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

Active ingredient

Composition

Active substance:

sildenafil (in the form of sildenafil citrate) 20 mg;

Auxiliary substances:

MCC – 62.632 mg;

calcium hydrophosphate – 20.878 mg;

Croscarmellose sodium – 6 mg;

Magnesium stearate – 2.4 mg;

Capsule film:

Opadry white II OY-LS-28914 (hypromellose, titanium dioxide, lactose monohydrate and triacetin) – 3 mg; Opadry clear YS-2-19114-A (hypromellose and triacetin) – 0.9 mg

How to take, the dosage

Ingestion. The recommended dose of Revacio® is 20 mg 3 times daily about 6-8 hours apart from meals. The maximum recommended dose is 60 mg.

With impaired renal function: No dose adjustment is necessary; however, if the drug is poorly tolerated, the dose is reduced to 20 mg 2 times daily.

Hepatic impairment: No dose adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), but the dose is reduced to 20 mg 2 times daily if the drug is poorly tolerated. In patients with severe hepatic impairment (greater than 9 points on the Child-Pugh scale) the use of the drug has not been studied (see “Contraindications”).

Elderly patients (≥65 years): No dose adjustment is required.

Children. The use of sildenafil in children under 18 years of age is not recommended (insufficient data on efficacy and safety).

The use in patients receiving concomitant therapy. Combined use of sildenafil and epoprostenol is discussed under “Pharmacodynamics” and “Side effects.

There have been no controlled studies to evaluate the efficacy and safety of sildenafil in combination with other drugs (bosentan, iloprost) for the treatment of pulmonary hypertension. Combined therapy with Revacio® with the above drugs should be performed with caution, the dose of sildenafil may need to be adjusted. However, there are no data on the need to increase the dose of sildenafil when used concomitantly with bozentan.

The efficacy and safety of Revacio® in combination with other FDE-5 inhibitors in patients with LAS has not been studied.

The concomitant use of sildenafil with strong CYP3A4 isoenzyme inhibitors (e.g., ketoconazole, itraconazole, ritonavir) is not recommended. However, if such combination is necessary, the dose of Revacio® should be reduced to 20 mg 2 times per day in patients who are already receiving such CYP3A4 isoenzyme inhibitors as erythromycin and saquinavir. If concomitant use with more potent CYP3A4 isoenzyme inducers, such as clarithromycin, telithromycin and nefazodone, the dose of Revacio® should be reduced to 20 mg once daily.

Interaction

The effect of other drugs on the pharmacokinetics of sildenafil

In vitro studies

The metabolism of sildenafil occurs mainly under the action of cytochrome P450 isoenzymes:CYP3A4 (major pathway) and CYP2C9 (minor pathway), so inhibitors of these isoenzymes can decrease sildenafil clearance and inducers can increase sildenafil clearance.

In vivo studies

In a study of healthy male volunteers, use of the endothelin antagonist bosentan, which is a moderate inducer of the CYP3A4, CYP2C9 and possibly CYP2C19 isoenzymes, in equilibrium (125 mg 2 times daily) resulted in decreased AUC and Cmax of sildenafil at equilibrium (80 mg 3 times daily) by 62.6 and 55.4%, respectively. Although co-administration of the two drugs was not accompanied by clinically significant changes in BP 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 twice daily), an HIV protease inhibitor and a potent CYP3A4 isoenzyme inhibitor, in combination with sildenafil (100 mg once) resulted in a 300% (4-fold) increase in Cmax of sildenafil and a 1000% (11-fold) increase in AUC. After 24 h, sildenafil plasma concentration was about 200 versus 5 ng/ml when administering sildenafil alone, which is consistent with the information about the pronounced effect of ritonavir on the pharmacokinetics of various cytochrome P450 substrates. Combined use of sildenafil with ritonavir is not recommended.

The co-administration of saquinavir (1200 mg 3 times daily), an HIV protease inhibitor and CYP3A4 isoenzyme, with sildenafil (100 mg once) increases Cmax sildenafil by 140% and AUC by 210% respectively. Sildenafil had no effect on the pharmacokinetics of saquinavir (see Administration and Dosage).

The strongest CYP3A4 isoenzyme inhibitors, such as ketoconazole and itraconazole, may have effects similar to those of ritonavir.

