Revacio, 20 mg 90 pcs.

Revacio has a vasodilatory effect.

Pharmacodynamics

Sildenafil is a potent selective inhibitor of cGMP-specific FDE-5. As FDE-5 responsible for cGMP decomposition is contained not only in corpora cavernosa of penis but also in pulmonary vessels, sildenafil, being an inhibitor of this enzyme, increases cGMP content in smooth muscle cells of pulmonary vessels and causes their relaxation. In patients with pulmonary hypertension, taking sildenafil causes dilation of pulmonary vessels and, to a lesser extent, of other vessels.

Sildenafil is selective against FDE-5 in vitro. Its activity against FDE-5 exceeds activity against other known FDE isoenzymes: FDE-6, involved in transmission of light signal in retina, – by 10 times; FDE-1 – 80 times; FDE-2, FDE-4, FDE-7 – FDE-11 – more than 700 times. The activity of sildenafil against FDE-5 is approximately 4,000 times greater than its activity against FDE-3, the cAMP-specific FDE involved in heart contraction.

Sildenafil causes a small and transient decrease in BP, which in most cases is not accompanied by clinical symptoms. After oral sildenafil at a dose of 100 mg, maximum reductions in BP and BP in the supine position averaged 8.3 and 5.3 mmHg, respectively. After sildenafil administration at a dose of 80 mg 3 times daily, healthy male volunteers showed maximal reductions in BP and BP in the supine position by an average of 9 and 8.4 mm Hg, respectively.

After taking sildenafil at a dose of 80 mg 3 times daily, patients with systemic arterial hypertension had an average decrease in BP and BPD of 9.4 and 9.1 mm Hg, respectively.

In patients with pulmonary hypertension receiving sildenafil at a dose of 80 mg 3 times daily, the decrease in BP was less pronounced: BP and BP decreased by 2 mm Hg.

On a single oral dose of up to 100 mg in healthy volunteers, sildenafil had no significant effect on ECG parameters. No clinically significant ECG changes were detected in patients with pulmonary hypertension when the drug was used in a dose of 80 mg 3 times daily.

In a study of the hemodynamic effects of sildenafil at a single oral dose of 100 mg in 14 patients with severe coronary atherosclerosis (stenosis of at least one coronary artery greater than 70%) the mean resting MAP and MAP decreased by 7 and 6% respectively compared to baseline. Systolic pulmonary artery pressure decreased by an average of 9%. Sildenafil had no effect on cardiac output and did not impair blood flow in stenosed coronary arteries.

In some patients, mild and transient impairment of color perception ability (blue/green) was detected 1 h after sildenafil administration at a dose of 100 mg using the Farnsworth-Mansell 100 test; 2 h after drug administration, these changes disappeared. The color vision impairment is thought to be caused by inhibition of FDE-6, which is involved in the transmission of light in the retina. Sildenafil has no effect on visual acuity, contrast perception, electroretinography data, IOP, or pupil diameter.

In patients with confirmed initial age-related macular degeneration, sildenafil at a single dose of 100 mg did not cause significant changes in visual function, particularly visual acuity as assessed by the Amsler grid, ability to distinguish traffic light colors as assessed by Humphrey perimetry, and transient visual disturbances as assessed by photostress.

Efficacy in adult patients with pulmonary hypertension. We examined the efficacy of sildenafil in 278 patients with primary pulmonary hypertension (63%) associated with diffuse connective tissue disease (30%) and pulmonary hypertension developed after surgical treatment of congenital heart disease (7%). Most patients had II (107; 39%) or III (160; 58%) functional class of pulmonary hypertension according to WHO classification, less frequently we detected I (1; 0.4%) or IV (9; 3%) functional classes. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 were not included in the study, as well as patients for whom bosentan therapy proved ineffective. Sildenafil in doses of 20, 40, or 80 mg was used along with standard therapy (control group patients received placebo). The primary endpoint was an increase in exercise tolerance by the 6-minute walk test 12 weeks after the start of treatment. In all three groups of patients who received sildenafil in different doses, it significantly increased compared to placebo. The increase in distance walked (placebo-adjusted) was 45, 46, and 50 m in patients receiving sildenafil in doses of 20, 40, and 80 mg, respectively. No significant differences were found between the sildenafil-treated groups.

A improvement in the results of the 6-minute walking test was observed after 4 weeks of therapy. This effect was maintained at 8 and 12 weeks of therapy. Mean therapeutic effect was consistently observed in 6-minute walk test results in all sildenafil groups compared to placebo in patient populations specifically selected for the following characteristics: demographics, geography and disease characteristics. Baseline parameters (walking test and hemodynamics) and effects were mostly similar in groups of patients with pulmonary hypertension of different WHO functional classes and different etiologies.

A statistically significant increase in the results of the 6-minute walk test was observed in the group of patients receiving 20 mg sildenafil. For patients with pulmonary hypertension of functional classes II and III the placebo-adjusted improvement in the 6-minute walk test was 49 and 45 m, respectively.

