Jenagra® 50

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DZHENAGRA® 25 (GENAG RA 25) DZHENAGRA® 50 (GENAGRA 50) DZHENAGRA® 100 (GENAGRA 100)

Composition:

Active substance: sildenafil;

One film-coated tablet contains sildenafil (in the form of sildenafil citrate) 25 mg or 50 mg or 100 mg;

Excipients: lactose, calcium hydrogen phosphate, microcrystalline cellulose, sodium croscarmellose, povidone (polyvinylpyrrolidone K-30), colloidal silicon dioxide, magnesium stearate, purified talc;

Film coating: hydroxypropylmethylcellulose, purified talc, titanium dioxide (E 171), polyethylene glycol 6000, indigo carmine dye (E 132), quinoline yellow lake (E 104).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets of grey-blue color with a greenish tint, in the shape of an elongated hexagon, biconvex, marked with "GENOM" on one side and "25" or "50" or "100" on the other side.

Pharmacotherapeutic group. Medicinal products 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 underlying erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Released nitric oxide activates the enzyme guanylate cyclase, which stimulates an increase in the level of cyclic guanosine monophosphate (cGMP), leading in turn to 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 a direct relaxing effect on isolated human corpus cavernosum tissue, but 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 demonstrated that sildenafil is selective for PDE5, which actively participates in the process of erection. 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 participates in phototransduction processes in the retina. At maximum recommended doses, sildenafil's selectivity for PDE5 exceeds its selectivity for PDE1 by 80-fold, and is 700-fold higher than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. In particular, sildenafil's selectivity for PDE5 exceeds its selectivity for PDE3 – the cAMP-specific phosphodiesterase isoform involved in regulation of cardiac contractility – by 4000-fold.

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), 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 increase in 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 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 protein binding of sildenafil and its major N-desmethyl metabolite to plasma proteins reaches 96%, the mean maximum free plasma concentration of sildenafil is about 18 ng/mL (38 nmol). The degree of protein binding is independent of total sildenafil concentrations.

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

Biotransformation. Sildenafil metabolism is primarily mediated by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite is formed via N-demethylation of sildenafil. The metabolite's selectivity for PDE5 is comparable to that of sildenafil, and its activity against PDE5 is approximately 50% of the parent compound. Plasma 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.

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

Pharmacokinetics in special patient populations.

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

Renal impairment. In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil remained unchanged after a single 50 mg oral dose. Mean AUC and Cmax of the N-desmethyl metabolite increased by up to 126% and 73%, respectively, compared to values in 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 of 100% and 88%, respectively, compared to age-matched volunteers without renal impairment. Additionally, AUC and Cmax of the N-desmethyl metabolite increased significantly by 200% and 79%, respectively.

Hepatic impairment. In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh classes A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (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 is recommended for use in men with erectile dysfunction, defined as the inability to achieve and maintain an erection sufficient for successful sexual intercourse.

For effective action of the medicinal product, 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 nitric oxide / cyclic guanosine monophosphate (cGMP) metabolic pathway and may potentiate the hypotensive effect of nitrates.

Concomitant use of phosphodiesterase type 5 (PDE5) inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated, as it may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").

Conditions in which sexual activity is not recommended (e.g., severe cardiovascular disorders such as unstable angina or severe heart failure).

Unilateral loss of vision due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this condition is associated with prior use of PDE5 inhibitors.

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), as the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on sildenafil.

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

In vivo studies. Population pharmacokinetic analysis of clinical trial data demonstrated reduced clearance of sildenafil when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increased incidence 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 inhibitor of P450, at steady-state concentrations (500 mg once daily) and sildenafil (single 100 mg dose) resulted in a 300% increase in sildenafil Cmax (4-fold) and a 1000% increase in plasma AUC (11-fold). After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL when sildenafil was administered alone, indicating a significant effect of ritonavir on a broad range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Based on 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 steady-state concentrations (1200 mg three times daily) and sildenafil (single 100 mg dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in systemic exposure (AUC) of sildenafil. No effect of sildenafil on saquinavir pharmacokinetics 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 100 mg dose) with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in systemic exposure to sildenafil (AUC). In healthy male volunteers, azithromycin (500 mg daily for 3 days) did not affect 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, increased plasma concentrations of sildenafil by 56% when co-administered with 50 mg sildenafil in healthy volunteers.

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

Single-dose 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 class (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, β-adrenergic receptor 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% reduction in AUC and a 55.4% reduction in Cmax of sildenafil. Therefore, concomitant use of potent CYP3A4 inducers such as rifampicin may lead to a more pronounced decrease in plasma concentrations of sildenafil.

Nicorandil is a hybrid agent combining a potassium channel opener and a nitrate. The nitrate component may lead to a serious interaction with sildenafil.

Effect of sildenafil on other medicinal products.

In vitro studies.

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

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

In vivo studies.

