Revatsio

General characteristics. Structure:

Active agent: sildenafit citrate ( 20 mg of a sildenafil are equivalent) Excipients: cellulose of microcrystallic 62,632 mg, calcium hydrophosphate of 20,878 mg, croscarmellose sodium of 6,000 mg, magnesium stearate of 2,400 mg; film cover: опадрай white  II OY-LS-28914 (monohydrate and triacetin) 3,000 mg contains a gipromelloza, titanium dioxide, lactoses, опадрай transparent YS-2-19114-A (contains a gipromelloza and triacetin) 0,900 mg.

Pharmacological properties:

Pharmacodynamics. Sildenafil – powerful selection inhibitor циклогуанозинмонофосфат (tsGMF) - specific phosphodiesterase-5 (FDE5). As FDE5 responsible for disintegration of tsGMF contains not only in a cavernous body of a penis, but also in vessels of lungs, sildenafit, being inhibitor of this enzyme, increases the maintenance of tsGMF in smooth muscle cells of pulmonary vessels and causes their relaxation. At patients with the pulmonary hypertensia (PH) reception of a sildenafil leads to vasodilatation of lungs and, to a lesser extent, other vessels. Sildenafil селективен concerning FDE5 in vitro. Its activity concerning FDE5 surpasses activity concerning other known isoenzymes of phosphodiesterase: FDE 6, participating in transfer of a light signal in a mesh cover of an eye – by 10 times; FDE1 – by 80 times; FDE2, FDE4, FDE7-FDE11 – more than by   700 times. Activity of a sildenafil concerning FDE5 approximately by 4 000 times surpasses its activity concerning FDE3, the tsAMF-specific phosphodiesterase participating in reduction of heart. Sildenafil causes a small and passing lowering of arterial pressure (ABP) which in most cases is not followed by clinical symptoms. After reception of a sildenafil inside in a dose of 100 mg the maximum decrease in the systolic and diastolic ABP in a prone position averaged 8,3   mm of mercury. and 5,3   mm of mercury., respectively. After reception of a sildenafil in a dose of 80 mg  3 times a day at healthy male volunteers were noted the maximum decrease in the systolic and diastolic ABP in a prone position on average on 9,0 mm of mercury. and 8,4   mm of mercury., respectively. After reception of a sildenafil in a dose of 80 mg 3 times a day at patients with system arterial hypertension systolic and diastolic the ABP decreased on average by 9,4 mm of mercury. and 9,1 mm of mercury., respectively. At patients from LG receiving sildenafit in a dose 80 mg 3 times a day, decrease in the ABP was less expressed: systolic and diastolic the ABP decreased by 2   mm of mercury. At a single dose inside in doses to 100 mg healthy volunteers sildenafit had no significant effect on ECG indicators. At use of drug in a dose of 80 mg 3 times a day at patients with LG clinically significant changes of an ECG did not come to light. When studying hemodynamic effects of a sildenafil at a single dose inside in a dose of 100 mg at 14 patients with heavy coronary atherosclerosis (a stenosis, at least, of one coronary artery more than 70%) average systolic and diastolic the ABP at rest decreased by 7% and 6%, respectively, in comparison with initial level. Systolic pressure in a pulmonary artery decreased on average by 9%. Sildenafil did not influence cordial emission and did not worsen a blood stream in stenosed coronary arteries. At some patients in 1 hour after reception of a sildenafil in a dose of 100 mg by Fansvorsa-Munsel's test 100 easy and passing disturbance of ability of color perception is revealed (blue/green flowers); in 2 hours after administration of drug these changes disappeared. It is considered that disturbance of color sight is caused by inhibition of FDE6 participating in the course of transfer of light in a mesh cover of an eye. Sildenafil does not exert impact on visual acuity, contrast perception, these elektroretinografiya, intraocular pressure or diameter of a pupil. At patients  with the confirmed initial age degeneration of a makula sildenafit at a single dose in a dose 100 mg did not cause essential changes of visual functions, in particular, of the visual acuity estimated by means of a lattice Amsler, abilities to distinguish the colors of the traffic light estimated by method of perimetry of Humphrey, and passing disturbances of the visual functions estimated by means of a photostress method. Efficiency at adult patients with LG   Investigated efficiency of a sildenafil at 278 patients from primary LG which was associated with diffusion diseases of connecting fabric (30%), and LG which developed after surgical treatment of inborn heart diseases (7%).   Was available for most of patients II (107; 39%) or III (160; 58%) functional class LG according to the WHO classification, were defined by I less often (1; 0,4%) or IV (9; 3%) functional classes.  