In patients receiving sildenafil at all doses, mean pulmonary artery pressure was significantly reduced compared with placebo. Adjusting for the placebo effect, the decrease in pulmonary artery pressure was 2.7, 3, and 5.1 mmHg in patients receiving sildenafil at doses of 20, 40, and 80 mg, respectively. There was no statistically significant difference between the effects of different doses of sildenafil. In addition, improvement was detected in the following indices: pulmonary vascular resistance, right atrial pressure, and cardiac output. Changes in HR and MAP were insignificant. The degree of pulmonary vascular resistance reduction exceeded the degree of peripheral vascular resistance reduction. Patients who received sildenafil showed a tendency to improve the clinical course of the disease, in particular, a decrease in the frequency of hospitalizations for pulmonary hypertension. Proportion of patients whose condition improved by at least one WHO functional class within 12 weeks was higher in sildenafil groups (28, 36 and 42% of patients who received sildenafil in doses of 20, 40 and 80 mg, respectively) than in placebo group (7%). In addition, sildenafil treatment compared with placebo resulted in improved quality of life, especially on measures of physical activity, and a tendency to improve the Borg dyspnea index. The percentage of patients who had to add another class of drug to standard therapy was higher in the placebo group (20%) than in the groups of patients receiving sildenafil at doses of 20 mg (13%), 40 mg (16%) and 80 mg (10%).

Long-term survival information. In an extended-release study, Revacio^® was found to improve survival in patients with pulmonary hypertension.

Efficacy in adult patients with pulmonary hypertension when coadministered with epoprostenol. The efficacy of sildenafil was studied in 267 patients with stable pulmonary hypertension on the background of IV administration of epoprostenol. Patients with primary pulmonary hypertension and pulmonary hypertension associated with diffuse connective tissue disease were included in the study.

Patients were randomized to placebo and sildenafil groups (with fixed titration, starting with a dose of 20, up to 40 and then 80 mg, 3 times daily) on combination therapy with intravenous epoprostenol administration. The primary endpoint was an increase in exercise tolerance by the 6-minute walk test at 16 weeks after treatment initiation. The increase in distance walked in the sildenafil group was 30.1 m versus 4.1 m in the placebo group. Average pulmonary artery pressure was significantly reduced by 3.9 mm Hg in patients taking sildenafil compared with the placebo group.

Clinical outcomes. Sildenafil therapy significantly increased the time to clinical deterioration of pulmonary hypertension compared with placebo. Kaplan-Meier estimated that patients receiving placebo had three times the risk of developing worsening. The time period before clinical deterioration was defined as the time from patients’ randomization to the first signs of deterioration (death, lung transplantation, initiation of bosentan therapy, or change of epoprostenol dose due to clinical deterioration). Twenty-three patients in the placebo group showed signs of clinical deterioration (17.6%), whereas 8 patients in the sildenafil group showed deterioration (6%). The proportion of patients with deterioration (Kaplan-Meier calculation, 95% confidence interval) was as follows: placebo, 0.187 (0.12-0.26); Revacio^®, 0.062 (0.002-0.1).

In patients with primary pulmonary hypertension, the mean deviation in the 6-minute walk test was noted: when used concomitantly with sildenafil, 26.39 m; when used with placebo, 11.84 m. In patients with pulmonary hypertension associated with systemic connective tissue diseases – 18.32 and 17.5 m, respectively.

The efficacy and safety of sildenafil in adult patients with pulmonary hypertension (when used concomitantly with bosentan). Overall, the side-effect profile in the two groups (concomitant use of sildenafil and bosentan and bosentan monotherapy) was similar and consistent with the side-effect profile of sildenafil.

Pharmacokinetics

Intake. Sildenafil is rapidly absorbed after oral administration. Absolute bioavailability is about 41% (25-63%). T_max of sildenafil in plasma is 30-120 min (on average 60 min) after oral intake on an empty stomach. After taking sildenafil 3 times daily in the dose range of 20 to 40 mg, the AUC and C_max increase in proportion to the dose. When taking sildenafil at a dose of 80 mg 3 times daily, its plasma concentrations increase nonlinearly. When concomitantly taken with fatty foods: T_max is increased by 60 min, and C_max is reduced by an average of 29%, but the degree of absorption is not significantly changed (AUC is reduced by 11%).

Distribution. V_ss of sildenafil averages 105L. After oral sildenafil at a dose of 20 mg 3 times daily, the C_max of sildenafil in the blood plasma in equilibrium is about 113 ng/ml. Binding of sildenafil and its main circulating N-demethyl metabolite with plasma proteins is about 96% and does not depend on the total concentration of sildenafil. Less than 0.0002% of the sildenafil dose (188 ng on average) was detected in the semen of healthy volunteers 90 min after drug administration.

Metabolism. Sildenafil is metabolized mainly in the liver by microsomal cytochrome P450 isoenzymes: CYP3A4 (main pathway) and CYP2C9 (minor pathway). The main circulating active metabolite is formed as a result of N-demethylation of sildenafil. Selectivity of this metabolite on FDE is comparable with that of sildenafil, and its activity against FDE-5 in vitro is about 50% of sildenafil activity. The concentration of this metabolite in blood plasma is about 40% of sildenafil concentration. N-demethyl metabolite undergoes further transformation; the final T_1/2 is about 4 h. In patients with pulmonary arterial hypertension (PAH), the ratio of concentrations of N-demethyl metabolite to sildenafil is higher. Plasma concentration of N-demethyl metabolite is about 72% of that of sildenafil (20 mg 3 times daily). The contribution of the metabolite to the pharmacological activity of sildenafil is 36%; its contribution to the clinical effect of the drug is unknown.

