Sildenafil 50 mg 20 tablets, film-coated

Indications

The use of SILDENAFIL is indicated for adult men with erectile dysfunction, characterized by the inability to achieve or maintain an erection sufficient for satisfactory sexual activity. The SILDENAFIL medication is effective only with sexual stimulation.

Method of Administration and Dosage

Dosing regimen

The recommended dose is 50 mg, which should be taken, if necessary, approximately 1 hour before anticipated 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 use is once a day. The onset of action of the drug SILDENAFIL may be delayed when taken with food compared to taking it on an empty stomach (see section 5.2).

Special patient categories

Use in elderly patients

In elderly patients (≥ 65 years), dose adjustment of the drug SILDENAFIL is not required.

Use in patients with renal impairment

In patients with mild to moderate renal insufficiency (creatinine clearance (CC) 30-80 ml/min), dose adjustment is not required; in severe renal insufficiency (CC < 30 ml/min), the dose of sildenafil should be reduced to 25 mg.Use in patients with hepatic impairmentSince the clearance of sildenafil is reduced in patients with liver dysfunction (particularly in cirrhosis), the dose of the drug SILDENAFIL should be reduced to 25 mg.Use in patients taking other medicationsExcept for ritonavir, which is not recommended to be taken simultaneously with sildenafil (see section 4.4), in patients taking inhibitors of YP3A4, consideration should be given to starting the drug at a dose of 25 mg (see section 4.5).To minimize the risk of developing orthostatic hypotension in patients taking alpha-adrenergic blockers, the administration of the drug SILDENAFIL should only begin after hemodynamic stabilization in these patients has been achieved. The appropriateness of reducing the initial dose of sildenafil should also be considered (see sections 4.4 and 4.5).Method of administrationThe drug SILDENAFIL is taken orally.

Section: Composition

Each film-coated tablet contains 50 mg of sildenafil (as citrate).
Excipients that should be considered in the composition of the medicinal product:
Lactose monohydrate
Microcrystalline cellulose type 102
Povidone K-25
Sodium croscarmellose
Colloidal silicon dioxide
Magnesium stearate
Coating composition:
Hydroxypropyl methylcellulose
Titanium dioxide
Macrogol 400
Dimethicone 100

Description of the dosage form

Round, biconvex, scored, coated with a white film. On a cross-section, two layers are visible, the inner layer is white or almost white.

• hypersensitivity to sildenafil and/or to any of the excipients listed in section 6.1;

• due to its known effect on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, sildenafil enhances the hypotensive effect of nitrates, and therefore its concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated (see section 4.5);

• concomitant use of phosphodiesterase type 5 inhibitors (PDE-5), including sildenafil, with guanylate cyclase stimulators, such as riociguat, as this may lead to symptomatic arterial hypotension (see section 4.5);

• concomitant use with other medications for the treatment of erectile dysfunction (see section 4.5);

• severe hepatic insufficiency (Child-Pugh class C);

• simultaneous use of ritonavir;

• medications for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual activity is inadvisable (e.g., patients with severe cardiovascular diseases such as severe heart failure, unstable angina, those who have had a stroke or myocardial infarction within the last six months, life-threatening arrhythmias, arterial hypertension (BP > 170/110 mmHg) or arterial hypotension (BP less than 90/50 mmHg));

• patients with vision loss in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this condition is related to previous use of PDE-5 inhibitors or not (see section 4.4);

• hereditary pigmentary retinopathy;

• children under 18 years of age;

• sildenafil is not intended for use in women;

• patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

With caution:

• anatomical deformation of the penis (angulation, cavernous fibrosis, or Peyronie's disease);

• conditions predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocytopenia);

• conditions associated with bleeding;

• peptic ulcer disease of the stomach and duodenum in the acute stage;

• mild to moderate liver failure;

• severe renal failure (creatinine clearance less than 30 ml/min);

• patients with a history of anterior non-arteritic ischemic optic neuropathy;

