Sildenafil - instructions for use, dose, side effects, contraindications

film sheath: [hypromellose; talc; titanium dioxide; macrogol 4000 (polyethylene glycol 4000)] or [dry film coating mixture containing hypromellose, talc, titanium dioxide, macrogol 4000 (polyethylene glycol 4000)].

Description:

Round biconvex tablets covered with a film coat of white or almost white color. On the cross section, the nucleus is white or almost white in color.

Pharmacotherapeutic group:Vasodilator

ATX: & nbsp

G.04.B.E Drugs for the treatment of erectile dysfunction

G.04.B.E.03 Sildenafil

Pharmacodynamics:

Sildenafil is a potent selective inhibitor of cyclic guanosine monophosphate (cGMP) - a specific phosphodiesterase type 5 (PDE5). Since PDE5, responsible for the disintegration of cGMP, is contained not only in the cavernous body of the penis, but also in the vessels of the lungs, 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 (LH), the use of sildenafil leads to an expansion of the lung vessels and, to a lesser extent, other vessels.

Sildenafil is selective for PDE5 in vitro. Its activity against PDE5 is higher than that of other known isoenzymes of phosphodiesterase: PDE6, which participates in transmission of a light signal in the retina of the eye - 10 times; FDE1 - 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. The activity of sildenafil with respect to PDE5 is more than 4000 times greater than its activity with respect to FDEZ, cAMP-specific phosphodiesterase, involved in myocardial contraction.

Sildenafil causes a small and transient decrease in blood pressure (BP), which in most cases is not accompanied by clinical symptoms. After taking sildenafil inside at a dose of 100 mg, the maximum decrease in systolic and the diastolic blood pressure in the prone position averaged 8.3 mm Hg. Art. and 5.3 mm Hg. Art. respectively. After taking sildenafil in a dose of 80 mg 3 times a day in healthy male volunteers, the maximum decrease in systolic and diastolic blood pressure in the prone position was 9.0 mm Hg on average. Art. and 8.4 mm Hg. Art. respectively.

After taking sildenafil in 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 in 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.

With a single oral intake in doses up to 100 mg by healthy volunteers sildenafil did not significantly affect the parameters of the electrocardiogram (ECG). When using sildenafil in a dose of 80 mg 3 times a day in patients with PH, clinically significant changes in the ECG were not detected.

In the study of hemodynamic effects of sildenafil with a single oral intake at a dose of 100 mg in 14 patients with severe coronary atherosclerosis (stenosis, at least,one coronary artery more than 70%), the average systolic and diastolic blood pressure at rest decreased by 7% and 6%, respectively, compared with the baseline level. Systolic pressure in the pulmonary artery was reduced by an average of 9%. Sildenafil did not affect cardiac output and did not worsen blood flow in the stenotic coronary arteries.

In some patients, 1 hour after taking 100 mg of sildenafil, the Funsworth-Munssel 100 test revealed a mild and transient impairment of the color perception (blue / green); 2 hours after taking sildenafil, these changes disappeared. It is believed that the violation of color vision is caused by the inhibition of PDE6, which participates in the process of light transmission in the retina of the eye. Sildenafil does not affect visual acuity, contrast perception, electroretinography data, intraocular pressure or pupil diameter.

