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The main active substance is sildenafil, presented in the form of citrate.
As excipients, anhydrous calcium hydrogen phosphate, magnesium stearate, croscarmellose sodium, titanium dioxide (E 171), triacetin, MCC, hypromellose, indigo carmine aluminum varnish (E 132), lactose are used.
Viagra is distributed in the form of coated tablets. Tablets are in a blister made of aluminum foil, which in turn is located in a carton.
Pharmacodynamics. Viagra is an oral medication that is used to treat erectile dysfunction in men. The drug is a citrate salt of Sildenafil, a selective cGMP viagra generic name inhibitor of specific PDE-5.
The physiological mechanism of penile erection is the release of nitric oxide (NO) in the cavernous body during sexual stimulation. NO activates the enzyme guanylate cyclase, which causes an increase in cGMP, relaxation of the smooth muscles of the cavernous body, and an increase in blood flow to them.
Sildenafil does not have a direct relaxing effect on the isolated cavernous body of a person, however, it significantly increases the effectiveness of NO by inhibiting PDE-5, which is responsible for the splitting of cGMP in the cavernous body. When the local release of NO occurs during sexual stimulation, the inhibition of PDE-5 by sildenafil leads to an increase in the concentration of cGMP in the cavernous body, resulting in relaxation of the smooth muscle and an increase in blood flow to the cavernous body. The use of sildenafil in recommended doses will be ineffective without sexual stimulation.
In vitro studies have established that sildenafil has selectivity for PDE5. Its effect on PDE-5 is more pronounced than in relation to other known PDEs (10 times stronger than in relation to PDE-6, 80 times compared to PDE-1, 700 times compared to PDE-2, PDE-3, PDE-4, PDE-7 – PDE-11. In particular, sildenafil has a 400 times better selectivity for PDE-5 than PDE-3, cGMP specific PDE isoform, which participates in the processes of heart contraction.
Visual impairment. When using Sildenafil at a dose of 100 mg in some patients, after 1 h, a slight transient disturbance of color distinction (blue / green) was detected using the Famsworth-Munsell 100 test; 2 hours after taking the drug, these disorders disappear. A possible mechanism for the violation of color vision is considered to be the inhibition of PDE-6, which takes part in the process of transmitting light in the retina. The in vitro results show that the effect of Sildenafil on PDE-6 is 10 times less than its activity relative to PDE-5. Sildenafil does not affect visual acuity, perception contrast, electroretinogram, intraocular pressure, or pupilometry.
Efficiency. The effectiveness of Sildenafil, which was evaluated relative to the ability of the drug to ensure the onset and preservation of an erection sufficient for sexual intercourse, was demonstrated and maintained with prolonged use of the drug (1 year).
In the study when taking sildenafil in doses of 25, 50, 100 mg, an improvement in erection was observed in 62, 74, 82%, respectively. In addition to improving erectile function, an analysis of the international index of erectile function showed that treatment with sildenafil enhances orgasm and a sense of satisfaction from sexual intercourse. In the treatment with Sildenafil, improvement was noted in 59% of patients with diabetes mellitus; in patients with radical prostatectomy – 43%, in patients with spinal cord injury – 83%.
Pharmacokinetics. Within the recommended dose range, Sildenafil pharmacokinetics is proportional to dose. The drug is eliminated from the body primarily by biotransformation in the liver (mainly with the participation of cytochrome P450 3A4) with the formation of an active metabolite with properties similar to sildenafil.
Suction. Sildenafil is rapidly absorbed after oral administration with an absolute bioavailability of 41% on average (25–63%). Sildenafil inhibits PDE-5 enzyme in vitro up to 50% at a concentration of 3.5 nM. The average concentration in the blood plasma after the use of Sildenafil at a dose of 100 mg is approximately 18 ng / ml or 38 nM. The maximum plasma concentration is reached in 30–120 minutes (on average 60 minutes) after oral administration on an empty stomach. Absolute bioavailability when administered orally is 40% (within 25–63%). If the drug is taken with fatty foods, the absorption rate decreases and the time to reach maximum plasma concentration increases by an average of 60 minutes, and the maximum plasma concentration decreases by an average of 29%, but the degree of absorption is not affected (AUC decreased by eleven%).