• simultaneous use of alpha-adrenergic blockers. Special instructions
To diagnose erectile dysfunction, determine its possible causes, and choose appropriate treatment, a complete medical history must be collected and a thorough physical examination conducted.
During post-marketing studies, cases of prolonged erection and priapism were reported. If an erection persists for more than 4 hours, medical attention should be sought immediately. If priapism therapy is not conducted promptly, it may lead to tissue damage of the penis and irreversible loss of potency.
Drugs intended for the treatment of erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable.
Sexual activity poses a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for an examination of the cardiovascular system.
Sexual activity is undesirable in patients with heart failure, unstable angina, a myocardial infarction or stroke within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP >170/100 mmHg) or hypotension (BP < 90/50 mmHg). The use of sildenafil in such patients is contraindicated (see section 4.3). Clinical studies have shown no differences in the incidence of myocardial infarction (1.1 per 100 person-years) or cardiovascular mortality (0.3 per 100 person-years) in patients receiving sildenafil compared to those receiving placebo. Cardiovascular complications During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse reactions such as severe cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) were reported, which had a temporal relationship with the use of sildenafil. Most of these patients, but not all, had risk factors for cardiovascular complications. Many of the reported adverse reactions occurred shortly after sexual activity, and some were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct relationship between the observed adverse events and the mentioned or other factors. Arterial hypotension Sildenafil has a systemic vasodilatory effect, leading to a transient decrease in BP, which is not a clinically significant phenomenon and does not lead to any consequences in 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 conditions, 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, characterized by severe dysregulation of BP by the autonomic nervous system. Since the combined use of sildenafil and α-adrenergic blockers may lead to symptomatic hypotension in certain sensitive patients, SILDENAFIL should be prescribed with caution to patients taking alpha-adrenergic blockers (see section 4.5). To minimize the risk of developing orthostatic hypotension in patients taking α-adrenergic blockers, the use of SILDENAFIL should only begin after hemodynamic parameters have stabilized in these patients. The appropriateness of reducing the initial dose of sildenafil should also be considered. The doctor should inform patients about what actions to take in case of symptoms of orthostatic hypotension. Visual disturbances In rare cases during post-marketing use of all PDE-5 inhibitors, including sildenafil, cases of NAION - a rare disease and cause of decreased or loss of vision - have been reported. Most of these patients had risk factors, including a reduced ratio of the diameters of the optic nerve head and cup ("disc edema"), age over 50 years, diabetes, hypertension, ischemic heart disease, hyperlipidemia, and smoking. An observational study assessed whether recent use of PDE-5 inhibitor drugs 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 PDE-5 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 event 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 of NAION. Therefore, the doctor should discuss this risk with such patients, as well as discuss the potential chance of adverse effects of PDE-5 inhibitors. PDE-5 inhibitors, including sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the risk. In patients with episodes of NAION with vision loss in one eye, the use of sildenafil is contraindicated. 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, so sildenafil should not be used in such patients. Hearing disturbances In some post-marketing studies, cases of sudden worsening or loss of hearing associated with the use of all PDE-5 inhibitors, including sildenafil, have been reported. Most of these patients had risk factors for sudden worsening or loss of hearing. A causal relationship between the use of PDE-5 inhibitors and sudden hearing loss or worsening of hearing has not been established. In the event of sudden hearing loss or worsening of hearing while taking sildenafil, medical attention should be sought immediately. Bleeding Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. Data on the safety of sildenafil in patients with a tendency to bleed or exacerbation of peptic ulcer disease of the stomach and duodenum are lacking, therefore the use of sildenafil in such patients is contraindicated. 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 arterial 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 PDE-5 inhibitors or other drugs for the treatment of pulmonary arterial hypertension containing sildenafil or other erectile dysfunction treatments have not been studied, therefore the use of such combinations is not recommended. Combined use with ritonavir The combined use of sildenafil and ritonavir is not recommended (see section 4.5). Excipients Patients with a rare hereditary intolerance to galactose, lactase deficiency, or glucose-galactose malabsorption should not take this medication.Fertility, pregnancy, and lactation SILDENAFIL is not intended for use in women.Effect on the ability to drive vehicles and operate machinery SILDENAFIL may have a minor effect on the ability to drive vehicles and operate machinery. Since clinical studies of sildenafil have reported the possibility of dizziness and visual disturbances, the patient should be aware of the possibility of these reactions when taking sildenafil before driving or operating complex machinery.

