Sildenafil 50 ananta

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SILDENAFIL 50 ANANTA SILDENAFIL 100 ANANTA (SILDENAFIL 50 ANANTA SILDENAFIL 100 ANANTA)

Composition:

Active substance: sildenafil;

One film-coated tablet contains sildenafil citrate equivalent to 50 mg or 100 mg of sildenafil;

Excipients: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium croscarmellose, magnesium stearate, Opadry II blue 31K80956 (lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, indigo carmine (E 132)), Opadry clear 02K19253 (hypromellose, triacetin), purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg tablets: blue, round, biconvex, film-coated tablets, with imprint «125» on one side and imprint «J» with a breakline on the other;

100 mg tablets: blue, round, biconvex, film-coated tablets, with imprint «126» on one side and imprint «J» with a breakline on the other.

Pharmacotherapeutic group. Agents used in erectile dysfunction.

ATC code G04B E03.

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 nitric oxide 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 breakdown. The effect of sildenafil on erection is peripheral. Sildenafil does not cause direct relaxant effects on isolated human corpus cavernosum tissue, but strongly enhances the relaxing effect of NO on this tissue. When the NO/cGMP metabolic pathway is activated during sexual stimulation, sildenafil-induced inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce the required pharmacological effect, sexual stimulation is necessary.

Effect on pharmacodynamics. In vitro studies have demonstrated the selective effect of sildenafil on 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 retinal phototransduction. At maximum recommended doses, the selectivity of sildenafil for PDE5 exceeds its selectivity for PDE1 by 80 times, for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11 by 700 times. Specifically, the selectivity of sildenafil for PDE5 exceeds its selectivity for PDE3—the cAMP-specific phosphodiesterase isoform involved in regulation of cardiac contractility—by 4000 times.

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. Maximum plasma concentration 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% (ranging 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 by 60 minutes and a mean reduction in Cmax by 29%.

Distribution. The mean steady-state volume of distribution (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 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.

Data indicate that 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 (main 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 clearance of sildenafil is 41 L/h, resulting in an elimination half-life of 3–5 hours. After both oral and intravenous administration, sildenafil is excreted primarily as metabolites 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. Data indicate that in healthy elderly volunteers (aged 65 years and older), clearance of sildenafil is reduced, 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 is approximately 40%.

Renal impairment. In patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil remained unchanged after a single 50 mg oral dose. Mean AUC and Cmax of the N-desmethyl metabolite increased by 126% and 73%, respectively, compared to age-matched volunteers 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), clearance of sildenafil was reduced, leading to 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 significantly increased by 200% and 79%, respectively.

Hepatic impairment. In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh classes A and B), clearance of sildenafil 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 or maintain an erection of the penis 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 potentiates 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 vision loss due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this condition is associated with prior use of PDE5 inhibitors.
• 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.

Sildenafil is metabolized primarily 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.

Reduced sildenafil clearance has been demonstrated when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increase in the frequency of adverse events has not been observed during concomitant use of sildenafil and CYP3A4 inhibitors, the recommended initial dose of sildenafil is 25 mg.

Concomitant administration of the HIV protease inhibitor ritonavir, a very potent inhibitor of P450, at steady-state concentration (500 mg once daily) and sildenafil (single dose 100 mg) resulted in a 300% increase (4-fold) in sildenafil Cmax and a 1000% increase (11-fold) in plasma AUC. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL when sildenafil was administered alone, indicating a significant effect of ritonavir on a wide range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Due to these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended; in any case, the maximum dose of sildenafil should not exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a dose providing steady-state concentration (1200 mg three times daily) and sildenafil (single dose 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. More potent CYP3A4 inhibitors, such as ketoconazole and itraconazole, are expected to have a more pronounced effect.

Administration of sildenafil (100 mg single dose) and erythromycin, a moderate CYP3A4 inhibitor, at steady-state (500 mg twice daily for 5 days) resulted in a 182% increase in systemic exposure of sildenafil (AUC). In healthy male volunteers, azithromycin (500 mg daily for 3 days) had no effect on AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg, when administered concomitantly with sildenafil 50 mg in healthy volunteers, increased plasma concentrations of sildenafil by 56%.

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

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

Although specific interaction studies with all medicinal products have not been conducted, population pharmacokinetic analysis data indicate that the pharmacokinetics of sildenafil were not altered when co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitor group (such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-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 such potent CYP3A4 inducers as rifampicin may lead to a more pronounced decrease in plasma concentrations of sildenafil.

