Instructions for use Erosil tablets 100 mg blister No. 4
Composition
active ingredient: sildenafil;
1 tablet contains sildenafil citrate equivalent to 100% sildenafil 50 mg or 100 mg;
excipients: lactose monohydrate; magnesium gluconate; powdered sugar; calcium stearate; lemon flavoring; tartrazine dye (E 102).
Dosage form
Pills.
Main physicochemical properties: biconvex tablets of yellow or yellow-brown color with interspersed lines on one side.
Pharmacotherapeutic group
Drugs used to treat erectile dysfunction. ATC code G04B E03.
Pharmacological properties
Pharmacodynamics
Erosil is an oral medication used to treat erectile dysfunction in men. The drug is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
The physiological mechanism of penile erection is the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO activates the enzyme guanylate cyclase, which causes an increase in cGMP levels, relaxation of the smooth muscles of the corpus cavernosum, and increased blood flow to them.
Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum, but enhances the effectiveness of nitric oxide (NO) by inhibiting PDE5, which is responsible for the degradation of cGMP in the corpus cavernosum.
When sexual stimulation results in local release of NO, sildenafil inhibition of PDE5 causes an increase in cGMP levels in the corpus cavernosum, resulting in smooth muscle relaxation and increased blood flow to the corpus cavernosum.
The use of sildenafil at recommended doses is ineffective in the absence of sexual stimulation.
In vitro studies have shown that sildenafil is selective for PDE5. Its effect on PDE5 is stronger than that of other known phosphodiesterases (10-fold stronger than PDE6, 80-fold stronger than PDE1, 700-fold stronger than PDE2, PDE3, PDE4, PDE7–PDE11). In particular, sildenafil has a 400-fold better selectivity for PDE5 than for PDE3, a cGMP-specific isoform of phosphodiesterase involved in the regulation of heart rate.
Visual impairment: When sildenafil was administered at a dose of 100 mg, some patients experienced mild, transient color vision impairment (blue/green) after 1 hour (using the Farnsworth-Munsell 100 test); these changes resolved 2 hours after administration.
The probable mechanism of color vision impairment is considered to be inhibition of PDE6, which is involved in the process of light transmission in the retina. In vitro studies show that the effect of sildenafil on PDE6 is 10 times less than its activity against PDE5. Sildenafil does not affect visual acuity, contrast perception, electroretinograms, intraocular pressure, or pupillometry.
Efficacy: The efficacy of sildenafil, assessed in terms of the drug's ability to achieve and maintain an erection sufficient for sexual intercourse, has been demonstrated and maintained with long-term use of the drug (1 year).
In a study, sildenafil at doses of 25 mg, 50 mg, and 100 mg improved erections in 62%, 74%, and 82% of men, respectively. In addition to improving erectile function, an analysis of the International Index of Erectile Function (IIEF) showed that sildenafil treatment also improved orgasm and sexual satisfaction.
When treated with sildenafil, improvement was noted in 59% of patients with diabetes mellitus; in patients who had undergone radical prostatectomy - 43%, in patients with spinal cord injury - 83%.
Pharmacokinetics
Sildenafil is rapidly absorbed. Peak plasma concentrations are reached within 30-120 min (median 60 min) after oral administration in the fasted state. The mean absolute oral bioavailability is 41% (range 25-63%). Over the recommended dose range (25-100 mg), the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of sildenafil increase in proportion to the dose after oral administration.
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%.
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 maximum total plasma concentration of sildenafil is approximately 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 maximum plasma concentration 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.
Sildenafil is metabolized primarily by the hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (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. The plasma concentration of this metabolite is approximately 40% of that of sildenafil in plasma. The N-demethylated metabolite undergoes further metabolism and has a half-life of approximately 4 hours.
The total clearance of sildenafil is 41 l/h, resulting in a half-life of 3-5 hours. After both oral and intravenous administration, sildenafil is excreted as metabolites mainly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
Elderly patients: In healthy elderly volunteers (aged 65 years and older), 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 to 80 ml/min), sildenafil pharmacokinetics were unchanged after a single oral dose of 50 mg. The mean AUC and Cmax of the N-desmethyl metabolite were increased by 126% and 73%, respectively, compared with those in age-matched volunteers without renal impairment. However, due to high interindividual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance below 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 Cmax (47%) compared to age-matched volunteers without hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.
Indication
Treatment of erectile dysfunction, defined as the inability to achieve and maintain a penile erection sufficient for successful sexual intercourse. Sexual arousal is required for Erosil to be effective.
Contraindication
– Hypersensitivity to sildenafil or to other components of the drug.
– Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form, as sildenafil is known to affect the nitric oxide/cyclic guanosine monophosphate (cGMP) metabolic pathways and potentiate the hypotensive effect of nitrates.
