Viagra film-coated tablets 50 mg blister 4 pcs

Pharmacodynamics.

Mechanism of action: Sildenafil is an oral drug indicated for the treatment of erectile dysfunction. Upon sexual arousal, the drug restores diminished 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 during 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 corpus cavernosum, contributing to increased blood flow.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase-5 (PDE-5) in the corpus cavernosum, where PDE5 is responsible for the breakdown of cGMP. The effects of sildenafil on erection are peripheral in nature. Sildenafil does not have a direct relaxant effect on the isolated human corpus cavernosum, but it potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, sildenafil’s inhibition of PDE5 leads to an increase in cGMP levels in the corpus cavernosum. Thus, sexual arousal is required for sildenafil to produce the desired pharmacological effect.

Effect on pharmacodynamics. In vitro studies have demonstrated the selectivity of sildenafil for PDE-5, which is actively involved in the erection process. The effect of sildenafil on PDE-5 is more potent than on other known phosphodiesterases. This effect is 10 times more potent 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 for PDE5 is 80 times higher than its selectivity for PDE-1, 700 times higher than for PDE-2, PDE3, PDE-4, PDE-7, PDE-8, PDE-9, PDE-10 and PDE-11. In particular, the selectivity of sildenafil for PDE5 is 4000 times higher than its selectivity for PDE3 – a cGMP-specific isoform of phosphodiesterase involved in the regulation of heart rate.

Pharmacokinetics

Absorption. Sildenafil is rapidly absorbed. Cmax _of the drug in blood plasma is achieved within 30-120 min (with a median of 60 min) after oral administration in the fasted state. The average absolute bioavailability after oral administration is 41% (with a range of values ​​25-63%). In the recommended dose range (25-100 mg), the AUC and Cmax _of sildenafil after oral administration increase proportionally to the dose.

When sildenafil is taken with food, the extent of absorption is reduced with a mean prolongation of Tmax to 60 min and a mean decrease in Cmax _by 29%.

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

In healthy volunteers who received a single dose of 100 mg of sildenafil, 0.0002% (average 188 ng) of the administered dose was detected in the ejaculate after 90 minutes.

Biotransformation. Sildenafil is metabolized primarily by the hepatic microsomal isoenzymes CYP 3A4 (major pathway) and CYP 2C9 (minor pathway). The major circulating metabolite is formed by N-demethylation of sildenafil. The selectivity of the metabolite for PDE5 is comparable to that of sildenafil, and the activity of the metabolite for PDE5 is approximately 50% of that of the parent compound. Plasma concentrations of this metabolite are approximately 40% of those of sildenafil. The N-demethylated metabolite undergoes further metabolism, and the half-life _is approximately 4 hours.

Elimination. The total clearance of sildenafil is 41 l / h, resulting in a T _½ of 3-5 h. After both oral and intravenous administration, sildenafil is excreted as metabolites mainly in the feces (about 80% of the administered oral dose) and to a lesser extent in the urine (about 13% of the administered oral dose).

Pharmacokinetics in special patient groups

Elderly patients: In healthy elderly volunteers (aged ≥65 years), a decrease in sildenafil clearance was observed, which resulted in an increase in plasma concentrations of sildenafil and its active N-demethylated metabolite by approximately 90% compared with the corresponding concentrations in healthy younger volunteers (18-45 years). Due to age-related differences in plasma protein binding, the corresponding increase in plasma concentrations of free sildenafil was approximately 40%.

Renal impairment. 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 mean AUC and Cmax _of the N-demethylated metabolite increased by 126 and 73%, respectively, compared with those in age-matched volunteers without renal impairment. However, due to high interindividual variation, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance 30 ml/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax _of 100 and 88%, respectively, compared with age-matched volunteers without renal impairment. In addition, the AUC and Cmax values _​​of the N-demethylated metabolite were significantly increased by 79 and 200%, respectively.

Hepatic impairment: In volunteers with mild to moderate liver cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increased AUC (84%) and C _max (47%) compared to age-matched volunteers without hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

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 sexual intercourse. Sexual arousal is necessary for Viagra to be effective.

The drug is intended for oral administration.

Adults. The recommended dose for adults is 50 mg, taken as needed approximately 1 hour before sexual intercourse. Based on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg.

The maximum recommended dose is once a day. When Viagra is taken with food, the effect of the drug may occur later than when taken on an empty stomach.