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

Effect of sildenafil on other medicinal products.

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.

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

Riociguat. Preclinical studies have demonstrated an additive systemic effect of lowering blood pressure when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. In patients participating in the study, no positive clinical effect was observed 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 alpha-adrenoreceptor blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most commonly occurs within 4 hours after sildenafil administration. In studies specifically investigating drug interactions, the alpha-adrenoreceptor blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were administered concomitantly to patients with benign prostatic hyperplasia whose condition was stabilized on doxazosin. In these populations, mean additional reductions in blood pressure in the supine position were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean reductions in blood pressure in the standing position were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Symptomatic orthostatic hypotension has been occasionally reported with concomitant use of sildenafil and doxazosin in patients whose condition was stabilized on doxazosin. These reports described episodes of dizziness and presyncope, 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 mean peak ethanol blood levels of 80 mg/dL.

In patients taking sildenafil, no differences in adverse effect profile were observed compared to placebo when concomitantly using classes of antihypertensive drugs such as diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and alpha-adrenoreceptor blockers. In a specific interaction study, concomitant administration of sildenafil (100 mg) and amlodipine to patients with arterial hypertension resulted in an additional 8 mm Hg reduction in supine systolic blood pressure. The corresponding reduction in diastolic blood pressure was 7 mm Hg. These additional reductions in blood pressure were comparable in magnitude to those observed with sildenafil alone in healthy volunteers.

Single-dose administration of sildenafil with sacubitril/valsartan at steady-state in patients with arterial hypertension was associated with a significantly greater reduction in blood pressure compared to sacubitril/valsartan alone. Therefore, sildenafil should be initiated with caution in patients receiving sacubitril/valsartan.

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

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

Special precautions for use.

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

Cardiovascular risk factors. Since sexual activity carries a certain cardiovascular risk, the physician should assess the cardiovascular status of the patient prior to starting any treatment for erectile dysfunction. Sildenafil has a vasodilatory effect, which manifests as mild and transient reduction in blood pressure. Before prescribing sildenafil, the physician must carefully consider whether this effect could have an adverse impact on patients with certain underlying diseases, especially in combination with sexual activity. Patients who are particularly sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic nervous system dysfunction in blood pressure regulation.

The drug potentiates the hypotensive effect of nitrates.

Serious cardiovascular adverse reactions have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, which occurred temporally in association with sildenafil use. In most, but not all 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 drug administration 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 contribute to their occurrence.

Priapism. Medications for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical penile deformities (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients with conditions predisposing to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia).

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

Concomitant use with other PDE5 inhibitors or other erectile dysfunction treatments. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other pulmonary arterial hypertension treatments containing sildenafil, or with other erectile dysfunction medications, have not been studied. Therefore, such combinations are not recommended.

Effect on vision. Spontaneous reports of visual disturbances associated with the use of sildenafil and other PDE5 inhibitors have been received (see section "Adverse reactions"). Spontaneous reports and data from observational studies have indicated cases of non-arteritic anterior ischaemic optic neuropathy (NAION), 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 loss occurs, they should discontinue the drug 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 taking α-adrenoreceptor blockers, their condition should be stabilized on α-blocker therapy before initiating sildenafil treatment. 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 in vitro, sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside. There is no information on the safety of sildenafil use in patients with bleeding disorders or active peptic ulcer. Therefore, the use of sildenafil in these patient groups should only be considered after careful benefit-risk assessment.

The tablet film coating contains lactose monohydrate. The drug should not be administered to men with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Fertility. No effect on sperm morphology or motility was observed in healthy volunteers after a 100 mg dose.

Hearing loss. Physicians should advise patients to discontinue PDE5 inhibitors, including sildenafil, and seek immediate medical help if they experience 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, including sildenafil-containing products. It is not possible to determine whether these events are related to the use of PDE5 inhibitors or to other factors.

Concomitant use with antihypertensive agents. Sildenafil 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 of systolic pressure by 8 mm Hg and diastolic pressure by 7 mm Hg.

Sexually transmitted diseases. The use of sildenafil does not protect against sexually transmitted diseases. Consideration should be given to informing patients about the necessary preventive measures to protect against sexually transmitted diseases, including human immunodeficiency virus (HIV).

Use during pregnancy or breastfeeding.

The drug is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery.

The drug may have a minor influence on the ability to drive or operate machinery. Since dizziness and visual disturbances have been reported with sildenafil use, patients should determine their individual response to the drug before driving 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. Depending on efficacy and tolerability, the dose may be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of administration is once daily. When 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 (≥ 65 years of age).