Elimination. The total clearance of sildenafil is 41 l/h, and the final T_1/2 is 3-5 h. After oral administration, sildenafil is excreted as metabolites, mainly through the intestine (about 80% of the dose) and, to a lesser extent, by the kidneys (about 13% of the dose).

Elderly patients. Elderly patients (65 years and older) have reduced sildenafil clearance and plasma concentrations of free sildenafil and its active N-demethyl metabolite are approximately 90% higher than those of younger patients (18-45 years). Since the binding of sildenafil to plasma proteins depends on the patient’s age, the plasma concentration of free sildenafil is about 40% higher in elderly patients.

Kidney function impairment. In mild to moderate renal impairment (C1 30-80 ml/min) the pharmacokinetics of sildenafil after a single oral dose of 50 mg is unchanged. In severe renal failure (creatinine Cl less than 30 ml/min) sildenafil clearance is decreased, resulting in AUC increase by 100% and C_max increase by 88% compared to values in normal renal function in patients of the same age group. In patients with severe renal impairment, the AUC and C_max of the N-demethyl metabolite are 200% and 79% higher, respectively, than in patients with normal renal function.

Hepatic impairment. In volunteers with mild to moderate hepatic dysfunction (Child-Pugh score 5-9), sildenafil clearance is decreased, resulting in higher AUC (85%) and C_max (47%) compared to those with normal hepatic function in patients of the same age group. Pharmacokinetics of sildenafil in patients with severe hepatic impairment (greater than 9 points on the Child-Pugh scale) have not been studied.

Population pharmacokinetics. When studying the pharmacokinetics of sildenafil in patients with LAS, the population pharmacokinetic model included age, sex, race, and renal and hepatic function scores. The data used for the population analysis included a wide range of demographic and laboratory parameters related to liver and renal function status. Demographic variables and liver or renal function parameters had no statistically significant effect on sildenafil pharmacokinetics in patients with LAS.

In patients with LAS, after taking sildenafil at doses of 20 to 80 mg 3 times daily, its meanC_ss was 20-50% higher than in healthy volunteers. The C_min of sildenafil in plasma was 2 times higher than in healthy volunteers. The findings indicate decreased clearance and/or increased bioavailability of sildenafil after oral administration in patients with LAS compared to healthy volunteers.