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

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

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

Patients receiving other treatments: If patients are receiving concomitant CYP 3A4 inhibitors (see Interactions), a starting dose of 25 mg should be considered (except for ritonavir, which is not recommended for use with sildenafil, see Interactions).

To minimize the risk of orthostatic hypotension, patients taking α-blockers should be stabilized before initiating sildenafil. A starting dose of 25 mg sildenafil should also be considered (see Interactions).

• Hypersensitivity to the active substance or any other component of the drug. Concomitant use with NO donors (such as amyl nitrite) or nitrates in any form is contraindicated, since sildenafil is known to affect the NO/cGMP metabolic pathway and potentiates the hypotensive effect of nitrates. Loss of vision in one eye due to non-arterial anterior ischemic optic neuropathy, regardless of whether this pathology is associated with previous use of phosphodiesterase-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 retinal diseases such as retinitis pigmentosa (a small number of such patients have genetic disorders of the PDE of the retina), since the safety of sildenafil has not been studied in patients in these subgroups.

The safety profile of Viagra is based on data from 9570 patients in 74 placebo-controlled clinical trials. The most commonly reported adverse reactions were headache, flushing, dyspepsia, visual disturbances, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia and blurred vision. Post-marketing data on adverse reactions were collected over a period of more than 10 years. As 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 estimated.

All clinically significant adverse reactions that were observed in clinical trials more often than with placebo are listed in the table below according to the classification “system – organ – class” and frequency: very common (≥1 / 10), common (≥100 and 1/10), uncommon (≥1000 and 1/100) and rare (≥10,000 and 1/1000). Within each frequency grouping, adverse reactions are listed in order of decreasing seriousness.

Infectious and invasive diseases.

Uncommon: rhinitis.

From the immune system.

Uncommon: hypersensitivity.

From the nervous system.

Very common: headache.

Common: dizziness.

Uncommon: drowsiness, hypoesthesia.

Rare: stroke, transient ischemic attack, convulsions*, recurrent convulsions*, syncope.

From the organ of vision.

Common: color perception disorder**, visual disturbance, blurred vision.

Uncommon: lacrimation disorder ***, eye pain, photophobia, photopsia, ocular hyperemia, visual brightness, conjunctivitis.

Rare: non-arteritic anterior ischemic optic neuropathy*, retinal vascular occlusion*, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floating vitreous opacities, iris disorders, mydriasis, halos in the field of vision, eye edema, eye swelling, eye disorders, conjunctival hyperemia, eye irritation, abnormal eye sensation, eyelid edema, sclera discoloration.

From the side of the organs of hearing and vestibular apparatus.

Uncommon: dizziness, tinnitus.

Rare: deafness.

From the heart.

Uncommon: tachycardia, palpitations.

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

From the side of the vessels.

Common: flushing, hot flushes.

Uncommon: hypertension, hypotension.

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

Common: nasal congestion.

Uncommon: epistaxis, sinus congestion.

Rare: feeling of tightness in the throat, swelling of the nasal mucosa, dryness in the nose.

From the gastrointestinal tract.

Common: nausea, dyspepsia.

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

Rare: oral hypoesthesia.

On the skin and subcutaneous tissue.

Uncommon: rash.

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

Musculoskeletal and connective tissue disorders.

Uncommon: muscle pain, pain in extremities.

From the urinary system.

Uncommon: hematuria.

From the reproductive system and mammary glands.

Rare: penile bleeding, priapism * hematospermia, prolonged erection.

General disorders and administration site reactions.

Uncommon: chest pain, fatigue, feeling hot.

Rare: irritation.

Examination.

Uncommon: tachycardia.

*Reported only during post-marketing surveillance.

** Color perception disorders: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.

*** Lacrimation disorders: dry eyes, lacrimation disorders and increased lacrimation.

The following events were observed in 2% of patients in controlled clinical trials; causality has not been established. The reports included events that had a probable relationship to the drug. The events that were not listed were mild and the reports were too imprecise to be of significance.

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

Cardiovascular system: angina pectoris, AV block, migraine, postural hypotension, myocardial ischemia, cerebral thrombosis, sudden cardiac arrest, ECG abnormalities, cardiomyopathy.

Gastrointestinal: glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding, gingivitis.

From the blood and lymphatic system: anemia, leukopenia.

Metabolism and nutrition disorders: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

Musculoskeletal system: arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia gravis, synovitis.

