Novagra euro

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NOVAGRA EURO (NOVAGRAEURO)

Composition:

Active substance: sildenafil;

One tablet contains sildenafil citrate equivalent to 50 mg of sildenafil

or one tablet contains sildenafil citrate equivalent to 100 mg of sildenafil;

Excipients: sodium croscarmellose; calcium hydrogen phosphate (dihydrate); microcrystalline cellulose; magnesium stearate; purified talc; Opadry Red II 85G55231 (contains the dye Ponceau 4R (E 124)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: purple-red, triangular, biconvex, film-coated tablets, embossed with "50" or "100" on one side.

Pharmacotherapeutic group. Medicinal products used in erectile dysfunction. Sildenafil. ATC code G04BE03.

Pharmacological Properties.

Pharmacodynamics.

Sildenafil is an oral medication indicated for the treatment of erectile dysfunction. In the presence of 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 cyclic guanosine monophosphate (cGMP) levels, resulting in relaxation of the smooth muscle of the corpus cavernosum and promoting blood inflow.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for cGMP degradation. The effects of sildenafil on erection are peripheral. Sildenafil does not directly cause relaxation of 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 with sexual stimulation, sildenafil's inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce its desired pharmacological effect, sexual stimulation is required.

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

To assess the duration during which sildenafil administration induces erection in response to sexual stimulation, specific clinical studies were conducted. In clinical trials involving patients who took sildenafil on an empty stomach, median time to onset of erection in patients achieving an erection with 60% rigidity (sufficient for sexual intercourse) was 25 minutes (range: 12–37 minutes), as measured by penile plethysmography. In another study, sildenafil was still able to induce erection 4–5 hours after administration.

Sildenafil causes mild and transient reduction in blood pressure, which in most cases has no clinical significance. The mean maximal decrease in systolic blood pressure in the supine position after oral administration of 100 mg sildenafil was 8.4 mm Hg. The corresponding change in diastolic blood pressure in the supine position was 5.5 mm Hg. This blood pressure reduction is consistent with the vasodilatory action of sildenafil, possibly due to increased cGMP levels in vascular smooth muscle. Single oral doses of sildenafil up to 100 mg in healthy volunteers did not cause any clinically significant changes on electrocardiograms.

In a study of hemodynamic effects of single oral 100 mg sildenafil administration in patients with severe ischemic heart disease (IHD) (with stenosis of at least one coronary artery by more than 70%), mean systolic and diastolic blood pressure at rest decreased by 7% and 6%, respectively, compared to baseline. Mean pulmonary systolic pressure decreased by 9%. Sildenafil did not alter cardiac output parameters and did not reduce blood flow through stenosed coronary arteries.

No clinically significant differences were observed in time to onset of angina-limiting exercise between sildenafil and placebo in exercise testing studies involving patients with erectile dysfunction and chronic stable angina who were receiving concomitant antianginal medications (except nitrates).

Mild and transient disturbances in color discrimination (blue/green) were observed in some patients 1 hour after administration of 100 mg sildenafil. These effects completely resolved within 2 hours after dosing. The possible mechanism for this color vision change is related to inhibition of PDE6, which participates in the phototransduction cascade in the retina. Sildenafil does not affect visual acuity or contrast sensitivity. In studies involving patients with documented macular degeneration, administration of sildenafil (single 100 mg dose) did not cause significant changes in visual test results (visual acuity, Amsler grid, traffic light color discrimination simulation, Humphrey perimeter, and photostress testing).

Single oral administration of sildenafil 100 mg in healthy volunteers did not affect sperm motility or morphology.

In clinical trials, sildenafil was administered to patients aged 19 to 87 years. The following patient groups were represented: elderly patients, patients with arterial hypertension, diabetes mellitus, ischemic heart disease, hyperlipidemia, spinal cord injuries, depression, transurethral resection of the prostate, and radical prostatectomy. The following patient groups were either insufficiently represented or not included in clinical trials: patients after pelvic surgery, patients after radiation therapy, patients with severe renal or hepatic impairment, and patients with certain cardiovascular diseases.

In fixed-dose studies, the number of patients reporting improvement in erectile function was higher than in the placebo group. In these studies, the discontinuation rate with sildenafil was low and similar to that in the placebo group.

In all these studies, patients reported improvement with sildenafil use in psychogenic erectile dysfunction, mixed erectile dysfunction, organic erectile dysfunction, in elderly age, diabetes mellitus, ischemic heart disease, hypertension, transurethral resection of the prostate, radical prostatectomy, spinal cord injuries, and depression. The safety and efficacy of sildenafil were confirmed by data from these long-term studies.

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 after oral administration.

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 distribution of the drug into body tissues. After single oral administration of 100 mg 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 18 ng/mL (38 nmol). The extent of plasma protein binding is independent of total sildenafil concentrations.

