Viagra 100mg 4 tablets — Made in France — Free Delivery

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Viagra 100mg 4 tablets — Made in France — Free Delivery
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Fareva Amboise Brand: Fareva Amboise

Pharmacological properties

Pharmacodynamics.

Mechanism of action. Sildenafil is an oral preparation for the treatment of erectile dysfunction. With sexual arousal, the preparation renews reduced erectile function by increasing blood flow to the penis.

The physiological mechanism of penile erection is the release of nitric oxide (NO) in the corpus cavernosum upon sexual stimulation. The released nitric oxide activates the enzyme guanylate cyclase, which stimulates an increase in cGMP levels, which, in turn, causes relaxation of the smooth muscles of the corpora cavernosa, promoting increased blood flow.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase-5 (PDE-5) in the corpus cavernosum, where PDE-5 is responsible for the breakdown of cGMP. The effects of sildenafil on erection are peripheral. Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum, but it powerfully enhances the relaxing effect of NO on this tissue. When the metabolic pathway NO / cGMP is activated, which occurs during sexual stimulation, inhibition of PDE-5 by sildenafil leads to an increase in the level of cGMP in the corpus cavernosum. Thus, in order for sildenafil to cause the desired pharmacological effect, sexual arousal is necessary.

Impact on pharmacodynamics. In vitro studies have demonstrated the selectivity of the effect of sildenafil on PDE-5, which is actively involved in the erection process. The effect of sildenafil on PDE-5 is more powerful than on other known PDEs. This effect is 10 times more powerful than the effect on PDE-6, which is involved in photoconversion processes in the retina. When using the maximum recommended doses, the selectivity of sildenafil to PDE-5 is 80 times higher than its selectivity to PDE-1, 700 times higher than to PDE-2, PDE-3, PDE-4, PDE-7, PDE-8, PDE -9, PDE-10 and PDE-11. In particular, the selectivity of sildenafil for PDE-5 is 4000 times higher than its selectivity for PDE-3, a cGMP-specific isoform of PDE, which is involved in the regulation of heart contractions.

Pharmacokinetics

Absorption. Sildenafil is rapidly absorbed. Cmax of the preparation in blood plasma is achieved within 30–120 minutes (with a median of 60 minutes) after oral administration on an empty stomach. The average absolute bioavailability after oral administration is 41% (with a range of 25–63%). In the recommended dose range (25–100 mg), the AUC and Cmax values ​​of sildenafil after oral administration increase in proportion to the dose.

When using sildenafil with food, the degree of absorption decreases with an average elongation of Tmax up to 60 minutes and an average decrease in Cmax by 29%.

Distribution. The average equilibrium volume of distribution (Vd) is 105 liters, which indicates the distribution of the preparation in the tissues of the body. After a single oral administration of sildenafil at a dose of 100 mg, the average Cmax of sildenafil is about 440 ng / ml (the coefficient of variation is 40%). Since the binding of sildenafil and its main N-desmethyl metabolite with blood plasma proteins reaches 96%, the average Cmax of free sildenafil reaches 18 ng / ml (38 nmol). The degree of binding to blood plasma proteins does not depend on the total concentrations of sildenafil.

In healthy volunteers who used sildenafil at a single dose of 100 mg, after 90 minutes, 0.0002% (on average - 188 ng) of the applied dose was determined in the ejaculate.

Biotransformation. Sildenafil metabolism is carried out mainly with the participation of microsomal isoenzymes of the liver CYP 3A4 (major pathway) and CYP 2C9 (minor pathway). The main circulating metabolite is formed by N-demethylation of sildenafil. The selectivity of the metabolite in relation to PDE-5 is comparable to that of sildenafil, and the activity of the metabolite in relation to PDE-5 is approximately 50% of the activity of the parent substance. Plasma concentrations of this metabolite are approximately 40% of the plasma concentrations of sildenafil. The N-demethylated metabolite undergoes further metabolism, and the T1 / 2 is approximately 4 hours.

Elimination. The total clearance of sildenafil is 41 l / h, predetermining a T½ of 3-5 hours. Both after oral administration and after intravenous administration, the excretion of sildenafil in the form of metabolites is carried out mainly with feces (about 80% of the administered oral dose) and less degree - with urine (about 13% of the administered oral dose).