Indications

Pulmonary hypertension

Pharmacological effect

Sildenafil is a powerful selective inhibitor of cycloguanosine monophosphate (cGMP) – a specific phosphodiesterase-5 (PDE5). Since PDE5, which is responsible for the breakdown of cGMP, is found not only in the corpus cavernosum of the penis, but also in the vessels of the lungs, sildenafil, being an inhibitor of this enzyme, increases the content of cGMP in the smooth muscle cells of the pulmonary vessels and causes their relaxation. In patients with pulmonary hypertension (PH), taking sildenafil leads to vasodilation of the lungs and, to a lesser extent, other vessels.
Sildenafil is selective for PDE5 in vitro. Its activity against PDE5 is 10 times greater than that against other known phosphodiesterase isoenzymes: PDE6, which is involved in transmitting the light signal in the retina of the eye; PDE1 – 80 times; PDE2, PDE4, PDE7-PDE11 – more than 700 times. Sildenafil’s activity against PDE5 is more than 4,000 times greater than its activity against PDE3, a cAMP-specific phosphodiesterase involved in heart contraction.
Sildenafil causes a slight and transient decrease in blood pressure (BP), which in most cases is not accompanied by clinical symptoms. After taking sildenafil orally at a dose of 100 mg, the maximum decrease in systolic and diastolic blood pressure in the supine position averaged 8.3 mmHg. Art. and 5.3 mm Hg. Art., respectively. After taking sildenafil at a dose of 80 mg 3 times a day, healthy male volunteers showed a maximum decrease in systolic and diastolic blood pressure in the supine position by an average of 9.0 mm Hg. Art. and 8.4 mm Hg. Art., respectively.
After taking sildenafil at a dose of 80 mg 3 times a day in patients with systemic arterial hypertension, systolic and diastolic blood pressure decreased by an average of 9.4 mm Hg. Art. and 9.1 mm Hg. Art., respectively.
In patients with PH who received sildenafil at a dose of 80 mg 3 times a day, the decrease in blood pressure was less pronounced: systolic and diastolic blood pressure decreased by 2 mm Hg. Art.
When administered orally in single doses of up to 100 mg to healthy volunteers, sildenafil did not have a significant effect on electrocardiogram (ECG) parameters. When using the drug at a dose of 80 mg 3 times a day in patients with PH, clinically significant ECG changes were not detected.
When studying the hemodynamic effects of sildenafil with a single oral dose of 100 mg in 14 patients with severe coronary atherosclerosis (stenosis of at least one coronary artery more than 70%), mean systolic and diastolic blood pressure at rest decreased by 7% and 6%, respectively, compared with baseline. Systolic pressure in the pulmonary artery decreased by an average of 9%. Sildenafil did not affect cardiac output and did not impair blood flow in stenotic coronary arteries.
In some patients, 1 hour after taking sildenafil at a dose of 100 mg, a mild and transient impairment of color perception (blue/green) was detected using the Fansworth-Munsel 100 test; 2 hours after taking the drug, these changes disappeared. It is believed that color vision impairment is caused by inhibition of PDE6, which is involved in light transmission in the retina of the eye. Sildenafil has no effect on visual acuity, contrast perception, electroretinography data, intraocular pressure or pupil diameter.
In patients with confirmed early age-related macular degeneration, sildenafil at a single dose of 100 mg did not cause significant changes in visual functions, in particular, visual acuity assessed using the Amsler grating, the ability to distinguish between traffic light colors assessed by Humphrey perimetry, and transient visual impairment assessed using the photostress method.
Efficacy in adult patients with PH
The effectiveness of sildenafil was studied in 278 patients with primary PH (63%), PH associated with systemic connective tissue diseases (30%), and PH that developed after surgical treatment of congenital heart defects (7%).
The majority of patients had II (107; 39%) or III (160; 58%) functional class of PH according to the WHO (World Health Organization) classification; less often, functional classes I (1; 0.4%) or IV (9; 3%) were determined. Patients with a left ventricular ejection fraction of less than 45% or a left ventricular shortening fraction of less than 0.2 were not included in the study, as were patients for whom bosentan therapy was ineffective. Sildenafil in doses of 20 mg, 40 mg or 80 mg was used together with standard therapy (patients in the control group received placebo). The primary endpoint was improvement in exercise capacity as measured by the 6-minute walk test 12 weeks after initiation of treatment. In all three groups of patients receiving sildenafil in different doses, it significantly increased compared to placebo. Increases in distance walked (adjusted for placebo) were 45 m, 46 m and 50 m in patients receiving sildenafil doses of 20 mg, 40 mg and 80 mg, respectively. There were no significant differences between the groups of patients taking sildenafil.
Improvement in 6-minute walk test results was noted after 4 weeks of therapy. This effect persisted at 8 and 12 weeks of therapy. A mean treatment effect was consistently observed in the 6-minute walk test across all sildenafil groups compared with placebo in patient populations specifically selected for demographic, geographic, and disease characteristics. Baseline parameters (gait test and hemodynamics) and effects were generally similar in groups of patients with PH of different WHO functional classes and different etiologies.
A statistically significant increase in 6-minute walk test results was observed in the group of patients receiving 20 mg of sildenafil. For patients with functional classes II and III PH, placebo-adjusted improvements in 6-minute walk test scores were 49 meters and 45 meters, respectively.
In patients receiving sildenafil at all doses, mean pulmonary artery pressure was significantly reduced compared to placebo. In patients receiving sildenafil in doses of 20 mg, 40 mg and 80 mg, the decrease in pulmonary artery pressure, adjusted for the placebo effect, was 2.7 mmHg. Art., 3.0 mm Hg. Art. and 5.1 mm Hg. Art., respectively. In addition, improvements were observed in the following parameters: pulmonary vascular resistance, right atrial pressure and cardiac output. Changes in heart rate (HR) and systemic blood pressure were insignificant. The degree of decrease in pulmonary vascular resistance exceeded the degree of decrease in peripheral vascular resistance. In patients receiving sildenafil, a trend towards improvement in the clinical course of the disease was revealed, in particular a decrease in the frequency of hospitalizations for PH. The proportion of patients who improved by at least one WHO functional class over 12 weeks was higher in the sildenafil groups (28%, 36% and 42% of patients receiving sildenafil 20 mg, 40 mg and 80 mg, respectively) than in the placebo group (7%). In addition, treatment with sildenafil compared with placebo resulted in improved quality of life, especially in terms of physical activity, and a trend towards improvement in the Borg dyspnea index. The percentage of patients who had to add another drug class to standard therapy was higher in the placebo group (20%) than in the groups of patients receiving sildenafil in doses of 20 mg (13%), 40 mg (16%) and 80 mg (10%).
Long-term survival information
In an extension study, Revatio® was found to improve survival in patients with PH.
Efficacy in adult patients with PH when combined with epoprostenol The effectiveness of sildenafil was studied in 267 patients with stable PH treated with intravenous epoprostenol. The study included patients with primary PH and PH associated with systemic connective tissue diseases.
Patients were randomized to placebo or sildenafil (fixed titration starting at 20 mg, up to 40 mg and then 80 mg, three times daily) in combination therapy with intravenous epoprostenol. The primary endpoint was improvement in exercise capacity as measured by the 6-minute walk test 16 weeks after treatment. The increase in distance traveled in the sildenafil group was 30.1 m versus 4.1 m in the placebo group.
In patients taking sildenafil, the mean pulmonary artery pressure significantly decreased by 3.9 mmHg. Art. compared to the placebo group.
Clinical outcomes
Sildenafil treatment significantly increased the time to clinical worsening of PH compared with placebo. According to Kaplan-Meier estimates, patients receiving placebo had a threefold greater risk of deterioration (see Table 1). Time to clinical deterioration was defined as the time from patient randomization to the first sign of deterioration (death, lung transplantation, initiation of bosentan therapy, or epoprostenol dose change due to clinical deterioration). Twenty-three patients in the placebo group showed signs of clinical deterioration (17.6%), while in the sildenafil group, deterioration was observed in 8 patients (6.0%).
Table 1
Number of patients with signs of clinical deterioration n (%)
Placebo: 23 (17.6)
Revatio®: 8 (6.0)
Proportion of patients worsening (Kaplan-Meier calculation) 95% confidence interval
Placebo: 0.187 (0.12 – 0.26)
Revatio®: 0.062 (0.02 – 0.10)
In patients with primary PH, the average deviation in the 6-minute walk test was noted: when used simultaneously with sildenafil – 26.39 m, when used with placebo – 11.84 m. In patients with PH associated with systemic connective tissue diseases – 18.32 m and 17.50 m, respectively.
Efficacy and safety of sildenafil in adult patients with PH (when used simultaneously with bosentan)
In general, the side effect profile in the two groups (simultaneous use of sildenafil and bosentan and bosentan monotherapy) was the same and corresponded to the side effect profile of sildenafil.

