Sildenafil VERTEX

To diagnose erectile dysfunction, determine its possible causes and select adequate treatment, it is necessary to obtain a complete medical history and conduct a thorough physical examination. Treatments for erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie's disease) or in patients with risk factors for the development of priapism (sickle cell anemia, multiple myeloma, leukemia) (see section "With caution") .

During post-marketing studies, cases of prolonged erection and priapism have been reported. If an erection persists for more than 4 hours, you should immediately seek medical help. If treatment for priapism is not carried out immediately, it can lead to damage to the tissue of the penis and irreversible loss of potency.

Medicines intended to treat erectile dysfunction should not be used by men for whom sexual activity is undesirable.

Sexual activity poses a certain risk in the presence of cardiovascular disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for an examination of the state of the cardiovascular system. Sexual activity is not advisable in patients with heart failure, unstable angina, myocardial infarction or stroke in the past six months, life-threatening arrhythmias, hypertension (BP > 170/100 mm Hg) or hypotension (BP < 90/50 mm Hg. Art.) (see section “Contraindications”). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of cardiovascular mortality (0.3 per 100 people per year) in patients taking sildenafil compared with patients taking sildenafil. those receiving placebo.

Cardiovascular complications

During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe 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 temporary association with the use of sildenafil. Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events occurred shortly after sexual activity, and some of them occurred after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the observed adverse events and these or other factors.

Hypotension

Sildenafil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. However, before using sildenafil, the physician should carefully assess the risk of possible adverse effects of vasodilating effects in patients with relevant diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, manifested by severe dysregulation of blood pressure from the autonomic nervous system.

Since the combined use of sildenafil and alpha-blockers may lead to symptomatic hypotension in selected sensitive patients, sildenafil should be used with caution in patients taking alpha-blockers (see sections "Precautions" and "Interactions with other drugs"). To minimize the risk of postural hypotension in patients taking alpha-blockers, sildenafil should be started only after hemodynamic stability has been achieved in these patients. You should also consider the advisability of reducing the initial dose of sildenafil (see section "Dosage and Administration"). The physician should inform the patient what actions to take if symptoms of postural hypotension occur.

Visual impairment

In rare cases, non-arteritic anterior ischemic optic neuropathy (NAIAON), a rare disease and cause of vision loss or reduction, has been reported during post-marketing use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors, including decreased papilledema/disc ratio (“congestive disc”), age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study assessed whether recent use of the PDE5 inhibitor class of drugs was associated with acute onset of NPINSID. Results indicate an approximately two-fold increase in the risk of NPINSID within 5 half-lives of PDE5 inhibitor use. According to the published literature, the annual incidence of NPINSID is 2.2-11.8 cases per 100,000 men over the age of 50 years in the general population. In case of sudden loss of vision, patients should be advised to stop sildenafil therapy and consult a doctor immediately. Individuals who have already had a case of NPIND have an increased risk of recurrent NPIND. Therefore, the physician should discuss this risk with such patients, as well as discuss with them the potential for adverse effects from PDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the potential risk. In patients with episodes of NPINS with loss of vision in one eye, sildenafil is contraindicated (see section "Contraindications").

A small number of patients with hereditary retinitis pigmentosa have genetically determined dysfunction of retinal phosphodiesterases. There is no information on the safety of sildenafil in patients with retinitis pigmentosa, therefore the use of sildenafil in such patients is contraindicated (see section "Contraindications").

Hearing impairment

Some post-marketing and clinical studies have reported cases of sudden deterioration or loss of hearing associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for developing sudden deterioration or loss of hearing. A cause-and-effect relationship between the use of PDE5 inhibitors and sudden hearing loss or deterioration has not been established. The patient should be warned that in the event of sudden deterioration or sudden loss of hearing, discontinue sildenafil therapy and consult a physician immediately.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside (nitric oxide donor) on human platelets in vitro. There are no data on the safety of sildenafil in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers, so sildenafil should be used with caution in these patients (see section "With caution"). The incidence of epistaxis in patients with PH 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 %). Patients receiving sildenafil in combination with a vitamin K antagonist had a higher incidence of epistaxis (8.8%) than patients not taking a vitamin K antagonist (1.7%).