Distribution. The average distribution of Sildenafil in the equilibrium state (Vss) is 105 liters over the counter viagra substitute, which indicates its penetration into the tissue. Both sildenafil and its main circulating N-dismethyl metabolite are approximately 96% bound to plasma proteins.
Protein binding does not depend on total concentrations of the drug.
In healthy volunteers who received Sildenafil (1 time in a dose of 100 mg), 90 minutes after taking the drug in the ejaculate were registered le; 0.0002% of the substance (average 188 ng) of the dose taken.
Metabolism. Sildenafil is metabolized mainly by liver isoenzymes localized in microsomes, CYP 3A4 (main route) and CYP 2C9 (secondary route).
The main circulating metabolite is formed due to N-dimethylation of Sildenafil. This metabolite is characterized by selectivity to PDE-5, similar to sildenafil, but its activity relative to PDE-5 in vitro is approximately 50% of the selectivity of the original preparation. Plasma concentrations of this metabolite make up approximately 40% of the respective concentrations of sildenafil. The N-dismethyl metabolite is metabolized and in the future, its final elimination half-life is approximately 4 hours.
Inference. The overall clearance of sildenafil is 41 l / h, the half-life is 3-5 hours. When administered orally, sildenafil is excreted as metabolites, mainly with feces (approximately 80% of the dose taken) and, to a lesser extent, with urine (approximately 13% of the dose taken) ).
Pharmacokinetics in special groups of patients.
Elderly patients. Elderly healthy volunteers (65 years and older) had reduced clearance of sildenafil, and concentrations of sildenafil and its N-dismethyl metabolite were approximately 90% higher than in healthy young volunteers (18–45 years). Given the age dependence in protein binding, the increase in plasma concentration of free sildenafil is almost 40%.
Patients with kidney failure. In volunteers with mild (creatinine clearance 50–80 ml / min) and moderately expressed (creatinine clearance 30–49 ml / min) insufficiency of the renal function, the pharmacokinetics of sildenafil after oral administration in a single dose of 50 mg did not change. In volunteers with severe (creatinine clearance le; 30 ml / min) insufficient renal function; clearance of sildenafil decreased, leading to an increase in AUC (by 100%) and an increase in the maximum blood concentration (by 88%) compared to volunteers of the same age without any renal impairment. In addition, AUC values and maximum blood concentrations for Nu; -dismetilovogo metabolite significantly increased (respectively by 200% and 79%) in patients with severe impaired renal function compared with patients with normal renal function.
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Patients with liver failure. In volunteers with mild and moderate liver cirrhosis (functional class A and B according to Child-Pugh classification), the clearance of sildenafil decreased, which led to an increase in AUC (by 84%) and an increase in the maximum plasma concentration (by 47%) compared to those of volunteers of the same age without liver failure. The pharmacokinetics of sildenafil in patients with severely impaired liver function has not been studied (Child-Pugh class C).
The results of preclinical studies, which were based on generally accepted studies of safety, toxicity of doses that are repeated, genotoxicity, carcinogenicity, and toxic effects on reproduction, revealed no particular risk to humans.
treatment of erectile dysfunction, which is defined as the inability to achieve and maintain an erection of the best place to buy viagra online penis, necessary for successful sexual intercourse. For effective action of Viagra you need sexual arousal.
tablets are intended for oral administration. To implement the effect of Sildenafil, sexual arousal is necessary.
Use in adults. The recommended dose for adults is 50 mg, which is taken as needed approximately 1 hour before sexual activity. Given the effectiveness and tolerability, the dose can be increased to 100 mg or reduced to 25 mg.
The maximum recommended dose is 100 mg. The maximum recommended frequency of admission – 1 time per day. The time of displaying the activity of Viagra can be increased when taken with food as compared with fasting viagra samples.
