Fareva Amboise

France

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VIAGRA^®

VIAGRA

Trade name of the drug: Viagra^®

Active substance (XPN): sildenafil

Dosage form: dispersible tablets in the oral cavity.

Contents:

Each tablet dispersed in the oral cavity contains:

active substance: sildenafil citrate (equivalent to 50 mg of sildenafil).

excipients: microcrystalline cellulose, colloidal hydrophobic silicon dioxide, sodium croscarmellose, magnesium stearate, indigocarmine-based aluminum lacquer (E132), sucralose, mannitol, crospovidone, polyvinyl acetate, povidone;

maltodextrin and dextrin-preserving flavorings;

a natural flavoring that preserves maltodextrin, glycerin (E422) and propylene glycol (E1520);

maltodextrin and alpha-tocopherol (E307) preservative lemon flavor.

Description: rhombic, blue round tablets with V50 engraving on one side and flat on the other.

Pharmacotherapeutic group: an agent for the treatment of erectile dysfunction - an inhibitor of FDE-5 (phosphodiesterase-5).

ATX code: G04BE03.

Pharmacological properties

Pharmacodynamics

The physiological mechanism responsible for penile erection involves the release of nitric oxide (NO) in porous bodies during sexual stimulation. Nitric oxide activates guanylate cyclase, which leads to an increase in cyclic guanosine monophosphate (sGMF) levels, causing the porous bodies to relax smooth muscle and increase blood flow.

Sildenafil is a potent selective inhibitor of sGMF-type 5 phosphodiesterase (FDE-5), which is responsible for the breakdown of sGMF in porous bodies. Sildenafil has a peripheral effect on erections. Sildenafil does not have a direct relaxing effect on the porous body isolated from humans, but nitric oxide enhances the relaxing effect of NO on this tissue. As in the case of sexual stimulation, in the activation of the metabolic pathway of NO / sGMF, inhibition of FDE-5 by sildenafil leads to an increase in sGMF levels in porous bodies. Therefore, sexual stimulation is necessary to achieve the desired therapeutic pharmacological effect as a result of the expected effects of sildenafil.

In vitro conditions have shown that sildenafil has a selective effect on FDE-5, which is involved in the regulation of the erection process. The drug is more potent than FDE5 compared to other known phosphodiesterases. This effect of the drug is involved in the process of photon regeneration in the retina of the eye  It is 6 times more effective than FDE10. When used at the maximum recommended doses, the selectivity of sildenifil to FDE5 is 1 times greater than its selectivity to FDE80, while its selectivity to FDE-2, 3, 4, 7, 8, 9, 10, and 11 is 700 times higher. In particular, the selectivity of sildenafil to FDE5 is 3 times higher than the selectivity of the sAMF-specific isoform of phosphodiesterase, which is involved in the regulation of heart contraction, compared to FDE4000.

Clinical efficacy and safety

After taking the drug, two specific clinical trials were conducted to assess the time interval during which sildenafil could cause an erection to occur in response to sexual stimulation. In clinical trials of patients who took sildenafil on an empty stomach, the median time of sildenafil before the onset of an erection (sufficient to have sexual intercourse) in patients with an erection with a rigidity of 60% during a penile plethysmography (RigiScan). was 25 minutes (the range of indicators was 12-37 minutes). In a separate study using RigiScan plethysmography, sildenafil was shown to be able to induce erections in response to sexual stimulation even 4–5 hours after ingestion.

Sildenafil causes a mild and transient decrease in blood pressure, which in most cases is not accompanied by clinical manifestations. The mean maximum maximum decrease in systolic blood pressure in the supine position after oral administration of sildenafil at a dose of 100 mg was 8,4 mm Hg. ust. formed. The corresponding change in diastolic blood pressure in the supine position is 5,5 mm Hg. ust. formed. Such a decrease in blood pressure is consistent with the vasodilator effect of sildenafil, which is probably associated with an increase in sGMF levels in smooth muscle. A single oral dose of sildenafil up to 100 mg did not cause any clinically significant changes in the ECG in healthy volunteers.