In patients with confirmed initial macular degeneration sildenafil with a single admission in a dose of 100 mg did not cause significant changes in visual functions, in particular, visual acuity assessed by the Amsler lattice, the ability to distinguish the colors of a traffic light,estimated by the Humphrey perimetry method, 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 LH (63%), LH associated with systemic connective tissue diseases (30%), and LH, which developed after the surgical treatment of congenital heart disease (7%). The majority of patients had II (107; 39%) or III (160.58%) functional class of PH according to the classification of the World Health Organization (WHO), less frequently I (1; 0.4%) or IV (9.3%) functional classes. Patients with left ventricular ejection fraction less than 45 % or a fraction of a shortening of the left ventricle size of less than 0.2 in the study was not included, as well as patients for whom bosentan therapy proved to be ineffective. Sildenafil in doses of 20 mg, 40 mg or 80 mg were used together with standard therapy (control group patients received a placebo). The primary endpoint was an increase in exercise tolerance for the 6-minute walk test at 12 weeks after initiation of treatment. In all three groups of patients who received sildenafil in different doses, it significantly increased in comparison with placebo. The increase in the distance covered (adjusted for placebo) was 45 m, 46 m and 50 m in patients who received sildenafil in doses of 20 mg, 40 mg and 80 mg respectively. Significant differences between the groups of patients who took sildenafil, not found. Improvement in the test results of a 6-minute walk was noted after 4 weeks of therapy. This effect persisted at the 8th and 12th weeks of therapy. The average therapeutic effect was consistently observed in the results of a 6-minute walk test in all sildenafil groups compared to placebo in populations of patients selected for demographic, geographical and disease characteristics. The basic parameters (walking test and hemodynamics) and effects were mainly similar in groups of patients with PH of different WHO functional classes and various etiologies.

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

In patients who received sildenafil in all doses, the mean pressure in the pulmonary artery was significantly lower compared with placebo. In patients who received sildenafil in doses of 20 mg, 40 mg and 80 mg, a reduction in pulmonary artery pressure adjusted for the placebo effect was: 2.7 mm Hg. article, 3.0 mm Hg. Art. and 5.1 mm Hg. Art. respectively. In addition, the following indicators were found to improve: pulmonary vascular resistance, right atrial pressure and cardiac output. Changes in heart rate and systemic BP were insignificant. The degree of decrease in the resistance of pulmonary vessels was superior to the degree of decrease in peripheral vascular resistance. In patients who received sildenafil, revealed a tendency to improve the clinical course of the disease, in particular, a reduction in the frequency of hospitalizations for LH. The proportion of patients whose condition improved to at least one functional class according to the WHO classification for 12 weeks in the sildenafil groups was higher (28%, 36% and 42% of patients receiving sildenafil in doses of 20 mg, 40 mg and 80 mg, respectively) than in the placebo group (7%). In addition, sildenafil treatment compared with placebo led to an improvement in the quality of life, especially in terms of physical activity, and a trend toward improving the Borg's dyspnea index.The percentage of patients who had to add another class to standard therapy was higher in the placebo group (20%) than in the groups receiving sildenafil in doses 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 LH.

Efficacy in adults with LH in combination with epoprostenol

Efficacy of sildenafil was studied in 267 patients with stable course of LH on intravenous epoprostenol. The study included patients with primary LH and LH associated with systemic connective tissue diseases.

Patients were randomized to placebo and sildenafil (fixed dose selection, dose ranging from 20 mg to 40 mg and then 80 mg three times a day) in combination therapy with intravenous epoprostenol. The primary endpoint was an increase in exercise tolerance test on 6 minute walk after 16 weeks of treatment. The increase in the distance traveled in the sildenafil group was 30.1 m compared to 4.1 m in the placebo group.In patients who took sildenafil, the average pressure in the pulmonary artery significantly decreased by 3.9 mm Hg. Art. compared with the placebo group.

Clinical outcomes

Sildenafil therapy significantly increased the time to clinical deterioration of LH compared with placebo. According to Kaplan-Mayer, in patients receiving placebo, the risk of developing impairment was three times higher (the proportion of patients with impairment in the placebo group was 0.187 (0.12-0.26), and in the sildenafil treatment group 0.062 (0, 02-0.10), a confidence interval of 95%). The time to clinical deterioration was defined as the time from randomization of patients to the first signs of impairment (death, lung transplantation, initiation of therapy with bosentan, or a change in the dose of epoprostenol due to clinical deterioration). In 23 patients from the placebo group, there were signs of clinical deterioration (17.6%), while in the sildenafil group, 8 patients (6%) showed impairment.

In patients with primary LH, there was an average deviation in the 6-minute walk test: when used with sildenafil - 26.39 m, when applied with placebo - 11.84 m. In patients with PH associated with systemic connective tissue diseases - 18, 32 mi 17.5 m respectively.