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

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

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

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-dimethylated metabolite compared to younger healthy volunteers (18–45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

Renal impairment. In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil remained unchanged after single 50 mg oral administration. Mean AUC and Cmax of the N-desmethyl metabolite increased by 126% and 73%, respectively, compared to age-matched volunteers with normal renal function. However, due to high inter-subject variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax by 100% and 88%, respectively, compared to age-matched volunteers with normal renal function. Additionally, AUC and Cmax of the N-desmethyl metabolite were significantly increased by 200% and 79%, respectively.

Hepatic impairment. In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, leading to increases in AUC by 84% and Cmax by 47% compared to age-matched volunteers with normal liver function. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

Treatment of erectile dysfunction defined as the inability to achieve or maintain an erection of the penis sufficient for successful sexual intercourse.

For the drug to be effective, 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) 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").
• Medicinal products for the treatment of erectile dysfunction, including sildenafil, are contraindicated in men for whom sexual activity is not recommended (e.g., patients with 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 related to previous use of PDE5 inhibitors.
• Severe hepatic impairment; arterial hypotension (blood pressure below 90/50 mmHg); 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) — the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on sildenafil.

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

In vivo studies. Population pharmacokinetic analysis of clinical trial data demonstrated reduced clearance of sildenafil when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increased incidence of adverse events was not observed during concomitant use of sildenafil and CYP3A4 inhibitors, the recommended initial dose of sildenafil is 25 mg.

Concomitant administration of 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 typically observed after sildenafil alone, indicating a significant effect of ritonavir on a broad range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Due to these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended (see section "Special precautions for use"); in any case, the maximum dose of sildenafil should not exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at 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 the pharmacokinetics of saquinavir was observed (see section "Dosage and administration"). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have a more pronounced effect.

Administration of sildenafil (single 100 mg dose) with erythromycin, a specific 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 sildenafil 50 mg 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 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 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, 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 inducers of CYP3A4 as rifampicin may lead to a more pronounced decrease in plasma concentrations of sildenafil.

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

Effects of sildenafil on other medicinal products.

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 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 sildenafil is known to affect the metabolism of nitric oxide/cyclic guanosine monophosphate (cGMP), it has been established that this drug potentiates the hypotensive effect of nitrates; therefore, its 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 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").

In some susceptible patients, concomitant use of sildenafil and alpha-adrenergic blockers may lead to symptomatic hypotension, most commonly occurring within 4 hours after sildenafil administration (see sections "Dosage and administration" and "Special precautions for use"). In studies specifically investigating drug interactions, the alpha-adrenergic 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 (BPH) whose condition had been stabilized with doxazosin. In these study populations, mean additional reductions in blood pressure in the supine position were 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, and mean reductions in blood pressure in the standing position were 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively. Symptomatic orthostatic hypotension has occasionally been reported with concomitant use of sildenafil and doxazosin in patients whose condition had been stabilized with 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 average maximum 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 classes of antihypertensive drugs such as diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive agents (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and alpha-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 mmHg was observed. The corresponding reduction in diastolic blood pressure was 7 mmHg. This additional reduction in blood pressure was comparable to that observed with sildenafil alone in healthy volunteers (see section "Pharmacological properties").

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

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

Adding a single dose of sildenafil to sacubitril/valsartan at steady state in patients with arterial hypertension was associated with a significantly greater reduction in blood pressure compared to sacubitril/valsartan alone. Therefore, caution should be exercised when initiating sildenafil 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 cardiovascular risk, physicians should assess the cardiovascular status of patients prior to initiating any treatment for erectile dysfunction. Sildenafil has a vasodilatory effect, which manifests as mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians should carefully consider whether such an effect might 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 of the manifestations of which is severe autonomic regulation of arterial blood pressure.

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

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 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 sildenafil 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 their occurrence 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 penile curvature, cavernosal fibrosis, or Peyronie's disease) and in patients with conditions that may predispose to priapism (such as sickle-cell anaemia, multiple myeloma, or leukaemia).

The safety and efficacy of concomitant use of sildenafil with other treatments for erectile dysfunction have not been studied; therefore, such combinations are not recommended.

Since the market release of sildenafil, cases of prolonged erection and priapism have been reported. If an erection lasts longer than 4 hours, patients should seek immediate medical help. Without prompt treatment, priapism may lead to penile tissue damage and permanent loss of potency.

Concomitant use with other PDE5 inhibitors or other erectile dysfunction treatments. 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 the use of sildenafil and other PDE5 inhibitors have been received (see section "Adverse reactions"). From spontaneous reports and observational study data, cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, have been reported in association with sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised that if sudden vision loss occurs, sildenafil use should be discontinued immediately and medical help sought (see section "Contraindications").