Less than 45 % or fraction of shortening of the size of a left ventricle less than 0,2 did not include patients with fraction of emission of a left ventricle in a research as well as patients for whom there was inefficient a therapy bozentany. Sildenafil in doses of 20 mg, 40 mg or 80 mg applied together with standard therapy (patients of control group received placebo). Increase in tolerance to an exercise stress according to the test of six-minute walking in 12 weeks after an initiation of treatment was primary final point. In all three groups of the patients receiving sildenafit in different doses, it authentically increased in comparison with placebo. Increase in the passable distance (adjusted for placebo) made 45 m,  the patients receiving have 46 m and 50 m sildenafit in doses 20 mg, 40 mg and 80 mg, respectively. Reliable distinctions between groups of the patients accepting sildenafit, it is not revealed. At the patients receiving sildenafit in all doses, average pulmonary pressure authentically decreased in comparison with placebo. Adjusted for effect of placebo pressure decrease in a pulmonary artery made at the patients receiving sildenafit 20 mg, 40 mg and 80 mg in doses: 2,7  mm of mercury., 3,0   mm of mercury. and 5,1   mm of mercury., respectively. Statistically reliable difference between effect of various doses of a sildenafil was not noted. Besides, improvement of the following indicators came to light: resistance of pulmonary vessels, pressure in the right auricle and cordial emission. Changes  of the heart rate (HR) and the system ABP were insignificant. Extent of decrease in resistance of pulmonary vessels surpassed extent of decrease in peripheric vascular resistance. At the patients receiving sildenafit, revealed a tendency to improvement of a clinical course of a disease, in particular decrease in frequency of hospitalization concerning LG. Dolyapatsiyentov which state improved, at least, on one functional class according to the WHO classification within 12 weeks in groups of a sildenafil was higher  (28%, 36% and 42% of the patients receiving sildenafit in doses 20 mg, 40 mg and 80 mg, respectively), than in group of placebo (7%). Besides, treatment sildenafily in comparison with placebo led to improvement of quality of life, especially on indicators of physical activity, and a tendency to improvement of an index of an asthma of Borg. The percent of patients who had to add drug of one more class to standard therapy in group of placebo was above (20%), than in groups of the patients receiving sildenafit in doses 20 mg (13%), 40 mg (16%) and 80 mg    (10%). 259 of 277 patients continued treatment. In one year  of 94% from them were live. Efficiency at adult patients with LG  at combined use with epoprostenoly Efficiency  of a sildenafil was studied at 267 patients with a stable current of LG against the background of intravenous administration of an epoprostenol.    Included patients from primary LG which was associated with diffusion diseases of connecting fabric, and LG which developed after surgical treatment of inborn heart diseases in a research. Patients were randomizirovana on groups of placebo and a sildenafil (with the fixed titration, since a dose of 20 mg, to 40 mg and then 80 mg, 3 times a day) at a combination therapy  with intravenous administration of an epoprostenol. Increase in tolerance to an exercise stress according to the test of six-minute walking in 16 weeks after an initiation of treatment was primary final point. Increase in the passable distance in group of a sildenafil made 30,1 m against 4,1 m in group of placebo.  At the patients accepting sildenafit, average pulmonary pressure authentically decreased by 3,9 mm of mercury. in comparison with group of placebo. Increase in a span up to deterioration in a clinical picture (death, transplantation of a lung, hospitalization concerning LG, therapy initiation bozentany or change of a dose of an epoprostenol because of clinical deterioration) was reached for all patients            (n = 265) and more at patients of group of a sildenafil in comparison with placebo was reliable.  

Pharmacokinetics. Absorption. Sildenafil is quickly soaked up after intake. Absolute bioavailability makes about 41 % (from 25 % to 63 %). The maximum concentration of a sildenafil in a blood plasma (Cmax) is reached in 30-120 min. (on average - in 60 min.) after intake on an empty stomach. After reception of a sildenafil 3 times a day in  the range of doses from 20 mg to 40 mg the area under a pharmacokinetic curve "concentration time" (AUC) and Cmax increase in proportion to a dose. At reception of a sildenafil in a dose of 80 mg 3 times a day its concentration in a blood plasma increases not linearly. At a concomitant use with greasy food the speed of absorption of a sildenafil decreases: time of achievement of the maximum concentration (TCmax) increases for 60 min., and Cmaxumenshayetsya on average by 29 %, however extent of absorption significantly does not change (AUC decreases by 11%).