A single administration of sildenafil at a dose of 100 mg against therapy with erythromycin, which is a moderate inhibitor of CYP3A4 isoenzyme, in equilibrium (500 mg twice daily for 5 days) showed an increase of sildenafil AUC by 182% (see “Dosage and administration”).

CYP3A4 isoenzyme inhibitors such as clarithromycin, telithromycin and nefazodone have been suggested to have effects similar to those of ritonavir. CYP3A4 isoenzyme inhibitors such as saquinavir or erythromycin can increase AUC by 7 times. Therefore, the dose of CYP3A4 isoenzyme inhibitors should be adjusted when concomitant use with sildenafil (see “Dosage and administration”).

In healthy male volunteers, azithromycin (500 mg/day for 3 days) had no effect on AUC, Cmax, Tmax, elimination rate constant or T1/2 of sildenafil and its major circulating metabolite.

Cimetidine (800 mg), a cytochrome P450 inhibitor and nonspecific inhibitor of the CYP3A4 isoenzyme, caused a 56% increase in plasma concentrations of sildenafil (50 mg) in healthy volunteers.

Single administration of antacids (magnesium hydroxide and aluminum hydroxide) had no effect on the bioavailability of sildenafil.

The co-administration of oral contraceptives (ethinylestradiol 30 µg and levonorgestrel 150 µg) had no effect on the pharmacokinetics of sildenafil.

CYP3A4 isoenzyme inhibitors and β-adrenoblockers

The clearance of sildenafil in patients with LAS has been found to decrease by approximately 30% when used concomitantly with mild to moderate CYP3A4 isoenzyme inhibitors and by 34% when used concomitantly with β-adrenoblockers. AUC of sildenafil when administered in a dose of 80 mg 3 times daily was 5 times higher than when administered in a dose of 20 mg 3 times daily. In studies of interaction with CYP3A4 isoenzyme inhibitors, such as saquinavir and erythromycin (excluding the strongest CYP3A4 isoenzyme inhibitors, such as ketoconazole, itraconazole, ritonavir), sildenafil AUC increased in this concentration range.

CYP3A4 isoenzyme inducers

The clearance of sildenafil is increased approximately 3-fold when used concomitantly with weak CYP3A4 isoenzyme inducers, which is consistent with the effect of bosentan on sildenafil clearance in healthy volunteers. It is expected that concomitant use of sildenafil with potent inducers of CYP3A4 isoenzyme will lead to a significant reduction in plasma concentration of sildenafil. Concomitant use of sildenafil (at a dose of 20 mg 3 times daily) in adult patients with LAS and bosentan at a stable dose (62.5-125 mg 2 times daily) resulted in the same reduction in sildenafil exposure as in healthy volunteers.

The effect of sildenafil on the pharmacokinetics of other drugs

In vitro studies

. Sildenafil is a weak inhibitor of the CYP1A2, CYP2C9, CYP2C19, CYP2D6,CYP2E1 and CYP3A4 cytochrome P450 isoenzymes (IC50 ≥150 μmol). Sildenafil is not expected to affect compounds that are substrates of these isoenzymes at clinically relevant concentrations.

In vivo studies

Sildenafil has an effect on the NO/ZMF system and enhances the hypotensive effects of nitrates. Its co-administration with nitric oxide donators or nitrates in any form is contraindicated.

When the α-adrenoblocker doxazosin (4 and 8 mg) and sildenafil (25, 50, and 100 mg) were administered simultaneously to patients with benign prostatic hyperplasia, the additional reduction in BP/ BPH in the prone position was 7/7, 9/5, and 8/4 mmHg, and in the standing position was 6/6, 11/4, and 4/5 mmHg, respectively. When sildenafil was administered to patients receiving doxazosin, there were rare cases of orthostatic hypotension accompanied by dizziness but not syncope.

The use of sildenafil in patients taking α-adrenoblockers may lead to clinically significant arterial hypotension in patients with BP lability.

In a study of the interaction of sildenafil (100 mg) with amlodipine in patients with arterial hypertension, there was an additional decrease of 8 and 7 mmHg in BP and BP in the supine position, respectively. A similar BP reduction was observed with sildenafil alone in healthy volunteers.

There are no signs of interaction of sildenafil (50 mg) with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP2C9 isoenzyme.