Pharmacokinetics in special patient groups

Elderly patients. In healthy elderly volunteers (aged ≥65 years), there was a decrease in the clearance of sildenafil, which predetermined an increase in plasma concentrations of sildenafil and its active N-demethylated metabolite by approximately 90% compared with the corresponding concentrations in healthy young volunteers (18–45 years) ... Due to age-related differences in binding to blood plasma proteins, the corresponding increase in the plasma concentration of free sildenafil was about 40%.

Renal failure In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 ml / min), the pharmacokinetics of sildenafil remained unchanged after a single oral dose of 50 mg. The average AUC and Cmax of the N-demethylated metabolite increased by 126 and 73%, respectively, compared with such indicators in volunteers of the same age without renal dysfunction. However, due to the high interindividual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance 30 ml / min), sildenafil clearance decreased, which led to average increases in AUC and Cmax by 100 and 88%, respectively, compared with volunteers of the same age without renal impairment. In addition, the AUC and Cmax values ​​of the N-demethylated metabolite were significantly increased by 79 and 200%, respectively.

Liver failure. In volunteers with mild to moderate liver cirrhosis (classes A and B according to the Child-Pugh classification), the clearance of sildenafil decreased, which led to an increase in AUC (84%) and Cmax (47%) compared with volunteers of the same age without liver dysfunctions ... The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Indications

Viagra is recommended for men with erectile dysfunction, which is defined as the inability to achieve or maintain an erection of the penis necessary for successful intercourse. for the effective action of the preparation Viagra, sexual arousal is necessary.

Application

The preparation is intended for oral administration.

Adults. The recommended dose for adults is 50 mg, which is taken as needed approximately 1 hour before intercourse. Given the efficacy and tolerability, the dose can be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg.

The frequency of application of the maximum recommended dose of the preparation is 1 time per day. When using the preparation Viagra during a meal, the effect of the preparation may occur later than when it is used on an empty stomach.

Elderly patients. There is no need for dose adjustment in elderly patients (≥65 years).

Patients with renal impairment. For patients with mild to moderate renal insufficiency (creatinine clearance 30–80 ml / min), the recommended dose is the same as indicated above in the section "Adults". Since the clearance of sildenafil is reduced in patients with severe renal impairment (creatinine clearance 30 ml / min), the preparation should be started with a dose of 25 mg. Depending on the effectiveness and tolerability of the preparation, the dose can be increased to 50 and 100 mg.

Patients with hepatic impairment. Since in patients with hepatic impairment the clearance of sildenafil is reduced, for example, in cirrhosis, the use of the preparation should be started with a dose of 25 mg. Depending on the effectiveness and tolerability of the preparation, the dose can be increased to 50 and 100 mg.

Patients undergoing other treatments. If patients are concomitantly using CYP 3A4 inhibitors (see INTERACTIONS), an initial dose of 25 mg should be considered (with the exception of ritonavir, which is not recommended concomitantly with sildenafil, see INTERACTIONS).

In order to minimize the risk of developing orthostatic hypotension, the condition of patients using α-adrenergic receptor blockers should be stabilized before using sildenafil. An initial dose of sildenafil 25 mg should also be considered (see INTERACTIONS).

Contraindications

Hypersensitivity to the active substance or any other component of the preparation. simultaneous use with NO donors (such as amyl nitrite) or nitrates in any form is contraindicated, since it is known that sildenafil affects the NO / cGMP pathways and potentiates the hypotensive effect of nitrates. loss of vision in one eye due to non-arterial anterior ischemic neuropathy of the optic nerve, regardless of whether this pathology is associated with previous use of PDE-5 inhibitors or not. the presence of the following diseases: severe liver dysfunction, arterial hypotension (blood pressure 90/50 mm Hg), recent stroke or myocardial infarction, and known hereditary degenerative diseases of the retina, such as retinitis pigmentosa (a small number of such patients have genetic FDE disorders retinal), since the safety of sildenafil has not been studied in patients of these subgroups.

Side effects

The safety profile of Viagra is based on data obtained from 9570 patients in 74 placebo-controlled clinical trials. The most commonly reported adverse reactions were headache, hot flashes, dyspepsia, visual disturbances, nasal congestion, back pain, dizziness, nausea, hot flashes, blurred vision, cyanopsia, and blurred vision. information on adverse reactions in the framework of post-marketing surveillance was collected over a period of more than 10 years. since not all adverse reactions were reported to the applicant and not all adverse reactions were included in the safety database, the frequency of such reactions cannot be reliably determined.

