Sildenafil (Tablets) Instructions for Use

ATC Code

C02KX (Antihypertensive agents for the treatment of pulmonary arterial hypertension)

Active Substance

Sildenafil

Clinical-Pharmacological Group

Phosphodiesterase-5 inhibitor. A drug for the treatment of pulmonary hypertension

Pharmacotherapeutic Group

Vasodilating agent

Pharmacological Action

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase-5 (PDE5). Since PDE5, which is responsible for the breakdown of cGMP, is present not only in the corpus cavernosum of the penis but also in the pulmonary vessels, Sildenafil, as an inhibitor of this enzyme, increases the cGMP content in the smooth muscle cells of the pulmonary vessels and causes their relaxation. In patients with pulmonary hypertension (PH), sildenafil administration leads to the dilation of pulmonary vessels and, to a lesser extent, other vessels.

Sildenafil is selective for PDE5 in vitro. Its activity against PDE5 exceeds its activity against other known phosphodiesterase isoenzymes: it is 10 times more active than PDE6, which is involved in phototransduction in the retina; 80 times more active than PDE1; and more than 700 times more active than PDE2, PDE4, PDE7-PDE11. The activity of sildenafil against PDE5 is more than 4000 times greater than its activity against PDE3, a cAMP-specific phosphodiesterase involved in cardiac contraction.

Sildenafil causes a slight and transient decrease in blood pressure, which in most cases is not accompanied by clinical symptoms. After a single oral dose of 100 mg sildenafil, the maximum reduction in supine systolic and diastolic blood pressure averaged 8.3 mm Hg and 5.3 mm Hg, respectively. After administration of sildenafil 80 mg three times a day in healthy male volunteers, the maximum reduction in supine systolic and diastolic blood pressure averaged 9.0 mm Hg and 8.4 mm Hg, respectively.

After administration of sildenafil 80 mg three times a day in patients with systemic arterial hypertension, systolic and diastolic blood pressure decreased by an average of 9.4 mm Hg and 9.1 mm Hg, respectively.

In patients with PH receiving Sildenafil 80 mg three times a day, the reduction in blood pressure was less pronounced: systolic and diastolic blood pressure decreased by 2 mm Hg.

After a single oral dose of up to 100 mg in healthy volunteers, Sildenafil did not have a significant effect on ECG parameters. When the drug was used at a dose of 80 mg three times a day in patients with PH, clinically significant ECG changes were not detected.

In a study of the hemodynamic effects of sildenafil after a single oral dose of 100 mg in 14 patients with severe coronary atherosclerosis (stenosis of at least one coronary artery greater than 70%), mean resting systolic and diastolic blood pressure decreased by 7% and 6%, respectively, compared to baseline. Systolic pulmonary artery pressure decreased by an average of 9%. Sildenafil did not affect cardiac output and did not impair blood flow in stenosed coronary arteries.

In some patients, 1 hour after taking sildenafil 100 mg, a mild and transient impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100 test; these changes disappeared 2 hours after taking the drug. The visual color disturbance is thought to be caused by inhibition of PDE6, which is involved in the phototransduction process in the retina. Sildenafil does not affect visual acuity, contrast perception, electroretinography data, intraocular pressure, or pupil diameter.

In patients with confirmed early age-related macular degeneration, a single dose of Sildenafil 100 mg did not cause significant changes in visual function, in particular, visual acuity assessed using the Amsler grid, the ability to distinguish traffic light colors assessed by Humphrey perimetry, and transient visual function impairments assessed by the photostress test method.