Efficacy and safety of sildenafil in adult patients with LH (with simultaneous use with bosentan)

In general, the profile of side effects in the two groups (simultaneous use of sildenafil and bosentan and bosentan monotherapy) was the same and corresponded to the side effects profile with sildenafil.

Pharmacokinetics:

Suction

Sildenafil is rapidly absorbed in the gastrointestinal tract after ingestion. Absolute bioavailability averages about 41% (from 25 % up to 63%). The maximum concentration of sildenafil in blood plasma (C_m_Oh) is achieved after 30-120 minutes (on average - after 60 minutes) after ingestion 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 pharmacokinetic curve "concentration-time" (AUC) and C_m_Oh increase in proportion to the dose. When taking sildenafil in a dose of 80 mg 3 times a day, its concentration in the blood plasma increases nonlinearly. With simultaneous intake with food, the suction of sildenafil decreases. At simultaneous reception with fat food time of achievement of the maximum concentration (TS_m_Oh) is increased by 60 min, and C_m_Oh 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 in the equilibrium state averages 105 liters. After ingestion of sildenafil in a dose of 20 mg 3 times a day, the maximum concentration of sildenafil in blood plasma in the equilibrium state is about 113 ng / ml. The connection between sildenafil and its main circulating N-detyl metabolite with plasma proteins is about 96% and does not depend on the total concentration of sildenafil. 90 minutes after taking sildenafil in the sperm of healthy volunteers, less than 0.0002 % dose of sildenafil (an average of 188 ng).

Metabolism

Sildenafil is metabolized mainly in the liver under the action of microsomal isoenzymes of cytochrome P450: isoenzyme CYP3A4 (main path) and isoenzyme CYP2C9 (an additional path). The main circulating active metabolite is formed as a result of N-detylation of sildenafil. The selectivity of this metabolite on PDE is comparable to that of sildenafil, and its activity in relation to PDE5 in vitro is about 50 % activity of sildenafil.The concentration of the metabolite in the blood plasma is about 40 % of the concentration of sildenafil. N-the demethyl metabolite undergoes further metabolism; the final half-life (T1/2) is about 4 hours. In patients with pulmonary arterial hypertension (PAH), the concentration ratio N-detyl metabolite and sildenafil above. Concentration N-detal 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.

Excretion

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

Pharmacokinetics in specific patient groups

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-detal metabolite in the blood plasma is approximately 90% higher than in patients of a younger age (18-45 years).Since the binding of sildenafil to plasma proteins depends on the patient's age, the concentration of free sildenafil in blood plasma in elderly patients is about 40% higher.

Patients with impaired renal function

With mild and moderate renal insufficiency (creatinine clearance 30 to 80 ml / min), the pharmacokinetics of sildenafil after single ingestion at a dose of 50 mg does not change. In severe renal failure (QC less than 30 ml / min), the clearance of sildenafil decreases, which leads to an increase AUC 100% and C_m_Oh on 88% in comparison with parameters at normal function of kidneys at patients of the same age group. In patients with severe renal failure AUC and C_max N-of the demethyl metabolite is higher by 200 % and 79 % respectively, than in patients with normal renal function.

Patients with impaired hepatic function

In volunteers with impaired liver function of mild or moderate degree (5-9 points on the Child-Pugh scale), the clearance of sildenafil decreases, which leads to an increase AUC (85%) and C_m_Oh (47%) compared with those with normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe impairment of liver function (more than 9 on the Child-Pugh scale) have not been studied.

Population pharmacokinetics

In the study of the pharmacokinetics of sildenafil in PAH patients in a population pharmacokinetic model included age, sex, race, indicators of renal and hepatic function. The data used for population analysis included a wide range of demographic and laboratory parameters associated with the state of liver and kidney function. Demographic indicators, as well as parameters of liver or kidney function, 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 equilibrium concentrations were 20-50 % higher than in healthy volunteers. The minimum concentration of sildenafil in the blood plasma (C_max) 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 ingestion in patients with PAH compared to healthy volunteers.