In a study of the hemodynamic effects of a single dose of 70 mg sildenafil in 14 patients with severe coronary heart disease (STI) (more than 100% had at least one coronary artery stenosis), systolic and diastolic blood pressure decreased by 7% and 6%, respectively, relative to baseline, at rest. Mean systolic blood pressure in the lungs decreased by 9%. Sildenafil did not affect the volume of blood flowing from the heart and did not reduce blood flow through the stenotic arteries.

A two-way latent placebo-controlled study using stress tests and physical exertion evaluated 144 patients with erectile dysfunction and chronic stable angina who regularly took antianginal drugs (excluding nitrates). No clinically significant differences were found between sildenafil and the placebo group until the onset of limited angina.

In some patients, a mild and transient impairment of the ability to distinguish colors (blue / green) using the 100-color Farnsworth-Munsell test was detected 1 hour after taking the drug at a dose of 100 mg, but at the same time all results were obtained after taking the drug dose. Completely lost after 2 hours. The approximate mechanism of these color separation disorders is due to inhibition of the enzyme FDE6, which is involved in the process of light transmission in the retina of the eye. Sildenafil does not affect visual acuity or contrast sensitivity. The use of sildenafil (single dose of 9 mg) in patients with age-related early macular degeneration (n = 100) proved in a small placebo-controlled study sharpness, Amsler grid, traffic light color separation modeling, Humphrey perimeter, and photostress) did not call for a significant change in inspection results.

In healthy volunteers, the effect of sildenafil on sperm and their morphology after a single oral dose of 100 mg was not determined.

Additional information on clinical trials

At the time of clinical trials, sildenafil was used in more than 19 patients aged 87–8000 years. The study included the following groups of patients: elderly patients (19,9%), patients with arterial hypertension (30,9%), patients with diabetes mellitus (20,3%), with ischemic heart disease (5,8%). ), patients with hyperlipidemia (19%), spinal cord injury (0,6%), patients with depression (5,2%), those who underwent transurethral resection of the prostate gland (3,7%) and underwent radical prostatectomy patients (3,3%). Subsequent groups of patients were not adequately cited or included in clinical trials: postoperative patients in the pelvic organs, patients after radiation therapy, patients with severe renal or hepatic impairment, as well as patients with certain cardiovascular diseases. lgan.

In studies using fixed doses of the drug, the proportion of patients who reported improvement in erection as a result of treatment was 25% (62 mg dose of sildenafil) and 25% (74 mg dose of sildenafil) compared with 50% in the placebo group. and 82% (100 mg dose of sildenafil). In controlled clinical trials, the frequency of discontinuation of sildenafil was insignificant and was the same as the frequency of discontinuation of placebo.

In all of these studies, the proportion of patients who reported improvement after taking sildenafil was as follows: patients with psychogenic erectile dysfunction (84%), patients with mixed erectile dysfunction (77%), and organic erectile dysfunction patients (68%), elderly patients (57%), patients with diabetes mellitus (59%), patients with ischemic heart disease (69%), patients with arterial hypertension (68%), patients underwent transurethral resection (TUR) of the prostate gland (61%), patients underwent radical prostatectomy (43%), patients with spinal cord injury (83%), patients with depressive conditions (75%) . The safety and efficacy of sildenafil have been confirmed by data from long-term studies.

Pharmacokinetics

Absorption

Sildenafil is rapidly absorbed. After oral administration of the drug on an empty stomach, the maximum observed concentration in plasma is reached over a period of 30 minutes to 120 minutes (average 60 minutes). The average absolute bioavailability of the drug when taken orally is 41% (range of indications 25-63%). AUC and C after taking sildenafil in the range of recommended doses (25-100 mg) orally_Max values ​​increase in direct proportion to the doses taken.

The rate of absorption of sildenafil when taken with food in film-coated tablets is T_Max with an average delay of up to 60 minutes and C_Max  decreases by an average of 29%.

In a clinical study involving 45 healthy men aged 36 years and older, the bioequivalence of 50 mg oral dispersible tablets taken without drinking with water to 50 mg film-coated tablets was determined. It was in this study that the AUC remained unchanged, but C_Max  The mean value of was 50% lower when taking oral dispersible tablets taken orally with a 50 mg dose of water than with film-coated tablets at a dose of 14 mg.