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

Concomitant use with alpha-blockers. Sildenafil should be used with caution in patients taking alpha-blockers, as this combination may lead to symptomatic arterial hypotension in some susceptible patients. Symptomatic arterial hypotension usually occurs within 4 hours after sildenafil administration. Due to the risk of orthostatic hypotension, sildenafil therapy should only be initiated in haemodynamically stable patients who are taking alpha-blockers. The recommended starting dose for such patients is 25 mg of sildenafil (see section "Dosage and administration"). In addition, patients should be informed about 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 acute peptic ulcer. Therefore, sildenafil use in these patient groups should only be considered 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 use of PDE5 inhibitors, including NOVAGRA EURO, and seek immediate medical help if sudden decrease or loss of hearing occurs. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE5 inhibitors, including this product. It is not possible to determine whether these events are directly related to the use of PDE5 inhibitors or to other factors.

Concomitant use with antihypertensive agents. The drug 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 blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg.

Sexually transmitted diseases. Sildenafil does not protect against sexually transmitted diseases. Patients should be instructed about necessary protective measures to prevent transmission of sexually transmitted diseases, including human immunodeficiency virus.

The film coating of NOVAGRA EURO tablets contains the colouring agent Ponceau 4R (E 124), which may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free". This information may be provided to patients on a low-sodium diet.

Use during pregnancy or breastfeeding.

The product is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery.

Novagra Euro 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 Novagra Euro before driving a vehicle or operating machinery.

Method of administration and dosage.

The medication should be administered orally.

For effective action, sexual stimulation is required.

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 medication 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 of 30–80 mL/min), the recommended dose is the same as that stated above in the section "Adults."

In patients with severe renal impairment (creatinine clearance < 30 mL/min), sildenafil clearance is reduced; therefore, 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.

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 to 50 mg or 100 mg.

Patients taking other medicinal products.

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

To minimize the risk of orthostatic hypotension, patients taking alpha-blockers should have their condition stabilized before initiating sildenafil therapy. Consideration should also be given to starting with a sildenafil dose of 25 mg* (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

* - use medicinal products containing sildenafil as the active substance at the appropriate dosage.

Children.

The medication 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 a higher incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances as described in the section "Adverse reactions").

In case of overdose, standard supportive measures should be implemented. Acceleration of sildenafil clearance by hemodialysis is unlikely due to the high degree of plasma protein binding and the absence 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.

All clinically significant adverse reactions observed during clinical trials more frequently than with placebo are listed below by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Adverse reactions are listed in decreasing order of frequency within each frequency category.

Infections and infestations.

Uncommon: Rhinitis.

Immune system disorders.

Uncommon: Hypersensitivity reactions.

Nervous system disorders.

Very common: headache,

Common: dizziness,

Uncommon: somnolence, hypoesthesia,

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

Eye disorders.

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

Uncommon: tear 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 oedema, 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*.

Vascular disorders.

Common: hot flushes, facial flushing,

Uncommon: arterial hypertension/hypotension.

Cardiac disorders.

Uncommon: palpitations, tachycardia,

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

Respiratory, thoracic and mediastinal disorders.

Common: nasal congestion,

Uncommon: epistaxis, nasal sinus congestion,

Rare: throat tightness, nasal mucosal oedema, nasal dryness.

Gastrointestinal disorders.

Common: dyspepsia, nausea,

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

Rare: oral hypoesthesia.

Skin and subcutaneous tissue disorders.

Uncommon: skin 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: priapism*, prolonged erection, haemospermia, penile haemorrhage.

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.

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

*** Tear disorders: dry eyes, tear secretion disorders, increased lacrimation.

The following events were observed in < 2% of patients; causal relationship not established. Reports included events with a probable relationship to the use of the drug. Events not listed were mild, and reports were too imprecise to be meaningful.

General: Facial oedema, photosensitivity reactions, shock, asthenia, pain, sudden fall, 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: 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.

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 swelling, anorgasmia.

Post-marketing experience. The following adverse reactions have been identified during post-approval use of sildenafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were reported due to their severity, frequency of reporting, lack of clear alternative cause, or a combination of these factors.

Cardiovascular, 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 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 directly related to sildenafil use, sexual activity, underlying risk factors, a combination of these factors, or other factors.

Blood and lymphatic system: Vaso-occlusive crisis. In a small, prematurely terminated study of sildenafil use in patients with pulmonary arterial hypertension secondary to sickle cell 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.

Special senses.

Hearing. Post-marketing reports have described cases of sudden decrease or loss of hearing temporally associated with sildenafil use. In some cases, medical conditions and other factors that could have contributed to hearing-related adverse events were reported. Follow-up medical information is mostly 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.

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

Rare cases of non-arteritic anterior ischaemic optic neuropathy (NAION), resulting in visual loss including permanent vision loss, have been reported post-marketing in temporal association with PDE5 inhibitors, including sildenafil. Many of these patients had underlying anatomical or vascular risk factors for NAION, such as 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 medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions in accordance with national regulatory requirements.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging.

1 film-coated tablet in a blister; 1 blister in a cardboard box; or 4 film-coated tablets in a blister; 1 or 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Unique Pharmaceutical Laboratories (a division of J. B. Chemicals & Pharmaceuticals Ltd.).

Manufacturer's address.

Plot No. 215-219, G.I.D.C., Industrial Area, Panoli - 394 116, Dist. Bharuch, India.