Distribution. The volume of distribution of a sildenafil in an equilibrium state averages 105 l. After intake of a sildenafil in a dose of 20 mg 3 times a day the maximum concentration of a sildenafil in a blood plasma in an equilibrium state makes about 113 ng/ml. Communication sildenafit and its main circulating metabolite N-demetilnogo with proteins of a blood plasma makes about 96% and does not depend on the general concentration of a sildenafil. Cmax of a free sildenafil in a blood plasma averages 4,52 ng/ml (9,5 nanometers).  In 90 min. after administration of drug in sperm of healthy volunteers less than 0,0002% of a dose of a sildenafil are revealed (on average 188 нг). Metabolism Sildenafil is metabolized, mainly, in a liver under the influence of microsomal isoenzymes of P450 cytochrome: CYP3A4 (main way) and CYP2C9 (minor way). The main circulating active metabolite is formed as a result of  N-demethylation of a sildenafil. Selectivity of action of this metabolite on FDE is comparable to that sildenafit, and its activity concerning FDE5 in vitro makes about 50% of activity of a sildenafil. Concentration of a metabolite in a blood plasma makes about 40% of concentration of a sildenafil. N-demetilny a metabolite is exposed to further transformation; the final period of its semi-removal (T1/2) makes near the 4th hour. Patients with LG have a ratio of concentration of N-demetilnogo of a metabolite and a sildenafil above. Concentration of N-demetilnogo of a metabolite in a blood plasma makes about 72% of that sildenafit (20 mg 3 times a day). The metabolite contribution to pharmacological activity of a sildenafil makes 36%, its contribution to clinical effect of drug is unknown. Removal the General clearance of a sildenafil makes 41 l/h, and a final elimination half-life of-3-5 h. After intake sildenafit it is removed in the form of metabolites, generally through intestines (about 80% of a dose) and, to a lesser extent, by kidneys (about 13 % of a dose). Elderly patients At elderly patients (65 years are also more senior) the clearance of a sildenafil is reduced, and concentration of a free sildenafil and its active N-demetilnogo of a metabolite in a blood plasma is about 90% higher, than at patients of younger age (18-45 years). As linkng of a sildenafil with proteins of a blood plasma depends on age of the patient, concentration of a free sildenafil in a blood plasma at elderly patients is about 40% higher. The renal failure At easy and moderate degree of a renal failure (the clearance of creatinine (CC) of 30-80 ml/min.) pharmacokinetics of a sildenafil after a single dose inside in a dose of 50 mg does not change. At a heavy renal failure (KK less than 30 ml/min.) the clearance of a sildenafil decreases that leads to increase in AUC by 100% and Cmax by 88 % in comparison with indicators at normal function of kidneys at patients of the same age group. At patients with a heavy renal failure of AUC and Cmax N-demetilnogo of a metabolite also 79%, respectively, than at patients with normal function of kidneys are 200% higher. The abnormal liver function At volunteers with abnormal liver functions of easy or average degree (a stage And yes In on classification of Chayld-Pyyu),  clearance of a sildenafil decreases that also Cmax (47%) in comparison with indicators at normal function of a liver at patients of the same age group leads to increase in AUC (85%). The pharmacokinetics of a sildenafil at patients with a heavy abnormal liver function (a class C on classification of Chayld-Pyyu) was not studied. Population pharmacokinetics  When studying pharmacokinetics of a sildenafil at patients with LG included age, sex, race, indicators of function of kidneys in population pharmacokinetic model and a liver. Data which used for the population analysis included a wide range of the demographic and laboratory parameters connected with a condition of function of a liver and kidneys. Demographic indicators, and also parameters of function of a liver or kidneys did not exert statistically significant impact on pharmacokinetics of a sildenafil of upatsiyent with LG. Patients with LG after reception of a sildenafil in doses from 20 mg to 80 mg 3 times a day had its average equilibrium concentration for 20% of-50% above, than at healthy volunteers. The minimum concentration of a sildenafil in a blood plasma (Cmin) was twice higher, than at healthy volunteers. The obtained data indicate decrease in clearance and/or increase in bioavailability of a sildenafil after intake at patients with LG in comparison with healthy volunteers.