Indications:

Pulmonary hypertension.

Contraindications:

- Hypersensitivity to sildenafil or to any other component of the drug;

- venous occlusion disease of the lungs;

- simultaneous application with donators of nitric oxide or nitrates in any form;

- simultaneous application with strong inhibitors of isoenzyme CYP3A4 (including ketoconazole, itraconazole and ritonavir) (see section "Interaction with other drugs");

- simultaneous use with PDE5 inhibitors, including sildenafil, antihypertensive agents - guanylate cyclase stimulants, such as riotsiguat, as this can lead to symptomatic arterial hypotension;

- loss of vision in one eye due to anterior non-artery ischemic neuropathy of the optic nerve, hereditary degenerative diseases of the retina of the eye (pigment retinitis);

- severe liver dysfunction (more than 9 on the Child-Pugh scale);

- stroke or myocardial infarction in anamnesis;

- severe arterial hypotension (systolic blood pressure less than 90 mm Hg, diastolic blood pressure less than 50 mm Hg);

- age under 18 years (studies of efficacy and safety have not been conducted).

Carefully:

- I or IV functional classes of PAH (efficacy and safety not established);

- anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie's disease) and diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia);

- diseases accompanied by bleeding, or exacerbation of peptic ulcer of the stomach and duodenum;

- heart failure, unstable angina, life-threatening arrhythmias, arterial hypertension (BP> 170/100 mm Hg), obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), a rare multiple systemic atrophy syndrome manifested by a severe violation of blood pressure regulation from the autonomic nervous system, hypovolemia;

- anterior non-arterial ischemic neuropathy of the optic nerve in anamnesis;

- simultaneous application with moderate isoenzyme inhibitors CYP3A4 (including erythromycin, saquinavir, clarithromycin, telithromycin and nefazodone) and α-adrenoblockers;

- simultaneous application with isoenzyme inducers CYP3A4.

Pregnancy and lactation:

In animal experiments sildenafil did not have a direct or indirect adverse effect on the course of pregnancy and the development of the embryo / fetus. Studies in animals have shown a toxic effect on postnatal development. Since adequate controlled trials of the use of sildenafil in pregnant women have not been conducted, use the drug Sildenafil during pregnancy is possible only if the benefit to the mother exceeds the potential risk to the fetus.

It is not known whether sildenafil in breast milk. If it is necessary to use the drug Sildenafil Breastfeeding should be discontinued.

Preclinical studies did not show a negative effect of sildenafil on fertility.

Dosing and Administration:

Inside. The recommended dose of the drug Sildenafil - 20 mg 3 times a day with an interval of about 6-8 hours, regardless of food intake. The maximum recommended dose is 60 mg.

Patients with impaired renal function

Correction of the dose is not required, however, with a poor tolerance of the drug, the dose is reduced to 20 mg twice a day.

Patients with impaired hepatic function

Dose adjustment in patients with mild or moderate impairment of liver function (5-9 points on the Child-Pugh scale) is not required, but if the drug is poorly tolerated, the dose is reduced to 20 mg twice a day. In patients with severe impairment of liver function (more than 9 on the Child-Pugh scale), the drug was not used (see "Contraindications").

Elderly patients (65 years and older)

Correction of the dose is not required.

Children

The use of sildenafil in children younger than 18 years is contraindicated (insufficient data on efficacy and safety).

Patients receiving concomitant therapy

Simultaneous use of sildenafil and epoprostenol is discussed in the sections "Pharmacodynamics" and "Side effect".

Controlled studies to evaluate the efficacy and safety of sildenafil in combination with other drugs (bosentan, iloprost) for LH treatment were not performed. Combined drug therapy Sildenafil with these drugs should be done with caution. It may be necessary to adjust the dose of sildenafil. Nevertheless, there is no evidence of the need to increase the dose of sildenafil with simultaneous use with bosentan.

The efficacy and safety of sildenafil in combination with other PDE5 inhibitors in patients with PAH has not been studied.

