Sildenafil

General characteristics. Structure:

Active ingredient: 25 mg, 50 mg or 100 mg of a sildenafil of citrate (in terms of sildenafit).

Excipients: lactoses monohydrate, cellulose microcrystallic, croscarmellose sodium, hypro rod (hydroxypropyl cellulose), silicon dioxide colloid, magnesium stearate.

Film cover: [the dry mix for a film covering containing polyvinyl alcohol (40%), titanium dioxide (22,1%), a macrogoal 3350 (polyethyleneglycols 3350) (20,2%), talc (14,8%), a varnish indigo carmine, aluminum on the basis of dye (2,8%), ferrous oxide yellow (ferrous oxide) (0,1%)].

Drug which recovers the broken erectile function due to strengthening of inflow of blood to a penis.

Pharmacological properties:

Pharmacodynamics. Sildenafil – powerful selection inhibitor циклогуанозинмонофосфат (tsGMF) - specific phosphodiesterase of the 5th type (FDE5).

Sale of the physiological mechanism of an erection is connected with release of nitrogen oxide (NO) in a cavernous body during sexual stimulation. It, in turn, leads to increase in the tsGMF level, the subsequent relaxation of smooth muscle tissue of cavernous body and increase in inflow of blood.

Sildenafil has no the direct weakening effect on the isolated cavernous body of the person, but strengthens effect of nitrogen oxide (NO) by means of inhibition of FDE5 which is responsible for disintegration of tsGMF.

At activation of communication of NO/tsGMF which happens under the influence of sexual incentives suppression of FDE5 sildenafily leads to increase in tsGMF in a cavernous body. Thus, sexual stimulation is necessary for development of desirable pharmacological action of a sildenafil.

Sildenafil селективен concerning FDE5 in vitro, its activity concerning FDE5 surpasses activity concerning other known isoenzymes of phosphodiesterase: FDE6 − by 10 times; FDE1 − more than by 80 times; FDE2, FDE4, FDE7-FDE11 − more than by 700 times. Sildenafil by 4000 times more селективен concerning FDE5 in comparison with FDE3 that is essential as FDE3 is one of key enzymes of regulation of contractility of a myocardium.

Sildenafil causes a small and tranzitorny lowering of arterial pressure (ABP) which in most cases has no clinical manifestations. Average maximum decrease in the systolic ABP in a prone position, after reception of a sildenafil inside in a dose   of 100 mg makes 8,3 mm of mercury. Corresponding change of the diastolic ABP makes 5,3 mm of mercury. The single dose in a sildenafil in a dose of 100 mg was not followed by clinically significant changes on the electrocardiogram (ECG) at healthy volunteers. Sildenafil does not exert impact on cordial emission and does not change a blood stream through stenosed arteries. More expressed, but also passing action on the ABP was noted at the patients accepting nitrates.

At some patients in 1 hour after reception of a sildenafil in a dose of 100 mg by Farnsvorta-Munsel's test 100 easy and passing disturbance of ability to distinguish shades of color (blue/green) is revealed. In 2 hours after administration of drug these changes were absent. It is considered that disturbance of color sight is caused by inhibition of FDE6 which participates in the course of transfer of light in an eye retina. Sildenafil does not exert impact on visual acuity, contrast perception, the electroretinogram, intraocular pressure or diameter of a pupil.

Pharmacokinetics. The pharmacokinetics of a sildenafil in the recommended range of doses has linear character.

Absorption. Sildenafil is quickly soaked up after intake. Absolute bioavailability averages about 40% (from 25% to 63%). In vitro sildenafit about 1,7 ng/ml (3,5 nanometers) in concentration suppresses activity of FDE5 of the person for 50%. After a single dose of a sildenafil in a dose of 100 mg average maximum concentration of a free sildenafil in a blood plasma (Cmax) of men makes about 18 ng/ml (38 nanometers). Cmax at reception of a sildenafil inside is on an empty stomach reached on average within 60 min. (from 30 min. to 120 min.). At reception in combination with greasy food the speed of absorption decreases: Cmax decreases on average by 29%, and time of achievement of the maximum concentration (Tmax) increases for 60 min., however extent of absorption authentically does not change (the area under a pharmacokinetic curve concentration time (AUC) decreases by 11%).