Patients with Renal Impairment.

For patients with mild to moderate renal impairment (creatinine clearance from 30 to 80 mL/min), the recommended dose is the same as that stated above for adults.

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance below 30 mL/min), the recommended dose is 25 mg. Depending on efficacy and tolerability, the dose may be increased to 50 mg or 100 mg.

Patients with Hepatic Impairment.

Since sildenafil clearance is reduced in patients with hepatic impairment (e.g., cirrhosis), the recommended dose is 25 mg. Depending on efficacy and tolerability, the dose may be increased to 50 mg or 100 mg.

Patients Taking Other Medications.

The recommended starting dose for patients taking CYP3A4 inhibitors (except ritonavir, which is not recommended for co-administration with sildenafil) is 25 mg.

To minimize the risk of orthostatic hypotension, patients taking alpha-adrenergic blockers should be stabilized before initiating sildenafil therapy. The recommended starting dose of sildenafil is 25 mg.

Children.

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

Overdose.

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

In case of overdose, standard supportive measures should be applied as needed. Hemodialysis is unlikely to accelerate sildenafil clearance due to the high degree of plasma protein binding and lack of urinary elimination of sildenafil.

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.

Adverse reactions are listed below by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10000 to < 1/1000). Within each frequency grouping, adverse reactions are presented 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, hypoaesthesia.

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

Eye disorders.

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

Uncommon: lacrimation disorders***, eye pain, photophobia, photopsia, eye hyperaemia, visual brightness, conjunctivitis.

Rare: non-arteritic anterior ischaemic optic neuropathy*, retinal vessel occlusion*, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, perception of halos around light sources in the visual field, eye swelling, eye oedema, eye disorders, conjunctival hyperaemia, eye irritation, abnormal sensations in the eye, eyelid oedema, scleral discolouration.

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 oedema, nasal dryness.

Gastrointestinal disorders.

Common: nausea, dyspepsia.

Uncommon: gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth.

Rare: oral hypoaesthesia.

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 disturbances: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.

*** Lacrimation disorders: dry eyes, lacrimation disorder, increased lacrimation.

The following events were observed in < 2% of patients during clinical trials; a causal relationship has not been established. Reports included events that were considered likely related to the use of sildenafil. Events not listed were mild and reports were too imprecise to be meaningful.

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

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

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

Blood and lymphatic system disorders: anaemia, leukopenia.

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

Musculoskeletal 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.

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

Genitourinary system: cystitis, nocturia, increased frequency of urination, gynaecomastia, urinary incontinence, ejaculation disorders, genital swelling, anorgasmia.

Adverse reactions reported from a population of unknown size. These events were reported due to their severity, frequency of reporting, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular, cerebrovascular, and vascular events. Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral haemorrhage, subarachnoid haemorrhage, intracerebral haemorrhage, and pulmonary haemorrhage, which occurred in temporal association with sildenafil 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 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 factors, or other factors.

Blood and lymphatic system disorders: vaso-occlusive crisis. In a small, prematurely terminated study of sildenafil in patients with pulmonary arterial hypertension secondary to sickle cell anaemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo. The clinical significance of this finding for patients using the drug for the treatment of erectile dysfunction is unknown.

Nervous system disorders: anxiety, transient global amnesia.

Special senses.

Ear disorders. Cases of sudden decrease or loss of hearing, occurring in temporal association with sildenafil use, have been reported. In some cases, medical conditions and other factors that may have contributed to hearing-related adverse events 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 factors, or other factors.

Eye disorders: transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal oedema, retinal vascular disorders or haemorrhage, vitreous detachment.

Cases of non-arteritic anterior ischaemic optic neuropathy, leading to visual impairment including permanent vision loss, have been reported in temporal association with PDE5 inhibitors, including sildenafil. In many, but not all, patients, anatomical or vascular risk factors for non-arteritic anterior ischaemic optic neuropathy were present, including (but not limited to): small cup-to-disc ratio (crowded optic disc), age ≥ 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 factors, or other factors.

Reporting 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 regulatory requirements.

Shelf life. 2 years.

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

Packaging.

4 tablets in a blister pack, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer.

Ananta Medicare Limited.

Manufacturer's address and location of operations.

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udiog Vihar, Sri Ganganagar-335002 (Rajasthan), India.

Marketing Authorisation Holder.

Ananta Medicare Ltd.

