacy but led to a higher incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In case of overdose, symptomatic treatment should be administered as necessary. Hemodialysis is unlikely to accelerate sildenafil clearance due to the high degree of plasma protein binding and the absence of urinary excretion of sildenafil.

Adverse Reactions

The safety profile of the iGRA® medication is based on data obtained from 9,570 patients during 74 double-blind, placebo-controlled clinical trials. 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 was 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 according to System Organ Class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Infections and infestations

Uncommon: Rhinitis

Immune system disorders

Uncommon: Hypersensitivity

Nervous system disorders

Very common: Headache

Common: Dizziness

Uncommon: Somnolence, hypoesthesia

Rare: Stroke, transient ischemic attack, seizures*, seizure recurrence*, syncope

Eye disorders

Common: Colour vision disturbance**, visual disturbances, blurred vision

Uncommon: Lacrimation disorders***, eye pain, photophobia, photopsia, eye hyperemia, visual brightness, conjunctivitis, eye irritation

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, halos around lights in the visual field, eye swelling, eye edema, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in the eyes, eyelid edema, scleral discoloration

Ear and labyrinth disorders

Uncommon: Dizziness, tinnitus

Rare: Deafness

Cardiac disorders

Uncommon: Tachycardia, palpitations

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

Vascular disorders

Common: Facial flushing, hot flushes

Uncommon: Hypertension, hypotension

Respiratory, thoracic and mediastinal disorders

Common: Nasal congestion

Uncommon: Epistaxis, nasal sinus congestion

Rare: Throat tightness, nasal mucosal edema, 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: Hematuria

Reproductive system and breast disorders

Rare: Penile hemorrhage, 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 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 during controlled clinical trials; a causal relationship has not been established. Reports included events likely related to the use of the medication. 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 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: 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: Urticaria, herpes, pruritus, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

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

Genitourinary system: Cystitis, nocturia, increased frequency of urination, gynecomastia, urinary incontinence, ejaculation disorder, genital swelling, anorgasmia.

Post-marketing experience. The following adverse reactions have been identified after marketing authorization. Since 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 are reported due to their severity, frequency of reporting, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular and cerebrovascular events. Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral hemorrhage, subarachnoid hemorrhage, intracerebral hemorrhage, and pulmonary hemorrhage, which occurred in temporal association with iGRA® use. Most, but not all, patients had underlying cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred shortly after iGRA® use without sexual activity. Other events occurred within hours or days after iGRA® use and sexual activity. It is not possible to determine whether these events are related to the drug, sexual activity, underlying risk factors, a combination of these, or other factors.

Blood and lymphatic system: 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. The clinical significance of this information for patients using iGRA® for erectile dysfunction is unknown.

Nervous system: Anxiety, transient global amnesia.

Specific senses.

Hearing. After marketing authorization, cases of sudden decrease or loss of hearing temporally associated with iGRA® use have been reported. In some cases, medical conditions and other factors that could contribute 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 iGRA® use, underlying risk factors for hearing loss, a combination of these, or other factors.

Vision: Temporary vision loss, eye redness, eye burning, increased intraocular pressure, retinal edema, retinal vascular disease or hemorrhage, vitreous detachment.

Rarely, after marketing authorization, cases of non-arteritic anterior ischemic optic neuropathy (NAION), leading to visual impairment including permanent vision loss, have been reported in temporal association with PDE5 inhibitors, including iGRA®. In many, but not all, patients, anatomical or vascular risk factors for NAION were present, including (but not limited to): low cup-to-disc ratio (crowded optic 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 PDE5 inhibitor use, underlying anatomical or vascular risk factors, a combination of these, or other factors.

Reporting suspected adverse reactions. Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medication. Healthcare professionals should report any suspected adverse reactions in accordance with applicable legislation.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at temperatures not exceeding 25 °C.

Keep out of reach of children.

Packaging. 1 chewable tablet per blister in a cardboard box.

4 chewable tablets per blister, 1 or 2 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Djenepharm S.A.

Manufacturer's location and address of its business premises.

18th km Marathonos Ave, Pallini Attiki, 15351, Greece.