Efficacy in adult patients with PH

The efficacy of sildenafil was studied in 278 patients with primary PH (63%), PH associated with systemic connective tissue diseases (30%), and PH developing after surgical treatment of congenital heart defects (7%). Most patients had WHO functional class II (107; 39%) or III (160; 58%) PH, while functional class I (1; 0.4%) or IV (9; 3%) were less common. Patients with a left ventricular ejection fraction of less than 45% or a left ventricular fractional shortening of less than 0.2 were not included in the study, as were patients for whom bosentan therapy was ineffective. Sildenafil at doses of 20 mg, 40 mg, or 80 mg was used along with standard therapy (patients in the control group received placebo). The primary endpoint was an increase in exercise tolerance according to the 6-minute walk test after 12 weeks of treatment. In all three groups of patients receiving Sildenafil at different doses, it increased significantly compared to placebo. The increase in distance walked (placebo-adjusted) was 45 m, 46 m, and 50 m in patients receiving Sildenafil at doses of 20 mg, 40 mg, and 80 mg, respectively. No significant differences were found between the groups of patients taking Sildenafil.

Improvement in the 6-minute walk test results was noted after 4 weeks of therapy. This effect persisted at weeks 8 and 12 of therapy. The average therapeutic effect was consistently observed in the 6-minute walk test results in all sildenafil groups compared to placebo in patient populations specifically selected based on the following characteristics: demographic, geographic, and disease characteristics. Baseline parameters (walk test and hemodynamics) and effects were generally similar across patient groups with different WHO functional classes and different etiologies of PH.

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

In patients receiving Sildenafil at all doses, mean pulmonary artery pressure significantly decreased compared to placebo. In patients receiving Sildenafil at doses of 20 mg, 40 mg, and 80 mg, the placebo-adjusted reduction in pulmonary artery pressure was: 2.7 mm Hg, 3.0 mm Hg, and 5.1 mm Hg, respectively. In addition, improvements in the following parameters were detected: pulmonary vascular resistance, right atrial pressure, and cardiac output. Changes in heart rate and systemic blood pressure were insignificant. The degree of reduction in pulmonary vascular resistance exceeded the degree of reduction in peripheral vascular resistance. In patients receiving Sildenafil, a trend towards improvement in the clinical course of the disease was revealed, in particular, a reduction in the frequency of hospitalizations for PH. The proportion of patients whose condition improved by at least one WHO functional class over 12 weeks in the sildenafil groups was higher (28%, 36%, and 42% of patients receiving Sildenafil at doses of 20 mg, 40 mg, and 80 mg, respectively) than in the placebo group (7%). Furthermore, treatment with sildenafil compared to placebo led to an improvement in quality of life, especially in terms of physical activity and a trend towards improvement in the Borg dyspnea index. The percentage of patients who required the addition of a drug from another class 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%).

Information on long-term survival

In an extended study, it was found that Sildenafil increases the survival of patients with PH.

Efficacy in adult patients with PH when used concomitantly with epoprostenol

The efficacy of sildenafil was studied in 267 patients with stable PH on background intravenous epoprostenol. The study included patients with primary PH and PH associated with systemic connective tissue diseases.

Patients were randomized to placebo and sildenafil groups (with fixed dose titration, starting from a dose of 20 mg, to 40 mg and then 80 mg, three times a day) during combination therapy with intravenous epoprostenol. The primary endpoint was an increase in exercise tolerance according to the 6-minute walk test after 16 weeks of treatment. The increase in distance walked in the sildenafil group was 30.1 m compared to 4.1 m in the placebo group. In patients taking Sildenafil, mean pulmonary artery pressure significantly decreased by 3.9 mm Hg compared to the placebo group.

Clinical outcomes

Sildenafil therapy significantly increased the time to clinical worsening of PH compared to placebo. According to the Kaplan-Meier estimate, patients receiving placebo had a 3 times higher risk of worsening (the proportion of patients with worsening in the placebo group was 0.187 (0.12-0.26), and in the sildenafil treatment group – 0.062 (0.02-0.10), 95% confidence interval). The time to clinical worsening was defined as the time from patient randomization to the first signs of worsening (death, lung transplantation, initiation of bosentan therapy, or change in epoprostenol dose due to clinical worsening). Clinical worsening was noted in 23 patients from the placebo group (17.6%), while in the sildenafil group, worsening was noted in 8 patients (6%).