All clinically significant adverse reactions that were observed in clinical trials more often than with placebo are shown in the table below in accordance with the system-organ-class classification and frequency: very often (≥1 / 10), often (≥100 and 1/10), sometimes (≥1000 and 1/100) and rarely (≥10,000 and 1/1000). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infectious and invasive diseases.

Uncommon: rhinitis.

From the immune system.

Uncommon: hypersensitivity.

From the nervous system.

Very common: headache.

Often: dizziness.

Uncommon: drowsiness, hypesthesia.

Rarely: stroke, transient ischemic attack, seizures *, recurrent seizures *, syncope.

On the part of the organ of vision.

Often: impaired color perception **, visual disturbances, blurred vision.

Uncommon: lacrimation disorders ***, eye pain, photophobia, photopsia, redness of the eyes, brightness of vision, conjunctivitis.

Rare: non-arterial anterior ischemic neuropathy of the optic nerve *, retinal vascular occlusion *, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floating opacities, vitreous disorders iris, mydriasis, the appearance of luminous circles around the light source (halo) in the field of view, eye edema, eye swelling, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in the eyes, eyelid edema, scleral discoloration.

On the part of the organ of hearing and vestibular apparatus.

Uncommon: dizziness, ringing in the ears.

Rarely: deafness.

From the side of the heart.

Uncommon: tachycardia, increased heart rate.

Rare: sudden coronary death *, myocardial infarction, ventricular arrhythmia *, atrial fibrillation, unstable angina.

From the side of the vessels.

Often: flushing of the face, hot flashes.

Uncommon: hypertension, hypotension.

On the part of the respiratory system, chest and mediastinum.

Often: nasal congestion.

Uncommon: epistaxis, sinus congestion.

Rarely: a feeling of constriction in the throat, swelling of the nasal mucosa, dryness in the nose.

From the gastrointestinal tract.

Often: nausea, dyspepsia.

Uncommon: gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth.

Rarely: oral hypoesthesia.

On the part of the skin and subcutaneous tissue.

Uncommon: rash.

Rarely: Stevens-Johnson syndrome *, toxic epidermal necrolysis *.

On the part of the musculoskeletal system and connective tissue.

Uncommon: myalgia, pain in the limbs.

From the urinary system.

Uncommon: hematuria.

On the part of the reproductive system and mammary glands.

Rare: bleeding from the penis, priapism * hematospermia, prolonged erection.

General disorders and reactions at the injection site.

Uncommon: chest pain, fatigue, fever.

Rarely: irritation.

Survey.

Uncommon: tachycardia.

* Reported only during a post-market study study.

** Impaired color perception: chloropsia, chromatopsia, cyanopsia, eritropsia, xanthopsia.

*** Violation of lacrimation: dry eyes, impaired lacrimation and increased lacrimation.

The following phenomena were observed in 2% of patients during controlled clinical trials; the causal relationship has not been determined. The reports included events that were likely to be related to the use of the preparation. The phenomena that were not listed were light and the reports were very imprecise to make a difference.

General: facial edema, photosensitivity, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury.

From the side of the cardiovascular system: angina pectoris, AV blockade, migraine, postural hypotension, myocardial ischemia, cerebral vascular thrombosis, sudden cardiac arrest, abnormal ECG results, cardiomyopathy.

From the gastrointestinal tract: glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, impaired liver function tests, rectal bleeding, gingivitis.

On the part of the blood and lymphatic system: anemia, leukopenia.

Metabolic and nutritional disorders: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

From the musculoskeletal system: arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia gravis, synovitis.

From the nervous system: ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.

From the respiratory system: BA, shortness of breath, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

From the side of the skin: urticaria, herpes, itching, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Specific sensations: sudden hearing loss or loss, ear pain, bleeding in the eye, cataracts, dry eyes.

On the part of the urogenital system: cystitis, nocturia, increased frequency of urination, enlargement of the mammary glands, urinary incontinence, impaired ejaculation, edema of the genitals, anorgasmia.