Absorption of sildenafil is reduced when dispersed oral tablets are taken with a high-fat meal, T_Max The average delay is about 3,4 hours, and C_Max and the mean value of AUC decreased by approximately 59% and 12%, respectively, compared with when oral tablets dispersed in the oral cavity were taken on an empty stomach.

Distribution

Equilibrium distribution volume (Vd) for sildenafil is 105 l, indicating the distribution of the drug in the tissues of the body. After a single oral dose of sildenafil at a dose of 100 mg, the mean maximum total plasma concentration of sildenafil was approximately 440 ng / ml (with a coefficient of variation of 40%). Because sildenafil (and its major circulating metabolite, N-desmethylsildenafil) is 69% bound to plasma proteins, the mean maximum plasma concentration of free sildenafil is 18 ng / ml (38 nM). The degree of protein binding does not depend on the total concentrations of the drug.

In healthy volunteers who received sildenafil (once at a dose of 100 mg), less than 90% of the dose (average 0,0002 ng) was detected in the sperm 188 minutes after ingestion.

Biotransformation

Biotransformation of sildenafil is mainly carried out in the presence of microsomal isoenzymes of the liver SYR3A4 (primary pathway) and SYR2S9 (secondary pathway). The major circulating metabolite is formed by the loss of the N-methyl group of sildenafil. The metabolite is characterized by the same level of selectivity as sildenafil in relation to phosphodiesterase, the metabolite vitro Its activity relative to FDE-5 is about 50% of the activity of the starting material of the drug. Plasma concentrations of this metabolite are approximately 40% of the concentrations characteristic of sildenafil. The metabolite, which loses the N-methyl group, is then metabolized again, with a final half-life of about 4 hours.

Release

The total clearance of sildenafil with a final terminal half-life of 3-5 hours is 41 l per hour. As with oral administration, sildenafil is excreted intravenously in the form of metabolites, mainly in the feces (approximately 80% of the oral dose) and to a lesser extent in the urine (approximately 13% of the oral dose).

Pharmacokinetics in a separate group of patients

Elderly patients

Plasma concentrations of sildenafil and its metabolite, which lost the active N-methyl group, in healthy volunteers in the elderly (65 years and older) were similar to those in younger (18-45 years) healthy volunteers. relatively, a decrease in the clearance of sildenafil was found, leading to an increase of about 90%. The corresponding increase in plasma concentrations of free sildenafil, which was associated with an age difference in binding to blood plasma proteins, was approximately 40%.

Kidney failure

The pharmacokinetics of sildenafil did not change after a single oral dose of 50 mg in volunteers with mild (creatinine clearance 80-30 ml per minute) and moderate (creatinine clearance 49-50 ml) impairment of renal function. The AUC and S of the metabolite that lost the N-methyl group_Max the mean rates increased by 126% and 73%, respectively, compared to similar indicators in volunteers of the same age without renal impairment. However, due to the high variability between patients, these differences were not statistically significant. Severe renal insufficiency (creatinine clearance)
In volunteers <30 ml / min), the clearance of sildenafil was reduced, which increased the area under the pharmacokinetic curve (AUC) and S_Max leads to an increase of about twice (88%). In addition, AUC and S for the metabolite that lost the N-methyl group_Max values ​​increased significantly - by 200% and 79%, respectively.

Liver failure

The clearance of sildenafil was reduced in volunteers with mild to moderate hepatic cirrhosis (Child-Pew A and B), which increased the AUC (84%) compared with volunteers without liver dysfunction at the same age. ) and S_Max (47%). The pharmacokinetics of sildenafil have not been studied in patients with severe hepatic impairment.

Application

Viagra is used in older men with erectile dysfunction characterized by the inability to maintain or achieve an erection sufficient for sexual intercourse.

Viagra is effective only in the presence of sexual stimulation.

Method of administration and dosage

Dosage regimen

Use in adults

Viagra should be taken about an hour before sex as needed. The recommended dose of the drug is 50 mg and is taken on an empty stomach, as taking at the same time with food slows absorption and delays the effect of the dispersible oral tablet.