Use in patients with impaired renal function. In patients with mild to moderate renal insufficiency (creatinine clearance 30–80 ml / min), the dosing regimen does not change. Since patients with severe renal failure (creatinine clearance le; 30 ml / min) the clearance of sildenafil is reduced, the use of the drug should be started with a dose of 25 mg.
Use in patients with impaired liver function. Since in patients with hepatic insufficiency the clearance of sildenafil is reduced, for example, in case of cirrhosis, the use of the drug should be started with a dose of 25 mg.
Use in patients who use other treatments. Given the degree of interaction in patients who receive concomitant ritonavir therapy, it is recommended not to exceed the maximum single dose of 25 mg Sildenafil for 48 hours. The starting dose of 25 mg should be recommended for patients who receive concomitant treatment with CYP 3A4 inhibitors (for example, erythromycin, saquinavir, ketoconazole, itraconazole) ).
In order to reduce the risk of postural hypotension, patients should be stabilized during therapy. α-blockers before using Viagra. In addition, the appointment of the drug should begin with lower doses.
Use in children. Viagra is not indicated for use by persons under 18 years of age.
Use for patients of advanced age. For elderly patients, a change in dosage is not required.
Viagra use is contraindicated in patients with hypersensitivity to the active substance or to any other component of the drug.
Due to its effect on the exchange of NO / cGMP, sildenafil enhances the hypotensive effect of nitrates when used once or for a long time, therefore its simultaneous use with NO donators, organic nitrates or organic nitrites in any form is permanently or periodically contraindicated.
Drugs for the treatment of erectile dysfunction, including sildenafil, should not be used in patients for whom sexual activity is undesirable (for example, patients with severe cardiovascular diseases such as unstable angina or severe heart failure).
Viagra administration is contraindicated in patients with vision loss in one eye due to non-arterial anterior ischemic optic neuropathy, regardless of whether this has occurred viagra prank as a result of taking a PDE-5 inhibitor or not.
The safety of Sildenafil has not been studied in such subgroups of patients, and therefore its use is contraindicated: for patients with severely impaired liver function, with arterial hypotension (BP) le; 90/50 mmHg Art.), with a recent stroke or myocardial infarction and with known hereditary degenerative diseases of the retina, such as retinitis pigmentosa (a smaller proportion of these patients have a genetic disease of retinal PDE).
were transient, light or moderately pronounced. During the study, the frequency and severity of side effects increased with increasing doses. The nature of side effects in variable dose studies, which to a large extent reflected the recommended dosing regimen, was similar to fixed dose studies. The most frequent side effects were headache and flushing.
Very frequent side effects (1/10)
On the part of the nervous system: headache.
Since the cardiovascular system: vasodilation (hot flashes).
Frequent (1 / 100–1 / 10)
From the nervous system: dizziness.
On the part of the organ of vision: abnormal vision (blurred vision, hypersensitivity to light), chromatopsia (moderate degree, transient, mainly color vision).
Since the cardiovascular system: palpitation (palpitations).
On the part of the respiratory system: rhinitis (nasal congestion).
On the part of the digestive tract: dyspepsia.
When using the drug in doses exceeding the recommended, side effects are similar, but occur more often.
The use of Sildenafil does not affect the incidence of myocardial infarction and the rate of mortality from cardiovascular diseases.
During the post-registration period, atypical or uncommon reactions were observed while taking the drug:
Immune system disorders: hypersensitivity reactions (including skin rashes).
On the part of the nervous system: an epileptic seizure, a relapse of an epileptic seizure.
Since the cardiovascular system: tachycardia, hypotension, syncope, nosebleeds.
On the part of the digestive tract: vomiting.
On the part of the organ of vision: pain in the eyes, redness of the eyes.
Reproductive system: prolonged erection and / or priapism.
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To diagnose erectile dysfunction, determine the possible causes of the disease and assign adequate treatment, it is necessary to carefully study the patient’s medical history and conduct a thorough medical examination. For effective action of Viagra, sexual stimulation is necessary.
