Intagra film-coated tablets 100 mg 1 ps.

Pharmacodynamics. Mechanism of action. Sildenafil is an oral drug intended for the treatment of erectile dysfunction. During sexual arousal, the drug normalizes reduced erectile function by increasing blood flow to the penis.

The physiological mechanism that leads to an erection involves the release of nitric oxide (NO) in the corpora cavernosa during sexual arousal. The released NO activates the enzyme guanylate cyclase, which stimulates an increase in cyclic guanosine monophosphate (cGMP), which in turn causes relaxation of the smooth muscles of the corpora cavernosa, facilitating blood flow.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase 5 (PDE5) 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 isolated human corpus cavernosum, but it potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated by 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 shown that sildenafil is selective for PDE5, 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 used in 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, -3, -4, -7, -8, -9, -10 and -11. In particular, the selectivity of sildenafil for PDE5 is 4000 times higher than its selectivity for PDE3 – a cAMP-specific isoform of phosphodiesterase, which is involved in the regulation of cardiac contractility.

Pharmacokinetics. Absorption. Sildenafil is rapidly absorbed. C _max of the drug in blood plasma is achieved within 30-120 min (median – 60 min) after oral administration on an empty stomach. The average bioavailability after oral administration is 41% (range of values ​​- 25 to 63%). In the recommended dose range (25-100 mg), the AUC and C _max of sildenafil after oral administration increase in proportion 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 dose of sildenafil at a dose of 100 mg, the average total C _max of sildenafil in blood plasma is ≈440 ng / ml (coefficient of variation – 40%). Since the binding of sildenafil and its main N-desmethyl metabolite to plasma proteins is 96%, the average C _max of free sildenafil in blood plasma 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 took sildenafil once at a dose of 100 mg, 0.0002% (on average – 188 ng) of the dose was detected in the ejaculate after 90 minutes.

Sildenafil biotransformation is mainly carried out with the participation of the liver microsomal isoenzymes 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 for PDE5 is comparable to that of sildenafil, and in vitro the activity of the metabolite for PDE5 is approximately 50% of the activity of the parent substance. Plasma concentrations of this metabolite are ≈40% of the plasma concentration of sildenafil. The N-demethylated metabolite undergoes further metabolism, and its T _½ is ≈4 h.

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

Pharmacokinetics in special patient groups

Elderly patients. In healthy elderly volunteers (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 ≈90% compared with the corresponding concentrations in healthy young volunteers (18-45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentrations was ≈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-desmethyl metabolite increased by 126 and 73%, respectively, compared with these values ​​in volunteers of the same age without renal impairment. However, due to high individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance 30 ml/min), sildenafil clearance decreased, resulting in a mean increase in AUC and Cmax _of 100 and 88%, respectively, compared with volunteers of the same age without renal impairment. In addition, the AUC and Cmax _of the N-desmethyl metabolite were significantly increased by 200 and 79%, 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.

The drug Intagra is recommended for use in men with erectile dysfunction, which is defined as the inability to achieve or maintain a penile erection necessary for successful sexual intercourse.

For Intagra IC to be effective, sexual arousal is necessary.

For oral use.

Adults. The recommended dose of Intagra IC 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 frequency of administration is once daily. The effectiveness of the drug may be delayed when taken with food compared to when taken on an empty stomach.

Elderly patients: No dose adjustment is required for 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 stated above in the Adults section.

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance 30 ml/min), a dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be increased gradually to 50 and 100 mg if necessary.

Patients with hepatic impairment: Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis), a dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be increased gradually to 50 and 100 mg if necessary.

Patients taking other medications: If patients are taking CYP 3A4 inhibitors concomitantly (see Interactions with other drugs), a starting dose of 25 mg should be considered (with the exception of ritonavir, the use of which with sildenafil is not recommended – see Precautions).

To minimize the potential for postural hypotension in patients taking α-blockers, their condition should be stabilized with α-blockers before initiating sildenafil. A starting dose of 25 mg should also be considered (see Precautions, Interactions).

Children: The drug is not indicated for use in persons under the age of 18 years.

Hypersensitivity to the active substance or to any other component of the drug.

Concomitant use with NO donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the NO/cGMP metabolic pathway and potentiate the hypotensive effect of nitrates.

Conditions in which sexual activity is not recommended (e.g. severe cardiovascular disorders such as unstable angina or severe heart failure).

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 diseases such as severe liver dysfunction, arterial hypotension (BP 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 retinal PDE), since the safety of sildenafil has not been studied in such subgroups of patients.

In double-blind, placebo-controlled clinical trials, the most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flashes, visual disturbances, cyanopsia, and blurred vision.