Indications to use:

Pulmonary hypertensia.

Route of administration and doses:

Inside. The recommended drug РевациоÒ dose  - 20 mg 3 times a day with an interval of about 6-8 hour  irrespective of meal. The Maksimalnayarekomenduyemy dose makes 60 mg. Elderly patients:  dose adjustment is not required. Renal failure: dose adjustment is not required, however at bad portability of drug the dose is reduced to 20 mg by 2 times a day. Abnormal liver function: dose adjustment with an easy or moderate abnormal liver function (classes A and B on classification of Chayld-Pyyu) is not required from patients, however at bad portability of drug the dose is reduced to 20 mg by 2 times a day. At patients with a heavy abnormal liver function (a class C on classification of Chayld-Pyyu) use of drug was not investigated. Efficiency and safety of use of a sildenafil for children are younger than 18 years were not investigated. Use for the patients receiving the accompanying therapy the Combined use of a sildenafil and epoprostenol is considered in the sections "Pharmacodynamics" and "Side effects". Controlled researches on assessment of efficiency and safety of use of a sildenafil in combination with other drugs (бозентан, илопрост), for treatment of pulmonary hypertensia were not conducted.  The combination therapy      should be carried out by the drug РевациоÒ with the specified drugs with care. Efficiency and safety of use of the drug РевациоÒ  in combination with other FDE-5 inhibitors at patients with pulmonary arterial hypertension is not studied.

Features of use:

In order to avoid complications to apply strictly on doctor's orders! Efficiency of drug of Revatsio  at patients with heavy pulmonary hypertensia (a functional class IV) is not proved. In case of an aggravation of symptoms of the patient against the background of therapy by the drug РевациоÒ it is necessary to consider the possibility of transition to the therapy used for treatment of this stage of pulmonary hypertensia (for example, epoprostenoly) (see the section "Route of Administration and Doses"). At combined use of the drug РевациоÒ  with bozentany or other inductors of an isoenzyme CYP3A4 dose adjustment can be required. The ratio advantage/risk of a sildenafil at patients with pulmonary gipertenziyeyi a functional class is not established. Researches on use of a sildenafil in treatment of secondary pulmonary hypertensia, except for the pulmonary hypertensia connected with diseases of connecting fabric and residual pulmonary hypertensia were not conducted. Hypotension Sildenafil has the systemic vazodilatiruyushchy action leading to small tranzitorny decrease in the ABP. Before purpose of drug it is necessary to estimate attentively risk of possible undesirable manifestations of vazodilatiruyushchy effect at patients with hypotension (the ABP <90/50 mm of mercury. at rest), a hypovolemia, heavy obstruction of an output path of a left ventricle (an aorta stenosis, a hypertrophic subaortic stenosis), and also with seldom found syndrome of a multiple system atrophy, the shown heavy disturbance of regulation of the ABP from the autonomic nervous system. As combined use of a sildenafil and α-adrenoblockers can lead to development of symptomatic hypotension in sensitive patients, sildenafit it is necessary to appoint with care to patients, принимающимα-адреноблокаторы. To minimize risk of development of postural hypotension in patients, принимающихα-адреноблокаторы, to begin to accept sildenafit follows only after stabilization of indicators of a hemodynamics at these patients is reached. The doctor has to inform patients on what actions should be taken in case of symptoms of postural hypotension. Cardiovascular complications during post-marketing use of a sildenafil for treatment of erectile dysfunction it was reported about such undesirable phenomena as serious cardiovascular complications (including a myocardial infarction,  unstable stenocardia, a sudden cardiac death, ventricular arrhythmia, a hemorrhagic stroke, the tranzitorny ischemic attack, hypertensia and hypotension)  which had temporary communication using a sildenafil. Most of these patients, but not all from them, had risk factors of cardiovascular complications. Many of the specified undesirable phenomena were observed soon after sexual activity, and some of them were noted after reception of a sildenafil without the subsequent  sexual activity. Existence is not possible to establish a feedforward between noted undesirable phenomena and the specified factors or other reasons. Visual disturbances Were noted exceptional cases of development of a lobby of a nearteriitny ischemic neuropathy of an optic nerve as sildenafit the reasons of deterioration or loss of sight against the background of use of all FDE5 inhibitors, including. Most of these patients had risk factors, such as excavation (deepening) of an optic disk, the age is more senior than 50 years, a diabetes mellitus, arterial hypertension, coronary heart disease, a lipidemia and smoking. Relationship of cause and effect between reception of FDE5 inhibitors and a front nearteriitny ischemic neuropathy of an optic nerve is not revealed. The doctor has to inform the patient on increase in risk of development of a front nearteriitny ischemic neuropathy of an optic nerve if earlier this state at it was already noted. In case of sudden loss of sight patients should provide necessary medical care immediately. A hearing disorder In some post-market and clinical trials it is reported about the cases of sudden deterioration or a hearing loss connected using all FDE5 inhibitors, including sildenafit. Most of these patients had risk factors of sudden deterioration or a hearing loss. To relationship of cause and effect between use of FDE5 inhibitors and sudden deterioration in hearing or a hearing loss it is not established. In case of sudden deterioration in hearing or a hearing loss against the background of reception of a sildenafil it is necessary to consult immediately with the doctor. Bleedings Sildenafil strengthens antiagregantny effect of Sodium nitroprussidum, the donator of nitrogen oxide, on thrombocytes of the person of in vitro. Data on safety of use of a sildenafil for patients with tendency to bleeding or an aggravation of a peptic ulcer of a stomach and a 12-perstny gut are absent therefore sildenafit at these patients it is necessary to apply with care. Frequency of nasal bleedings at patients from LG connected with diffusion diseases of connecting fabric was higher (sildenafit 12,9 %, placebo of 0 %), than upatsiyent with primary pulmonary hypertensia (sildenafit 3,0 %, placebo of 2,4 %). At the patients  receiving  sildenafit    in combination with  the antagonist of vitamin K, the frequency of nasal bleedings was higher  (8,8 %), than at the patients who were not accepting the antagonist of vitamin K (1,7 %). Influence on ability to drive the car and to control of mechanisms Against the background of reception of a sildenafil of any negative influence on ability to drive the car or other technical means was not observed. However as at reception of a sildenafil decrease in the ABP, development of a chromatopsia, the obscured sight, etc. in by-effects are possible, it is necessary to show consideration for individual effect of drug in the specified situations, especially in an initiation of treatment and at change of the mode of dosing.