Some degree of risk is associated with sexual activity due to the possibility of a heart attack. Before starting the course of any treatment of erectile dysfunction, the doctor must check the patient’s cardiovascular system. Drugs intended to treat erectile dysfunction should not be used in patients for whom sexual activity is undesirable.
In the period after the introduction of the drug into a wide medical practice, serious cardiovascular complications were reported, which over time coincide with the intake of sildenafil. These include myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage and transient ischemic attack. Most of these patients had a history of cardiovascular risk factors. The prevailing number of such cases was observed during or immediately after the sexual load, a small part – after a short period after taking Sildenafil without sexual activity. Other cases occurred within hours or days after using sildenafil and sexual activity. Thus, it is impossible to establish a direct dependence of such cases with the use of Sildenafil, sexual load, with concomitant cardiovascular diseases, a combination of these factors or other factors. In healthy volunteers with a single dose of sildenafil in doses up to 100 mg, no clinically significant changes in the ECG were detected. The average maximum decrease in systolic blood pressure in a horizontal position after oral administration of the drug at a dose of 100 mg was 8.34 mm Hg. Art. The corresponding change in diastolic blood pressure in a horizontal position was 5.3 mmHg. Art. Lower than ever, but briefly, blood pressure cost of viagra decreased in patients who simultaneously took nitrates.
In studies, Sildenafil showed a systemic vasodilating effect, which led to a transient decrease in blood pressure. This effect is of little or no effect at all in most patients. However, when prescribing Sildenafil, the physician must carefully weigh the risk of adverse effects of the vasodilating action of the drug in patients with certain concomitant diseases, especially against the background of sexual activity. Hypersensitivity to vasodilators is observed in patients with left ventricular obstruction (aortic stenosis, obstructive hypertrophic cardiomyopathy), as well as with multiple manifestations of systemic atrophy, which are observed in isolated cases and manifest severe violations of autonomic control of blood pressure.
Viagra at a dose of 100 mg 1 time per day when taken orally in patients with severe heart disease (stenosis of 70% of at least one coronary artery) reduces the average systolic rest BP and diastolic BP by 7% and 6%, respectively, compared with the initial level. The mean pulmonary systolic pressure is reduced by 9%. Sildenafil has no effect on cardiac output and blood flow in stenotic coronary arteries due to an improvement (approximately 13%) in adenosine-stimulated blood flow reserve (in coronary arteries with and without stenosis).
In patients with erectile dysfunction and canadian viagra stable angina, who regularly took antianginal drugs (with the exception of nitrates) and used Sildenafil 100 mg 1 time per day, there was an increase in the duration of the treadmill test (19.9 s; 95% confidence interval 0.9 –38.9 c) and the average exercise time until exacerbation of angina pectoris is 423.6 and 403.7 s compared to placebo.
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In patients with concomitant hypertension who take 2 or more antihypertensive drugs at the same time, Sildenafil at a dose of 100 mg 1 time per day orally improved erection by 71%, increased the number of successful sexual attempts by 62%. The number of side effects was the same compared with patients in other populations who took 3 or more antihypertensive drugs.
In all studies using PDE-5 inhibitors, including Sildenafil, non-arterial anterior ischemic optic neuropathy (NAION) has been reported, which is the cause of reduced or loss of vision. Most of these patients had such risk factors as a reduced depth / area ratio (“stagnant disc”), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. No causal link has been established between the use of PDE-5 inhibitors and the occurrence of NAION. The physician should warn patients who have already had manifestations of NAION about a possible recurrence of NAION. Patients should be warned of the need to immediately consult a doctor in the event of a sudden deterioration of vision.
In patients with age-related retinal degeneration, Sildenafil at a dose of 100 mg 1 time per day was well tolerated and did not cause a clinical effect in the study of visual functions in tests (visual acuity, Amsler mesh, color recognition, artificial light flow, Gamfrey perimetry and photo-stress ).