The dose can be increased to 100 mg, taking into account the effectiveness and absorption of the drug. The maximum recommended dose of the drug is 100 mg. Patients who need to increase the dose of the drug to 100 mg should take two consecutive oral tablets of 50 mg. The maximum recommended number of doses of the drug - 1 time per day. If it is necessary to take a dose of 25 mg of the drug, it is recommended to take 25 mg film-coated tablets.

Separate categories of patients

Elderly patients

No dose adjustment is required in elderly patients (≥ 65 years).

Patients with impaired renal function

The recommendations for dosing in the section "Use in adults" also apply to patients with mild and moderate renal impairment (creatinine clearance 30-80 ml per minute).

Due to the decreased clearance of sildenafil in patients with severe renal impairment (creatinine clearance <30 ml / min), the drug should be reconsidered at a dose of 25 mg. Depending on the effectiveness and absorption of the drug, it is necessary to gradually adjust the dose.
It can be increased up to 50 mg and up to 100 mg.

Jigar patients with impaired performance

Due to the decreased clearance of sildenafil in patients with impaired liver function (eg, cirrhosis), the possibility of using the drug in a dose of 25 mg should be considered. Depending on the effectiveness and absorption of the drug, its dose can be gradually increased to 50 mg and 100 mg, if necessary.

Patient children

Viagra is not indicated for use in patients under 18 years of age.

Use in patients taking other drugs.

In addition to ritonavir, which is not recommended for concomitant use with sildenafil, it should be considered that the drug can be used in an initial dose of 3 mg in patients receiving concomitant treatment with CYP4A25 inhibitors.

In order to reduce the risk of developing postural arterial hypotension in patients treated with alpha-blockers, their condition should be stabilized before starting treatment with sildenafil. It should also be considered that sildenafil can be used starting at a dose of 25 mg.

Method of application

It is prescribed for oral use.

The dispersible tablet in the oral cavity should be placed on the tongue in the mouth and wait for it to dissolve completely before swallowing with or without water. The tablet should be taken immediately after the blister is removed from the package. Patients who need a second tablet dispersed orally at a dose of 100 mg to reach the final dose of 50 mg should take the second tablet after the first tablet is completely dissolved.

In the case of tablets dispersed in the oral cavity with a high fat content, I observed a significant delay in the absorption of the drug compared to taking the drug on an empty stomach. It is recommended to take tablets dispersed in the oral cavity on an empty stomach. Tablets dispersed in the oral cavity can be taken with or without water.

 

Side effects

Brief information about the security profile

The most common adverse reactions reported during clinical trials in patients treated with sildenafil were headache, hyperemia, dyspepsia, nasal congestion, dizziness, fever, visual disturbances, cyanopia, and blurred vision. 'lgan.

List of adverse reactions in tabular form

In clinical trials using the drug, all medically significant adverse reactions that occurred more frequently than placebo were classified as follows, depending on the system-organ class and frequency of occurrence: very common (≥ 1/10 ), frequent (≥ 1/100 i <1/10), infrequent (≥ 1/1 000 i <1/100), rare (≥ 1/10 000 and <1/1000). The frequency of adverse events in each group is listed in order of decreasing severity.

Infection and parasitic diseases: not often - rhinitis.

Immune by the system: not often - hypersensitivity.

Disorders of the nervous system: very often - headache; often - dizziness; not often - drowsiness, hypoaesthesia; in rare cases - Acute circulatory disorders in the brain, transient ischemic attack, seizures^*, recurrence of fatigue attacks^*, fainting.

Disorders by the viewing member: often - color disturbances (chloropsy, chromatopsia, cyanopsia; erythropsy and xanthopsia), visual disturbances, blurred vision, not often - disorders with tear separation (dry eye, tear gland dysfunction and severe aging of the eye), eye pain, photophobia, photopsy, vascular hyperemia, light exposure rash, conjunctivitis; in rare cases - anterior ischemic neuropathy of the optic nerve with noarteritis (NAION)^*, retinal vascular occlusion, retinal hemorrhage, arteriosclerotic retinopathy, retinal diseases, glaucoma, visual field deficiency, diplopia, visual acuity decrease, myopia, asthenopia, glaucoma of the vitreous body, rainbow diseases of the eye, mydriasis, the presence of rainbow circles around the light source in the visual field, swelling of the eye, swelling of the eye, eye diseases, conjunctival hyperemia, abnormal sensations in the eye, swelling of the eyelids, discoloration of the sclera.