Side effects:

The undesirable phenomena at therapy by Revatsio's drug  were noted at 1% of patients. By-effects on system of classification of MedDRA by systems of bodies and frequency: very frequent (> 1/10), frequent (> 1/100, <1/10), rare (> 1/1000, <1/100) and very rare which frequency cannot be determined on the basis of the available data.  

Infections and invasions: Frequent: an inflammation of hypodermic cellulose,  flu, not specified sinusitis

From system of blood and lymphatic system: Frequent: not specified anemia Metabolism and food: Frequent: liquid delay Mental disturbances: Frequent: sleeplessness, uneasiness

From the central nervous system: Very frequent: headache Frequent: not specified migraine, a tremor, paresthesia, not specified burning sensation, a gipoesteziya

From an organ of sight: Frequent: hemorrhage in a mesh cover of an eye, not specified vision disorders, the obscured sight, photophobia, a chromatopsia, blue vision, an inflammation of eyes, reddening of eyes Rare: decrease in visual acuity, diplopia, disturbance of sensitivity of an eye

From an acoustic organ and a labyrinth: Frequent: вертиго Very rare: sudden deafness Vascular disorders: Very frequent: hyperemia

From respiratory system, a thorax and a mediastinum: Frequent: not specified bronchitis, nasal bleeding, not specified rhinitis, cough, a nose congestion

From digestive tract: Very frequent: diarrhea, dyspepsia Frequent: not specified gastritis, not specified gastroenteritis, a gastroesophageal reflux disease, gemorroidit, abdominal distention, dryness in a mouth

From skin and hypodermic fabrics: Frequent: alopecia, erythema, night sweats Rare: skin rash from a musculoskeletal system and connecting fabric: Very frequent: extremity pain Frequent: mialgiya, dorsodynia

From reproductive system and a mammary gland: Frequent: gynecomastia Very rare: a priapism, a long erection the General disturbances and reactions in an injection site: Frequent: fever the General frequency of the termination of treatment by the drug РевациоÒ in the recommended dose of 20 mg 3 times a day was low and did not differ from that in group of placebo (2,9%). In a platsebokontroliruyemy research studied effect adjuvant terapiipreparaty РевациоÒ as additions to intravenous administration of an epoprostenol. 134 patients with LG received the drug РевациоÒ in daily doses from 20 mg to 80 mg 3 times a day and эпопростенол, and 131 patients received placebo and эпопростенол. Duration of treatment made 16 weeks. The general frequency of the termination of therapy because of adverse events  in group sildenafil/epoprostenol made 5,2 % in comparison with 10,7 % in group of placebo / эпопростенол.