Summary of the safety profile
The most common adverse reactions associated with the use of sildenafil were headache and "flushing." Generally, adverse reactions are mild to moderate in severity and transient in nature. The frequency of some adverse reactions is dose-dependent.
Summary of adverse reactions
The frequency of adverse effects is classified according to the recommendations of the World Health Organization: very common (≥1/10); common (≥1/100, but

Section: Overdose

Symptoms
In a single dose of sildenafil up to 800 mg, the adverse reactions were the same as those observed with lower doses, but occurred more frequently.
The use of a 200 mg dose did not lead to an increase in the drug's effectiveness; however, the frequency of adverse reactions (headache, "flushing," dizziness, dyspepsia, nasal congestion, visual disturbances) increased.
Treatment
Symptomatic treatment. Hemodialysis does not accelerate the clearance of sildenafil, as it actively binds to plasma proteins and is not excreted by the kidneys.

Interaction

Influence of other drugs on the pharmacokinetics of sildenafil
Sildenafil is primarily metabolized by cytochrome P450 isoenzymes (CYP) - 3A4 (main pathway) and 2C9 (additional pathway), therefore inhibitors of these isoenzymes may reduce the clearance of sildenafil, while inducers of these isoenzymes may increase the clearance of sildenafil. A decrease in the clearance of sildenafil has been noted when used concurrently with inhibitors of the CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a non-specific inhibitor of the CYP3A4 isoenzyme, when taken together with sildenafil (50 mg), causes an increase in the plasma concentration of sildenafil by 56%. A single dose of 100 mg of sildenafil taken with erythromycin (500 mg twice a day for 5 days), a moderate inhibitor of the CYP3A4 isoenzyme, while achieving a steady-state concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%. When sildenafil (100 mg single dose) is taken together with saquinavir (1200 mg three times a day), an HIV protease inhibitor and CYP3A4 isoenzyme inhibitor, while achieving a steady-state concentration of saquinavir in the blood, the Cmax of sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil does not affect the pharmacokinetics of saquinavir. Stronger inhibitors of the CYP3A4 isoenzyme, such as ketoconazole and itraconazole, may cause even greater changes in the pharmacokinetics of sildenafil. The simultaneous use of sildenafil (100 mg single dose) and ritonavir (500 mg twice a day), an HIV protease inhibitor and a strong inhibitor of cytochrome P450, while achieving a steady-state concentration of ritonavir in the blood, led to an increase in the maximum concentration (Cmax) of sildenafil by 300% (4 times) and the area under the pharmacokinetic concentration-time curve (AUC) by 1000% (11 times). After 24 hours, the concentration of sildenafil in the plasma remained at 200 ng/ml compared to 5 ng/ml after a single dose of sildenafil alone. This is consistent with the pronounced effect of ritonavir on a number of drugs that are substrates of cytochrome P450. Sildenafil did not affect the pharmacokinetics of ritonavir. Based on the results of pharmacokinetic studies, the combined use of sildenafil and ritonavir is not recommended (see section 4.4), and under no circumstances should the maximum dose of sildenafil exceed 25 mg within 48 hours. If sildenafil is taken in recommended doses, patients receiving strong inhibitors of the CYP3A4 isoenzyme simultaneously will have a Cmax of free sildenafil not exceeding 200 nM, and the drug is well tolerated. A single dose of an antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil. In studies involving healthy volunteers, the simultaneous use of the endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19) at a steady-state concentration (125 mg twice a day) and sildenafil at a steady-state concentration (80 mg three times a day) resulted in a decrease in the AUC and Cmax of sildenafil by 62.6% and 52.4%, respectively. Sildenafil increased the AUC and Cmax of bosentan by 49.8% and 42%, respectively. It is assumed that the simultaneous use of sildenafil with strong inducers of the CYP3A4 isoenzyme, such as rifampicin, may lead to a greater reduction in the concentration of sildenafil in the plasma. Inhibitors of the CYP2C9 isoenzyme (tolbutamide, warfarin), the CYP2D6 isoenzyme (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors, and calcium antagonists do not affect the pharmacokinetics of sildenafil. Azithromycin (500 mg/day for 3 days) does not affect the AUC, Cmax, Tmax, elimination rate constant, and T1/2 of sildenafil or its main circulating metabolite.