Address of Marketing Authorisation Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

INSTRUCTIONS

for medical use of the medicinal product

SILDENAFIL 50 ANANTA

SILDENAFIL 100 ANANTA

(SILDENAFIL 50 ANANTA

SILDENAFIL 100 ANANTA)

Composition:

Active substance: sildenafil;

1 film-coated tablet contains sildenafil citrate equivalent to sildenafil 50 mg or 100 mg;

Excipients: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium croscarmellose, magnesium stearate, Opadry II Blue 31K80956 (lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, indigo carmine (E 132)), Opadry Clear 02K19253 (hypromellose, triacetin), purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg tablets: blue, round, biconvex, film-coated tablets, with "125" engraved on one side and "J" and a break line on the other;

100 mg tablets: blue, round, biconvex, film-coated tablets, with "126" engraved on one side and "J" and a break line on the other.

Pharmacotherapeutic group. Agents used in erectile dysfunction.

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 responsible for 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), 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 cause direct relaxant effects on isolated human corpus cavernosum tissue, but it strongly potentiates the relaxant effect of NO on this tissue. When the NO/cGMP metabolic pathway is activated during sexual stimulation, sildenafil's inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce the required pharmacological effect, sexual stimulation is necessary.

Effect on pharmacodynamics. In vitro studies have demonstrated sildenafil's selectivity for PDE5, which actively participates in the erectile process. The inhibitory effect of sildenafil on PDE5 is stronger than on other known phosphodiesterases. This effect is 10 times more potent than its effect on PDE6, which is involved in phototransduction processes in the retina. At maximum recommended doses, sildenafil's selectivity for PDE5 exceeds its selectivity for PDE1 by 80-fold, for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11 by 700-fold, and its selectivity for PDE5 exceeds that for PDE3 – a cAMP-specific phosphodiesterase isoenzyme involved in the regulation of cardiac contractility – by 4000-fold.

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. Maximum plasma concentration is achieved within 30–120 minutes (median 60 minutes) after oral administration on an empty stomach. The mean absolute bioavailability after oral administration is 41% (ranging from 25% to 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 delay in Tmax to 60 minutes and a mean reduction in Cmax by 29%.

Distribution. The mean steady-state volume of distribution (Vd) is 105 liters, indicating extensive distribution of the drug into body tissues. After a single 100 mg oral dose of sildenafil, the mean 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 about 96%, the mean maximum free plasma concentration of sildenafil reaches approximately 18 ng/mL (38 nmol). The degree of protein binding is independent of total sildenafil concentrations.

Data indicate that 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 occurs primarily via hepatic microsomal isoenzymes CYP3A4 (main pathway) and CYP2C9 (minor pathway). The major circulating metabolite is formed by 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 approximately 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 clearance of sildenafil is 41 L/h, resulting in an elimination half-life of 3–5 hours. After both oral and intravenous administration, sildenafil is excreted primarily as metabolites 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. Data indicate that 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 patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil remained unchanged after a single 50 mg oral dose. Mean AUC and Cmax of the N-desmethyl metabolite increased by 126% and 73%, respectively, compared to 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 by 100% and 88%, respectively, compared to age-matched volunteers without renal impairment. Additionally, AUC and Cmax values 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 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 drug 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 drug, 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 it is known that sildenafil affects the nitric oxide/cyclic guanosine monophosphate (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).
• Sudden 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.
• 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.

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

Reduced clearance of sildenafil has been demonstrated when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increase in the frequency of adverse effects has not been observed during concomitant use of sildenafil and CYP3A4 inhibitors, the recommended initial dose of sildenafil is 25 mg.

Concomitant administration of the HIV protease inhibitor ritonavir, a very potent P450 inhibitor, at steady-state concentration (500 mg once daily) and sildenafil (single 100 mg dose) resulted in a 300% increase (4-fold) in sildenafil Cmax and a 1000% increase (11-fold) in plasma AUC. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL when sildenafil was administered alone, indicating a significant effect of ritonavir on a broad range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Due to these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended; in any case, the maximum dose of sildenafil should not exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady-state dose (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). No effect of sildenafil on saquinavir pharmacokinetics was observed. 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, when co-administered with 50 mg sildenafil in healthy volunteers, increased plasma concentrations of sildenafil by 56%.

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

Single administration of antacids (magnesium hydroxide/aluminum hydroxide) does 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 inhibitors (such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-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 lead to a serious interaction with sildenafil.

Effect of sildenafil on other medicinal products.