Disorders of the auditory organ and vestibular apparatus: not often - vertigo, ringing in the ears; in rare cases - deafness.

Disorders of the heart: not often - tachycardia, feeling the heartbeat, in rare cases - Sudden death due to heart disease *, myocardial infarction, ventricular arrhythmia *, fibrillation of the heart chambers, unstable angina.

Disorders of blood vessels: often - hyperemia, fever; not often - arterial hypertension, arterial hypotension.

Disorders of the respiratory system, chest and thoracic cavity: often - nasal congestion; not often - bleeding from the nose, clogging of the additional cavities of the nose; in rare cases - a feeling of tightness in the throat, swelling of the nasal mucosa, dryness of the nasal mucosa.

Disorders of the gastrointestinal tract: often - nausea, dyspepsia; not often - gastroesophageal reflux disease, vomiting, pain in the upper abdomen, dry mouth; in rare cases - Hypesthesia of the oral mucosa.

By the skin and subcutaneous tissue Disorders: not often - skin rash; in rare cases - Stevens-Johnson syndrome (SDS) *, toxic epidermal necrolysis (TEN) *.

Disorders of the musculoskeletal system and connective tissue: not often - myalgia, pain in limbs.

By the kidneys and urinary tract Disorders: not often - hematuria.

By the genitals and mammary glands disorders: in rare cases - bleeding from the penis, priapism *, hematospermia, increased erection.

General Disorders and Disorders at the Place of Sending: not often - chest pain, severe fatigue, feeling of overheating; in rare cases - jealousy.

Laboratory and instrumental test data: not often - increase in the number of heartbeats.

* Only recorded during postmarketing observations.

Contraindications

Hypersensitivity to sildenafil or any other components of the drug.

Due to the known effect of the drug on the metabolic pathway of nitric oxide / cyclic gunosin monophosphate (sGMF), sildenafil has been shown to enhance the hypotensive effect of nitrates, so it can be treated with nitric oxide donors (agents such as amylnitrite) or nitrates of any form. cannot be applied at the time.

FDE 5 inhibitors should not be used in combination with guanilate cyclase stimulants, including riosiguat, as this may lead to symptomatic hypotension.

Drugs to treat erectile dysfunction, including sildenafil, should not be used in men whose sexual activity is not recommended (e.g., in patients with severe cardiovascular disease such as unstable angina or severe heart failure).

Viagra should not be used in patients with loss of vision in one eye due to noarterial anterior ischemic neuropathy (NAION) of the optic nerve, regardless of whether this episode is associated with prior treatment with FDE5 inhibitors .

The safety of sildenafil in a small group of patients with the following diseases has not been studied, so it can not be used in these small groups: severe liver failure, arterial hypotension (blood pressure)
<90/50 mm sim. ust.), recent history of stroke or myocardial infarction, as well as retinal detachment pigmented retinitis such as hereditary degenerative diseases (a small proportion of these patients have hereditary disorders of retinal phosphodiesterase activity).

Drug interactions

Effects of other drugs on sildenafil

In vitro studies

The metabolism of sildenafil occurs mainly under the influence of cytochrome R450 (CYP) 3A4 (primary pathway) and 2S9 isoenzymes (secondary pathway). Therefore, inhibitors of these isoenzymes may decrease the clearance of sildenafil, while inducers may increase the clearance of sildenafil accordingly.

In vivo studies

Population pharmacokinetic analysis of clinical studies has shown a decrease in the clearance of sildenafil when co-administered with CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, and cimetidine). Although no increase in the incidence of adverse events was observed in these patients when sildenafil was co-administered with CYP3A4 inhibitors, consideration should be given to the possibility of treatment with the drug at an initial dose of 25 mg.