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

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

Skin: urticaria, herpes, itching, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Specific sensations: sudden decrease or loss of hearing, earache, hemorrhage in the eye, cataract, dry eyes.

From the urogenital system: cystitis, nocturia, increased frequency of urination, breast enlargement, urinary incontinence, ejaculation disorders, swelling of the genitals, anorgasmia.

Post-marketing Experience: The following adverse reactions have been identified during post-marketing experience. Because these reactions are reported voluntarily and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were noted both because of their seriousness, the frequency of reporting, the lack of a clear alternative relationship, and a combination of these factors.

Cardiovascular and cerebrovascular events. Serious cardiovascular, cerebrovascular and vascular events, including cerebrovascular hemorrhage, subarachnoid and intracerebral hemorrhage, and pulmonary hemorrhage, have been reported in temporal association with the use of Viagra. Most, but not all, patients had pre-existing cardiovascular risk factors. Many of these events have been reported to occur during or immediately after sexual activity, and a few have occurred immediately after the use of Viagra without sexual activity. Others have occurred in the hours or days following the use of Viagra and sexual activity. It is not possible to determine whether these events are directly related to the use of the drug, to sexual activity, to pre-existing risk factors, or to a combination of these factors, or to other factors.

Blood and lymphatic system: Vaso-occlusive crisis. In a small, prematurely stopped study of Revatio (sildenafil) in patients with pulmonary hypertension secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil 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. Cases of sudden hearing loss or hearing impairment associated with the use of Viagra have been reported in the post-marketing setting. In some cases, underlying medical conditions and other factors that may have contributed to the development of hearing adverse reactions have been reported. In many cases, follow-up information is not available. It is not possible to determine whether these events are directly related to Viagra, to pre-existing risk factors for hearing loss, to a combination of these factors, or to other factors.

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

Rare cases of non-arteritic anterior ischemic optic neuropathy, which causes visual impairment, including permanent vision loss, have been reported in post-marketing experience and have been associated with the use of phosphodiesterase-5 inhibitors, including Viagra. Many, but not all, of the patients had anatomical or vascular risk factors for the development of non-arteritic anterior ischemic optic neuropathy, including (but not necessarily limited to) the following: low optic disc diameter ratio (congestive optic disc), age over 50 years, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are directly related to the use of phosphodiesterase-5 inhibitors or to the existing anatomical or vascular risk factors, or to a combination of all of these factors, or to other factors.

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after the registration of a medicinal product is important. This allows for continuous monitoring of the balance between benefits and risks associated with the use of this medicine. Physicians should report any suspected adverse reactions in accordance with legal requirements.

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.

Cardiovascular risk factors. Since sexual activity carries a certain cardiac risk, the physician should assess the cardiovascular status of a patient with erectile dysfunction before initiating any treatment. Sildenafil has a vasodilating effect, which is manifested by a mild and transient decrease in blood pressure. Before prescribing sildenafil, the physician should carefully consider whether this effect may have an adverse effect on patients with certain underlying diseases, especially in combination with sexual activity. Individuals with increased sensitivity to vasodilators include patients with obstruction of the outflow tract of the left ventricle (e.g. aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare syndrome of multiple system atrophy, one of the manifestations of which is severe dysregulation of blood pressure by the autonomic nervous system.

Viagra potentiates the hypotensive effect of nitrates.

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

Priapism: Treatment of erectile dysfunction, including sildenafil, should be administered with caution to patients with anatomical deformities of the penis (such as angulation, cavernous fibrosis, or Peyronie’s disease) or to patients with conditions predisposing to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Cases of prolonged erection and priapism have been reported in post-marketing experience. If an erection lasts more than 4 hours, patients should seek immediate medical attention. If not treated promptly, priapism can lead to penile tissue damage and permanent loss of potency.

Concomitant use with other phosphodiesterase-5 inhibitors or other drugs for the treatment of erectile dysfunction. The safety and efficacy of concomitant use of sildenafil with other phosphodiesterase-5 inhibitors or other drugs for the treatment of pulmonary arterial hypertension containing sildenafil (e.g. Revatio), or with other drugs for the treatment of erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Effects on vision. Spontaneous reports of visual defects have been associated with the use of sildenafil and other phosphodiesterase-5 inhibitors (see Adverse Reactions). Cases of non-arteritic anterior ischemic optic neuropathy, a rare condition, have been spontaneously reported and reported in an observational study in association with the use of sildenafil and other phosphodiesterase-5 inhibitors (see Adverse Reactions). Patients should be advised that in the event of sudden visual impairment, Viagra should be discontinued and a physician should be consulted immediately (see Adverse Reactions).