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.

Since it is known that sildenafil affects the nitric oxide/cyclic guanosine monophosphate (cGMP) metabolism, it has been established that the drug potentiates the hypotensive effect of nitrates; therefore, concomitant use with nitric oxide donors or nitrates in any form is contraindicated.

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

Concomitant use of sildenafil and alpha-adrenoreceptor blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most commonly occurs within 4 hours after sildenafil administration. In drug interaction studies, the alpha-adrenoreceptor blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were administered concomitantly to patients with benign prostatic hyperplasia whose condition was stabilized on doxazosin. In these populations, mean additional reductions in blood pressure were observed in the supine position of 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and in the standing position of 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Concomitant use of sildenafil and doxazosin in patients stabilized on doxazosin has occasionally been associated with symptomatic orthostatic hypotension. These reports included 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 caused by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers at average 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, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and alpha-adrenoreceptor 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. The corresponding reduction in diastolic blood pressure was 7 mm Hg. In magnitude, these additional reductions in blood pressure were comparable to those observed with sildenafil alone in healthy volunteers.

Administration of a single dose of sildenafil with sacubitril/valsartan at steady state in patients with arterial hypertension was associated with significantly greater blood pressure reduction compared to sacubitril/valsartan alone. Therefore, sildenafil should be initiated with caution in patients receiving sacubitril/valsartan.

Sildenafil 100 mg did not affect the pharmacokinetic parameters of 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.

Special precautions for use.

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

Cardiovascular risk factors. Since sexual activity carries a certain cardiovascular risk, physicians should assess the cardiovascular status of patients before starting any treatment for erectile dysfunction. Sildenafil has a vasodilatory effect, which manifests as a mild and transient decrease in blood pressure. Before prescribing sildenafil, physicians should carefully consider whether this effect could have an adverse impact on patients with underlying cardiovascular conditions, especially when combined with sexual activity. Patients particularly sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) and patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic nervous system dysregulation of blood pressure.

The drug potentiates the hypotensive effect of nitrates.

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, but not all, patients, risk factors for cardiovascular disease were present. Many of these adverse events occurred during or immediately after sexual intercourse, and only a few occurred shortly after drug administration 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 influenced by other factors.

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

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

Concomitant use with other PDE5 inhibitors or other erectile dysfunction medications. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other medications for pulmonary arterial hypertension containing sildenafil, or with other erectile dysfunction treatments, have not been studied. Therefore, such combinations are not recommended.

Visual effects. Spontaneous reports of visual disturbances associated with sildenafil and other PDE5 inhibitors have been received (see section "Adverse reactions"). Spontaneous reports and data from a surveillance study have indicated 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 to discontinue the drug and seek immediate medical attention in case of sudden visual impairment (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 taking α-adrenoreceptor blockers, their condition should be stabilized with α-blocker therapy before initiating sildenafil treatment. Consideration should also be given to starting with a 25 mg dose (see section "Dosage and administration"). Patients should also be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Effects on bleeding. Studies on human platelets have demonstrated that in vitro, sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside. There is no information on the safety of sildenafil use in patients with bleeding disorders or active peptic ulcer. Therefore, sildenafil use in these patient groups should only be considered after careful benefit-risk assessment.

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

Fertility. No effects on sperm morphology or motility were observed after administration of a 100 mg dose to healthy volunteers.

Hearing loss. Physicians should advise patients to discontinue PDE5 inhibitors, including sildenafil, and seek immediate medical help if they experience 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 inhibitors, including sildenafil-containing products. It is not possible to determine whether these events are related to PDE5 inhibitor use or to other factors.

Concomitant use with antihypertensive agents. Sildenafil 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 a mean additional reduction of systolic blood pressure by 8 mm Hg and diastolic blood pressure by 7 mm Hg.

Sexually transmitted diseases. Sildenafil does not protect against sexually transmitted diseases. Consideration should be given to informing patients about appropriate preventive measures to protect against sexually transmitted diseases, including human immunodeficiency virus.

Use during pregnancy or breastfeeding.

The drug is not intended for use in women.

Ability to affect reaction rate when driving or operating machinery.

The drug may have a minor influence on the ability to drive or operate machinery. Since dizziness and visual disturbances have been reported with sildenafil use, patients should determine their individual response to the drug before driving a vehicle or operating machinery.

Administration and Dosage.

The drug is administered orally.

Adults.