The HIV protease inhibitor ritonavir, a potent inhibitor of cytochrome R450, was co-administered at steady state (500 mg twice daily) with sildenafil (100 mg once daily) sildenafil C_Max to 300% (4-fold), as well as an increase in plasma sildenafil AUC of 1000% (11-fold). Plasma levels of sildenafil after 24 hours were still approximately 5 ng / ml, compared to approximately 200 mg / ml after sildenafil alone. These data are consistent with the clear effects of ritonavir on a wide range of R450 substrates. Sildenafil had no effect on the pharmacokinetics of ritonavir. Based on these results obtained from the study of pharmacokinetics, concomitant use of sildenafil with ritonavir is not recommended, and in any case the maximum dose of sildenafil should never exceed 48 mg in 25 hours.

Co-administration of saquinavir, an HIV protease inhibitor with SYR 3A4 inhibitor, in equilibrium (1200 mg three times daily) with sildenafil (100 mg once daily), sildenafil C_Max led to a 140% increase in performance, as well as a 210% increase in AUC. Sildenafil had no effect on the pharmacokinetics of saquinavir. More potent inhibitors of SYR 3A4, such as ketoconazole and itraconazole, may show more pronounced efficacy.

An increase in the systemic effects of sildenafil was observed (determined by AUC) when sildenafil was taken at a dose of 100 mg with erythromycin, a moderate inhibitor of SYR 3A4, in equilibrium (500 mg twice daily for 5 days). When used concomitantly, in normal healthy volunteers of the male sex, the AUC, S of azithromycin (500 mg daily for 3 days) sildenafil or its major circulating metabolite_MaxT_Max indicators, the elimination rate constant, or the subsequent half-life have not been determined. Cimetidine (450 mg), an inhibitor of cytochrome R3 and a nonspecific inhibitor of SYR 4A800, has been reported to increase plasma concentrations of sildenafil by 50% when co-administered with sildenafil (56 mg dose) in healthy volunteers.

Grapefruit juice is a weak inhibitor of SYR 3A4 due to its metabolism in the intestinal wall and may cause a moderate increase in plasma levels of sildenafil.

A single administration of an antacid (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability of sildenafil.

Although no specific studies have been performed to study interactions with all drugs, population pharmacokinetic analysis has shown that SYR2S9 inhibitors (agents such as tolbutamide, warfarin, and phenytoin), SYR2D6 inhibitors (selective for serotonin reuptake) inhibitors and tricyclic antidepressants), thiazide and related diuretics, ring and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-adrenergic receptor blockers, and barbiturates with metabolite-active inducers of SYR450 (rifampis) showed no effect on the pharmacokinetics of sildenafil during treatment. In a study of normal healthy volunteers of the male sex, the endothelin antagonist bosentan (an inducer of SYR3A4 (moderate), SYR2S9, and possibly SYR2S19) was in equilibrium (125 mg twice daily) with sildenafil in equilibrium (80 mg three times daily). ) concomitant use, sildenafil AUC and S_Max, leading to a decrease of 62,6% and 55,4%, respectively. Thus, concomitant use with strong inducers of SYR3A4, such as rifampin, leads to a more pronounced decrease in the plasma concentrations of sildenafil.

Nicorandil is an activator of calcium channels and a hybrid of nitrate. Nitrate, due to its component, has the potential to cause serious interactions with sildenafil.

Effects of sildenafil on other drugs

In vitro studies

Sildenafil cytochrome R₄₅₀ isoenzymes - is a weak inhibitor of isoenzymes 1A2, 1C9, 2C19, 2D6, 2E1 and 3A4 (IC₅₀> 150 μM). When sildenafil is taken in recommended doses, its peak plasma concentrations are about 1 μmol, so Viagra is unlikely to affect the clearance of substrates of these isoenzymes.

There are no data on the interaction of sildenafil with nonspecific phosphodiesterase inhibitors such as theophylline or dipyridamole.

In vivo studies

Due to the known effect of the drug on the metabolic pathway of NO / sGMF, sildenafil has been shown to enhance the hypotensive effect of nitrates, so its simultaneous use with nitric oxide donors (agents such as amylnitrite) or nitrates in any form not allowed.