Concomitant use with ritonavir. Concomitant use of sildenafil and ritonavir is not recommended (see Interactions with other medicinal products).

Concomitant use of α-adrenergic blockers. Sildenafil should be used with caution in patients taking α-adrenergic blockers, as this combination may lead to symptomatic hypotension in some susceptible patients. Symptomatic hypotension usually occurs within 4 hours of sildenafil administration. To minimize the potential for postural hypotension in patients taking α-adrenergic blockers, patients should be stabilized with α-adrenergic blockers prior to initiating sildenafil. A starting dose of 25 mg should also be considered (see Dosage & Administration). Patients should also be instructed on what to do if they develop symptoms of orthostatic hypotension.

Effects on bleeding. The results of a study on human platelets indicate that sildenafil potentiates the antiaggregatory effects of sodium nitroprusside in vitro. There is no information on the safety of sildenafil in patients with coagulation disorders or acute gastrointestinal ulcers. Therefore, the use of sildenafil in these patients should only be considered after careful assessment of the benefit/risk ratio.

The film-coating of the tablets contains lactose. Viagra should not be used in men with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

After administration of 100 mg to healthy volunteers, no effect on sperm morphology or motility was observed (see Pharmacodynamics).

Hearing loss. Physicians should advise patients to discontinue use of phosphodiesterase-5 inhibitors, including Viagra, and seek immediate medical attention if they experience sudden hearing loss or hearing loss. These events, which may also be accompanied by tinnitus and dizziness, have been reported in association with the use of phosphodiesterase-5 inhibitors, including Viagra. It is not possible to determine whether these events are directly related to the use of phosphodiesterase-5 inhibitors or to other factors.

Concomitant use with antihypertensive drugs. Viagra has a systemic vasodilator effect and may further reduce blood pressure in patients taking antihypertensive drugs. In a separate drug interaction study of concomitant use of amlodipine (5 or 10 mg) and Viagra (100 mg) orally, a mean additional decrease in blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg was observed.

Sexually transmitted diseases. 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.

Pregnancy and breastfeeding: Viagra is not intended for use in women.

Children: This medicine is not indicated for use in persons under 18 years of age.

Ability to influence the reaction rate when driving vehicles or working with mechanisms. Studies of the effect of the drug on the ability to drive vehicles and work with mechanisms have not been conducted. Since cases of dizziness and visual disturbances were reported in clinical studies of sildenafil, before driving a vehicle or working with complex mechanisms, patients should find out their individual reaction to the use of Viagra.

Effects of other drugs on sildenafil

In vitro studies

Sildenafil is metabolized primarily by cytochrome P450 (CYP) isoform 3A4 (major pathway) and isoform 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance.

In vivo studies

Population pharmacokinetic analysis of clinical trial data has shown a decrease in sildenafil clearance when co-administered with CYP 3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although no increase in the incidence of adverse events was observed when sildenafil was co-administered with CYP 3A4 inhibitors, the recommended starting dose of sildenafil is 25 mg.

Co-administration of the HIV protease inhibitor ritonavir, a very potent P450 inhibitor, at steady state (500 mg once daily) with sildenafil (single dose of 100 mg) resulted in a 300% (4-fold) increase in sildenafil Cmax _and a 1000% (11-fold) increase in sildenafil plasma AUC. After 24 h, plasma sildenafil levels were still around 200 ng/ml compared to around 5 ng/ml when sildenafil was administered alone, consistent with the significant effect of ritonavir on a wide range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Based on these pharmacokinetic data, co-administration of sildenafil and ritonavir is not recommended; in any case, the maximum dose of sildenafil should not exceed 25 mg within 48 h.

Co-administration of the HIV protease inhibitor saquinavir, a CYP 3A4 inhibitor, at a steady-state dose (1200 mg 3 times daily) with sildenafil (100 mg once daily) resulted in a 140% increase in sildenafil Cmax _and a 210% increase in sildenafil systemic exposure (AUC). Sildenafil had no effect on the pharmacokinetics of saquinavir. More potent CYP 3A4 inhibitors, such as ketoconazole and itraconazole, are expected to have a more pronounced effect.