In patients with primary PH, the mean deviation in the 6-minute walk test was: with concomitant use of sildenafil – 26.39 m, with placebo – 11.84 m. In patients with PH associated with systemic connective tissue diseases – 18.32 m and 17.5 m, respectively.

Efficacy and safety of sildenafil use in adult patients with PH (with concomitant use of bosentan)

Overall, the adverse event profile in the two groups (concomitant use of sildenafil and bosentan and bosentan monotherapy) was similar and corresponded to the adverse event profile for sildenafil use.

Pharmacokinetics

Absorption

Sildenafil is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is about 41% (range 25% to 63%). The C_max of sildenafil in plasma is reached within 30-120 minutes (on average, 60 minutes) after oral administration on an empty stomach. After administration of sildenafil three times a day in the dose range from 20 mg to 40 mg, AUC and C_max increase proportionally to the dose. When sildenafil is taken at a dose of 80 mg three times a day, its plasma concentration increases non-linearly. Concurrent food intake reduces the rate of absorption of sildenafil. When taken with a high-fat meal, the time to reach maximum concentration (T_max) increases by 60 minutes, and C_max decreases by an average of 29%, but the extent of absorption does not change significantly (AUC decreases by 11%).

Distribution

The V_d of sildenafil at steady state averages 105 L. After oral administration of sildenafil 20 mg three times a day, the C_max of sildenafil in plasma at steady state is about 113 ng/mL. The binding of sildenafil and its main circulating N-desmethyl metabolite to plasma proteins is about 96% and is independent of the total sildenafil concentration. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in the semen of healthy volunteers 90 minutes after drug administration.

Metabolism

Sildenafil is metabolized primarily in the liver by microsomal cytochrome P450 isoenzymes: isoenzyme CYP3A4 (major pathway) and isoenzyme CYP2C9 (minor pathway). The main circulating active metabolite is formed by N-desmethylation 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 plasma concentration of the metabolite is about 40% of the sildenafil concentration. The N-desmethyl metabolite undergoes further conversion; its terminal T_1/2 is about 4 hours. In patients with pulmonary arterial hypertension (PAH), the ratio of the concentrations of the N-desmethyl metabolite and sildenafil is higher. The plasma concentration of the N-desmethyl metabolite is about 72% of that of sildenafil (20 mg three times a day). The metabolite’s contribution to the pharmacological activity of sildenafil is 36%; its contribution to the clinical effect of the drug is unknown.

Excretion

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

Pharmacokinetics in special patient groups

Elderly patients

In elderly patients (65 years and older), the clearance of sildenafil is reduced, and the plasma concentrations of free sildenafil and its active N-desmethyl metabolite are approximately 90% higher than in younger patients (18-45 years). Since the binding of sildenafil to plasma proteins is age-dependent, the plasma concentration of free sildenafil in elderly patients is approximately 40% higher.

Renal impairment

In mild to moderate renal impairment (creatinine clearance 30-80 mL/min), the pharmacokinetics of sildenafil after a single oral dose of 50 mg are not altered. In severe renal impairment (creatinine clearance less than 30 mL/min), the clearance of sildenafil is decreased, leading to an increase in AUC by 100% and C_max by 88% compared to patients with normal renal function of the same age group. In patients with severe renal impairment, the AUC and C_max of the N-desmethyl metabolite are 200% and 79% higher, respectively, than in patients with normal renal function.

Hepatic impairment

In volunteers with mild or moderate hepatic impairment (5-9 points on the Child-Pugh scale), the clearance of sildenafil is decreased, leading to an increase in AUC (85%) and C_max (47%) compared to patients with normal hepatic function of the same age group. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale) have not been studied.

Population pharmacokinetics

In a study of the pharmacokinetics of sildenafil in patients with PAH, age, sex, race, and indicators of renal and hepatic function were included in the population pharmacokinetic model. The data used for the population analysis included a wide range of demographic and laboratory parameters related to hepatic and renal function. Demographic indicators, as well as parameters of hepatic or renal function, did not have a statistically significant effect on the pharmacokinetics of sildenafil in patients with PAH.

