Effex Sildenafil 50 mg 6 tablets blister film-coated

Indications

Treatment of erectile dysfunction, characterized by the inability to achieve or maintain an erection of the penis sufficient for satisfactory sexual intercourse.
EFFEX® Sildenafil is effective only with sexual stimulation.

Method of administration and doses

Orally.
The recommended dose for most adult patients is 50 mg of sildenafil approximately 1 hour before sexual activity.
Depending on efficacy and tolerability, the dose may be increased to 100 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once a day.
Elderly patients
Dose adjustment of EFFEX® Sildenafil is not required.
Renal function impairment
For patients with mild to moderate renal insufficiency (creatinine clearance 30-80 ml/min), dose adjustment is not required.
Co-administration with other medications
To minimize the risk of developing postural hypotension in patients taking α-adrenergic blockers, sildenafil should be initiated only after hemodynamic stabilization in these patients has been achieved. The appropriateness of reducing the initial dose of sildenafil should also be considered (see the section "Interactions with other medications" and "Special instructions").

Composition per tablet 50 mg
Active ingredient: sildenafil citrate - 70.25 mg (calculated as sildenafil) 50.00 mg
Excipients:
Microcrystalline cellulose - 126.37 mg
Calcium hydrogen phosphate - 41.25 mg
Pre-gelatinized corn starch - 27.50 mg
Magnesium stearate - 4.13 mg
Sodium croscarmellose - 2.75 mg
Colloidal silicon dioxide - 2.75 mg
Coating composition: Hydroxypropyl methylcellulose - 4.30 mg, Macrogol 4000 (polyethylene glycol 4000) - 0.86 mg,
Titanium dioxide - 2.58 mg, Polysorbate 80 - 1.29 mg, Talc - 0.86 mg, Iron oxide red dye - 0.02 mg, Iron oxide yellow dye - 0.09 mg.

Tablets are round, biconvex, coated with a film coating from pale orange with a pinkish tint to pale brown with a pinkish tint; on a cross-section, the core is from white to almost white in color.