When sildenafil (100 mg once) and erythromycin, a specific CYP 3A4 inhibitor, were used at steady state (500 mg 2 times a day for 5 days), an increase in sildenafil AUC by 182% was observed. In healthy male volunteers, no effect of azithromycin (500 mg/day for 3 days) on the AUC, C _max, T max, elimination rate constant and subsequent T _½ of sildenafil or its main circulating metabolite was observed. Cimetidine (a cytochrome P450 inhibitor and a non-specific CYP 3A4 inhibitor) at a dose of 800 mg when administered 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 modest increase in plasma levels of sildenafil.

Single administration of antacids (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

Although specific drug interaction studies have not been conducted, population pharmacokinetic analysis suggests that sildenafil pharmacokinetics were not altered by concomitant use of drugs that belong to the CYP 2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP 2D6 inhibitor group (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium antagonists, β-blockers, or inducers of CYP 450 metabolism (such as rifampicin, barbiturates).

In a study in healthy male volunteers, co-administration of the endothelin antagonist bosentan (a moderate inducer of CYP 3A4, CYP 2C9 and possibly CYP 2C19) at steady state (125 mg twice daily) and sildenafil at steady state (80 mg three times daily) resulted in a 62.6% and 55.4% decrease in sildenafil AUC and Cmax, _respectively . Therefore, co-administration of potent CYP 3A4 inducers such as rifampicin may result in a more pronounced decrease in sildenafil plasma concentrations.

Nicorandil is a hybrid of a calcium channel activator and a nitrate. The nitrate component makes it possible for it to have a serious interaction with sildenafil.

Effect of sildenafil on other drugs

In vitro studies

Sildenafil is a weak inhibitor of cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC ₅₀ 150 μmol). Since sildenafil C _max 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 non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.

In vivo studies

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

In some susceptible patients, concomitant use of sildenafil and α-adrenergic blockers may result in symptomatic hypotension, most often occurring within 4 hours of sildenafil administration. In 3 specific drug interaction studies, the α-adrenergic blockers doxazosin (4 and 8 mg) and sildenafil (25; 50 and 100 mg) were administered concomitantly to patients with benign prostatic hyperplasia (BPH) who were stabilized on doxazosin. In these study populations, mean additional reductions in supine blood pressure of 7/7; 9/5 and 8/4 mm Hg and mean reductions in standing blood pressure of 6/6; 11/4 and 4/5 mm Hg, respectively, were observed. Symptomatic orthostatic hypotension has occasionally been reported with concomitant use of sildenafil and doxazosin in patients stabilized on doxazosin. These reports included dizziness and fainting, but without syncope.

Concomitant use of sildenafil and α-blockers may lead to symptomatic hypotension in some susceptible patients. This reaction has often occurred within 4 hours of sildenafil administration (see Dosage and Administration and Precautions). In three specific drug interaction studies of the α-adrenoceptor blockers doxazosin (4 and 8 mg) and sildenafil (25; 50 and 100 mg) administered concomitantly in patients with benign prostatic hyperplasia who were stabilized on doxazosin, mean additional decreases in supine blood pressure of 7/7; 9/5 and 8/4 mm Hg and mean decreases in standing blood pressure of 6/6; 11/4 and 4/5 mm Hg, respectively, were observed in these populations. Symptomatic orthostatic hypotension has occasionally been reported with concomitant use of sildenafil and doxazosin in patients stabilized on doxazosin. These reports included dizziness and fainting, but without 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 prolong bleeding time induced by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) potentiated the hypotensive effect of alcohol in healthy volunteers at mean maximum blood ethanol levels of 80 mg/dl.

In patients taking sildenafil, no differences in the side effect profile were observed compared to placebo when using such classes of antihypertensive drugs as diuretics, β-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers and α-blockers. In a specific interaction study, when sildenafil (100 mg) was used concomitantly with amlodipine in patients with hypertension, an additional decrease in supine blood pressure of 8 mm Hg was observed. The corresponding decrease in diastolic blood pressure was 7 mm Hg. These additional blood pressure reductions were comparable in magnitude to those observed with sildenafil alone in healthy volunteers (see Pharmacological properties).

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

In healthy male volunteers, the use of sildenafil at steady state (80 mg 3 times a day) resulted in an increase in AUC and C _max of bosentan (125 mg 2 times a day) by 49.8 and 42%, respectively.

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

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

In case of overdose, if necessary, resort to the usual supportive measures. Acceleration of sildenafil clearance during hemodialysis is unlikely due to the high degree of binding of the drug to plasma proteins and the lack of elimination of sildenafil in the urine.

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