Post-market experience. After the preparation was launched on the market, the following adverse reactions were identified. Since these reactions are voluntarily reported and reported from populations of unknown size, it is not always possible to reliably estimate their frequency and establish a causal relationship to preparation exposure. These phenomena were noted both because of their severity, frequency of reporting, lack of clear alternative link, and through a combination of these factors.

Cardiovascular and cerebrovascular phenomena. Serious cardiovascular, cerebrovascular and vascular events have been reported, including cerebrovascular bleeding, subarachnoid and intracerebral bleeding, and pulmonary hemorrhage, which were associated in time with the use of Viagra. Most of the patients, but not all, had existing cardiovascular risk factors. It has been reported that many of these phenomena occurred during or immediately after sexual activity, and several phenomena occurred immediately with the use of Viagra without sexual activity. Other phenomena occurred within the next hours or days after the use of Viagra and sexual activity. It is impossible to establish whether these phenomena are directly related to the use of the preparation, with sexual activity, with existing risk factors or with a combination of these factors, or with other factors.

Circulatory and lymphatic systems: vaso-occlusive crisis. In a small, pre-suspended study of the use of the preparation Revazio (sildenafil) for patients with pulmonary hypertension secondary to sickle cell anemia, with sildenafil, the development of vaso-occlusive crises that required hospitalization was reported more often than with placebo. The clinical significance of this information for patients taking Viagra for the treatment of erectile dysfunction is unknown.

Nervous system: anxiety, transient global amnesia.

Specific sensations

Hearing. After the release of the preparation on the market, cases of sudden hearing loss or loss associated with time with the use of Viagra were reported. In some cases, the presence of medical conditions and other factors have been reported that may play a role in the development of adverse reactions from hearing. In many cases, there is no information on further medical follow-up. It is impossible to determine whether these phenomena are directly related to the use of Viagra, with existing risk factors for hearing loss, with a combination of these factors or with other factors.

Vision: temporary loss of vision, redness of the eyes, burning in the eyes, increased intraocular pressure, retinal edema, retinal vascular disease or bleeding, detachment of the vitreous humor.

After the preparation was launched on the market, cases of non-arterial anterior ischemic neuropathy of the optic nerve were rarely reported, which is the cause of visual impairment, including permanent loss of vision, which were associated with the use of PDE-5 inhibitors, including the preparation Viagra. Many, but not all, of the patients had anatomical or vascular risk factors for developing non-arterial anterior ischemic optic neuropathy, including, but not necessarily limited to: a low excavation diameter to optic nerve head (stagnant optic disc) ratio, age over 50 , hypertension, coronary artery disease, hyperlipidemia, and smoking. It is impossible to determine whether these events are directly related to the use of PDE-5 inhibitors or with existing anatomical or vascular risk factors, or with a combination of all of these factors, or with other factors.

Report suspected adverse reactions. The reporting of suspected adverse reactions after the registration of a medicinal product is essential. This allows continuous monitoring of the balance between benefits and risks associated with the use of this preparation. Physicians should report any suspected adverse reactions as required by law.

Special instructions

Before starting therapy, it is necessary to collect a medical history from the patient and conduct a physical examination to diagnose erectile dysfunction and determine its possible causes.

Risk factors for cardiovascular disease. Since sexual activity is accompanied by a certain risk from the heart, the doctor should assess the state of the cardiovascular system before starting any treatment for a patient with erectile dysfunction. Sildenafil has a vasodilating effect, which is manifested by a mild and short-term decrease in blood pressure. Before prescribing sildenafil, the physician should carefully weigh whether such an effect could have an adverse effect on patients with certain underlying medical conditions, especially in combination with sexual activity. Persons with hypersensitivity to vasodilators include patients with obstruction of the left ventricular outflow tract (eg, aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with a rare syndrome of multisystem atrophy, one of the manifestations of which is severe impairment of blood pressure regulation by the autonomic nervous system.

Viagra potentiates the hypotensive effect of nitrates.

In the post-marketing period, severe adverse reactions from the cardiovascular system were reported, including myocardial infarction, unstable angina pectoris, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension and arterial hypotension, which coincided in time with the use of the preparation. Most, but not all, patients had cardiovascular risk factors. Many of these adverse reactions were observed during or immediately after intercourse, and only a few - soon after using the preparation without sexual activity. Therefore, it is impossible to determine whether the development of such adverse reactions is directly related to risk factors, or their development is due to other factors.