Sildenafil is recommended to be used with caution to patients who simultaneously apply αβ-blockers, as in some cases it can lead to symptomatic hypotension. In order to minimize the risk of postural hypotension, stabilization of blood pressure should be achieved by α-blockers before applying sildenafil. Sildenafil should be started with low doses. In addition, doctors should tell patients what to do in case of symptoms of postural hypotension.
Some patients with congenital retinitis pigmentosa have genetic defects in retinal PDE. There is no information regarding the safety of prescribing Sildenafil to patients with retinitis pigmentosa, therefore, this group of patients should be prescribed Sildenafil with caution.
An in vitro human platelet study suggests that sildenafil enhances the antiaggregation effect of sodium nitroprusside (NO donator). There is no safety information regarding the administration of Sildenafil to patients with a tendency to bleeding or with acute gastric ulcer, therefore, this group of patients should be prescribed Sildenafil with caution.
Preparations for treating erectile dysfunction should be used with caution in patients with anatomical deformities of the penis (such as angulations, cavernous fibrosis, or Peyronie’s disease) or in patients with diseases that may lead to the development of priapism (such as sickle cell anemia, multiple myeloma, or leukemia ).
The safety and efficacy of combinations of Sildenafil with other types of treatment for erectile dysfunction have not been studied, so the use of such combinations is not recommended.
After oral administration of a single dose of 100 mg of Sildenafil, no effect on the motility and morphological properties of spermatozoa was viagra and alcohol observed in healthy volunteers.
A sudden decline and loss of hearing was reported in a small number of cases in post-marketing studies with the use of PDE-5 inhibitors, including sildenafil.
Most of these patients had risk factors for sudden hearing loss or loss. The causal relationships of the use of PDE-5 inhibitors and the sudden decrease and hearing loss in patients have not been established. In the event of a sudden decrease and hearing loss, patients should be advised to discontinue Sildenafil and consult a physician immediately.
During pregnancy and breastfeeding. Viagra is not intended for use in women.
Children. Viagra is not indicated for use by persons under 18 years of age.
The ability to influence the reaction rate when driving or working with other mechanisms. Studies of the effect of the drug on the ability to drive and work with mechanisms were not performed. Since dizziness and visual impairment were observed during a clinical trial of Sildenafil, patients should know their reaction to taking Viagra before driving or working with mechanisms.
Effect of other drugs on sildenafil.
In vitro studies: Sildenafil metabolism is mediated mainly by cytochrome P450 (CYP), in particular its ZA4 isoforms (primary pathway) and 2C9 (minor pathway) isoforms. Thus, inhibitors of these isoenzymes can reduce the elimination of Sildenafil, and the inducers of these enzymes can increase its excretion.
In vivo studies: a population-based pharmacokinetic analysis of the results of a clinical trial demonstrated a decrease in the clearance of sildenafil while it was used with inhibitors of CYP 3A4 (such as ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), an inhibitor of cytochrome P450 and a nonspecific inhibitor of CYP 3A4, with simultaneous administration to healthy volunteers at a dose of 50 mg, caused an increase in plasma concentration of Sildenafil by 56%. In the case of Viagra in a dose of 100 mg simultaneously with erythromycin, a specific CYP 3A4 inhibitor (500 mg 2 times a day for 5 days), an increase in AUC of Sildenafil by 182% was observed.
The simultaneous administration of HIV protease inhibitor saquinavir (1200 mg 3 times daily), which is also an inhibitor of CYP 3A4 and sildenafil, led to an increase in the maximum serdenafil concentration in blood serum by 140% and an increase in AUC by 210%. Viagra does not affect saquinavir pharmacokinetics. Strong inhibitors of CYP 3A4, such as ketoconazole and itraconazole, exhibit a more pronounced effect.