Effect of sildenafil on other drugs
Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes - 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 µM) of cytochrome P450. 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 taken simultaneously with the α-adrenoceptor blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional decrease in systolic/diastolic blood pressure in the supine position was 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, respectively, and in the standing position - 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Rare cases of symptomatic orthostatic hypotension have been reported in such patients, manifesting as dizziness (without fainting). In some sensitive patients receiving α-adrenoceptor 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 the HIV protease inhibitor saquinavir, which is a substrate of the CYP3A4 isoenzyme, at its steady-state level 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 42%, 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 averaging 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 in the supine position is 8 mm Hg (systolic) and 7 mm Hg (diastolic). The use of sildenafil in combination with antihypertensive agents does not lead to the occurrence of additional adverse reactions.

Section: Pharmacodynamics

Mechanism of action
Sildenafil is a potent selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE-5).
The physiological mechanism of erection is associated with the release of nitric oxide in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the corpus cavernosum, and increased blood flow.
Sildenafil does not have a direct relaxing effect on isolated human corpus cavernosum but enhances the effect of nitric oxide by inhibiting PDE-5, which is responsible for the breakdown of cGMP.
A prerequisite for the effectiveness of sildenafil is sexual stimulation. Sildenafil restores impaired erectile function under conditions of sexual stimulation by increasing blood flow to the corpus cavernosum of the penis.
Pharmacodynamic effects
Sildenafil is selective for PDE-5 in vitro, with its activity against PDE-5 exceeding its activity against other known isoenzymes of phosphodiesterase: PDE-6 by 10 times; PDE-1 by more than 80 times; PDE-2, PDE-4, PDE-7-PDE-11 by more than 700 times. Sildenafil is 4000 times more selective for PDE-5 compared to PDE-3, which is critically important since PDE-3 is one of the key enzymes regulating myocardial contractility.
Clinical efficacy and safety
Cardiological studies
The use of sildenafil at doses up to 100 mg did not lead to clinically significant changes in ECG in healthy volunteers. The maximum decrease in systolic blood pressure in the supine position after taking 100 mg of sildenafil was 8.3 mm Hg, and diastolic pressure was 5.3 mm Hg. A more pronounced but also transient effect on blood pressure (BP) was noted in patients taking nitrates (see sections 4.3 and 4.5).
In a study of the hemodynamic effect of a single dose of 100 mg of sildenafil in 14 patients with severe ischemic heart disease (IHD) (more than 70% of patients had stenosis of at least one coronary artery), resting systolic and diastolic blood pressure decreased by 7% and 6%, respectively, while pulmonary systolic pressure decreased by 9%. Sildenafil did not affect cardiac output and did not disrupt blood flow in stenosed coronary arteries, and also led to an increase (approximately 13%) in adenosine-induced coronary flow in both stenosed and intact coronary arteries.
In a double-blind placebo-controlled study, 144 patients with erectile dysfunction and stable angina, taking antianginal medications (excluding nitrates), performed physical exercises until the severity of angina symptoms decreased. The duration of exercise was significantly longer (19.9 seconds; 0.9-38.9 seconds) in patients taking sildenafil at a single dose of 100 mg compared to patients receiving placebo.
In a randomized double-blind placebo-controlled study, the effect of varying doses of sildenafil (up to 100 mg) was studied in men (n=568) with erectile dysfunction and arterial hypertension, taking more than two antihypertensive medications. Sildenafil improved erection in 71% of men compared to 18% in the placebo group. The frequency of adverse reactions was comparable to that in other patient groups, as well as in individuals taking more than three antihypertensive medications.
Studies on visual disturbances
In some patients, one hour after taking 100 mg of sildenafil, a slight and transient impairment in the ability to distinguish color shades (blue/green) was detected using the Farnsworth-Munsell 100 test. These changes were absent two hours after taking the drug. It is believed that the color vision disturbance is caused by the inhibition of PDE-6, which is involved in the light transmission process in the retina. Sildenafil did not affect visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter.
In a placebo-controlled crossover study of patients with proven early age-related macular degeneration (n=9), sildenafil at a single dose of 100 mg was well tolerated. No clinically significant changes in vision were detected, assessed by specific visual tests (visual acuity, Amsler grid, color perception, color passage modeling, Humphrey perimeter, and photostress).