Suction
Sildenafil is rapidly absorbed from the gastrointestinal tract after oral administration. Absolute bioavailability is about 41% (from 25% to 63%). The maximum concentration of sildenafil in blood plasma (Cmax) is achieved 30-120 minutes (on average 60 minutes) after oral administration on an empty stomach. After taking sildenafil 3 times a day in the dose range from 20 mg to 40 mg, the area under the concentration-time pharmacokinetic curve (AUC) and Cmax increase proportionally to the dose. When taking sildenafil at a dose of 80 mg 3 times a day, its concentration in the blood plasma increases nonlinearly. When taken simultaneously with food, the rate of absorption of sildenafil is reduced. When taken simultaneously with fatty foods: the time to reach maximum concentration (TCmax) increases by 60 minutes, and Cmax decreases by an average of 29%, but the degree of absorption does not change significantly (AUC decreases by 11%).
Distribution
The volume of distribution of sildenafil at steady state averages 105 liters. After oral administration of sildenafil at a dose of 20 mg 3 times a day, the maximum concentration of sildenafil in blood plasma at steady state is about 113 ng/ml. 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 sildenafil. 90 minutes after taking the drug, less than 0.0002% of the dose of sildenafil (on average 188 ng) was found in the sperm of healthy volunteers.
Metabolism
Sildenafil is metabolized mainly in the liver under the influence of microsomal cytochrome P450 isoenzymes: the CYP3A4 isoenzyme (major pathway) and the CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite is formed as a result of N-demethylation of sildenafil. 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 is about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further conversion; its final half-life (T1/2) is about 4 hours. In patients with pulmonary arterial hypertension (PAH), the concentration ratio of the N-demethyl metabolite to sildenafil is higher. The concentration of N-demethyl metabolite in blood plasma is about 72% of that of sildenafil (20 mg 3 times a day). The contribution of the metabolite to the pharmacological activity of sildenafil is 36%, its contribution to the clinical effect of the drug is unknown.
Removal
The total clearance of sildenafil is 41 l/h, and the terminal half-life is 3-5 hours. After oral administration, sildenafil is excreted in the form of metabolites, mainly through the intestines (about 80% of the dose) and, to a lesser extent, by the kidneys (about 13% of the dose).
Elderly patients
In elderly patients (65 years and older), the clearance of sildenafil is reduced, and the concentration of free sildenafil and its active N-demethyl metabolite in the blood plasma is approximately 90% higher than in younger patients (18-45 years). Since the binding of sildenafil to plasma proteins depends on the age of the patient, the concentration of free sildenafil in the blood plasma in elderly patients is approximately 40% higher.
Renal dysfunction
In mild to moderate renal failure (creatinine clearance (CC) 30-80 ml/min), the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (creatinine clearance less than 30 ml/min), the clearance of sildenafil is reduced, resulting in an increase in AUC by 100% and Cmax by 88% compared to values ​​with normal renal function in patients of the same age group. In patients with severe renal impairment, the AUC and Cmax of the N-demethyl metabolite are 200% and 79% higher, respectively, than in patients with normal renal function.
Liver dysfunction
In volunteers with mild to moderate hepatic impairment (Child-Pugh score 5 – 9), the clearance of sildenafil is reduced, resulting in an increase in AUC (85%) and Cmax (47%) compared to values ​​with normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severely impaired liver function (more than 9 points on the Child-Pugh scale) have not been studied.
Population pharmacokinetics
When studying the pharmacokinetics of sildenafil in patients with PAH, the population pharmacokinetic model included age, gender, race, and indicators of renal and liver function. The data used for the population-based analysis included a wide range of demographic and laboratory parameters associated with liver and kidney function. Demographics and liver or kidney function parameters did not have a statistically significant effect on the pharmacokinetics of sildenafil in patients with PAH.
In patients with PAH, after taking sildenafil in doses from 20 mg to 80 mg 3 times a day, its average steady-state concentrations were 20% – 50% higher than in healthy volunteers. The minimum concentration of sildenafil in blood plasma (Cmin) was 2 times higher than in healthy volunteers. The data obtained indicate a decrease in clearance and/or an increase in the bioavailability of sildenafil after oral administration in patients with PAH compared to healthy volunteers.