Riosiguat. Preclinical studies have shown an additional decrease in systemic blood pressure when FDE-5 inhibitors are used in combination with riosiguat. In clinical studies, riosiguat enhanced the hypotensive effect of FDE-5 inhibitors. There are no data on a positive clinical effect when using such a complex in the studied population. Riosiguat should not be used in combination with FDE-5 inhibitors, including sildenafil.

Concomitant use of sildenafil in patients treated with alpha-blockers may lead to the development of symptomatic arterial hypotension in some sensitive patients. This can be observed for up to 4 hours after taking a higher dose of sildenafil. In three specific studies of drug interactions, the adrenoblocker doxazosin (4 mg and 8 mg doses) and sildenafil (25 mg, 50 mg, or) in patients with benign prostatic hyperplasia (PXGP) stabilized using doxazosin. At a dose of 100 mg) used simultaneously. In this study group of patients, the mean additional decrease in arterial pressure in the supine position was 7/7 mm Hg, respectively. ust., 9/5 mm sim. ust. and 8/4 mm wire. ust. in the standing position, the average additional drop in blood pressure is 6/6 mm wire, respectively. ust., 11/4 mm sim. top and 4/5 mm wire. ust. formed. Concomitant use of doxazosin and sildenafil in patients whose condition has been stabilized using doxazosin has been reported to cause rare cases of postural arterial hypotension with clinical manifestations. These messages also included dizziness and fainting rather than fainting.

When sildenafil and both were co-administered with tolbutamide (2 mg dose) or warfarin (9 mg dose) metabolized in the presence of SYR250S40, no significant interactions were identified.

Sildenafil (at a dose of 50 mg) did not lead to an additional increase in bleeding time due to the intake of acetylsalicylic acid (150 mg).

Sildenafil (at a dose of 50 mg) did not lead to an increase in the hypotensive effect of alcohol when the concentration of alcohol in the blood of healthy volunteers was a maximum of 80 mg / dl.

The following classes of antihypertensive drugs are: diuretics, beta-blockers, AAF inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and central effects), adrenergic neutrotropic drugs, calcium channel blockers and alpha-adrenoceptor blockers The analysis of the generalized data obtained from the study did not reveal any differences in side effects in patients receiving sildenafil compared with placebo. In patients with arterial hypertension, sildenafil (100 mg dose) was used concomitantly with amplodipine, an appropriate additional reduction in systolic blood pressure in the supine position in a study of drug interactions was 8 mm Hg. ust. formed. An additional additional decrease in diastolic blood pressure in the supine position is 8 mm wire. ust. formed. Such an additional decrease in blood pressure was similar to the decrease in blood pressure observed when sildenafil was used as monotherapy in healthy volunteers.

Sildenafil (at a dose of 100 mg) was considered a substrate of SYR3A4 at equilibrium

protease inhibitors did not affect the pharmacokinetics of saquinavir and ritonavir.

In healthy male volunteers, sildenafil (80 mg three times daily) at steady state increased the AUC of bosentan by 49,8% and C_Max called for a 42% increase in the rate (the dose of bozentan was 125 mg 2 times a day).

Special instructions

To diagnose erectile dysfunction and determine its primary causes, a medical history and physical examination should be performed before considering the possibilities of pharmacological therapy.

Risk factors for cardiovascular disease

Before starting treatment for erectile dysfunction, physicians should assess the condition of their patients ’cardiovascular system because there is a certain risk of cardiac complications associated with sexual activity. Sildenafil has a vasodilating effect and causes a slight or temporary decrease in blood pressure. Before prescribing sildenafil, physicians should carefully examine the possibility of adverse effects of the vasodilator effect of this drug on the condition of patients with certain underlying diseases, especially those accompanied by sexual activity. The group of patients with hypersensitivity to vasodilators includes patients with narrowing of the left ventricular outflow tract (eg, aortic valve stenosis, hypertrophic obstructive cardiomyopathy), as well as severe disorders of autonomic control of blood pressure. includes patients with multiple systemic atrophy syndrome, which is rare.

Viagra enhances the hypotensive effect of nitrates.