The recommended dose is 50 mg, taken as needed approximately one 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 onset of action may be delayed compared to administration 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 of 30–80 mL/min), the recommended dose is the same as that indicated above for adults.

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min), the recommended dose is 25 mg. Depending on efficacy and tolerability, the dose may be increased to 50 mg or 100 mg.

Patients with hepatic impairment.

Since sildenafil clearance is reduced in patients with hepatic impairment (e.g., cirrhosis), the recommended dose is 25 mg. Depending on efficacy and tolerability, the dose may be increased to 50 mg or 100 mg.

Patients taking other medicinal products.

The recommended starting dose for patients taking CYP3A4 inhibitors (except ritonavir, the concomitant use of which with sildenafil is not recommended) is 25 mg.

To minimize the risk of orthostatic hypotension, the condition of patients taking alpha-adrenoreceptor blockers should be stabilized before initiating sildenafil treatment. The recommended starting dose of sildenafil is 25 mg.

Children.

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

Overdose.

When single doses of sildenafil up to 800 mg were administered, adverse reactions 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 applied as necessary. Hemodialysis is unlikely to accelerate sildenafil clearance due to the high degree of drug binding to plasma proteins 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.

Adverse reactions are listed below by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping, adverse reactions are listed in decreasing order of 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*, recurrence of seizures*, syncope.

Eye disorders.

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

Uncommon: lacrimation disorders***, eye pain, photophobia, photopsia, eye hyperaemia, brightness of vision, conjunctivitis.

Rare: non-arteritic anterior ischaemic optic neuropathy*, retinal vascular occlusion*, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, halos around lights in the visual field, eye swelling, eye swelling, eye disorders, conjunctival hyperaemia, eye irritation, abnormal sensations in the eye, eyelid oedema, scleral discolouration.

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 oedema, nasal dryness.

Gastrointestinal disorders.

Common: nausea, dyspepsia.

Uncommon: gastro-oesophageal 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, sensation of warmth.

Rare: irritation.

Investigations.

Uncommon: increased heart rate.

* Reported only during post-marketing surveillance of sildenafil.

** Colour vision disorders: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.

*** Lacrimation disorders: dry eyes, lacrimation disorder, increased lacrimation.

The following events were observed in < 2% of patients during clinical trials; a causal relationship has not been established. Reports included events that were likely related to sildenafil use. Events not listed were mild and reports were too imprecise to be meaningful.

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

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

Gastrointestinal system: glossitis, colitis, dysphagia, gastritis, gastroenteritis, oesophagitis, stomatitis, abnormal liver function tests, rectal haemorrhage, gingivitis.

Blood and lymphatic system disorders: anaemia, leukopenia.

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

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

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

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

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

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

Urogenital system: cystitis, nocturia, increased frequency of urination, breast enlargement, urinary incontinence, ejaculation disorders, genital oedema, anorgasmia.

Adverse reactions reported from a population of unknown size. These events were reported due to their severity, frequency, lack of clear alternative cause, or a combination of these factors.

Cardiovascular, cerebrovascular and vascular 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, 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 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 factors, or other factors.

Blood and lymphatic system disorders: vaso-occlusive crisis. In a small, prematurely terminated study of sildenafil in patients with pulmonary arterial hypertension secondary to sickle cell anaemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo. The clinical significance of this information for patients taking the drug for the treatment of erectile dysfunction is unknown.

Nervous system disorders: anxiety, transient global amnesia.

Special senses.

Ear disorders. Sudden decrease or loss of hearing, occurring in temporal association with sildenafil use, has been reported. In some cases, medical conditions and other factors that could have contributed to hearing-related adverse reactions were reported. In many cases, follow-up medical information is lacking. It is not possible to determine whether these events are directly related to sildenafil use, underlying risk factors for hearing loss, a combination of these factors, or other factors.

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

Cases of non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision including permanent vision loss, have been reported in temporal association with PDE5 inhibitors, including sildenafil. In many, but not all, patients, anatomical or vascular risk factors for NAION were present, including (but not limited to): small cup-to-disc ratio (crowded disc), age ≥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 factors, 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 applicable legislation.

Shelf life. 2 years.

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

Packaging.

4 tablets in a blister, 1 blister per carton.

1 tablet in a blister, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer.

Artura Pharmaceuticals Pvt. Ltd.

Manufacturer’s address and location of operations.

1505 Portia Road, Sri City SEZ, Sityavedu Mandal, Chittoor District - 517 588, Andhra Pradesh, India.

Marketing Authorization Holder.

Ananta Medicare Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.