Pharmacokinetics

Absorption
After oral administration, sildenafil is rapidly absorbed. The absolute bioavailability averages about 40% (ranging from 25% to 63%). In vitro, sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human PDE-5 activity by 50%. After a single dose of 100 mg of sildenafil, the average maximum concentration of free sildenafil in the plasma (Cmax) in men is about 18 ng/ml (38 nM). Cmax after oral administration of sildenafil on an empty stomach is reached on average within 60 minutes (ranging from 30 minutes to 120 minutes). When taken with a fatty meal, the absorption rate decreases: Cmax is reduced by an average of 29%, and the time to reach maximum concentration (Tmax) increases by 60 minutes; however, the extent of absorption is not significantly altered (the area under the pharmacokinetic concentration-time curve (AUC) decreases by 11%).
Distribution
The volume of distribution of sildenafil at steady state averages about 105 liters. The binding of sildenafil and its main circulating N-demethylated metabolite to plasma proteins is about 96% and is independent of the total drug concentration. Less than 0.0002% of the sildenafil dose (on average 188 ng) is found in semen 90 minutes after taking the drug.
Biotransformation
Sildenafil is metabolized primarily in the liver by the action of the isoenzyme cytochrome CYP3A4 (the main pathway) and the isoenzyme cytochrome CYP2C9 (the additional pathway).
The main circulating active metabolite formed from the 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 PDE-5 in vitro is about 50% of sildenafil's activity. The concentration of the metabolite in the plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethylated metabolite undergoes further metabolism; its half-life (T1/2) is about 4 hours.
Elimination
The total clearance of sildenafil is 41 l/h, and the terminal T1/2 is 3-5 hours. After oral administration, as well as after intravenous administration, sildenafil is eliminated as metabolites, primarily through the intestines (about 80% of the oral dose) and, to a lesser extent, through the kidneys (about 13% of the oral dose).
Elderly individuals
In healthy elderly volunteers (over 65 years), the clearance of sildenafil is reduced, and the concentration of free sildenafil in the plasma is approximately 40% higher than in healthy young volunteers (18-45 years). Age does not have a clinically significant effect on the frequency of adverse effects.
Renal insufficiency
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 ≤ 30 ml/min), the clearance of sildenafil is reduced, leading to approximately a twofold increase in AUC (100%) and Cmax (88%) compared to these parameters in patients with normal kidney function of the same age group.
Hepatic insufficiency
In patients with mild to moderate liver cirrhosis (Child-Pugh classes A and B), the clearance of sildenafil is reduced, resulting in an increase in AUC (84%) and Cmax (47%) compared to these parameters in patients with normal liver function of the same age group. The pharmacokinetics of sildenafil in patients with severe liver insufficiency (Child-Pugh class C) has not been studied.