Simultaneous use of sildenafil with strong inhibitors of isoenzyme CYP3A4 (eg, ketoconazole, itraconazole, ritonavir) is contraindicated.

If it is necessary to simultaneously apply with moderate isoenzyme inhibitors CYP3A4, such as erythromycin and saquinavir, the dose of the drug Sildenafil should be reduced to 20 mg twice a day in patients.

If it is necessary to simultaneously apply with more powerful moderate inhibitors of the isoenzyme CYP3A4, such as clarithromycin, telithromycin and nefazodone, the dose of the drug Sildenafil should be reduced to 20 mg once a day.

Side effects:

Classification of the incidence of adverse events according to recommendations

World Health Organization (WHO):

very often ≥ 1/10;

often from ≥ 1/100 to <1/10;

infrequently from ≥ 1/1000 to <1/100;

rarely from ≥ 1/10000 to <1/1000;

very rarely <1/10000, including individual messages;

the frequency is unknown - it is not possible to establish the frequency of occurrence from the available data.

Infections and invasions:

often - inflammation of the subcutaneous tissue, influenza, unspecified sinusitis.

Mental disorders:

often - insomnia, anxiety.

Disturbances from the nervous system:

very often - headache;

often - tremor, paresthesia, unspecified burning sensation, hypoesthesia; frequency is unknown - migraine.

Vascular disorders:

very often - congestion (redness of the skin of the face);

frequency unknown - decrease in blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs:

often - unspecified bronchitis, epistaxis, unspecified rhinitis, cough, nasal congestion.

Gastrointestinal disorders:

very often - diarrhea, indigestion;

often - unspecified gastritis, unspecified gastroenteritis, gastroesophageal reflux disease, hemorrhoids, bloating, dryness of the oral mucosa.

Disturbances from muscular, skeletal and connective tissue:

very often - pain in the limbs; often - myalgia, back pain.

Disturbances from the skin and subcutaneous tissues:

often - alopecia, erythema, increased sweating at night; frequency unknown - skin rash.

Metabolic and nutritional disorders: often - fluid retention (edema).

Disorders from the side of the organ of vision:

often - hemorrhage into the retina, unspecified visual impairment, blurred vision, photophobia, chromatopsy, cyanopsy, inflammation of the eyes, reddening of the eyes;

rarely - reduced visual acuity, diplopia, impaired eye sensitivity.

Violations from the organ of hearing and labyrinth: often - vertigo;

frequency unknown - sudden deafness.

Disorders from the reproductive system and mammary glands:

often - gynecomastia, hemospermia;

frequency unknown - priapism, prolonged erection.

Violations from the blood and lymphatic system:

often - unspecified anemia.

Common disorders and reactions at the site of administration:

often a fever.

The overall frequency of discontinuation of sildenafil treatment at the recommended 20 mg dose 3 times a day was low and did not differ from that in the placebo group (2.9%).

In a placebo-controlled study, the effect of adjuvant therapy with sildenafil was studied as a supplement to the intravenous administration of epoprostenol. 134 patients with PAH received sildenafil in daily doses from 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 discontinuation rate due to adverse events in the sildenafil / epoprostenol group was 5.2% compared with 10.7% in the placebo / epoprostenol group.

Overdose:

Symptoms

Headache, "tides" of blood to the skin of the face, dizziness, indigestion, nasal congestion, impaired vision of the body.

Measures to help with overdose

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

Interaction:

Studies of the interaction of sildenafil with other drugs were performed on healthy volunteers, except for the cases indicated separately. These results are valid for other groups of patients and methods of administration.

The effect of other drugs on the pharmacokinetics of sildenafil in vitro

The metabolism of sildenafil occurs mainly under the action of cytochrome P450 isoenzymes: isoenzyme CYP3A4 (main path) and isoenzyme CYP2C9 (an additional pathway), so inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inductors - to increase its clearance.