Interaction with other medicines:

The researches in vitro Metabolism of a Sildenafil occurs, generally under the influence of P450 cytochrome isoenzymes: CYP3A4 (the main way) and CYP2C9 (a minor way) therefore inhibitors of these isoenzymes can reduce clearance of a sildenafil, and inductors - to increase its clearance. The researches in vivo It is established that at patients with LG the clearance of a sildenafil decreases and/or its bioavailability after intake at combined use of substrates of an isoenzyme of CYP3A4 and combination of a substratovizoferment of CYP3A4 and β-adrenoblockers increases.......... The pharmacokinetics of a sildenafil at patients with LG statistically significantly changed only under the influence of the specified drugs. AUC of a sildenafil at the patients receiving substrates of an isoenzyme CYP3A4 or substrates of an isoenzyme CYP3A4 in combination with β-adrenoblockers, was 43% higher also than 66%, respectively, than at patients who did not accept similar medicines. AUC of a sildenafil at its use in a dose of 80 mg three times a day was 5 times higher, than at purpose of drug in a dose of 20 mg 3 times a day. In interaction researches from CYP3A4 ingibitoramiizoferment, such, as саквинавир and erythromycin   (excepting     more powerful  inhibitors   of an isoenzyme  CYP3A4,   such  as кетоконазол, итраконазол, ритонавир) AUC of a sildenafil in this range of concentration increased. In a research on healthy male volunteers use of the antagonist of endothelin of a bozentan which is the moderate inductor of isoenzymes CYP3A4, CYP2C9 and, perhaps CYP2C19, in an equilibrium state (125 mg 2 times a day) led to decrease in AUC and Cmax of a sildenafil in an equilibrium state (80 mg 3 times a day) for 62,6 % and 55,4 %, respectively. Though joint reception of two drugs was not followed by clinically significant changes of the ABP in situation "lying" and "standing" and was well transferred by healthy volunteers, sildenafit together with bozentany it is necessary to apply with care. Use of a ritonavir (500 mg 2 times a day), inhibitor of HIV protease and powerful inhibitor of an isoenzyme CYP3A4, in a combination with sildenafily (100 mg once) led to increase in Cmax of a sildenafil by 300 % (by 4 times) and AUC for 1000 % (by 11 times). In 24 hours concentration of a sildenafil in a blood plasma made about 200 ng/ml against 5 ng/ml at purpose only of a sildenafil that will be coordinated with information on the expressed effect of a ritonavir on pharmacokinetics of various substrates of P450 cytochrome. The combined use of a sildenafil with ritonaviry is not recommended. Combined use of a sakvinavir (1200 mg 3 times a day), inhibitor of HIV protease and an isoenzyme of CYP3A4, with sildenafily (100 mg once) leads to increase in Cmax of a sildenafil by 140% and AUC by 210%, respectively. Sildenafil did not exert impact on pharmacokinetics of a sakvinavir. At the combined use of a sildenafil with sakvinaviry dose adjustment is not required. More powerful inhibitors of an isoenzyme CYP3A4, such as кетоконазол иитраконазол, can have more expressed effect on pharmacokinetics of a sildenafil. At a single dose of a sildenafil in a dose of 100 mg against the background of terapiieritromitsiny, the being specific inhibitor of an isoenzyme CYP3A4, in an equilibrium state (500 mg 2 times a day within 5 days) revealed increase in AUC of a sildenafil by 182%. At the combined use of a sildenafil with erythromycin of dose adjustment it is not required. At healthy male volunteers azithromycin (500 mg/days within 3 days) did not exert impact on AUC, Cmax, Tmax, a constant of speed of elimination or T1/2 of a sildenafil and its main circulating metabolite. Cimetidinum (800 mg), inhibitor of P450 cytochrome and nonspecific inhibitor of an isoenzyme CYP3A4, caused increase in concentration of a sildenafil (50 mg) in a blood plasma of healthy volunteers for 56%. The single dose of antacids (magnesium of hydroxide and aluminum of hydroxide) did not exert impact on bioavailability of a sildenafil. Combined use of oral contraceptives (ethinylestradiol of 30 mkg and levonorgestrel of 150 mkg) did not exert impact on pharmacokinetics of a sildenafil. Influence of a sildenafil on pharmacokinetics of other medicines of the Research in vitro Sildenafil is weak inhibitor of isoenzymes     CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 of P450 cytochrome (IC50 > of 150 microns). The researches in vivo Sildenafil has effect on the NO/tsGMF system and strengthens hypotensive effect of nitrates. Its combined use with donators of nitrogen oxide or nitrates in any forms is contraindicated. At co-administration of α-adrenoblocker of a doksazozin (((((((((( (4 mg and 8 mg) and a sildenafila (25 mg, 50 mg and 100 mg) to patients with a benign hyperplasia of a prostate additional decrease in the systolic/diastolic ABP in a prone position made 7/7, 9/5 and 8/4 mm of mercury., and in a standing position – 6/6, 11/4 and 4/5   mm of mercury., respectively. At purpose of a sildenafil to the patients receiving доксазозин exceptional cases of development of the orthostatic hypotension which was followed by dizziness, but not a faint are celebrated. Use of a sildenafil for the patients accepting α-adrenoblockers, can lead to clinically significant arterial hypotension at patients with lability of the ABP. When studying interaction of a sildenafil (100 mg) with amlodipiny at patients sarterialny hypertensia noted additional decrease in the systolic and diastolic ABP in a prone position on 8 mm of mercury. and 7 mm of mercury., respectively. Similar decrease in the ABP was noted at use of one sildenafil for healthy volunteers. Signs of interaction of a sildenafil (50 mg) with Tolbutamidum (250 mg) ilivarfariny (40 mg) which it is metabolized under the influence of CYP2C9 isoenzyme are not revealed. Sildenafil (50 mg) did not cause additional increase in the bleeding time caused by acetylsalicylic acid (150 mg). Sildenafil (50 mg) did not strengthen hypotensive effect of ethanol at healthy volunteers at the maximum concentration  of ethanol in blood of 80 mg/dl. At healthy volunteers sildenafit in an equilibrium state (80 mg 3 times a day) caused increase in AUC and Cmax  of a bozentan (125 mg 2 times a day) for 49,8% and 42%, respectively. Sildenafil in a single dose of 100 mg did not exert impact on equilibrium pharmacokinetics of inhibitors of HIV protease of a sakvinavir and a ritonavir which are CYP3A4 isoenzyme substrates. Sildenafil did not exert clinically significant impact on kontsentratsiyuperoralny contraceptives in a blood plasma (ethinylestradiol of 30 mkg and levonorgestrel of 150 mkg).