In patients with PAH after administration of sildenafil in doses from 20 mg to 80 mg three times a day, its mean C_ss was 20-50% higher than in healthy volunteers. The C_min of sildenafil in plasma was 2 times higher than in healthy volunteers. These data indicate a decrease in clearance and/or an increase in the oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.

Indications

• Pulmonary hypertension.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally, regardless of meals.

20 mg three times a day at intervals of approximately 6-8 hours. The maximum recommended dose is 60 mg.

In elderly patients (≥65 years), dose adjustment is not required.

In renal impairment, dose adjustment is not required; however, if the drug is poorly tolerated, the dose should be reduced to 20 mg twice a day.

Dose adjustment in patients with mild to moderate hepatic impairment (Child-Pugh classes A and B) is not required; however, if the drug is poorly tolerated, the dose should be reduced to 20 mg twice a day. The use of the drug in patients with severe hepatic impairment (Child-Pugh class C) has not been studied.

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

Use in patients receiving concomitant therapy

Concomitant use of sildenafil and epoprostenol is discussed in the “Pharmacological Action” and “Adverse Reactions” sections.

Controlled studies evaluating the efficacy and safety of sildenafil in combination with other drugs (bosentan, iloprost) for the treatment of pulmonary hypertension have not been conducted. Combination therapy with the drug Sildenafil Cardio with the specified drugs should be carried out with caution; dose adjustment of sildenafil may be required. However, there are no data on the need to increase the dose of sildenafil when used concomitantly with bosentan.

The efficacy and safety of the drug Sildenafil Cardio in combination with other PDE5 inhibitors in patients with pulmonary arterial hypertension have not been studied.

Concomitant use of sildenafil with potent inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole, ritonavir) is not recommended. However, if such a combination is necessary, the dose of the drug Sildenafil Cardio should be reduced to 20 mg twice a day in patients already receiving such CYP3A4 isoenzyme inhibitors as erythromycin and saquinavir. If concomitant use with more potent inducers of the CYP3A4 isoenzyme, such as clarithromycin, telithromycin, and nefazodone, is necessary, the dose of the drug Sildenafil Cardio should be reduced to 20 mg once a day.

Adverse Reactions

The overall rate of discontinuation of treatment with sildenafil at the recommended dose of 20 mg three 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 sildenafil as an addition to intravenous epoprostenol. 134 patients with PAH received Sildenafil in daily doses from 20 mg to 80 mg three times a day and epoprostenol, and 131 patients received placebo and epoprostenol. The duration of treatment was 16 weeks. The overall rate of therapy discontinuation due to adverse events in the Sildenafil/epoprostenol group was 5.2% compared to 10.7% in the placebo/epoprostenol group.

Adverse reactions are classified according to the MedDRA system by organ system and frequency: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (<1/1000), frequency not known (frequency cannot be estimated from the available data).

Contraindications

• Hypersensitivity to sildenafil or to any of the excipients of the drug;
• Pulmonary veno-occlusive disease;
• Concomitant use with nitric oxide donors or nitrates in any form;
• Concomitant use with potent inhibitors of the CYP3A4 isoenzyme (including ketoconazole, itraconazole and ritonavir);
• Concomitant use with antihypertensive agents – guanylate cyclase stimulators, such as riociguat (as this may lead to symptomatic arterial hypotension);
• Vision loss in one eye due to non-arteritic anterior ischemic optic neuropathy;
• Hereditary degenerative retinal diseases (retinitis pigmentosa);
• Severe hepatic impairment (Child-Pugh class C);
• History of stroke or myocardial infarction;
• Severe arterial hypotension (systolic BP less than 90 mm Hg, diastolic BP less than 50 mm Hg);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
• Age under 18 years (studies of efficacy and safety have not been conducted).