Research in vivo

In a study on healthy male volunteers, the use of the bosentan endothelin antagonist, which is a moderate inducer of isoenzymes CYP3A4, CYP2C9 and, possibly, CYP2C19, in an equilibrium state (125 mg twice a day) resulted in a decrease AUC and C_m_Oh sildenafil in an equilibrium state (80 mg 3 times a day) by 62.6% and 55.4 % respectively. Although co-administration of two drugs was not accompanied by clinically significant changes in blood pressure in the "lying" and "standing" position 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 strong isoenzyme inhibitor CYP3A4, in combination with sildenafil (100 mg once) led to an increase in C_m_Oh sildenafil by 300% (4 times) and AUC on 1000% (in 11 times). After 24 hours, the concentration of sildenafil in blood plasma was about 200 ng / ml versus 5 ng / ml with only sildenafil, which is consistent with information on the pronounced effect of ritonavir on the pharmacokinetics of various substrates of cytochrome P450. Simultaneous use of sildenafil with ritonavir is contraindicated.

The strongest inhibitors of isoenzyme CYP3A4, such as ketoconazole and itraconazole, may have an effect similar to that of ritonavir. Simultaneous use of sildenafil with ketoconazole and itraconazole is contraindicated. Simultaneous application of saquinavir (1200 mg 3 times a day), HIV protease inhibitor and isoenzyme CYP3A4, with sildenafil (100 mg once) leads to an increase in C_m_Oh sildenafil at 140 % and AUC by 210% respectively. Sildenafil did not influence the pharmacokinetics of saquinavir (see the section "Dosing and Administration").

With a single admission of sildenafil in a dose of 100 mg against the background of therapy with erythromycin, which is a moderate inhibitor of the isoenzyme CYP3A4, in an equilibrium state (500 mg twice a day for 5 days), an increase AUC sildenafil at 182 % (see section "Method of administration and dose").

Such inhibitors of isoenzyme CYP3A4, how clarithromycin, telithromycin and nefazodone may presumably have an effect similar to that of ritonavir. Such inhibitors of isoenzyme CYP3A4, how saquinavir or erythromycin can increase AUC in 7 times. In this regard, with the simultaneous use of these inhibitors isoenzyme CYP3A4 with sildenafil should be careful and adjust the dose of inhibitors of isoenzyme CYP3A4 (see section "Method of administration and dose").

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

Cimetidine (800 mg), a cytochrome P450 inhibitor and a nonspecific isoenzyme inhibitor CYP3A4, with a joint admission with sildenafil (50 mg) caused an increase in the concentrations of sildenafil in the blood plasma of healthy volunteers by 56%. A single intake of antacids (magnesium hydroxide and aluminum hydroxide) had no effect on the bioavailability of sildenafil.

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

Inhibitor inhibitors CYP3A4 and β-blockers

It was found that in patients with PAH, the clearance of sildenafil decreases by approximately 30 % with simultaneous application with weak or medium inhibitors of isoenzyme CYP3A4 and 34% with simultaneous use with β-blockers. AUC sildenafil at its application in a dose of 80 mg 3 times a day was 5 times higher than when using sildenafil in a dose of 20 mg 3 times a day. In studies of interaction with inhibitors of isoenzyme CYP3A4, such as saquinavir and erythromycin (excluding the strongest isoenzyme inhibitors CYP3A4, such as ketoconazole, itraconazole, ritonavir) AUC sildenafil in this concentration range increased.

Inductors of isoenzyme CYP3A4

The clearance of sildenafil increases approximately 3 times with simultaneous application with weak isoenzyme inducers CYP3A4, which corresponds to the effect of bosentan on the clearance of sildenafil in healthy volunteers. It is expected that the simultaneous use of sildenafil with strong isoenzyme inducers CYP3A4 will lead to a significant decrease in the concentration of sildenafil in blood plasma. With the simultaneous use of sildenafil (20 mg 3 times daily) in adult patients with PAH and bosentan in a stable dose (62.5-125 mg twice a day), the same decrease in the exposure of sildenafil was observed, as in the case of healthy volunteers .