Contraindications:

Hypersensitivity to any component of drug. Venookklyuzionny pulmonary disease. Combined use with donators of nitrogen oxide or nitrates in any form. Combined use with powerful inhibitors of an isoenzyme CYP3A4 (including ketokonazoly, itrakonazoly and ritonaviry) (see the section "Interaction with Other Medicines"). Loss of sight in one eye owing to a front nearteriitny ischemic neuropathy of an optic nerve, hereditary degenerative diseases of a mesh cover of an eye (a pigmental retinitis). A heavy abnormal liver function (a class C on classification of Chayld-Pyyu). A stroke or a myocardial infarction in the anamnesis. Heavy arterial hypotension (systolic ABP  less than 90   mm of mercury., diastolic ABP less than 50   mm of mercury.). Lactose intolerance, galactosemia or syndrome of glyukozo-galaktozny malabsorption. Age up to 18 years (researches of efficiency and safety were not conducted).

Overdose:

Symptoms: a headache, rushes of blood to face skin, dizziness, dyspepsia, a nose congestion, disturbance from an organ of sight. Treatment:  symptomatic. Dialysis does not accelerate removal  of a sildenafil as the last actively contacts proteins of a blood plasma and is not removed by kidneys.

Storage conditions:

To store in the dry place at a temperature not above 30 °C. To store in the places unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 20 mg. 15 tablets in the blister from PVC / aluminum foil. 6 blisters in a cardboard pack together with the application instruction.