Distribution. The volume of distribution of a sildenafil in an equilibrium state averages 105 l. 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 drug. Less than 0,0002% of a dose of a sildenafil (on average 188 нг) are revealed in sperm in 90 min. after administration of drug.

Metabolism. Sildenafil is metabolized, mainly, in a liver under the influence of a CYP3A4 cytochrome isoenzyme (the main way) and a CYP2C9 cytochrome isoenzyme (an additional way). The main circulating active metabolite which is formed as a result of N-demethylation of a sildenafil is exposed to further metabolism. Selectivity of action of this metabolite concerning 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 of healthy volunteers made about 40% of concentration of a sildenafil. N-demetilny a metabolite is exposed to further metabolism; the period of its semi-removal (T1/2) makes near the 4th hour.

Removal. The general clearance of a sildenafil makes 41 l/hour, and final T1/2 − 3-5 hour. After intake sildenafit it is removed in the form of metabolites, generally by intestines (about 80% of a dose) and to a lesser extent kidneys (about 13% of a dose).

Pharmacokinetics at special groups of patients. Elderly patients. At healthy elderly patients (65 years are more senior) the clearance of a sildenafil is reduced, and concentration of a free sildenafil in a blood plasma is about 40% higher, than at young people (18-45 years). The age does not exert clinically significant impact on the frequency of development of side effects.

Patients with a renal failure. At easy (the clearance of creatinine (CC) of 50-80 ml/min.) and moderated (KK of 30-49 ml/min.) degrees of a renal failure the pharmacokinetics of a sildenafil after a single dose inside in a dose of 50 mg does not change. At a heavy renal failure (KK ≤ 30 ml/min.) the clearance of a sildenafil decreases that also Cmax (88%) in comparison with those indicators at normal function of kidneys at patients of the same age group leads to approximately double increase in AUC value (100%).

Patients with an abnormal liver function. At patients with cirrhosis (stages And yes In on classification of Chayld-Pyyu) the clearance of a sildenafil decreases that also Cmax (47%) in comparison with those indicators at normal function of a liver at patients of the same age group leads to increase in AUC value (84%). The pharmacokinetics of a sildenafil at patients with heavy abnormal liver functions (a stage With on classification of Chayld-Pyyu) was not studied.

Indications to use:

Treatment of the erectile dysfunction which is characterized by inability to achievement or preservation of an erection of a penis sufficient for satisfactory sexual intercourse. It is effective only at sexual stimulation.

Route of administration and doses:

Inside. The recommended dose for most of adult patients makes 50 mg approximately in 1 hour prior to sexual activity.

Taking into account efficiency and portability the dose can be increased to 100 mg or is lowered to 25 mg. The maximum recommended dose makes 100 mg. The maximum recommended frequency rate of use – once a day.

At easy and medium-weight degree of a renal failure (KK of 30-80 ml/min.) correction of a dose is not required, at a heavy renal failure (KK <30 ml/min.) should lower a dose of a sildenafil to 25 mg.
As removal of a sildenafil is broken at patients with injury of a liver (in particular, at cirrhosis), the dose of a sildenafil should be lowered to 25 mg.

Correction of a dose of a sildenafil is not required from elderly patients.

At combined use with CYP3A4 cytochrome isoenzyme inhibitors (erythromycin, sakvinaviry, ketokonazoly, itrakonazoly) the initial dose of a sildenafil has to make 25 mg (see the section "Interaction with Other Medicines").

To minimize risk of development of postural hypotension in the patients accepting alpha adrenoblockers reception of a sildenafil should be begun only after achievement of stabilization of a hemodynamics at these patients. The initial dose sildenafit – 25 mg

Features of use:

Use at pregnancy and during breastfeeding. According to the registered indication drug is not intended for use for women.

For diagnosis of disturbances of an erection, definition of their possible reasons and the choice of adequate treatment it is necessary to collect the full medical anamnesis and to conduct careful physical examination. Remedies for erectile dysfunction have to be used with care at patients with anatomic deformation of a penis (a penis angulation, cavernous fibrosis, Peyroni's disease) or patients with risk factors have development of a priapism (drepanocytic anemia, a multiple myeloma, leukemia).

Men to whom sexual activity is undesirable should not appoint the drugs intended for treatment of disturbances of an erection.