Sildenafil (50 mg) did not cause an additional increase in bleeding time caused by acetylsalicylic acid as an antiaggregant (150 mg).

Sildenafil (50 mg) did not increase the hypotensive effects of ethanol in healthy volunteers atCmax blood ethanol 80 mg/dL.

In healthy volunteers, sildenafil at equilibrium (80 mg 3 times daily) caused a 49.8% and 42% increase in the AUC and Cmax of bosentan (125 mg 2 times daily), respectively.

Concomitant use of bosentan at an initial dose of 62.5-125 mg 2 times daily in adult patients with LAS and sildenafil at a dose of 20 mg 3 times daily showed a smaller increase in the AUC of bosentan compared with healthy volunteers receiving sildenafil at a dose of 80 mg 3 times daily.

Sildenafil in a single dose of 100 mg had no effect on the equilibrium pharmacokinetics of HIV protease inhibitors saquinavir and ritonavir, which are substrates of CYP3A4 isoenzyme.

Sildenafil had no clinically significant effect on plasma concentrations of oral contraceptives (ethinylestradiol 30 µg and levonorgestrel 150 µg).

Special Instructions

To avoid complications, use strictly as directed by the physician.

The efficacy and safety of Revacio® in patients with severe pulmonary hypertension (functional class IV) has not been proven. If the patient’s condition worsens during therapy with Revacio®, the possibility of switching to the therapy used for the treatment of this stage of pulmonary hypertension (e.g., epoprostenol) should be considered (see “Dosage and administration”). When co-administering Revacio® with bosentan or other CYP3A4 isoenzyme inducers, a dose adjustment may be required.

The benefit/risk ratio of sildenafil in patients with functional class I pulmonary hypertension has not been established. Studies on the use of sildenafil in the treatment of secondary pulmonary hypertension, with the exception of pulmonary hypertension associated with connective tissue disease and residual pulmonary hypertension, have not been performed.

Arterial hypotension

Sildenafil has a systemic vasodilatory effect leading to a slight transient decrease in BP. Before prescribing the drug, the risk of possible adverse events of vasodilatory effects in patients with hypotension (BP)

Because co-administration of Revacio® and α-adrenoblockers may result in symptomatic arterial hypotension in sensitive patients, Revacio® should be prescribed with caution in patients taking α-adrenoblockers. To minimize the risk of postural hypotension in patients taking α-adrenoblockers, Revacio® should be started only after hemodynamic stabilization has been achieved in these patients. The physician should inform patients what to do if symptoms of postural hypotension occur.

Cardiovascular Complications

In the post-marketing use of Revacio® for the treatment of erectile dysfunction, adverse events such as serious cardiovascular complications (including myocardial infarction) have been reported.including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) that were temporarily associated with sildenafil use. Most, but not all, of these patients had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some were noted after taking Revacio® without subsequent sexual activity. There is no direct correlation between the reported adverse events and these factors or other causes.

Sight impairment. There have been rare cases of anterior nonarteritic ischemic optic neuropathy as a cause of visual impairment or loss with all FDE-5 inhibitors, including Revacio®. Most of these patients had risk factors such as optic disc excavation (deepening), age over 50 years, diabetes mellitus, arterial hypertension, CHD, hyperlipidemia and smoking. In case of sudden loss of vision, patients should immediately stop taking Revacio® and seek medical attention.

Patients with a history of anterior nonarteritic ischemic optic neuropathy have an increased risk of developing this condition. Therefore, the physician should discuss possible risks with the patient when using FDEP-5 inhibitors. In these patients, Revacio® should be used with caution and after careful assessment of the benefit/risk ratio.

Hearing impairment

Some postmarketing and clinical studies have reported cases of sudden hearing impairment or loss associated with the use of all FDE-5 inhibitors, including Revacio®. Most of these patients had risk factors for sudden deterioration or hearing loss. A causal relationship between the use of FDE-5 inhibitors and sudden hearing impairment or hearing loss has not been established. Consult a physician immediately if there is sudden hearing impairment or hearing loss while taking Revacio®.