Priapism. Preparations for the treatment of patients with erectile dysfunction, including sildenafil, should be used with caution in individuals with anatomical deformities of the penis (such as angulation, cavernous fibrosis, or Peyronie's disease), or in patients with conditions conducive to the development of priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

After the preparation was launched on the market, cases of prolonged erection and priapism were reported. If an erection lasts more than 4 hours, patients should seek immediate medical attention. In the absence of immediate treatment, priapism can damage the tissues of the penis and lead to a permanent loss of potency.

Simultaneous use with other PDE-5 inhibitors or other preparations for the treatment of erectile dysfunction. The safety and efficacy of concomitant use of sildenafil with other PDE-5 inhibitors or other preparations for the treatment of pulmonary artery hypertension containing sildenafil (eg Revacio), or with other preparations for the treatment of erectile dysfunction have been studied. Therefore, the use of such combinations is not recommended.

Effects on vision. Spontaneous reports of visual defects have been reported associated with the use of sildenafil and other PDE-5 inhibitors (see SIDE EFFECTS). Cases of non-arterial anterior ischemic optic neuropathy, which is a rare condition, have been spontaneously reported and reported in a surveillance study associated with the use of sildenafil and other PDE5 inhibitors (see SIDE EFFECTS). Patients should be warned that in case of sudden visual impairment, the use of Viagra should be discontinued and immediately consult a doctor (see CONTRAINDICATIONS).

Concomitant use with ritonavir. Concomitant use of sildenafil and ritonavir is not recommended (see INTERACTIONS).

Simultaneous use of α-adrenergic receptor blockers. Patients taking α-adrenergic receptor blockers should use sildenafil with caution, since this combination can lead to symptomatic hypotension in some predisposed patients. Symptomatic hypotension usually occurs within 4 hours after using sildenafil. In order to minimize the possible development of postural hypotension in patients taking α-adrenergic receptor blockers, their condition must be stabilized with α-adrenergic receptor blockers before starting the use of sildenafil. You should also consider using an initial dose of 25 mg (see APPLICATION). In addition, patients should be informed how to act in the event of symptoms of orthostatic hypotension.

Effect on bleeding. The results of a study of human platelets indicate that in vitro sildenafil potentiates the antiaggregatory effects of sodium nitroprusside. There is no information on the safety of using sildenafil in patients with bleeding disorders or acute gastrointestinal ulcers. Thus, the use of sildenafil in patients of this group is possible only after a careful assessment of the benefit / risk ratio.

The film coat of the tablets contains lactose. Viagra should not be used by men with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

After taking 100 mg in healthy volunteers, there was no effect on the morphology or motility of spermatozoa (see Pharmacodynamics).

Loss of hearing. Physicians should advise patients to stop using PDE-5 inhibitors, including Viagra, and seek immediate medical attention in cases of sudden hearing loss or loss. These phenomena, which can also be accompanied by tinnitus and dizziness, have been reported with an association in time with the use of PDE-5 inhibitors, including Viagra. It is impossible to determine whether these phenomena are directly related to the use of PDE-5 inhibitors or to other factors.

Simultaneous use with antihypertensive preparations. Viagra has a systemic vasodilator effect and can further lower blood pressure in patients using antihypertensive preparations. In a separate study of the preparation interaction of the simultaneous use of amlodipine (5 or 10 mg) and Viagra (100 mg) orally, an additional average decrease in systolic blood pressure of 8 mm Hg was observed. Art. and diastolic blood pressure - by 7 mm Hg. Art.

Sexually transmitted diseases. The use of the preparation Viagra does not protect against sexually transmitted diseases. Consideration should be given to instructing patients on the necessary precautions to protect against sexually transmitted diseases, including HIV.

During pregnancy and breastfeeding. Viagra is not intended for use in women.

Children. Not indicated for use by persons under the age of 18.

The ability to influence the reaction rate when driving or operating machinery. Studies of the effect of the preparation on the ability to drive vehicles and work with mechanisms have not been carried out. Since in clinical studies of the use of sildenafil, cases of dizziness and visual disturbances have been reported, before getting behind the wheel of a vehicle or working with mechanisms, patients need to find out their individual reaction to the use of Viagra.