Use in conjunction with other means of treating erectile dysfunction

The safety and effectiveness of using sildenafil in combination with other drugs for the treatment of erectile dysfunction have not been studied, therefore the use of such combinations is not recommended (see section “Contraindications”).

Sildenafil

Sildenafil is a powerful selective inhibitor of cycloguanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Mechanism of action

The physiological mechanism of erection is associated with the release of nitric oxide (NO) 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 relaxant effect on the isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the breakdown of cGMP.

Sildenafil is selective for PDE5 in vitro, its activity against PDE5 exceeds that of other known phosphodiesterase isoenzymes: PDE6 - 10 times; PDE1 - more than 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to PDEZ, which is of utmost importance since PDEZ is one of the key enzymes in the regulation of myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

Clinical data

Cardiac research

The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum decrease in systolic pressure in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mmHg. Art., and diastolic pressure - 5.3 mm Hg. Art. A more pronounced, but also transient effect on blood pressure was observed in patients taking nitrates.

In a study of the hemodynamic effect of sildenafil at a single dose of 100 mg in 14 patients with severe coronary artery disease (more than 70% of patients had stenosis of at least one coronary artery), resting systolic and diastolic blood pressure decreased by 7% and 6%, accordingly, and pulmonary systolic pressure decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenotic coronary arteries, and also resulted in an increase (by approximately 13%) in adenosine-induced coronary flow in both stenotic and intact coronary arteries.

In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until their angina symptoms improved. The duration of the exercise was significantly longer (19.9 seconds; 0.9 - 38.9 seconds) in patients taking sildenafil in a single dose of 100 mg compared to patients receiving placebo.

A randomized, double-blind, placebo-controlled study examined the effect of varying the dose of sildenafil (up to 100 mg) in men (n = 568) with erectile dysfunction and hypertension taking more than two antihypertensive medications. Sildenafil improved erections in 71% of men compared to 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in individuals taking more than three antihypertensive drugs.

Visual impairment studies

In some patients, 1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Munsell 100 test revealed a mild and transient impairment in the ability to distinguish shades of color (blue/green). 2 hours after taking the drug, these changes were absent. Color vision impairment is thought to be caused by inhibition of PDE6, which is involved in light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, electro-retinogram, intraocular pressure or pupil diameter.

In a placebo-controlled crossover study of patients with proven early-onset macular degeneration (n = 9), sildenafil in a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision assessed by specific visual tests (visual acuity, Amsler grating, color perception, color transmission simulation, Humphrey perimeter, and photostress).

Efficiency

The efficacy and safety of sildenafil was assessed in 21 randomized, double-blind, placebo-controlled studies lasting up to 6 months in 3,000 patients aged 19 to 87 with erectile dysfunction of various etiologies (organic, psychogenic or mixed). The effectiveness of the drug was assessed globally using an erection diary, the International Index of Erectile Function (a validated questionnaire about the state of sexual function) and a partner interview.

The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all studies conducted and was confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportion of patients who reported that therapy improved their erections was: 62% (sildenafil 25 mg dose), 74% (sildenafil 50 mg dose), and 82% (sildenafil 100 mg dose) compared with 25%. in the placebo group. Analysis of the International Index of Erectile Function showed that in addition to improving erection, treatment with sildenafil also increased the quality of orgasm, achieved satisfaction from sexual intercourse and overall satisfaction.

According to the pooled data, among patients who reported improved erections with sildenafil treatment, 59% of patients with diabetes, 43% of patients who had undergone radical irostatectomy and 83% of patients with spinal cord injuries (versus 16%, 15% and 12% in the placebo group, respectively) ).

Pharmacokinetics

The pharmacokinetics of sildenafil in the recommended dose range is linear.