Bleeding

Revacio® increases the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on safety of Revacio® in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcer, therefore, Revacio® should be used with caution in these patients. The incidence of nasal bleeding in patients with LAH associated with diffuse connective tissue disease was higher (Revacio® – 12.9%, placebo – 0%) than in patients with primary LAH (sildenafil – 3%, placebo – 2.4%). Patients who received Revacio® in combination with a vitamin K antagonist had a higher rate of nasal bleeding (8.8%) than patients who did not take a vitamin K antagonist (1.7%).

Priapism

If an erection lasts longer than 4 hours, immediate medical attention should be sought. If immediate medical intervention is not performed, penile tissue damage and complete loss of potency may occur.

Concomitant use with bosentan

The use of Revacio® on initial therapy with bosentan showed no improvement in patients (assessment by 6-minute walk test) compared to use of bosentan monotherapy. The results of the 6-minute walk test differed between patients with primary LAS and LAS associated with systemic connective tissue diseases. Patients with LAS associated with systemic connective tissue disease had worse outcomes with concomitant use of Revacio® and bosentan than with bosentan monotherapy, but better than patients with primary LAS who received bosentan monotherapy. Thus, the physician should evaluate the treatment outcome of concomitant use of Revacio® and bosentan in patients with primary LAS based on his or her experience with LAS. Concomitant use of Revacio® and Bozentan in patients with LAS associated with systemic connective tissue disease is not recommended.

Concomitant use with other FDE-5 inhibitors

The efficacy and safety of concomitant use of Revacio® with other FDE-5 inhibitors, including Viagra.The efficacy and safety of concomitant use of Revacio® with other FDE-5 inhibitors, including Viagra®, in patients with LAS have not been studied, so this combination is not recommended.

Impact on the ability to drive vehicles and operate mechanisms.Revacio® slightly affects the ability to drive vehicles or other mechanisms. However, since the use of Revacio® may cause marked decrease in BP, dizziness, development of chromatopsia, blurred vision and other adverse events, the individual action of the drug in the above situations should be carefully considered, especially at the beginning of treatment and when changing the dosing regimen.

Contraindications

Side effects

Infections and invasions: often – inflammation of the subcutaneous tissue, influenza, unspecified sinusitis.

Blood and lymphatic system disorders: often – unspecified anemia.

Metabolism and nutrition: often – fluid retention (edema).

Mental disorders: often – insomnia, anxiety.

CNS disorders: very common – headache; common – tremor, paresthesia, unspecified burning sensation, hypoesthesia; frequency unknown – migraine.

An organ of vision: frequently – retinal hemorrhage, unspecified visual disturbances, blurred vision, photophobia, chromatopsia, cyanopsia, eye inflammation, red eyes; rarely – decreased visual acuity, diplopia, impaired eye sensitivity.

Hearing organ and labyrinth disorders: frequent – vertigo; frequency unknown – sudden deafness.

vascular disorders: very common – hyperemia (redness of the skin of the face); frequency unknown – decrease in BP.

Respiratory system, chest and mediastinum: often – unspecified bronchitis, nasal bleeding, unspecified rhinitis, cough, nasal congestion.

Gastrointestinal disorders: very common – diarrhea, dyspepsia; common – unspecified gastritis, unspecified gastroenteritis, gastroesophageal reflux disease, hemorrhoids, bloating, dry oral mucosa.

Skin and subcutaneous tissue: common – alopecia, erythema, increased sweating at night; frequency unknown – skin rash.

Musculoskeletal and connective tissue disorders: very often – pain in the extremities; often – myalgia, back pain.

Reproductive system and the mammary gland: often – gynecomastia, hemospermia; frequency unknown – priapism, prolonged erection.

General disorders and reactions at the site of administration: often – fever.

Overdose

Symptoms: headache, facial flushing, dizziness, dyspepsia, nasal congestion, visual disturbances.

Treatment: symptomatic. Hemodialysis is ineffective (sildenafil actively binds to plasma proteins).

Pregnancy use

In animal experiments, Revacio had no direct or indirect adverse effects on pregnancy, embryo/fetal development, labor, or postnatal development.

Because adequate controlled studies of sildenafil use in pregnant women have not been conducted, Revacio should only be used in pregnancy if the benefit to the mother outweighs the potential risk to the fetus.

It is not known whether sildenafil is excreted into the breast milk. Breast-feeding should be stopped if use of Revacio is necessary during lactation.

Similarities