Interactions

Effect of other preparations on sildenafil

In vitro study

Sildenafil metabolism occurs predominantly with the participation of isoform 3A4 (major pathway) and isoform 2C9 (minor pathway) of cytochrome P450 (CYP). Therefore, inhibitors of these isoenzymes are able to reduce the clearance of sildenafil.

In vivo study

Population pharmacokinetic analysis of clinical trial data demonstrated a decrease in the clearance of sildenafil when used simultaneously with CYP 3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although with the simultaneous use of sildenafil and CYP 3A4 inhibitors, there was no increase in the frequency of side effects, the recommended initial dose of sildenafil is 25 mg.

The simultaneous use of the HIV protease inhibitor ritonavir, a very potent inhibitor of P450, in a state of equilibrium concentration (500 mg once a day) and sildenafil (a single dose of 100 mg) led to an increase in the Cmax of sildenafil by 300% (4 times) and an increase in plasma AUC sildenafil by 1000% (11 times). After 24 hours, plasma levels of sildenafil were still about 200 ng / ml, compared with about 5 ng / ml for sildenafil alone, consistent with the significant effect of ritonavir on a wide range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Given these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended; in any case, the maximum dose of sildenafil should under no circumstances exceed 25 mg over 48 hours.

The simultaneous use of the HIV protease inhibitor saquinavir, an inhibitor of CYP 3A4, in a dose that provides an equilibrium concentration (1200 mg 3 times a day), and sildenafil (100 mg once a day) led to an increase in the Cmax of sildenafil by 140% and an increase in systemic exposure (AUC) sildenafil by 210%. No effect of sildenafil on the pharmacokinetics of saquinavir was found. More potent CYP 3A4 inhibitors such as ketoconazole and itraconazole are expected to have a more pronounced effect.

When using sildenafil (100 mg once) and erythromycin, a specific inhibitor of CYP 3A4, in an equilibrium state (500 mg twice a day for 5 days), an increase in the AUC of sildenafil by 182% was observed. In healthy male volunteers, there was no effect of azithromycin (500 mg / day for 3 days) on AUC, Cmax, Tmax, elimination rate constant and further T½ of sildenafil or its main circulating metabolite. Cimetidine (an inhibitor of cytochrome P450 and a nonspecific inhibitor of CYP 3A4) at a dose of 800 mg, when used simultaneously with sildenafil at a dose of 50 mg in healthy volunteers, led to an increase in plasma concentrations of sildenafil by 56%.

Grapefruit juice is a weak inhibitor of CYP 3A4 in the intestinal wall and may cause a moderate increase in plasma levels of sildenafil.

A single use of antacids (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability of sildenafil.

Although studies of specific interaction with all preparations have not been conducted, according to population pharmacokinetic analysis, the pharmacokinetics of sildenafil did not change when it was used simultaneously with preparations that belong to the group of CYP 2C9 inhibitors (tolbutamide, warfarin, phenytoin), the group of CYP 2D6 inhibitors (such as selective inhibitors of serotonin reuptake, tricyclic antidepressants), a group of thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium antagonists, β-adrenoreceptor antagonists (such as CYP metabolism inducers).

In a study with healthy male volunteers, the simultaneous use of the endothelin antagonist bosentan (a moderate inducer of CYP 3A4, CYP 2C9 and possibly CYP 2C19) in an equilibrium state (125 mg 2 times a day) and sildenafil in an equilibrium state (80 mg 3 times per day) led to a decrease in AUC and Cmax of sildenafil by 62.6 and 55.4%, respectively. Therefore, the simultaneous use of such powerful inducers of CYP 3A4, as rifampicin, can lead to a more pronounced decrease in the concentration of sildenafil in blood plasma.

Nicorandil is a hybrid of a calcium channel activator and nitrate. The nitrate component determines the possibility of its serious interaction with sildenafil.

Effect of sildenafil on other medicinal products

In vitro study

Sildenafil is a weak inhibitor of cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 150 μmol). Since the Cmax of sildenafil is approximately 1 μmol, the effect of Viagra on the clearance of substrates of these isoenzymes is unlikely.

There are no data on the interaction of sildenafil and such non-specific PDE inhibitors as theophylline and dipyridamole.