Suction

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (from 25% to 63%). In vitro, sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human PDE5 activity by 50%. After a single dose of sildenafil at a dose of 100 mg, the average Cmax of free sildenafil in the blood plasma of men is about 18 ng/ml (38 nM). Cmax when taking sildenafil orally on an empty stomach is achieved on average within 60 minutes (from 30 minutes to 120 minutes). When taken in combination with fatty foods, the rate of absorption decreases: Cmax decreases by an average of 29%, and TCmax increases by 60 minutes, but the degree of absorption does not significantly change (the area under the concentration-time pharmacokinetic curve (AUC) decreases by 11%).

Distribution

The volume of distribution of sildenafil at steady state averages 105 liters. The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in semen 90 minutes after dosing.

Metabolism

Sildenafil is metabolized mainly in the liver under the influence of the cytochrome isoenzyme CYP3A4 (major pathway) and the cytochrome isoenzyme CYP2C9 (minor pathway). The main circulating active metabolite, resulting from N-demethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism; T1/2 is about 4 hours.

Removal

The total clearance of sildenafil is 41 l/hour, and the final T1/2 is 3-5 hours. After oral administration, as after intravenous administration, sildenafil is excreted in the form of metabolites, mainly by the intestines (about 80% of the oral dose) and, to a lesser extent, by the kidneys (about 13% of the oral dose).

Pharmacokinetics in special groups of patients

Elderly patients

In healthy elderly patients (over 65 years of age), the clearance of sildenafil is reduced, and the concentration of free sildenafil in the blood plasma is approximately 40% higher than in young patients (18-45 years of age). Age does not have a clinically significant effect on the incidence of side effects.

Renal dysfunction

With mild (creatinine clearance (CL) 50-80 ml/min) and moderate (CL 30-49 ml/min) degrees of renal failure, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (creatinine clearance <30 ml/min), the clearance of sildenafil is reduced, leading to an approximately twofold increase in AUC (100%) and Cmax (88%) compared with those with normal renal function in patients of the same age group.

Liver dysfunction

In patients with liver cirrhosis (stages A and B according to the Child-Pyot classification), the clearance of sildenafil is reduced, which leads to an increase in AUC (84%) and Cmax (47%) compared to those with normal liver function in patients of the same age groups. The pharmacokinetics of sildenafil in patients with severe liver dysfunction (stage C according to the Child-Pyot classification) has not been studied.

Sildenafil Vertex, 1 piece, 25 mg, film-coated tablets

Sildenafil is a powerful selective inhibitor of cGMP-specific PDE-5. Mechanism of action The physiological mechanism of erection is associated with the release of nitric oxide (NO) 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 relaxant effect on the isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the breakdown of cGMP.

Sildenafil is selective against PDE-5 in vitro, its activity against PDE-5 exceeds that against other known PDE isoenzymes: PDE-6 - 10 times; PDE-1 - more than 80 times; PDE-2, PDE-4, PDE-7 - PDE-11 - more than 700 times. Sildenafil is 4000 times more selective for PDE-5 compared to PDE-3, which is of utmost importance since PDE-3 is one of the key enzymes in the regulation of myocardial contractility. A prerequisite for the effectiveness of sildenafil is sexual stimulation. Clinical data Cardiac studies. The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum reduction in SBP in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mmHg, and DBP was 5.3 mmHg. A more pronounced, but also transient effect on blood pressure was observed in patients taking nitrates. In a study of the hemodynamic effect of sildenafil at a single dose of 100 mg in 14 patients with severe coronary artery disease (more than 70% of patients had stenosis of at least one coronary artery), resting SBP and DBP decreased by 7 and 6%, respectively, and pulmonary SBP decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenotic coronary arteries, and also led to an increase (by approximately 13%) in adenosine-induced coronary flow in both stenotic and intact coronary arteries.

In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until their angina symptoms improved. The duration of the exercise was significantly longer (19.9 s; 0.9–38.9 s) in patients taking sildenafil in a single dose of 100 mg compared to patients receiving placebo.