Sexual activity represents a certain risk in the presence of heart diseases therefore before any therapy concerning disturbances of an erection the doctor should direct the patient to inspection of a condition of cardiovascular system. Use of a sildenafil is contraindicated at patients with heart failure, unstable stenocardia, the myocardial infarction postponed for the last six months or a stroke, hypotonia (the ABP <90/50 mm of mercury.). In clinical trials lack of distinctions in the frequency of development of a myocardial infarction is shown (1,1 on 100 people a year) or to the frequency of mortality from cardiovascular diseases (0,3 on 100 people a year) at the patients receiving sildenafit, in comparison with the patients receiving placebo. 

Cardiovascular complications. At 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 these or those factors.

Hypotension. Sildenafil has the systemic vazodilatiruyushchy action leading to passing decrease in the ABP that is not clinically significant phenomenon and does not lead to any effects at most of patients. Nevertheless, before purpose of a sildenafil the doctor has to estimate carefully risk of possible undesirable manifestations of vazodilatiruyushchy action at patients with the corresponding diseases, especially against the background of sexual activity. The raised susceptibility to vazodilatator is observed at patients with 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 alpha adrenoblockers can lead to symptomatic hypotension at certain sensitive patients, sildenafit it is necessary to appoint with care to the patients accepting alpha adrenoblockers (see the section "Interaction with Other Medicines"). To minimize risk of development of postural hypotension in the patients accepting alpha adrenoblockers reception of a sildenafil should be begun only after achievement of stabilization of indicators of a hemodynamics at these patients. It is also necessary to consider expediency of decrease in an initial dose of a sildenafil (see the section "Route of Administration and Doses"). The doctor has to inform the patient on what actions should be taken in case of symptoms of postural hypotension.

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. However in most cases these patients had risk factors of development of this pathology. To relationship of cause and effect between use of FDE5 inhibitors and sudden deterioration in hearing or a hearing loss it is not established. The patient should be warned that in case of sudden decrease or a sudden hearing loss it is necessary to stop therapy sildenafily and to consult immediately with the doctor.

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 (see the section "With Care").

Safety and efficiency of use of a sildenafil together with other remedies for disturbances of an erection were not studied therefore use of similar combinations is not recommended.

Influence on ability of control of vehicles and mechanisms. As at reception of a sildenafil decrease in the ABP, development of a chromatopsia, the obscured sight, etc. in by-effects is 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:

Classification of frequency of development of side effects (WHO): very often> 1/10; often from> 1/100 to <1/10; infrequently from> 1/1000 to <1/100; seldom from> 1/10000 to <1/1000; very seldom <1/10000, including separate messages; frequency is unknown: according to the available data it is not possible to establish emergence frequency.

From a nervous system: very often – a headache; often – dizziness; infrequently – drowsiness, a hypesthesia; seldom – cerebrovascular events, a syncope; frequency is unknown – the tranzitorny ischemic attack, spasms, including recurrent.

From an organ of sight: often – vision disorders, passing disturbances of color perception (a chromatopsia; infrequently – defeat of a conjunctiva, disturbance of a slezoobrazovaniye; frequency is unknown – front ischemic optical neuropathy of not arterial genesis, occlusion of vessels of a retina, defects of fields of vision.

From an acoustic organ: infrequently – dizziness, a sonitus; seldom – deafness.

From cardiovascular system: often – rushes of blood to face skin;
infrequently – a heart consciousness, tachycardia; seldom – increase or a lowering of arterial pressure, a myocardial infarction, fibrillation of auricles; frequency is unknown – ventricular arrhythmia, unstable stenocardia, a sudden cardiac standstill.

From respiratory system: often – a nose congestion; seldom – nasal bleeding.

From digestive tract: often – dyspepsia; infrequently – vomiting, nausea, dryness of a mucous membrane of an oral cavity.

Allergic reactions: infrequently – skin rash; frequency is unknown – Stephens-Johnson's syndrome, a toxic epidermal necrolysis (scalded skin syndrome).

From a musculoskeletal system: infrequently – a mialgiya.

From generative organs: infrequently – a gematospermiya, bleeding from a penis; frequency is unknown – a priapism, a long erection.

Others: infrequently – a stethalgia, increased fatigue.