In vivo study

Since sildenafil is known to affect the metabolism of nitric oxide / cGMC, it was found that this preparation potentiates the hypotensive effect of nitrates, therefore, its simultaneous use with nitric oxide donors or with nitrates in any form is contraindicated (see CONTRAINDICATIONS).

In some patients predisposed to this, the simultaneous use of sildenafil and α-adenoreceptor blockers can lead to the development of symptomatic hypotension, which most often occurred within 4 hours after the use of sildenafil. In 3 studies of specific preparation interactions, the α-adrenergic receptor blocker doxazosin (4 and 8 mg) and sildenafil (25; 50 and 100 mg) were used simultaneously in patients with benign prostatic hyperplasia (BPH), the stabilization of which was achieved with the use of doxazosin ... In these study populations, there was an average additional reduction in blood pressure in the supine position of 7/7; 9/5 and 8/4 mm Hg. Art. and an average decrease in blood pressure in the standing position by 6/6; 11/4 and 4/5 mm Hg. Art. respectively. With the simultaneous use of sildenafil and doxazosin in patients whose condition stabilization was achieved with the use of doxazosin, the development of symptomatic orthostatic hypotension was sometimes reported. These reports dealt with cases of dizziness and lightheadedness, but no syncope.

The simultaneous use of sildenafil and blockers of α-adrenergic receptors can lead to the development of symptomatic hypotension in some predisposed patients. This reaction often occurred within 4 hours after the use of sildenafil (see APPLICATION and SPECIAL INSTRUCTIONS). In the course of three studies of the specific interaction of preparations with α-adrenergic receptor blockers doxazosin (4 and 8 mg) and sildenafil (25; 50 and 100 mg), used simultaneously in patients with benign prostatic hyperplasia, stabilization of which was achieved with the use of doxazosin. In these populations, a mean additional reduction in blood pressure in the supine position of 7/7 was observed; 9/5 and 8/4 mm Hg. Art. and an average decrease in blood pressure in the standing position by 6/6; 11/4 and 4/5 mm Hg. Art. respectively. With the simultaneous use of sildenafil and doxazosin in patients whose condition stabilization was achieved with the use of doxazosin, the development of symptomatic orthostatic hypotension was sometimes reported. These reports reported cases of dizziness and lightheadedness, but no syncope.

No significant interactions were observed with the simultaneous use of sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP 2C9.

Sildenafil (50 mg) did not lead to an increase in bleeding time caused by the use of acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers at an average maximum blood ethanol level of 80 mg / dL.

In patients taking sildenafil, there were no differences in the profile of side effects compared to placebo with the simultaneous use of such classes of antihypertensive preparations as diuretics, β-adrenergic blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive preparations (vasodilators and central action) , blockers of adrenergic neurons, blockers of calcium channels and blockers of α-adrenergic receptors. In a special study of the interaction with the simultaneous use of sildenafil (100 mg) and amlodipine in patients with hypertension, an additional decrease in systolic blood pressure in the supine position by 8 mm Hg was noted. Art. The corresponding decrease in diastolic blood pressure was 7 mm Hg. Art. In terms of magnitude, these additional reductions in blood pressure were comparable to those observed with the use of sildenafil alone in healthy volunteers (see PHARMACOLOGICAL PROPERTIES).

Sildenafil at a dose of 100 mg did not affect the pharmacokinetic parameters of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of CYP 3A4.

In healthy male volunteers, the use of sildenafil in an equilibrium state (80 mg 3 times a day) led to an increase in AUC and Cmax of bosentan (125 mg 2 times a day) by 49.8 and 42%, respectively.

Overdose

In studies on healthy volunteers with a single dose of the preparation in doses up to 800 mg, side effects were similar to those observed when taking Viagra in lower doses, but the frequency and severity increased.

The use of sildenafil at a dose of 200 mg did not lead to an increase in effectiveness, but caused an increase in the number of cases of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In case of overdose, use the usual supportive measures as necessary. An acceleration of the clearance of sildenafil during hemodialysis is unlikely due to the high degree of binding of the preparation to blood plasma proteins and the lack of elimination of sildenafil in the urine.

Storage conditions

At a temperature not exceeding 30 ° C, out of the reach of children.

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