A randomized, double-blind, placebo-controlled study examined the effect of varying the dose of sildenafil (up to 100 mg) in men (n=568) with erectile dysfunction and hypertension taking more than two antihypertensive medications. Sildenafil improved erections in 71% of men compared to 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in individuals taking more than three antihypertensive drugs.

Studies of visual impairments. In some patients, 1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Mansel 100 test revealed a mild and transient impairment in the ability to distinguish shades of color (blue/green). 2 hours after taking the drug, these changes were absent. Color vision impairment is thought to be caused by inhibition of PDE6, which is involved in light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, IOP, or pupil diameter.

In a placebo-controlled crossover study of patients with proven early-onset macular degeneration (n=9), sildenafil in a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision assessed by specific visual tests (visual acuity, Amsler grating, color perception, color transmission simulation, Hamuri perimeter and photostress).

Efficacy The effectiveness and safety of sildenafil were assessed in 21 randomized, double-blind, placebo-controlled studies lasting up to 6 months in 3,000 patients aged 19 to 87 years with erectile dysfunction of various etiologies (organic, psychogenic or mixed). The effectiveness of the drug was assessed globally using an erection diary, the International Index of Erectile Function (a validated questionnaire about the state of sexual function) and a partner interview.

The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all studies conducted and confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportions of patients who reported that therapy improved their erections were: 62% (25 mg sildenafil dose), 74% (50 mg sildenafil dose), and 82% (100 mg sildenafil dose) versus 25 % in the placebo group). Analysis of the International Index of Erectile Function showed that in addition to improving erection, treatment with sildenafil also increased the quality of orgasm, achieved satisfaction from sexual intercourse and overall satisfaction.

According to the pooled data, among patients who reported improved erections with sildenafil treatment were 59% of patients with diabetes, 43% of patients who had undergone radical prostatectomy, and 83% of patients with spinal cord injuries (versus 16, 15, and 12% in the placebo group, respectively).

Pharmacokinetics The pharmacokinetics of sildenafil in the recommended dose range is linear. Absorption After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (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 sildenafil in a dose of 100 mg, the average Cmax of free sildenafil in the blood plasma of men is about 18 ng/ml (38 nM) and is achieved when sildenafil is taken orally on an empty stomach for an average of 60 minutes (from 30 to 120 minutes). When taken in combination with fatty foods, the rate of absorption decreases: Cmax decreases by an average of 29%, and Tmax increases by 60 minutes, but the degree of absorption does not change significantly (AUC decreases by 11%).

The Vss distribution of sildenafil averages 105 L. The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in semen 90 minutes after taking the drug.

Metabolism Sildenafil is metabolized mainly in the liver under the influence of the cytochrome CYP3A4 isoenzyme (major pathway) and the cytochrome CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite, resulting from N-demethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity against PDE-5 in vitro is about 50% of the activity of sildenafil.

The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism; T1/2 is about 4 hours.

Excretion The total clearance of sildenafil is 41 l/h, and the final T1/2 is 3–5 hours. After oral administration, as well as after intravenous administration, sildenafil is excreted in the form of metabolites, mainly by the intestines (about 80% of the oral dose) and to a lesser extent - by the kidneys (about 13% of the oral dose).

Pharmacokinetics in special groups of patients Elderly patients. In healthy elderly patients (over 65 years of age), the clearance of sildenafil is reduced, and the concentration of free sildenafil in the blood plasma is approximately 40% higher than in young patients (18–45 years of age). Age does not have a clinically significant effect on the incidence of side effects.

Renal dysfunction. With mild (Cl creatinine - 50-80 ml/min) and moderate (Cl creatinine - 30-49 ml/min) degree of renal failure, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (Cl creatinine ≤30 ml/min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared with those with normal renal function in patients of the same age group .

Liver dysfunction. In patients with liver cirrhosis (stages A and B according to the Child-Pugh classification), the clearance of sildenafil is reduced, which leads to an increase in AUC (84%) and Cmax (47%) compared with those with normal liver function in patients of the same age groups. The pharmacokinetics of sildenafil in patients with severe liver dysfunction (Child-Pugh stage C) has not been studied.