All clinically significant adverse reactions observed in clinical trials more often than with placebo are listed below according to the classification “System / organ / class” and frequency: very common (≥1 / 10), common (≥1 / 100 1/10), uncommon (≥1000-1 / 100) and rare (≥1 / 10 000-1 / 1000). In addition, the frequency of clinically significant adverse reactions reported in the context of post-marketing experience is defined as unknown. Within each frequency grouping, adverse reactions are listed in order of decreasing seriousness.

Infectious and invasive diseases: often – rhinitis.

On the part of the immune system: infrequently – hypersensitivity.

From the nervous system: very often – headache; often – dizziness; infrequently – drowsiness, hypoesthesia; rarely – stroke, transient ischemic attack, convulsions *, recurrent convulsions *, syncope.

On the part of the organ of vision: often – color perception disorders (chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia), visual disorders, blurred vision; infrequently – lacrimation disorders (dry eyes, lacrimation disorders and increased lacrimation), eye pain, photophobia, photopsia, eye hyperemia, visual brightness, conjunctivitis; rarely – non-arterial 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, the appearance of luminous circles around the light source (halo) in the field of vision, eye edema, eye swelling, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in the eyes, eyelid edema, sclera discoloration.

From the organs of hearing and vestibular apparatus: infrequently – dizziness, tinnitus; rarely – deafness.

On the part of the heart: infrequently – tachycardia, palpitations (increased heart rate); rarely – sudden cardiac death *, myocardial infarction, ventricular arrhythmia *, atrial fibrillation, unstable angina.

Vascular: often – flushing, hot flashes; infrequently – hypertension, arterial hypotension.

From the respiratory system, chest and mediastinum: often – nasal congestion; infrequently – nosebleeds, sinus congestion; rarely – a feeling of tightness in the throat, swelling of the nasal mucosa, dryness in the nose.

On the part of the digestive system: often – nausea, dyspepsia; infrequently – gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth; rarely – oral hypoesthesia.

Skin and subcutaneous tissue disorders: infrequently – rash; rarely – Stevens-Johnson syndrome*, toxic epidermal necrolysis*.

Musculoskeletal and connective tissue disorders: uncommon – muscle pain, pain in extremities.

From the urinary system: infrequently – hematuria.

From the reproductive system and mammary glands: rarely – bleeding from the penis, priapism *, hematospermia, prolonged erection.

General disorders and administration site conditions: uncommon – chest pain, fatigue, feeling hot; rare – irritation.

Examination: infrequently – increased heart rate.

* Only reported in post-marketing studies of sildenafil.

The following events were reported in 2% of patients in controlled clinical trials of sildenafil; causality has not been established. The reports included events that had a probable relationship to sildenafil use. 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.

On the part of the digestive system: 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 mellitus, 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.

From the sensory organs: sudden decrease or loss of hearing, ear pain, 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 with sildenafil. 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 are noted due to their seriousness, frequency of reporting, lack of a clear alternative relationship, or a combination of these factors.

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

Blood and lymphatic system: Vaso-occlusive crisis. In a small, prematurely terminated study of sildenafil in patients with pulmonary arterial 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 finding for patients taking sildenafil for the treatment of erectile dysfunction is unknown.

Nervous system: anxiety, transient amnesia.

Sense organs

Hearing. Cases of sudden hearing loss or hearing impairment associated with sildenafil use 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 sildenafil use, 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, causing visual impairment, including permanent vision loss, have been reported in post-marketing experience with sildenafil, and have been associated with the use of phosphodiesterase-5 inhibitors, including sildenafil. 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 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, the patient’s medical history should be collected and a physical examination should be performed 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 patient’s cardiovascular status before initiating any treatment for erectile dysfunction. 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 adversely affect patients with certain underlying diseases, especially in combination with sexual activity. Patients with increased sensitivity to vasodilators include those with obstruction of the left ventricular outflow tract (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.

Sildenafil potentiates the hypotensive effect of nitrates (see Side effects).

Serious cardiovascular adverse reactions, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, and hypotension, have been reported in the postmarketing setting in patients taking sildenafil. Most, but not all, patients had risk factors for cardiovascular disease. Many of these adverse reactions occurred during or immediately after sexual intercourse, and only a few occurred shortly after taking sildenafil without sexual activity. Therefore, it is not possible to determine whether these adverse reactions are directly related to the risk factors or whether they are caused by other factors.

Priapism: Erectile dysfunction medications, including sildenafil, should be prescribed with caution in patients with anatomical deformities of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients with conditions that predispose to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Cases of prolonged erection and priapism have been reported since sildenafil was marketed. If an erection lasts more than 4 hours, patients should seek immediate medical attention. If not treated promptly, priapism can lead to damage to the penile tissues 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 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 associated 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, sildenafil 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 minimise the risk of postural hypotension in patients taking α-adrenergic blockers, their condition should be stabilised with α-adrenergic blockers before starting sildenafil. An initial dose of 25 mg should also be considered (see Dosage & Administration). Patients should also be advised what to do if they develop symptoms of orthostatic hypotension.