With caution

• Functional Class I or IV PAH (efficacy and safety not established);
• Anatomical deformation of the penis (angulation, cavernosal fibrosis or Peyronie’s disease) and diseases predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia);
• Diseases accompanied by bleeding, or exacerbation of gastric and duodenal ulcer;
• Heart failure, unstable angina, life-threatening arrhythmias, arterial hypertension (BP >170/100 mm Hg), left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), the rare syndrome of multiple system atrophy, manifested by severe impairment of BP regulation by the autonomic nervous system, hypovolemia;
• History of non-arteritic anterior ischemic optic neuropathy;
• Concomitant use with moderate inhibitors of the CYP3A4 isoenzyme (including erythromycin, saquinavir, clarithromycin, telithromycin and nefazodone) and alpha-blockers;
• Concomitant use with inducers of the CYP3A4 isoenzyme.

Use in Pregnancy and Lactation

Pregnancy

In animal experiments, the drug did not have 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 on the use of sildenafil in pregnant women have not been conducted, Sildenafil Cardio can be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

Adequate controlled studies on the use of the drug in lactating women have not been conducted. According to limited data, Sildenafil and its active metabolite penetrate into breast milk in insignificant amounts. The amount of the drug absorbed by the infant is not expected to cause adverse reactions. The clinical need for prescribing Sildenafil Cardio to the mother and potential adverse reactions in the infant should be carefully assessed. If it is necessary to use Sildenafil Cardio during lactation, breastfeeding should be discontinued.

Fertility

Preclinical studies have not shown a negative effect of sildenafil on fertility.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment (more than 9 points on the Child-Pugh scale).

Dose adjustment in patients with mild or moderate hepatic impairment (5-9 points on the Child-Pugh scale) is not required, however, if the drug is poorly tolerated, the dose should be reduced.

Use in Renal Impairment

In case of renal impairment, dose adjustment is not required, however, if the drug is poorly tolerated, the dose should be reduced.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years (studies of efficacy and safety have not been conducted).

Geriatric Use

In elderly patients (≥65 years), dose adjustment is not required.

Special Precautions

To avoid complications, the drug should be used strictly as prescribed by a doctor.

The efficacy and safety of Sildenafil Cardio in patients with severe pulmonary hypertension (functional class IV) has not been proven. In case of deterioration of the patient’s condition during therapy with Sildenafil Cardio, the possibility of switching to therapy used for the treatment of this stage of pulmonary hypertension (for example, with epoprostenol) should be considered. When Sildenafil Cardio is used concomitantly with bosentan or other inducers of the CYP3A4 isoenzyme, dose adjustment may be required.

The benefit/risk ratio of Sildenafil Cardio in patients with functional class I pulmonary hypertension has not been established. Studies on the use of Sildenafil Cardio in the treatment of secondary pulmonary hypertension, except for pulmonary hypertension associated with connective tissue diseases and residual pulmonary hypertension, have not been conducted.

Arterial hypotension

Sildenafil Cardio has a systemic vasodilating effect, leading to a small transient decrease in BP. 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 left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, manifested by severe impairment of BP regulation by the autonomic nervous system. Since the concomitant use of Sildenafil Cardio and alpha-blockers can lead to the development of symptomatic arterial hypotension in sensitive patients, Sildenafil Cardio should be prescribed with caution to patients taking alpha-blockers. To minimize the risk of postural hypotension in patients taking alpha-blockers, Sildenafil Cardio should be started only after hemodynamic parameters have stabilized in these patients. The physician should inform patients about what actions to take in case of symptoms of postural hypotension.

Cardiovascular complications

During post-marketing use of Sildenafil Cardio 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) have been reported, which had a temporal relationship with the use of sildenafil. Most of these patients, but not all, had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some were noted after taking Sildenafil Cardio without subsequent sexual activity. It is not possible to establish the presence of a direct connection between the noted adverse events and the indicated factors or other reasons.