Sildenafil Vertex tablet p/o film 100mg 1 piece

Pharmacological group:

Erectile dysfunction is treated with a PDE5 inhibitor.
Pharmacodynamics:
Sildenafil is a powerful selective inhibitor of cycloguanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Restores impaired erectile function by increasing blood flow to the penis.

When the NO/cGMP bond is activated, which occurs under the influence of sexual stimuli, suppression of PDE5 by sildenafil leads to an increase in cGMP in the corpus cavernosum. Thus, sexual stimulation is necessary for the development of the desired pharmacological action of sildenafil.

Sildenafil is selective for PDE5 in vitro, its activity against PDE5 is superior to that against other known phosphodiesterase isoenzymes:

PDE6 - 10 times; PDE1 - more than 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to PDE3, which is of utmost importance since PDE3 is one of the key enzymes in the regulation of myocardial contractility.

Sildenafil causes a slight and transient decrease in blood pressure (BP), which in most cases has no clinical manifestations. The average maximum decrease in systolic blood pressure in the supine position after taking sildenafil orally at a dose of 100 mg is 8.3 mm Hg. Art. The corresponding change in diastolic blood pressure is 5.3 mmHg. Art. A single oral dose of sildenafil 100 mg was not accompanied by clinically significant changes in the electrocardiogram (ECG) in healthy volunteers. Sildenafil has no effect on cardiac output and does not alter blood flow through stenotic arteries. A more pronounced, but also transient effect on blood pressure was observed in patients taking nitrates.

In some patients, 1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Munsell 100 test revealed a mild and transient impairment in the ability to distinguish shades of color (blue/green). 2 hours after taking the drug, these changes were absent. Color vision impairment is thought to be caused by inhibition of PDE6, which is involved in light transmission in the retina. Sildenafil has no effect on visual acuity, contrast perception, electroretinogram, intraocular pressure or pupil diameter.

Pharmacokinetics:

The pharmacokinetics of sildenafil in the recommended dose range is linear.

Suction

Sildenafil is rapidly absorbed after oral administration. Absolute bioavailability averages about 40% (from 25% to 63%). In vitro, sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human PDE5 activity by 50%. After a single dose of sildenafil 100 mg, the average maximum plasma concentration of free sildenafil (Cmax) in men is about 18 ng/ml (38 nM). Cmax when taking sildenafil orally on an empty stomach is achieved on average within 60 minutes (from 30 minutes to 120 minutes). When taken in combination with fatty foods, the rate of absorption decreases: Cmax decreases by an average of 29%, and the time to reach maximum concentration (Tmax) increases by 60 minutes, but the degree of absorption does not significantly change (the area under the concentration-time pharmacokinetic curve (AUC) decreases by 11%).

Distribution

The volume of distribution of sildenafil at steady state averages 105 liters.

The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in semen 90 minutes after dosing.

Metabolism

Sildenafil is metabolized mainly in the liver under the influence of the cytochrome isoenzyme CYP3A4 (main route) and the cytochrome isoenzyme CYP2C9 (additional route). The main circulating active metabolite, resulting from N-demethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism; its half-life (T1/2) is about 4 hours.

Removal

The total clearance of sildenafil is 41 l/hour, and the final T1/2 is 3-5 hours. After oral administration, sildenafil is excreted in the form of metabolites, mainly by the intestines (about 80% of the dose) and to a lesser extent by the kidneys (about 13% of the dose).

Pharmacokinetics in special groups of patients

Elderly patients

Patients with impaired renal function

Patients with liver dysfunction

In patients with liver cirrhosis (stages A and B according to the Child-Pugh classification), the clearance of sildenafil is reduced, which leads to an increase in AUC (84%) and Cmax (47%) compared with those with normal liver function in patients of the same age groups. The pharmacokinetics of sildenafil in patients with severe liver dysfunction (Child-Pugh stage C) has not been studied.