Special instructions

To avoid complications, use strictly as prescribed by your doctor!
The effectiveness and safety of Revatio in patients with severe pulmonary hypertension (functional class IV) has not been proven. If the patient’s condition worsens during therapy with Revatio, the possibility of switching to therapy used to treat this stage of pulmonary hypertension (for example, epoprostenol) should be considered (see section “Dosage and Administration”). When using Revatio together with bosentan or other inducers of the CYP3A4 isoenzyme, dose adjustment may be required.
The benefit/risk ratio of Revatio in patients with functional class I pulmonary hypertension has not been established. Studies on the use of Revatio in the treatment of secondary pulmonary hypertension, with the exception of pulmonary hypertension associated with connective tissue diseases and residual pulmonary hypertension, have not been conducted.
Arterial hypotension
Revatio has a systemic vasodilating effect, leading to a slight transient decrease in blood pressure. Before prescribing the drug, it is necessary to carefully assess the risk of possible undesirable manifestations of the vasodilating effect in patients with arterial hypotension (BP < 90/50 mm Hg at rest), hypovolemia, severe 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 Revatio and α-blockers may lead to the development of symptomatic arterial hypotension in sensitive patients, Revatio should be administered with caution to patients taking α-blockers. To minimize the risk of postural hypotension in patients taking α-blockers, start taking Revatio only after stabilization of hemodynamic parameters in these patients has been achieved. Physicians should inform patients about what actions to take if symptoms of postural hypotension occur.
Cardiovascular complications
During post-marketing use of Revatio 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, arterial hypertension and arterial hypotension) were reported, which were temporarily associated with the use 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 Revatio without subsequent sexual activity. It is not possible to establish a direct connection between the observed adverse events and the specified factors or other reasons.
Visual impairment
Rare cases of anterior non-arteritic ischemic optic neuropathy as a cause of deterioration or loss of vision have been reported with the use of all PDE5 inhibitors, including Revatio®. Most of these patients had risk factors such as optic disc excavation, age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. In the event of sudden loss of vision, patients should immediately stop taking Revatio® and seek medical help.
Patients who have previously had cases of anterior non-arteritic ischemic optic neuropathy have an increased risk of developing this disease. In this regard, the doctor should discuss with the patient the possible risks of using PDE5 inhibitors. In such patients, Revatio® should be used with caution and after a careful benefit-risk assessment.
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 Revatio®. Most of these patients had risk factors for 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. If there is a sudden deterioration in hearing or hearing loss while taking Revatio®, you should consult your doctor immediately.
Bleeding
Revatio® enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of using Revatio® in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers, so Revatio® should be used with caution in these patients. The incidence of epistaxis in patients with PAH associated with systemic connective tissue diseases was higher (Revacio® 12.9%, placebo 0%) than in patients with primary PAH (Revacio® 3.0%, placebo 2.4%). In patients receiving Revatio® in combination with a vitamin K antagonist, the incidence of nosebleeds was higher (8.8%) than in patients not taking a vitamin K antagonist (1.7%).
Priapism
If an erection lasts more than 4 hours, you should immediately seek medical help. If immediate medical intervention is not carried out, damage to the tissues of the penis and complete loss of potency are possible.
Concomitant use with bosentan
When using the drug Revatio® against the background of initial therapy with bosentan, there was no improvement in the condition of patients (assessed using the 6-minute walk test) compared with the use of bosentan monotherapy. The results of the 6-minute walk test differed between patients with primary PAH and PAH associated with systemic connective tissue diseases. In patients with PAH associated with systemic connective tissue diseases, the outcome of concomitant use of Revatio® and bosentan was worse than with bosentan monotherapy, but better than in patients with primary PAH receiving bosentan monotherapy. Thus, the physician should evaluate the outcome of therapy when using the drug Revatio® and bosentan simultaneously in patients with primary PAH, based on their experience in treating PAH. The simultaneous use of Revatio® and bosentan in patients with PAH associated with systemic connective tissue diseases is not recommended.

Active ingredient

Sildenafil

Composition

1 film-coated tablet contains:
Active ingredient: sildenafil citrate (equivalent to 20 mg sildenafil)
Excipients: microcrystalline cellulose 62.632 mg, calcium hydrogen phosphate 20.878 mg, croscarmellose sodium 6,000 mg, magnesium stearate 2,400 mg; film coating: opadry white II OY-LS-28914 (contains: hypromellose, titanium dioxide, lactose monohydrate and triacetin) 3,000 mg, opadry transparent YS-2-19114-A (contains: hypromellose and triacetin) 0,900 mg.

Pregnancy

In animal experiments, the drug did not have any direct or indirect adverse effects on the course of pregnancy and the development of the embryo/fetus. Animal studies have shown toxic effects on postnatal development. Since adequate controlled studies of the use of sildenafil in pregnant women have not been conducted, Revatio can be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus. Adequate controlled studies of the use of the drug in lactating women have not been conducted. According to limited data, sildenafil and its active metabolite passes into breast milk in small quantities. The amount of drug absorbed by the infant does not imply the development of adverse reactions. It is necessary to carefully evaluate the clinical need for prescribing Revatio to the mother and potential adverse reactions in the infant. If it is necessary to use the drug Revatio during lactation, breastfeeding should be discontinued.
Preclinical studies have not shown a negative effect of sildenafil on fertility.

Contraindications

Hypersensitivity to any component of the drug.
Veno-occlusive pulmonary disease.
Combined use with nitric oxide donors or nitrates in any form. Concomitant use with potent inhibitors of the CYP3A4 isoenzyme (including ketoconazole, itraconazole and ritonavir) (see section “Interaction with other drugs”).
Concomitant use of PDE5 inhibitors, including sildenafil, with antihypertensive drugs that stimulate guanylate cyclase, such as riociguat, as this may lead to symptomatic hypotension.
Loss of vision in one eye due to anterior non-arteritic ischemic optic neuropathy, hereditary degenerative diseases of the retina (retinitis pigmentosa).
Severe liver dysfunction (more than 9 points on the Child-Pugh scale).
History of stroke or myocardial infarction.
Severe arterial hypotension (systolic blood pressure less than 90 mm Hg, diastolic blood pressure less than 50 mm Hg).
Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.
Age under 18 years (effectiveness and safety studies have not been conducted).