Visual disturbances

Rare cases of development of non-arteritic anterior ischemic optic neuropathy as a cause of deterioration or loss of vision during the use of all PDE5 inhibitors, including Sildenafil Cardio, have been noted. Most of these patients had risk factors such as optic disc cupping, age over 50 years, diabetes mellitus, arterial hypertension, coronary artery disease, hyperlipidemia and smoking. In case of sudden vision loss, patients should immediately stop taking Sildenafil Cardio and seek medical help.

In patients who have previously had cases of non-arteritic anterior ischemic optic neuropathy, there is an increased risk of developing this disease. In this regard, the physician should discuss the possible risks with the patient when using PDE5 inhibitors. In such patients, Sildenafil Cardio should be used with caution and after careful assessment of the benefit-risk ratio.

Hearing impairment

Some post-marketing and clinical studies have reported cases of sudden hearing deterioration or loss associated with the use of all PDE5 inhibitors, including Sildenafil Cardio. Most of these patients had risk factors for sudden hearing deterioration or loss. A causal relationship between the use of PDE5 inhibitors and sudden hearing deterioration or hearing loss has not been established. In case of sudden hearing deterioration or hearing loss while taking Sildenafil Cardio, you should immediately consult a doctor.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of Sildenafil Cardio in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers, therefore Sildenafil Cardio should be used with caution in these patients. The frequency of nosebleeds in patients with PAH associated with systemic connective tissue diseases was higher than in patients with primary PAH. In patients receiving Sildenafil Cardio in combination with a vitamin K antagonist, the frequency of nosebleeds was higher than in patients not taking a vitamin K antagonist.

Priapism

If an erection lasts more than 4 hours, you should immediately seek medical help. If immediate medical intervention is not performed, damage to the penile tissues and complete loss of potency are possible.

Concomitant use with bosentan

When Sildenafil Cardio was used against the background of initial bosentan therapy, no improvement in the patients’ condition (assessment using the 6-minute walk test) was noted compared with bosentan monotherapy. The results of the 6-minute walk test differed in patients with primary PAH and PAH associated with systemic connective tissue diseases. In patients with PAH associated with systemic connective tissue diseases, the result of concomitant use of Sildenafil Cardio 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 result of therapy with concomitant use of Sildenafil Cardio and bosentan in patients with primary PAH, based on his experience in the therapy of PAH. Concomitant use of Sildenafil Cardio and bosentan in patients with PAH associated with systemic connective tissue diseases is not recommended.

Concomitant use with other PDE5 inhibitors

The efficacy and safety of concomitant use of Sildenafil Cardio with other PDE5 inhibitors, including the drug Viagra^®, in patients with PAH have not been studied, therefore the use of such a combination is not recommended.

Effect on ability to drive vehicles and mechanisms

Sildenafil Cardio has a slight effect on the ability to drive vehicles or other mechanisms. However, since a pronounced decrease in BP, dizziness, development of chromatopsia, blurred vision and other adverse reactions are possible when taking Sildenafil Cardio, one should be attentive to the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosage regimen.

Overdose

Symptoms with a single dose of sildenafil in doses up to 800 mg, adverse reactions were similar to those at lower doses, but the frequency and severity increased. When sildenafil was taken in single doses of 200 mg, the frequency of adverse reactions (headache, flushing (redness of the facial skin), dizziness, dyspepsia, nasal congestion and visual disturbances) was increased.

Treatment is symptomatic. Hemodialysis is ineffective because Sildenafil is tightly bound to blood plasma proteins and is not excreted by the kidneys.

Drug Interactions

Studies of the interaction of sildenafil with other drugs were conducted in healthy volunteers, except where indicated separately. These results are valid for other patient groups and methods of administration.

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: isoenzyme CYP3A4 (main pathway) and isoenzyme CYP2C9 (minor pathway), therefore inhibitors of these isoenzymes may reduce the clearance of sildenafil, and inducers may increase its clearance.