Contraindications

Increased sensitivity to sildenafil or to any other component of the drug.
Use in patients receiving continuously or intermittently nitric oxide donors, organic nitrates, or nitrites in any form, as EFFEX® Sildenafil enhances the hypotensive effect of nitrates (see the section "Interaction with other medicinal products").
The safety and efficacy of EFFEX® Sildenafil when used in combination with other treatments for erectile dysfunction have not been studied, therefore the use of such combinations is not recommended (see the section "Special instructions").
Co-administration with ritonavir.
Liver function disorders.
Severe chronic renal failure.
Severe heart failure, unstable angina, stroke or myocardial infarction within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mmHg) or hypotension (BP 170/100 mmHg), or hypotension (BP < 90/50 mmHg) (see the "Contraindications" section). Clinical studies have shown no differences in the incidence of myocardial infarction (1.1 per 100 person-years) or cardiovascular disease mortality (0.3 per 100 person-years) in patients receiving sildenafil compared to those receiving placebo.Cardiovascular Complications During the post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as serious cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) have been reported, which had a temporal association with the use of sildenafil. Most of these patients, but not all, had risk factors for cardiovascular complications. Many of the reported adverse events occurred shortly after sexual activity, and some were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct link between the reported adverse events and the mentioned or other factors.Hypotension Sildenafil has a systemic vasodilatory effect, leading to a transient decrease in blood pressure, which is not clinically significant and does not result in any consequences for most patients. However, before prescribing sildenafil, the doctor should carefully assess the risk of possible adverse manifestations of the vasodilatory effect in patients with relevant diseases, especially in the context of sexual activity. Increased sensitivity to vasodilators is observed in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as in those with the rare syndrome of multiple system atrophy, which manifests as severe blood pressure regulation disorders by the autonomic nervous system. Since the concomitant use of sildenafil and α-adrenergic blockers may lead to symptomatic hypotension in some sensitive patients, sildenafil should be prescribed with caution to patients taking α-adrenergic blockers (see the "Interactions with Other Medications" section). To minimize the risk of postural hypotension in patients taking α-adrenergic blockers, sildenafil should only be initiated after hemodynamic parameters have stabilized in these patients. The appropriateness of reducing the initial dose of sildenafil should also be considered (see the "Dosage and Administration" section). The doctor should inform patients about what actions to take in case of symptoms of postural hypotension.Visual Disturbances In rare cases during post-marketing use of all PDE5 inhibitors, including sildenafil, non-arteritic anterior ischemic optic neuropathy (NAION) has been reported—a rare disease and cause of vision loss. Most of these patients had risk factors, including a reduced cup-to-disc ratio ("swollen disc"), age over 50, diabetes, hypertension, ischemic heart disease, hyperlipidemia, and smoking. An observational study evaluated whether recent use of PDE5 inhibitor medications was associated with the acute onset of NAION. The results indicate approximately a 2-fold increase in the risk of NAION within 5 half-lives after the use of a PDE5 inhibitor. According to published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 men aged ≥ 50 years in the general population. Patients should be advised that in the case of sudden vision loss, they should discontinue sildenafil therapy and consult a doctor immediately. Individuals who have previously experienced NAION are at increased risk of recurrence. Therefore, the doctor should discuss this risk with such patients and also discuss the potential chance of adverse effects from PDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in these patients and only in situations where the expected benefit outweighs the risk.A small number of patients with hereditary retinitis pigmentosa have genetically determined dysfunctions of retinal phosphodiesterase. There is no safety data on the use of sildenafil in patients with retinitis pigmentosa; therefore, the drug should be used with caution (see the "Caution" section).Hearing Impairment In some post-marketing and clinical studies, cases of sudden hearing deterioration or loss associated with the use of all PDE5 inhibitors, including sildenafil, have been reported; most of these patients had risk factors for sudden hearing deterioration or loss. A causal relationship between the use of PDE5 inhibitors and sudden hearing deterioration or loss has not been established. In the event of sudden hearing deterioration or loss while taking sildenafil, medical advice should be sought immediately.Bleeding Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There is no safety data on the use of sildenafil in patients with a tendency to bleed or exacerbation of peptic ulcer disease of the stomach and duodenum; therefore, sildenafil should be used with caution in these patients (see the "Caution" section). The incidence of nasal bleeding in patients with pulmonary hypertension associated with diffuse connective tissue diseases was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (sildenafil 3.0%, placebo 2.4%). In patients receiving sildenafil in combination with a vitamin K antagonist, the incidence of nasal bleeding was higher (8.8%) than in patients not taking a vitamin K antagonist (1.7%).Use in Combination with Other Erectile Dysfunction Treatments The safety and efficacy of sildenafil in combination with other PDE5 inhibitors or other medications for the treatment of pulmonary hypertension containing sildenafil (e.g., Revatio®) or other erectile dysfunction treatments have not been studied; therefore, the use of such combinations is not recommended (see the "Contraindications" section).Effect on the Ability to Drive Vehicles and Operate Machinery: Since dizziness, decreased blood pressure, chromatic vision, blurred vision, and other side effects may occur with sildenafil use, caution should be exercised when driving vehicles and engaging in other potentially dangerous activities that require increased attention and quick psychomotor reactions. Individual responses to the drug in these situations should also be carefully considered, especially at the beginning of treatment and when changing the dosing regimen.

The most common side effects were headache and "flushing." Usually, the side effects of the drug EFFEX® Sildenafil are mild or moderate and transient in nature. Studies using a fixed dose have shown that the frequency of some adverse events increases with the dose. The frequency of adverse reactions is presented according to the following classification: Very common ≥ 10% Common ≥ 1% and < 10% Uncommon ≥ 0.1% and < 1% Rare ≥ 0.01% and 150 μmol). When sildenafil is taken in recommended doses, its Cmax is about 1 μmol, so it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.
Sildenafil enhances the hypotensive effect of nitrates both with prolonged use of the latter and when prescribed for acute indications. Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.
When α-adrenergic blocker doxazosin (4 mg and 8 mg) is taken together with sildenafil (50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional decrease in systolic/diastolic blood pressure while lying on the back was 9/5 mmHg and 8/4 mmHg, respectively, and while standing - 11/4 mmHg and 4/5 mmHg, respectively. Rare cases of symptomatic postural hypotension have been reported in such patients, manifested as dizziness (without fainting). In some sensitive patients receiving α-adrenergic blockers, the simultaneous use of sildenafil may lead to symptomatic hypotension.
No significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the CYP2C9 isoenzyme, has been found.
Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the CYP3A4 isoenzyme, at their steady-state levels in the blood.
The simultaneous use of sildenafil at steady state (80 mg three times a day) leads to an increase in the AUC and Cmax of bosentan (125 mg twice a day) by 49.8% and 12%, respectively.
Sildenafil (50 mg) does not cause an additional increase in bleeding time when taken with acetylsalicylic acid (150 mg).
Sildenafil (50 mg) does not enhance the hypotensive effect of alcohol in healthy volunteers at a maximum blood alcohol concentration of approximately 0.08% (80 mg/dL).
In patients with arterial hypertension, no signs of interaction between sildenafil (100 mg) and amlodipine have been found. The average additional decrease in blood pressure while lying down is 8 mmHg (systolic) and 7 mmHg (diastolic). The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.