Side Effects

Adverse events are classified according to the MedDRA classification system by organ system and frequency: very common (> 1/10), common (> 1/100, 1/1000, < 1/100), very rare (< 1/1000), frequency unknown (frequency cannot be determined based on available data).
Infections and infestations:
Common: inflammation of the subcutaneous tissue, influenza, unspecified sinusitis.
From the blood and lymphatic system:
Common: unspecified anemia.
Metabolism and nutrition:
Common: fluid retention (edema).
Mental disorders:
Common: insomnia, anxiety.
From the central nervous system:
Very common: headache.
Common: tremor, paresthesia, unspecified burning sensation, hypoesthesia.
Frequency unknown: migraine.
From the side of the organ of vision:

Common: retinal hemorrhage, unspecified visual disturbances, blurred vision, photophobia, chromatopsia, cyanopsia, eye inflammation, eye redness.
Rare: decreased visual acuity, diplopia, impaired eye sensitivity.
Hearing and labyrinthine disorders:
Common: vertigo.
Frequency unknown: sudden deafness.
Vascular disorders:
Very common: hyperemia (redness of the facial skin).
Frequency unknown: decreased blood pressure.
From the respiratory system, chest and mediastinum:
Common: unspecified bronchitis, nosebleeds, unspecified rhinitis, cough, nasal congestion.
From the gastrointestinal tract:
Very common: diarrhea, dyspepsia.
Common: unspecified gastritis, unspecified gastroenteritis, gastroesophageal reflux disease, hemorrhoids, bloating, dry oral mucosa. From the skin and subcutaneous tissues:
Common: alopecia, erythema, increased sweating at night.
Frequency unknown: skin rash.
From the musculoskeletal system and connective tissue:
Very common: pain in the limbs.
Common: myalgia, back pain.
From the reproductive system and mammary gland:
Common: gynecomastia, hemospermia.
Frequency unknown: priapism, prolonged erection. General disorders and administration site reactions: Common: fever.
The overall rate of discontinuation of treatment with Revatio at the recommended dose of 20 mg 3 times a day was low and did not differ from that in the placebo group (2.9%).
A placebo-controlled study examined the effect of adjuvant therapy with Revatio as an addition to intravenous epoprostenol. 134 patients with PAH received Revatio in daily doses of 20 mg to 80 mg 3 times a day and epoprostenol, and 131 patients received placebo and epoprostenol. The duration of treatment was 16 weeks. The overall rate of discontinuation due to adverse events in the sildenafil/epoprostenol group was 5.2% compared with 10.7% in the placebo/epoprostenol group.