Interaction with other medicines:

Influence of other medicines on pharmacokinetics of a sildenafil. Metabolism of a sildenafil happens generally in a liver under the influence of CYP3A4 cytochrome isoenzymes (the main way) and CYP2C9 therefore inhibitors of these isoenzymes can reduce clearance of a sildenafil, and inductors, respectively, to increase clearance of a sildenafil. Decrease in clearance of a sildenafil at simultaneous use of inhibitors of an isoenzyme of CYP3A4 cytochrome is noted (кетоконазол, erythromycin, Cimetidinum). Cimetidinum (800 mg), nonspecific inhibitor of an isoenzyme of CYP3A4 cytochrome, at joint reception with sildenafily (50 mg) causes increase in concentration of a sildenafil in plasma for 56%.

The single dose of 100 mg of a sildenafil together with erythromycin (on 500 mg/days 2 times a day within 5 days), specific inhibitor of an isoenzyme of CYP3A4 cytochrome, against the background of achievement of constant concentration of erythromycin in blood, leads to increase in AUC of a sildenafil by 182%.

At joint reception of a sildenafil (once 100 mg) and the sakvinavira (1200 mg/day 3 times a day), inhibitor of HIV protease and an isoenzyme of CYP3A4 cytochrome, against the background of achievement of constant concentration of a sakvinavir in Cmax blood of a sildenafil increased by 140%, and AUC increased by 210%. Sildenafil does not exert impact on pharmacokinetics of a sakvinavir. Stronger inhibitors of an isoenzyme of CYP3A4 cytochrome, such as кетоконазол and итраконазол, can cause also stronger changes of pharmacokinetics of a sildenafil.

Simultaneous use of a sildenafil (once 100 mg) and a ritonavira (on 500 mg 2 times a day), inhibitor of HIV protease and strong inhibitor of P450 cytochrome, against the background of achievement of constant concentration of a ritonavir in blood leads 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 makes about 200 ng/ml (after single use of one sildenafil − 5 ng/ml).

Grapefruit juice, weak CYP3A4 inhibitor, can moderately increase plasma concentration of a sildenafil.

If sildenafit the patients receiving at the same time strong inhibitors of an isoenzyme of CYP3A4 cytochrome accept in the recommended doses, then Cmax of a free sildenafil does not exceed 200 nanometers, and drug is well transferred.

The single dose of an antacid (hydroxide aluminum hydroxide magnesium) does not influence bioavailability of a sildenafil.

CYP2C9 cytochrome isoenzyme inhibitors (such as Tolbutamidum, warfarin), a CYP2D6 cytochrome isoenzyme (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and tiazidopodobny diuretics, APF inhibitors (angiotensin-converting enzyme) and antagonists of calcium do not exert impact on pharmacokinetic parameters of a sildenafil.

Azithromycin (500 mg/days within 3 days) does not exert impact on AUC, Cmax, Tmax, a constant of speed of removal and T1/2 of a sildenafil or its main circulating metabolite.

Nikorandil represents a hybrid of nitrate and the activator of potassium channels. Because of existence of a nitrate component he can enter serious interactions with sildenafily.

Influence of a sildenafil on other medicines. Sildenafil is weak inhibitor of isoenzymes of system of P450 cytochrome − 1A2, 2S9, 2S19, 2D6, 2E1 and 3A4 (IK50> 150 µmol). At reception of a sildenafil in the recommended doses of its Cmax makes about 1 µmol therefore it is improbable that sildenafit can affect clearance of substrates of these isoenzymes.

Sildenafil strengthens hypotensive effect of nitrates both at prolonged use of the last, and at their appointment according to acute indications. In this regard use of a sildenafil in combination with nitrates or donators of nitrogen oxide contraindicated.

At a concomitant use of alpha adrenoblocker of a doksazozin (4 mg and 8 mg) and a sildenafila (25 mg, 50 mg and 100 mg) at patients with a benign hyperplasia of a prostate with a stable hemodynamics average additional decrease in the systolic/diastolic ABP in a dorsal decubitus made 7/7 mm of mercury., 9/5 mm of mercury. and 8/4 mm of mercury. respectively, and in a standing position − 6/6 mm of mercury., 11/4 mm of mercury. and 4/5 mm of mercury. respectively. It is reported about exceptional cases of development in such patients of the symptomatic postural hypotension shown in the form of dizzinesses (without faint). At the certain sensitive patients receiving alpha adrenoblockers, simultaneous use of a sildenafil can lead to symptomatic hypotension.