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

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

Concomitant use of sildenafil and alpha-adrenergic blockers may lead to symptomatic hypotension in some susceptible patients, most commonly occurring within 4 hours after sildenafil administration (see sections "Dosage and administration" and "Special precautions for use"). In drug interaction studies, the alpha-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were co-administered to patients with benign prostatic hyperplasia whose condition was stabilized on doxazosin. In these studies, mean additional reductions in supine blood pressure were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean reductions in standing blood pressure were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Cases of symptomatic orthostatic hypotension have been reported with concomitant use of sildenafil and doxazosin in patients stabilized on doxazosin. These reports described episodes of dizziness and pre-syncope, but not 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 mean peak blood ethanol levels of 80 mg/dL.

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

Sildenafil at a dose of 100 mg did not affect the pharmacokinetic parameters of the 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.

Concomitant use of sildenafil with sacubitril/valsartan was associated with a greater reduction in blood pressure compared to sacubitril/valsartan alone. Therefore, sildenafil should be initiated with caution in patients receiving sacubitril/valsartan.

Special precautions for use.

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

Cardiovascular risk factors. Since sexual activity carries a certain degree of cardiac risk, physicians must assess the cardiovascular status of patients before starting 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 this effect could adversely affect patients with underlying cardiovascular conditions, particularly when combined with sexual activity. Patients who are more sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) and patients with the rare multisystem atrophy syndrome, one manifestation of which is severe autonomic nervous system dysfunction in blood pressure regulation.

Sexual activity is associated with a certain level of cardiovascular risk due to the potential for cardiac events. Therefore, before initiating any treatment for erectile dysfunction, physicians must evaluate the patient's cardiovascular status. Medications intended for the treatment of erectile dysfunction must not be used in patients for whom sexual activity is inadvisable.

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

Serious cardiovascular adverse reactions, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, arterial hypertension, and arterial hypotension, have been reported in temporal association with sildenafil use. In most 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 sildenafil administration without subsequent sexual activity. Therefore, it is not possible to determine whether the occurrence of such adverse reactions is directly related to risk factors or is influenced 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 (such as angulation, cavernosal fibrosis, or Peyronie’s disease) and in patients with conditions that may predispose to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

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

Concomitant use with other PDE5 inhibitors or other medications for erectile dysfunction. 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 medications for erectile dysfunction have not been studied. Therefore, such combinations are not recommended.

Effect on vision. Visual disturbances and cases of non-arteritic anterior ischemic optic neuropathy (NAION) associated with the use of sildenafil and other PDE5 inhibitors have been reported. Patients should be advised to discontinue the medication and seek immediate medical attention in case of sudden vision loss.

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 risk of orthostatic hypotension, sildenafil therapy should only be initiated in hemodynamically stable patients already receiving α-adrenoreceptor blockers. The recommended initial dose for such patients is 25 mg of sildenafil (see section "Method of administration and dosage"). Additionally, patients should 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 on the safety of sildenafil use in patients with bleeding disorders or active peptic ulceration. Therefore, sildenafil may be used in such patients only after careful assessment of benefit-risk ratio.

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

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

Concomitant use with antihypertensive agents. The medicinal product 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. The use of the medication does not protect against sexually transmitted diseases. Consideration should be given to advising patients on necessary protective measures to prevent sexually transmitted infections, including human immunodeficiency virus.

Excipients.

The medicinal product contains lactose and therefore should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

The dyes indigo carmine and quinoline yellow contained in the medicinal product may cause allergic reactions.

Use during pregnancy or breastfeeding.

The medication is not intended for use in women.

Ability to influence reaction speed when driving or operating machinery.

Viagra® 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 the medication before driving a vehicle or operating machinery.

Method of Administration and Dosage

The medicinal product is administered orally.

Adults.

The recommended dose is 50 mg, taken as needed approximately 1 hour before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of administration is once daily. When the drug is taken with food, its effect may occur later than when taken on an empty stomach.

Elderly patients.

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

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 recommended above in the section "Adults."

In patients with severe renal impairment (creatinine clearance < 30 mL/min), sildenafil clearance is reduced; therefore, the recommended dose is 25 mg. Depending on efficacy and tolerability, the dose may be gradually increased as needed to 50 mg and 100 mg.

Patients with hepatic impairment.

In patients with hepatic impairment (e.g., cirrhosis), sildenafil clearance is reduced; therefore, the recommended dose is 25 mg. Depending on efficacy and tolerability, the dose may be increased as needed to 50 mg and 100 mg.

Patients taking other medicinal products.

If patients are concurrently using CYP3A4 inhibitors, except for ritonavir (the concomitant use of which with sildenafil is not recommended; see section "Special Warnings and Precautions for Use"), consideration should be given to initiating treatment with a 25 mg dose.

To minimize the potential development of postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized on α-adrenoreceptor blockers before starting sildenafil therapy. Additionally, consideration should be given to initiating treatment with a 25 mg dose (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children.