Interaction

Interaction studies of sildenafil with other drugs were conducted in healthy volunteers, except where otherwise noted. These results are valid for other patient groups and administration methods.
The influence of other drugs on the pharmacokinetics of sildenafil
In vitro studies
The metabolism of sildenafil occurs mainly under the influence of cytochrome P450 isoenzymes: the CYP3A4 isoenzyme (major pathway) and the CYP2C9 isoenzyme (minor pathway), therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers can increase its clearance.
In vivo studies
In a study in healthy male volunteers, administration of the endothelin antagonist bosentan, which is a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19, at steady state (125 mg twice daily) resulted in a decrease in the AUC and Cmax of sildenafil at steady state (80 mg three times daily) by 62.6% and 55.4%, respectively. Although the combined use of the two drugs was not accompanied by clinically significant changes in blood pressure in the supine and standing positions and was well tolerated by healthy volunteers, sildenafil together with bosentan should be used with caution.
The use of ritonavir (500 mg 2 times a day), an HIV protease inhibitor and a strong inhibitor of the CYP3A4 isoenzyme, in combination with sildenafil (100 mg once) led to an increase in sildenafil Cmax by 300% (4 times) and AUC by 1000% (11 times). After 24 hours, the concentration of sildenafil in the blood plasma was about 200 ng/ml versus 5 ng/ml when sildenafil was administered alone, which is consistent with the information about the pronounced effect of ritonavir on the pharmacokinetics of various cytochrome P450 substrates. The combined use of sildenafil with ritonavir is not recommended.
Co-administration of saquinavir (1200 mg 3 times daily), an HIV protease inhibitor and CYP3A4 isoenzyme, with sildenafil (100 mg once) leads to an increase in sildenafil Cmax by 140% and AUC by 210%, respectively. Sildenafil had no effect on the pharmacokinetics of saquinavir (see section “Dosage and Administration”).
The most potent CYP3A4 inhibitors, such as ketoconazole and itraconazole, may have effects similar to those of ritonavir.
With a single dose of sildenafil in a dose of 100 mg during therapy with erythromycin, which is a moderate inhibitor of the CYP3A4 isoenzyme, at steady state (500 mg 2 times a day for 5 days), an increase in the AUC of sildenafil by 182% was detected (see section “Dosage and Administration”).
Inhibitors of the CYP3A4 isoenzyme such as clarithromycin, telithromycin and nefazodone may have an effect similar to that of ritonavir. Inhibitors of the CYP3A4 isoenzyme such as saquinavir or erythromycin can increase AUC by 7 times. In this regard, when used simultaneously with sildenafil, the dose of inhibitors of the CYP3A4 isoenzyme should be adjusted (see section “Dosage and Administration”).
In healthy male volunteers, azithromycin (500 mg/day for 3 days) had no effect on the AUC, Cmax, TCmax, elimination rate constant, or T1/2 of sildenafil and its main circulating metabolite.
Cimetidine (800 mg), an inhibitor of cytochrome P450 and a nonspecific inhibitor of the CYP3A4 isoenzyme, caused an increase in the concentrations of sildenafil (50 mg) in the blood plasma of healthy volunteers by 56%.
A single dose of antacids (magnesium hydroxide and aluminum hydroxide) had no effect on the bioavailability of sildenafil.
The combined use of oral contraceptives (ethinyl estradiol 30 mcg and levonorgestrel 150 mcg) did not affect the pharmacokinetics of sildenafil.
CYP3A4 isoenzyme inhibitors and β-blockers
It has been established that in patients with PAH, the clearance of sildenafil is reduced by approximately 30% when used simultaneously with weak or moderate inhibitors of the CYP3A4 isoenzyme and by 34% when used simultaneously with β-blockers. The AUC of sildenafil when administered at a dose of 80 mg three times a day was 5 times higher than when administered at a dose of 20 mg three times a day. In interaction studies with CYP3A4 inhibitors such as saquinavir and erythromycin (excluding the most potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir), the AUC of sildenafil increased in this concentration range.
Inducers of the isoenzyme CYP3A4
The clearance of sildenafil increases approximately threefold when administered concomitantly with weak inducers of the CYP3A4 isoenzyme, which is consistent with the effect of bosentan on the clearance of sildenafil in healthy volunteers. It is expected that simultaneous use of sildenafil with strong inducers of the CYP3A4 isoenzyme will lead to a significant decrease in the concentration of sildenafil in the blood plasma.
When sildenafil (at a dose of 20 mg three times daily) was used simultaneously in adult patients with PAH and bosentan at a stable dose (62.5 – 125 mg twice daily), the same reduction in sildenafil exposure was observed as when used in healthy volunteers.
Effect of sildenafil on the pharmacokinetics of other drugs
In vitro studies
Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 (IC50 >150 µM). Sildenafil is not expected to affect compounds that are substrates of these isoenzymes at clinically significant concentrations.
In vivo studies
Sildenafil acts on the NO/cGMP system and enhances the hypotensive effect of nitrates. Its combined use with nitric oxide donors or nitrates in any form is contraindicated.
With the simultaneous administration of the α-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) to patients with benign prostatic hyperplasia, an additional decrease in systolic/diastolic blood pressure in the supine position was 7/7, 9/5 and 8/4 mmHg. Art., and in a standing position – 6/6, 11/4 and 4/5 mm Hg. Art., respectively. When sildenafil is prescribed to patients receiving doxazosin, rare cases of orthostatic hypotension, accompanied by dizziness, but not fainting, have been reported.
The use of sildenafil in patients taking α-blockers may lead to clinically significant arterial hypotension in patients with blood pressure lability.
When studying the interaction of sildenafil (100 mg) with amlodipine in patients with arterial hypertension, an additional decrease in systolic and diastolic blood pressure in the supine position by 8 mm Hg was noted. Art. and 7 mm Hg. Art., respectively. A similar reduction in blood pressure was observed with the use of sildenafil alone in healthy volunteers.
There were no signs of interaction between sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the CYP2C9 isoenzyme.
Sildenafil (50 mg) did not cause an additional increase in bleeding time caused by acetylsalicylic acid (ASA) as an antiplatelet agent (150 mg).
Sildenafil (50 mg) did not enhance the hypotensive effect of ethanol in healthy volunteers at a maximum ethanol blood concentration of 80 mg/dl.
In healthy volunteers, sildenafil at steady state (80 mg 3 times daily) caused an increase in the AUC and Cmax of bosentan (125 mg 2 times daily) by 49.8% and 42%, respectively.
Co-administration of bosentan at a starting dose of 62.5 mg to 125 mg twice daily in adults with PAH and sildenafil 20 mg three times daily resulted in a smaller increase in bosentan AUC compared to healthy volunteers receiving sildenafil 80 mg three times daily.
Sildenafil in a single dose of 100 mg had no effect on the steady-state pharmacokinetics of the HIV protease inhibitors saquinavir and ritonavir, which are substrates of the CYP3A4 isoenzyme.
Sildenafil did not have a clinically significant effect on the plasma concentrations of oral contraceptives (ethinyl estradiol 30 mcg and levonorgestrel 150 mcg).

Overdose

Symptoms: headache, flushes of blood to the skin of the face, dizziness, dyspepsia, nasal congestion, visual impairment.
Treatment: symptomatic.
Hemodialysis is ineffective (sildenafil actively binds to plasma proteins).

Storage conditions

Store at a temperature not exceeding 30 °C.

Keep out of the reach of children.

Shelf life

5 years.

Do not use after the expiration date indicated on the package.

Manufacturer

Fareva Amboise, France