In vivo studies

In a study in healthy male volunteers, the use of the endothelin antagonist bosentan, which is a moderate inducer of the CYP3A4, CYP2C9 and possibly CYP2C19 isoenzymes, at steady state (125 mg 2 times/day) led to a decrease in the AUC and C_max of sildenafil at steady state (80 mg 3 times/day) by 62.6% and 55.4%, respectively. Although the concomitant use 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 should be used with caution in combination with bosentan.

The use of ritonavir (500 mg 2 times/day), an HIV protease inhibitor and a potent inhibitor of the CYP3A4 isoenzyme, in combination with sildenafil (100 mg single dose) led to an increase in the C_max of sildenafil by 300% (4 times) and AUC by 1000% (11 times). After 24 hours, the concentration of sildenafil in blood plasma was about 200 ng/ml compared to 5 ng/ml when only sildenafil was prescribed, which is consistent with information about the pronounced effect of ritonavir on the pharmacokinetics of various cytochrome P450 substrates. Concomitant use of Sildenafil Cardio with ritonavir is contraindicated.

Concomitant use of saquinavir (1200 mg 3 times/day), an HIV protease inhibitor and an inhibitor of the CYP3A4 isoenzyme, with sildenafil (100 mg single dose) leads to an increase in the C_max of sildenafil by 140% and AUC by 210%, respectively. Sildenafil did not affect the pharmacokinetics of saquinavir.

The most potent inhibitors of the CYP3A4 isoenzyme, such as ketoconazole and itraconazole, may have an effect similar to that of ritonavir. With a single dose of sildenafil 100 mg against the background of therapy with erythromycin, which is a moderate inhibitor of the CYP3A4 isoenzyme, at steady state (500 mg 2 times/day for 5 days), an increase in the AUC of sildenafil by 182% was revealed.

Such inhibitors of the CYP3A4 isoenzyme as clarithromycin, telithromycin and nefazodone are presumed to have an effect similar to that of ritonavir. Such inhibitors of the CYP3A4 isoenzyme as saquinavir or erythromycin may increase the AUC by 7 times. In this regard, when used concomitantly with sildenafil, the dose of inhibitors of the CYP3A4 isoenzyme should be adjusted.

In healthy male volunteers, azithromycin (500 mg/day for 3 days) did not affect the AUC, C_max, T_max, elimination rate constant or T_1/2 of sildenafil and its main circulating metabolite.

Cimetidine (800 mg), an inhibitor of cytochrome P450 and a non-specific inhibitor of the CYP3A4 isoenzyme, caused an increase in the plasma concentrations of sildenafil (50 mg) in healthy volunteers by 56%. A single dose of antacids (magnesium hydroxide and aluminum hydroxide) did not affect the bioavailability of sildenafil.

Concomitant use of oral contraceptives (ethinylestradiol 30 mcg and levonorgestrel 150 mcg) did not affect the pharmacokinetics of sildenafil.

Inhibitors of the CYP3A4 isoenzyme and beta-blockers

It has been established that in patients with PAH, the clearance of sildenafil decreases by approximately 30% when used concomitantly with weak or moderate inhibitors of the CYP3A4 isoenzyme and by 34% when used concomitantly with beta-blockers. The AUC of sildenafil when used at a dose of 80 mg 3 times/day was 5 times higher than when the drug was prescribed at a dose of 20 mg 3 times/day. In interaction studies with inhibitors of the CYP3A4 isoenzyme, such as saquinavir and erythromycin (excluding the most potent inhibitors of the CYP3A4 isoenzyme, such as ketoconazole, itraconazole, ritonavir), the AUC of sildenafil in this concentration range increased.

Inducers of the CYP3A4 isoenzyme

The clearance of sildenafil increases approximately 3 times when used concomitantly with weak inducers of the CYP3A4 isoenzyme, which corresponds to the effect of bosentan on the clearance of sildenafil in healthy volunteers. Concomitant use of sildenafil with potent inducers of the CYP3A4 isoenzyme is expected to lead to a significant decrease in the plasma concentration of sildenafil.