Effect of sildenafil on the pharmacokinetics of other drugs

Research in vitro

Sildenafil is a weak inhibitor of isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 systems of cytochrome P450 (IC₅₀ ≥ 150 μM). It is not expected that sildenafil will have an effect on compounds that are substrates of these isoenzymes in clinically significant concentrations.

Research in vivo

Sildenafil has an effect on the system NO/ cGMP and enhances the antihypertensive effect of nitrates. Its simultaneous use with donators of nitric oxide or nitrates in any form is contraindicated.

With simultaneous use of α-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia, an additional decrease in systolic / diastolic blood pressure in the prone position was 7/7, 9 / 5 and 8/4 mm Hg. st., and in the "standing" - 6/6, 11/4 and 4/5 mm Hg. Art. respectively. When sildenafil is used by patients receiving doxazosin, rare cases of development of orthostatic hypotension, accompanied by dizziness, but not fainting, were noted.

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

When studying the interaction of sildenafil (100 mg) with amlodipine in patients with arterial hypertension, there was an additional decrease in systolic and diastolic blood pressure in the "lying" position by 8 mm Hg. Art. and 7 mm Hg. Art. respectively.A similar decrease in blood pressure was noted with the use of one sildenafil in healthy volunteers.

Signs of interaction of sildenafil (50 mg) with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by isoenzyme CYP2C9, it is not revealed. Sildenafil (50 mg) did not cause an additional increase in bleeding time caused by acetylsalicylic acid as an antiplatelet agent (150 mg). Sildenafil (50 mg) did not increase the antihypertensive effect of ethanol in healthy volunteers at C_m_Oh ethanol in blood 80 mg / dl.

In healthy volunteers sildenafil in an equilibrium state (80 mg 3 times a day) caused an increase AUC and C_m_Oh bosentan (125 mg twice daily) by 49.8% and 42%, respectively.

With the simultaneous use of bosentan in adult patients with PAH at an initial dose of 62.5-125 mg twice daily and sildenafil at a dose of 20 mg 3 times a day, there is a smaller increase AUC bosentan compared to healthy volunteers receiving sildenafil in a dose of 80 mg 3 times a day.

Sildenafil in a single dose of 100 mg did not affect the equilibrium pharmacokinetics of HIV protease inhibitors saquinavir and ritonavir, which are substrates of the isoenzyme CYP3A4.

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

Special instructions:

To avoid complications, use strictly according to the doctor's prescription!

The efficacy and safety of sildenafil in patients with severe LH (functional class IV) has not been proven. In case of worsening of the patient's condition against the background of drug therapy Sildenafil should consider the possibility of switching to therapy used to treat this stage of pulmonary hypertension (for example, epoprostenol) (see section "Method of administration and dose"). When the drug is used together Sildenafil with bosentan or other isoenzyme inducers CYP3A4 a dose adjustment may be required.

The benefit / risk ratio of sildenafil in patients with LH I functional class is not established. Studies on the use of sildenafil in the treatment of secondary LH, with the exception of LH associated with connective tissue diseases, and residual LH, have not been conducted.

Arterial hypotension

Sildenafil has a systemic vasodilating effect, leading to a small transient decrease in blood pressure. Before prescribing Sildenafil it is necessary to carefully evaluate the risk of possible undesirable manifestations of 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), and rare syndrome of multiple systemic atrophy, manifested a severe violation of the regulation of blood pressure from the autonomic nervous system.

Since the joint use of sildenafil and α-blockers can lead to the development of symptomatic arterial hypotension in sensitive patients, the drug Sildenafil should be used with caution in patients taking α-blockers. To minimize the risk of postural hypotension in patients taking α-adrenoblockers, start taking the drug Sildenafil should only after the stabilization of hemodynamics in these patients has been achieved. The doctor should inform patients about what actions should be taken in case of symptoms of postural hypotension.

Cardiovascular complications

The reported such adverse events as serious cardiovascular events (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) during the post-marketing use of sildenafil for the treatment of erectile dysfunction, who had a temporary connection with the use of sildenafil. Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events were observed soon after sexual activity, and some of them were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish the presence of a direct link between the observed undesirable phenomena and the factors mentioned or for other reasons.