Pharmacodynamics

Sildenafil is a potent selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiological mechanism of erection is based on the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, resulting in the relaxation of smooth muscle tissue in the corpus cavernosum and enhanced blood flow to the corpus cavernosum. Sildenafil does not have a direct relaxing effect on isolated corpus cavernosum but enhances the relaxing effect of nitric oxide by inhibiting PDE5, which is responsible for the breakdown of cGMP in the corpus cavernosum. The pharmacological effect is achieved only in the presence of sexual stimulation. In vitro studies have shown that sildenafil is selective for PDE5. Its activity against other known isoenzymes is much lower: PDE6 - 10 times, PDE1 - more than 80 times, PDE2, PDE4, PDE7-11 - more than 700 times. Sildenafil is 4000 times more active against PDE5 compared to PDE3, which is significant since PDE3 is one of the key enzymes regulating myocardial contractility. A prerequisite for the effectiveness of sildenafil is sexual stimulation. The use of sildenafil in doses up to 100 mg led to a slight transient decrease in blood pressure. The hypotensive effect is associated with the vasodilating action of sildenafil, linked to the increase in cGMP levels in the smooth muscle cells of blood vessels. In some patients, one hour after taking the drug at a dose of 100 mg, a slight and transient impairment in the ability to distinguish between color shades (blue/green) was detected using the Farnsworth-Munsell 100 test. Color perception returned to normal after two hours. The color vision impairment is caused by the inhibition of PDE6, which is involved in the process of light transmission in the retina. Sildenafil does not affect visual acuity, contrast perception, electroretinogram parameters, intraocular pressure, or pupil diameter.

Section: Pharmacokinetics

Absorption
After oral administration, it is rapidly absorbed. The maximum concentration in plasma is reached within 30-120 minutes (on average 60 minutes) when taken on an empty stomach. Bioavailability varies from 25 to 63%.
When taken in combination with fatty food, the absorption rate decreases: Cmax decreases on average by 29%, and the time to reach maximum concentration (Tmax) increases by 60 minutes; however, the degree of absorption does not significantly change (the area under the pharmacokinetic concentration-time curve (AUC) decreases by 11%).
Distribution
The volume of distribution of sildenafil at steady state averages 105 liters. The binding of sildenafil to plasma proteins and its main circulating N-demethylated metabolite is approximately 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the dose (on average 188 ng) is found in semen 90 minutes after taking sildenafil.
Metabolism
Sildenafil is primarily metabolized in the liver by the action of microsomal isoenzymes of cytochrome P450: CYP3A4 (main pathway) and CYP2C9 (secondary pathway). The main circulating metabolite formed as a result of N-demethylation of sildenafil undergoes further metabolism. The selectivity of this metabolite's action on PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of sildenafil's activity. The concentration of the metabolite in plasma is about 40% of the concentration of sildenafil. The N-demethylated metabolite undergoes further metabolism; its terminal half-life is about 4 hours.
Excretion
The total clearance of sildenafil is 41 l/hour, and the terminal half-life is 3-5 hours. After oral administration, sildenafil is excreted as metabolites, mainly by the intestines (approximately 80% of the oral dose) and, to a lesser extent, by the kidneys (approximately 13% of the oral dose).
Pharmacokinetics in special patient groups
Elderly patients
In healthy elderly patients (65 years and older), the clearance of sildenafil is reduced, and the concentration of free sildenafil in plasma is approximately 40% higher than in younger patients (18-45 years). Age does not have a clinically significant effect on the frequency of adverse effects.
Renal function impairment
In mild (creatinine clearance (CC) 50-80 ml/min) and moderate (CC 30-49 ml/min) renal insufficiency, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change.
In severe renal insufficiency (CC