When sildenafil (at a dose of 20 mg 3 times/day) was used concomitantly in adult patients with PAH and bosentan at a stable dose (62.5-125 mg 2 times/day), the same decrease in sildenafil exposure was observed as when used in healthy volunteers.

Concomitant use of sildenafil and epoprostenol leads to a decrease in mean pulmonary artery pressure.

Concomitant use of sildenafil with iloprost for the treatment of pulmonary hypertension has not been conducted, therefore therapy with Sildenafil Cardio should be carried out with caution, and dose adjustment of sildenafil may be required.

When sildenafil was used concomitantly with ambrisentan, a slight increase in the C_max of sildenafil in plasma was observed, which is not considered clinically significant.

Concomitant use of sildenafil with other PDE5 inhibitors in patients with pulmonary arterial hypertension has not been studied, therefore the use of such a combination is not recommended.

Concomitant use of sildenafil with potent CYP3A4 inducers (carbamazepine, phenytoin, phenobarbital, preparations of St. John’s wort, rifampicin) may lead to a significant decrease in the plasma concentration of sildenafil.

Grapefruit juice, a weak inhibitor of CYP3A4, may moderately increase the plasma concentrations of sildenafil.

Concomitant use of sildenafil with nicorandil is contraindicated, as it may lead to a sharp decrease in BP.

Effect of sildenafil on the pharmacokinetics of other drugs

In vitro studies

Sildenafil is a weak inhibitor of the 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 affects the NO/cGMP system and enhances the hypotensive effect of nitrates. Its concomitant use with nitric oxide donors or nitrates in any form is contraindicated.

When the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were co-administered to patients with benign prostatic hyperplasia, the additional reduction in supine systolic/diastolic blood pressure was 7/7, 9/5, and 8/4 mmHg, respectively, and in the standing position – 6/6, 11/4, and 4/5 mmHg, respectively. Rare cases of orthostatic hypotension accompanied by dizziness, but not fainting, were observed when sildenafil was administered to patients receiving doxazosin.

The use of sildenafil in patients taking alpha-blockers may lead to clinically significant arterial hypotension in patients with labile blood pressure.

In a study of the interaction between sildenafil (100 mg) and amlodipine in patients with arterial hypertension, an additional reduction in supine systolic and diastolic blood pressure of 8 mmHg and 7 mmHg, respectively, was noted. A similar reduction in blood pressure was observed with sildenafil alone in healthy volunteers.

No signs of interaction were found 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 additional prolongation of bleeding time induced 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 blood ethanol concentration of 80 mg/dL.

In healthy volunteers, sildenafil at steady state (80 mg three times/day) caused an increase in the AUC and C_max of bosentan (125 mg twice/day) by 49.8% and 42%, respectively.

When bosentan at an initial dose of 62.5-125 mg twice/day was co-administered to adult patients with PAH and sildenafil at a dose of 20 mg three times/day, a smaller increase in the AUC of bosentan was observed compared to healthy volunteers receiving sildenafil at a dose of 80 mg three times/day.

A single 100 mg dose of sildenafil did not affect the steady-state pharmacokinetics of the HIV protease inhibitors saquinavir and ritonavir, which are substrates of the CYP3A4 isoenzyme.

Sildenafil had no clinically significant effect on the plasma concentration of oral contraceptives (ethinylestradiol 30 mcg and levonorgestrel 150 mcg).

Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated, as riociguat enhances the hypotensive effect of PDE5 inhibitors.

Concomitant use of sildenafil and non-specific PDE inhibitors (theophylline and dipyridamole) is contraindicated.

Concomitant use with acenocoumarol may lead to an increased risk of bleeding.

The combination of atorvastatin and sildenafil for the treatment of pulmonary hypertension has significant therapeutic advantages. Concomitant use with atorvastatin reduces hypoxia-induced pulmonary hypertension. The effect on vascular remodeling and right ventricular hypertrophy is greater with the combination of medications than with monotherapy.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.