Visual disorders

Rare cases of development of anterior non-artery ischemic neuropathy of the optic nerve were noted as a cause of impairment or loss of vision against the background of the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors, such as optic disc excavation, age over 50, diabetes, hypertension, ischemic heart disease, hyperlipidemia and smoking. In case of sudden loss of vision, patients should immediately stop taking the drug Sildenafil and seek medical help.

Patients who previously had cases of anterior non-artery ischemic optic nerve neuropathy have an increased risk of developing this disease. In this regard, the doctor should discuss with the patient the possible risks with the use of PDE5 inhibitors. In such patients, the drug Sildenafil should be used with caution and after a thorough assessment of the benefit-risk relationship.

A small number of patients with hereditary pigment retinitis have genetically determined impairments of the functions of the retina phosphodiesterase. Information on the safety of sildenafil in patients with pigment retinitis absent, so the use of sildenafil in such patients is contraindicated.

Hearing Impairment

Some post-marketing and clinical studies report cases of sudden deterioration or hearing loss associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or loss of hearing. The causal relationship between the use of PDE5 inhibitors and sudden deterioration of hearing or loss of hearing is not established. In the event of sudden deterioration of hearing or hearing loss on the background of taking the drug Sildenafil should immediately consult a doctor.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a donator of nitric oxide, on human platelets in vitro. Data on the safety of sildenafil in patients with a tendency to bleeding or exacerbation of peptic ulcer of the stomach and duodenum are absent, therefore, the drug Sildenafil these patients should be used with caution. The frequency of nasal bleeding in patients with PAH associated with diffuse connective tissue diseases was higher (sildenafil - 12.9%, placebo - 0%) than in patients with primary PAH (sildenafil - 3%, placebo - 2.4%).In patients who received sildenafil in combination with antagonist of vitamin K, the frequency of nasal bleeding was higher (8.8%) than in patients who did not take a vitamin K antagonist (1.7%).

Anatomic deformation of the penis and priapism

Sildenafil should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie's disease) or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia).

If the duration of the erection is more than 4 hours, you should immediately seek medical help. In the event that immediate medical intervention was not carried out, damage to the tissues of the penis and complete loss of potency are possible.

Simultaneous application with bosentan

When sildenafil was used against the background of initial therapy with bosentan, there was no improvement in the patients' state (6-minute walk test) compared with bosentan alone. The results of a 6-minute walk test were different 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 simultaneous use of sildenafil and bosentan was worse than with bosentan monotherapy, but better than in patients with primary PAH who received bosentan monotherapy. Thus, the doctor should evaluate the result of therapy with the simultaneous use of sildenafil and bosentan in patients with primary PAH, based on their experience with PAH therapy. Simultaneous use of the drug Sildenafil and bosentan in patients with PAH associated with systemic connective tissue diseases are not recommended.

Simultaneous use with other PDE5 inhibitors

The efficacy and safety of simultaneous use of sildenafil with other PDE5 inhibitors in patients with PAH have not been studied, so the use of this combination is not recommended.

Effect on the ability to drive transp. cf. and fur:

Since dizziness, dizziness, lowering of blood pressure, development of chromatopsy, blurred vision and other side effects are possible with sildenafil, caution should be exercised when driving vehicles and engaging in other potentially dangerous activities requiring increased attention and speed of psychomotor reactions.Also, you should carefully consider the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosage regimen.

Form release / dosage:

Tablets, film-coated, 20 mg.

Packaging:

15 tablets in a contoured cell pack of a polyvinylchloride or polyvinylchloride / polyvinylidene chloride film and aluminum foil.

90 tablets in a can of high-density polyethylene.

6 contour cell packs of 15 tablets or one bank along with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

4 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004413

Date of registration:15.08.2017

Expiration Date:15.08.2022

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Information update date: & nbsp11.09.2017

Illustrated instructions

Instructions

Sildenafil (Sildenafil)