Simultaneous administration of ritonavir, an HIV protease inhibitor that is a highly viagra connect specific inhibitor of P450, in equilibrium (500 mg 2 times a day) with sildenafil (100 mg once) leads to an increase of up to 300% (4 times) in the maximum serden Sildenafil concentration to an increase of 1000% (11 times) AUC of sildenafil in the blood plasma. After 24 h, the concentration of Sildenafil in the blood plasma was approximately 200 ng / ml, whereas in the case of receiving only Sildenafil, its concentration was 5 ng / ml. This is due to the effect of ritonavir on P450 isoenzymes. Sildenafil does not affect ritonavir pharmacokinetics. When the dose of Sildenafil for subjects who received a CYP 3A4 inhibitor was applied as recommended, the concentration of Sildenafil in the blood plasma did not exceed 200 nM for any patient, and the drug had good tolerance.
A single antacid (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability of sildenafil.
CYP 2C9 inhibitors (such as tolbutamide, warfarin), CYP 2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors, calcium channel blockers, did not affect the pharmacokinetics of hearths, diuretics, ACE inhibitors, calcium channel blockers, had no effect on the pharmacokinetics of hearths, diuretics, ACE inhibitors, calcium channel blockers, had no effect on the pharmacokinetics of hearths;
In healthy volunteers, the effect of azithromycin (500 mg / day for 3 days) on AUC, the maximum concentration in the blood and the time to achieve it, the clearance and the half-life of sildenafil and its major metabolites have not been proven.
The effect of Viagra on other drugs.
In vitro studies: Sildenafil is a weak inhibitor of the cytochrome P450 isoforms, namely, the 1A2, 2C9, 2C19, 2D6, 2E1 and ZA4 isoenzymes (IK50 150 mu; M). In the case of its use in recommended doses, the maximum concentration of Sildenafil in the blood plasma reaches about 1 mu; M, because it is unlikely that Viagra is able to change the pharmacokinetics of the substrates of these isoenzymes.
In vivo studies: Sildenafil enhances the hypotensive effect with short-term and long-term use of nitrates, therefore one-time or course use of NO donators, organic nitrates generic viagra online or organic nitrites in any form with Sildenafil is contraindicated.
When sildenafil (25; 50 and 100 mg) was used in patients with benign prostatic hyperplasia simultaneously with therapy α-Blocker doxazosin (4 and 8 mg), which was maintained at a stable level, was followed by an additional decrease in blood pressure at 7/7 Hg. Art. 9/5 Hg. Art. and 8/4 Hg. Art. respectively, the average additional reduction of blood pressure of 6/6 Hg. Art. 11/4 Hg. Art. and 4/5 Hg. Art. respectively. When sildenafil and doxazosin were administered simultaneously to patients resistant to doxazosin therapy, infrequent cases of symptomatic postural hypotension were observed. Its signs are dizziness and incoordination under the action of light, but without loss of consciousness. Concomitant Treatment with Sildenafil Patients Who Apply α-adrenergic blocking therapy may cause symptomatic hypotension in some patients.
There are no signs of significant interaction of Sildenafil (50 mg) with tolbutamide (250 mg) or warfarin (40 mg), each of which is metabolized by CYP 2C9.
Sildenafil (100 mg) does not change the equilibrium state of the pharmacokinetics of HIV protease inhibitors, saquinara and ritonavir, which are CYP 3A4 inhibitors.
Sildenafil (50 mg) does not lead to an increase in the duration of bleeding caused by acetylsalicylic acid (150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers, who had a maximum blood alcohol level of 0.08% (80 mg / dl).
Sildenafil (100 mg) and amlodipine interactions were not observed in patients with hypertension. The average additional reduction in systolic blood pressure is 8 mmHg. Art. and 7 mm Hg. Art. – diastolic.
The safety analysis showed no difference in the profile of adverse reactions in patients taking sildenafil as monotherapy and in combination with antihypertensive drugs.
in studies on healthy volunteers with a single dose of the drug in doses up to 800 mg, the side effects were similar to those observed when taking Viagra in lower doses, but their incidence and severity increased. In case of overdose, maintenance therapy is necessary as necessary. Dialysis does not accelerate the elimination of the drug, since Sildenafil binds strongly to plasma proteins and is not excreted in the urine.
at a temperature up to 25 ° C.