Effects on bleeding. Studies on human platelets have shown 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 peptic ulcer disease. Therefore, the use of sildenafil in these patients should only be considered after careful benefit/risk assessment.

The drug contains lactose, so it should not be used in men with rare hereditary disorders such as 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 Pharmacological properties).

Hearing loss. Physicians should advise patients to discontinue use of phosphodiesterase-5 inhibitors, including sildenafil, and seek immediate medical attention if they experience sudden decrease or loss of hearing. These events, which may also be accompanied by tinnitus and dizziness, have been reported in association with the use of phosphodiesterase-5 inhibitors, including sildenafil. 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. Sildenafil has a systemic vasodilator effect and may further reduce blood pressure in patients taking antihypertensive drugs. In a separate drug interaction study, concomitant use of amlodipine (5 or 10 mg) and sildenafil (100 mg) orally resulted in a mean additional reduction in blood pressure of 8 mm Hg systolic and 7 mm Hg diastolic.

Sexually transmitted diseases. Use of Intagra IC 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.

Use during pregnancy and breastfeeding. Intagra IC is not used in women.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Studies of the effect of the drug on the ability to drive vehicles or work with complex mechanisms have not been conducted.

Since dizziness and visual disturbances were observed during clinical studies of sildenafil, patients should be aware of their reaction to Intagra IC before driving or operating machinery.

Effects of other drugs on sildenafil

In vitro studies: Sildenafil metabolism is primarily mediated by cytochrome P450 (CYP) isoform 3A4 (major pathway) and isoform 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, and inducers of these enzymes may increase 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 adverse events was observed when sildenafil was co-administered with CYP 3A4 inhibitors, the 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 twice 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 AUC. After 24 hours, plasma sildenafil levels were still ≈200 ng/mL, compared to ≈5 ng/mL when sildenafil was administered alone, consistent with the significant effect of ritonavir on a broad spectrum 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 (see Precautions); In any case, the maximum dose of sildenafil should not exceed 25 mg within 48 hours under any circumstances.

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 AUC. Sildenafil did not appear to have an effect on the pharmacokinetics of saquinavir (see Dosage & Administration). 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 systemic exposure to sildenafil by 182% (AUC) 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 caused an increase in the concentration of sildenafil in the blood plasma 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 use of antacids (magnesium hydroxide, aluminum hydroxide) does not affect the bioavailability of sildenafil.

Although specific drug interaction studies have not been performed, population pharmacokinetic analysis suggests that sildenafil pharmacokinetics were not altered by concomitant use of drugs belonging 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, ACE 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 CYP 3A4 inducer, CYP 2C9 and possibly CYP 2C19 inducer) 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.

Effects 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 the C _max of sildenafil in plasma is approximately 1 μmol, the effect of Intagra IC on the clearance of substrates of these isoenzymes is unlikely.

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

In vivo studies. Since sildenafil is known to affect NO/cGMP metabolism, it has been shown to potentiate the hypotensive effect of nitrates, and its concomitant use with NO donors or nitrates in any form is contraindicated (see Adverse Reactions).

In some predisposed patients, concomitant use of sildenafil and α-blockers may result in symptomatic hypotension, most often occurring within 4 hours of sildenafil administration (see DOSAGE AND ADMINISTRATION, Precautions for Use). In a specific drug interaction study, the α-blockers doxazosin (4 and 8 mg) and sildenafil (25; 50 and 100 mg) were administered concomitantly to patients with benign prostatic hyperplasia who were stabilized on doxazosin. In these 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.

No significant interactions were found 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 found compared to placebo when using such classes of antihypertensive drugs as diuretics, β-adrenergic blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neurone blockers, calcium channel blockers and α-adrenergic blockers.

In a special interaction study with the simultaneous use of sildenafil (100 mg) and amlodipine in patients with hypertension, an additional decrease in supine blood pressure of 8 mm Hg and a decrease in diastolic blood pressure of 7 mm Hg were noted. The magnitude of this additional decrease in blood pressure was comparable to that observed with the use of sildenafil alone in healthy volunteers.

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 clinical trials involving volunteers, when using a single dose of sildenafil up to 800 mg, adverse reactions were similar to those observed with lower doses of sildenafil, but were more frequent and severe. The use of sildenafil at a dose of 200 mg led to increased efficacy, but caused an increase in the number of cases of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

Treatment. In case of overdose, resort to usual supportive measures if necessary. 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.

In the original packaging at a temperature not exceeding 25 °C.