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

Overdose.

In studies involving healthy volunteers, adverse reactions following single doses of sildenafil up to 800 mg were similar to those observed with lower doses but occurred more frequently and were more severe. Administration of sildenafil at a dose of 200 mg did not increase efficacy but led to an increased incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In case of overdose, standard supportive measures should be implemented as needed. Enhanced elimination of sildenafil by hemodialysis is unlikely due to the high degree of protein binding of the drug and the absence of sildenafil elimination in urine.

Adverse Reactions

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

All clinically significant adverse reactions observed during clinical trials more frequently than with placebo are listed below by system organ class and frequency category: 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 grouping, 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 ischaemic attack, seizures*, seizure recurrence*, syncope

Eye disorders

Common: Colour vision disturbance**, visual disturbance, 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 lights, eye swelling, eye oedema, eye disorders, conjunctival hyperaemia, eye irritation, abnormal sensations in eye, eyelid oedema, sclera 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 swelling, nasal dryness

Gastrointestinal disorders

Common: Nausea, dyspepsia
Uncommon: Gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth
Rare: Oral hypoesthesia

Skin and subcutaneous tissue disorders

Uncommon: Rash
Rare: Stevens-Johnson syndrome*, toxic epidermal necrolysis*

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia, limb pain

Renal and urinary disorders

Uncommon: Haematuria

Reproductive system and breast disorders

Rare: Penile haemorrhage, priapism*, haemospermia, prolonged erection

General disorders and administration site conditions

Uncommon: Chest pain, increased fatigue, feeling of warmth
Rare: Irritation

Investigations

Uncommon: Increased heart rate

* Reported only during post-marketing surveillance of sildenafil.
** 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 of sildenafil; a causal relationship has not been established. Reports included events considered likely related to drug use. Events not listed were mild and reported too imprecisely to be meaningful.

General disorders: Facial oedema, photosensitivity reactions, shock, asthenia, pain, sudden collapse, abdominal pain, sudden injury
Cardiovascular system: Angina pectoris, atrioventricular block, migraine, postural hypotension, myocardial ischaemia, cerebral vessel thrombosis, cardiac arrest, ECG abnormalities, cardiomyopathy
Gastrointestinal tract: Glossitis, colitis, dysphagia, gastritis, gastroenteritis, oesophagitis, stomatitis, abnormal liver function tests, rectal haemorrhage, gingivitis
Blood and lymphatic system: Anaemia, leucopenia
Metabolism and nutrition: Thirst, oedema, gout, unstable diabetes, hyperglycaemia, peripheral oedema, hyperuricaemia, hypoglycaemia, hypernatraemia
Musculoskeletal system: Arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis
Nervous system: Ataxia, neuralgia, neuropathy, paraesthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes
Respiratory system: Asthma, dyspnoea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough
Skin: Urticaria, herpes, pruritus, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis
Sensory organs: Sudden decrease or loss of hearing, ear pain, eye haemorrhage, cataract, dry eyes
Genitourinary system: Cystitis, nocturia, increased urinary frequency, gynaecomastia, urinary incontinence, ejaculation disorder, genital swelling, anorgasmia

Post-marketing experience
After the marketing of sildenafil, the following adverse reactions have been identified. Because these are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were included due to their seriousness, frequency of reporting, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular and cerebrovascular events: Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral haemorrhage, subarachnoid haemorrhage, intracerebral haemorrhage, and pulmonary haemorrhage, 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 sildenafil use, 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 anaemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo. The clinical significance of this information for patients using sildenafil for the treatment of erectile dysfunction is unknown.

Nervous system: Anxiety, transient global amnesia

Sensory organs

Hearing
After the marketing of sildenafil-containing products, cases of sudden decrease or loss of hearing, occurring in temporal association with sildenafil use, have been reported. In some cases, underlying medical conditions and other factors that may have contributed to the development of 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.

After the marketing of sildenafil-containing products, rare cases of non-arteritic anterior ischaemic optic neuropathy (NAION), leading to visual impairment including permanent vision loss, have been reported in temporal association with PDE5 inhibitors, including sildenafil. Many patients had underlying anatomical or vascular risk factors for NAION, including: small cup-to-disc ratio (crowded optic disc), age over 50 years, hypertension, coronary artery disease, hyperlipidaemia, and smoking. It is not possible to determine whether these events are directly related to PDE5 inhibitor use, underlying anatomical or vascular risk factors, a combination of these, or other factors.

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

Shelf life
3 years

Storage conditions
Store in the original packaging at a temperature not exceeding 25°C.
Keep out of the reach of children.

Packaging
1 or 4 tablets in a blister; 1 blister per cardboard box.

Prescription status
Prescription only

Manufacturer
Genome Biotech Pvt. Ltd.

Manufacturer's address and location of operations
Plot No. D-121, 122, 123, MIDC Malegaon, Tal. Sinnar, Nashik 422103, Maharashtra, India