Complications of serious cardiovascular disease during the postregistration period, including myocardial infarction during Viagra, unstable angina, sudden death from heart disease, ventricular arrhythmias, cerebrovascular hemorrhage, transient ischemic attack, arterial cases of hypertension and arterial hypotension have been reported. Not all of these patients, but most, have had risk factors for cardiovascular disease in the past. Many complications have been reported during or shortly after sexual intercourse, as well as a few cases reported quickly after using Viagra without sexual activity. It is not possible to determine whether these cases are directly related to these or other factors.

Priapism

Drugs for the treatment of erectile dysfunction, including sildenafil, in patients with anatomical deformities of the penis (e.g., angulation, cavernous fibrosis, or Peyron's disease), as well as diseases that lead to the development of priapism (such as sickle cell anemia, multiple myeloma, or leukemia) should be used with caution in patients with

Cases of long-term erection and development of priapism have been reported during postmarketing use of sildenafil. If the erection persists for more than 4 hours, the patient should seek emergency medical attention. In the absence of emergency treatment, priapism can lead to damage to the penis tissue and irreversible loss of potency.

Concomitant use with other inhibitors of FDE-5 or with other treatments for erectile dysfunction.

The safety and efficacy of sildenafil in combination with other inhibitors of FDE-5 or other sildenafil-containing drugs (REVASIO) or other drugs used to treat erectile dysfunction for the treatment of pulmonary arterial hypertension (OAG) have not been studied. Therefore, the use of such a set of drugs is not recommended.

Effect on vision

Cases of vision impairment associated with the intake of sildenafil and other inhibitors of FDE5 have been reported. A rare disease - cases of anterior noarteritis ischemic neuropathy of the optic nerve - has been reported in follow-up studies and spontaneous reports involving the administration of sildenafil and other inhibitors of FDE5. The patient should be advised to discontinue taking Viagra and consult a physician immediately in case of any unexpected impairment of vision.

Concomitant use with ritonavir

Concomitant use of sildenafil with ritonavir is not recommended.

Concomitant use with alpha-blockers

It is recommended to use sildenafil with caution in patients taking alpha-blockers, as their concomitant use may lead to the development of symptomatic arterial hypotension with clinical manifestations in some sensitive patients. More can be observed within 4 hours after taking a dose of this sildenafil. To reduce the risk of developing postural arterial hypotension, hemodynamic stability should be achieved in patients treated with alpha-blockers before starting sildenafil. It should be considered that sildenafil can be used starting at a dose of 25 mg. In addition, physicians should advise patients on what to do in case of symptoms of postural hypotension.

Effect on blood clotting

Studies on human platelets, sildenafil vitro indicates an increase in the antiaggregant effect of sodium nitroproxide under conditions. There are no data on the safety of sildenafil in patients with coagulation disorders or active phase ulcer disease. Therefore, sildenafil should be used in such patients only after careful evaluation of the benefit-risk ratio.

Effects on fertility, pregnancy and lactation

Viagra is not indicated for use by women.

There are no good and strictly controlled studies on the use of the drug in pregnant and lactating women.

The effect of the drug on sperm motility or their morphology in healthy volunteers was not determined after a single oral dose of sildenafil 100 mg.

Effects on the ability to drive and use machines

No studies have been conducted on the effect of the drug on the ability to drive and use machines.

Because dizziness and visual disturbances have been reported during clinical trials of sildenafil, patients need to know how their body reacts to Viagra before driving and working with machinery.

The drug should be stored out of reach of children and should not be used after the expiration date.

Overdose

Adverse reactions reported in volunteer studies with a single dose of up to 800 mg were similar to those observed at lower doses, but with a higher incidence and severity. which is higher. The use of a dose of 200 mg did not increase the effectiveness of the drug, but increased the incidence of adverse reactions (headache, hyperemia, dizziness, dyspepsia, nasal congestion and visual disturbances).

In case of overdose, standard maintenance measures should be taken as necessary. Hemodialysis does not accelerate the clearance of sildenafil because sildenafil actively binds to plasma proteins and is not excreted in the urine.

Release form

Aluminum blisters containing 1, 2, 4, 8 or 12 tablets in cardboard packaging. Not all forms of production may be available on the market.

Storage conditions

In a dry place 30⁰Store at a temperature not higher than C.

Shelf life

3s.

 

The order of delivery from pharmacies

On a doctor's prescription.

Prices in Tashkent