Signs of considerable interaction of a sildenafil (50 mg) with Tolbutamidum (250 mg) or warfarin (40 mg) which are metabolized by a CYP2C9 cytochrome isoenzyme are not revealed.

Sildenafil (100 mg) does not exert impact on pharmacokinetics of inhibitors of HIV protease, the sakvinavir and a ritonavir who is CYP3A4 cytochrome isoenzyme substrates at their constant level in blood.

Sildenafil (50 mg) does not cause additional increase in a bleeding time at reception of acetylsalicylic acid (150 mg).

Sildenafil (50 mg) does not strengthen hypotensive effect of ethanol at healthy volunteers at the maximum concentration of ethanol in blood on average of 0,08% (80 mg/dl).

At patients with arterial hypertension of signs of interaction of a sildenafil (100 mg) with amlodipiny it is not revealed. Average additional decrease in the ABP in a prone position makes 8 mm of mercury. (systolic) and 7 mm of mercury. (diastolic).

Use of a sildenafil in combination with antihypertensives does not lead to emergence of additional side effects.

Contraindications:

- hypersensitivity to a sildenafil or to any other component of drug; 
- use for the patients receiving constantly or with breaks donators of nitrogen oxide organic nitrates or nitrites in any forms as sildenafit strengthens hypotensive effect of nitrates (see the section "Interaction with Other Medicines"); 
- use for patients to whom sexual activity is undesirable (for example,      with a serious cardiovascular illness, such as heavy heart failure, unstable stenocardia); 
- arterial hypotension (arterial pressure is less than 90/50 mm of mercury.); 
- the disturbance of cerebral circulation postponed within the last six months or a myocardial infarction; 
- hereditary degenerative diseases of a retina, including a pigmental retinitis (a smaller part of such patients has a genetic disorder of phosphodiesterase of a retina); 
- lactose intolerance, deficit of lactase, glyukozo-galaktozny malabsorption; 
- heavy liver failure; 
- concomitant use of a ritonavir; 
- a concomitant use of other medicines for treatment of erectile dysfunction; 
- age up to 18 years; 
- use of drug for women.

With care:
- arterial hypertension (arterial pressure> of 170/100 mm of mercury.); 
- zhizneugrozhayushchy arrhythmias; 
- obstructive diseases of output department of a left ventricle of heart (aorta stenosis, hypertrophic subaortic stenosis); 
- anatomic deformation of a penis (angulation, cavernous fibrosis or Peyroni's disease); 
- to patients with episodes of development of front nearteriitny ischemic neuropathy of an optic nerve in the anamnesis; 
- the diseases contributing to development of a priapism (a sickemia, a multiple myeloma, a leukosis, a trombotsitemiya); 
- the diseases which are followed by bleeding; 
- a peptic ulcer in an aggravation stage; 
- concomitant use of alpha adrenoblockers.

Overdose:

Symptoms: a headache, "inflows" of blood to face skin, dizziness, dyspepsia, a nose congestion, a vision disorder.

At a single dose of a sildenafil in a dose to 800 mg the undesirable phenomena were comparable to those at administration of drug in lower doses, but met more often. Treatment: symptomatic. The hemodialysis does not accelerate clearance of a sildenafil as the last actively contacts proteins of plasma and is not removed by kidneys.

Storage conditions:

In the place protected from light at a temperature not over 25 ºС. To store in the place, unavailable to children. Period of validity 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 25 mg, 50 mg and 100 mg. 1, 2, 3, 4, 5, 6 or 10 tablets in a blister strip packaging from a film of polyvinyl chloride and aluminum foil. 10 tablets in bank from polyethylene of high density. 1 or 2 blister strip packagings on 1 tablet, 1 or 2 blister strip packagings on 2 tablets, 4 blister strip packagings on 3 tablets, 1, 2, 3 or 5 blister strip packagings on 4 tablets, 2 or 4 blister strip packagings on 5 tablets, 2 blister strip packagings on 6 tablets, 1 or 2 blister strip packagings on 10 tablets or one bank together with the instruction on a medical use in a pack from a cardboard.