– Diseases in which sexual activity is not recommended (e.g. severe cardiovascular disorders such as unstable angina and severe heart failure).
– Loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this pathology is associated with previous use of PDE5 inhibitors.
– Severe hepatic impairment, arterial hypotension (blood pressure below 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 phosphodiesterases), as the safety of sildenafil has not been studied in patients with such diseases.
Interaction with other medicinal products and other types of interactions
Effects of other drugs on sildenafil.
In vitro studies.
Sildenafil metabolism occurs mainly 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 sildenafil clearance.
In vivo studies.
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 hours, plasma sildenafil levels were still approximately 200 ng/ml compared to approximately 5 ng/ml with sildenafil 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 hours.
Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 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 CYP3A4 inhibitors, such as ketoconazole and itraconazole, are expected to have a more pronounced effect.
When sildenafil (100 mg once) and erythromycin, a specific CYP3A4 inhibitor, were administered at steady state (500 mg twice daily for 5 days), a 182% increase in sildenafil systemic exposure (AUC) was observed. In healthy male volunteers, there was no effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, and subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and nonspecific CYP3A4 inhibitor) at a dose of 800 mg when co-administered with sildenafil at a dose of 50 mg in healthy volunteers resulted in a 56% increase in plasma concentrations of sildenafil.
Grapefruit juice is a weak inhibitor of CYP3A4 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 belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 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-adrenoceptor antagonists, or inducers of CYP450 metabolism (such as rifampicin, barbiturates).
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 (IC50 > 150 μmol). Since peak plasma concentrations of sildenafil are approximately
1 μmol, the effect of sildenafil 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 have an effect on nitric oxide/cyclic guanosine monophosphate (cGMP) 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.
In some susceptible patients, concomitant use of sildenafil and α-blockers may result in symptomatic hypotension, most often occurring within 4 hours of sildenafil administration. In a specific drug interaction study, the α-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) were co-administered to patients with benign prostatic hyperplasia who were stabilized on doxazosin. In these study populations, mean additional reductions in supine blood pressure of 7/7 mmHg, 9/5 mmHg and 8/4 mmHg and mean reductions in standing blood pressure of 6/6 mmHg, 11/4 mmHg and 4/5 mmHg, respectively, were observed. Symptomatic orthostatic hypotension has occasionally been reported in patients stabilized on doxazosin when sildenafil and doxazosin were co-administered. These reports included dizziness and fainting, but without syncope.
No significant interactions were observed with the concomitant use of sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP2C9.
Sildenafil (50 mg) did not prolong bleeding time induced by acetylsalicylic acid (150 mg).
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 neurone blockers, calcium channel blockers and α-adrenergic blockers. In a specific interaction study, when sildenafil (100 mg) was used concomitantly with amlodipine in patients with arterial hypertension, an additional reduction in supine systolic blood pressure of 8 mm Hg was observed.
The corresponding reduction 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.
Sildenafil at a dose of 100 mg did not affect the pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, which are CYP3A4 substrates.
Application features
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.
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, 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. Patients 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.
Sildenafil potentiates the hypotensive effect of nitrates.
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 association with sildenafil use. Most, but not all, patients had cardiovascular risk factors. Many of these adverse reactions occurred during or shortly after sexual intercourse, and only a few occurred shortly after sildenafil use in the absence of sexual activity. Therefore, it is not possible to determine whether these adverse reactions are directly related to the risk factors or are mediated by other factors.
Erectile dysfunction drugs, 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 predisposing to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
The safety and efficacy of concomitant use of sildenafil with other treatments for erectile dysfunction have not been studied, therefore the use of such combinations is not recommended.
Visual disturbances and cases of non-arteritic anterior ischemic optic neuropathy have been reported with the use of sildenafil and other PDE5 inhibitors. Patients should be advised that in the event of sudden visual impairment, Erosil should be discontinued and a physician should be consulted immediately.
Concomitant use of sildenafil and ritonavir is not recommended.
Sildenafil should be administered with caution to patients taking α-adrenergic blockers, as the combination may lead to symptomatic hypotension in some susceptible patients. Symptomatic hypotension usually occurs within 4 hours of sildenafil administration. To minimize the risk of orthostatic hypotension, sildenafil therapy should only be initiated in hemodynamically stable patients taking α-adrenergic blockers. The recommended starting dose for such patients is 25 mg sildenafil. In addition, patients should be informed of what to do if symptoms of orthostatic hypotension occur.
Studies in 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. Therefore, the use of sildenafil in these patients should only be considered after careful consideration of the benefit-risk ratio.
Erosil contains lactose and should not be used in men with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding
The drug is not used in women.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of the drug on the ability to drive a car or operate other mechanisms have not been conducted.
Since dizziness and visual disturbances were observed during clinical studies of sildenafil, patients should be aware of their individual reaction to Erosil before driving or operating other machinery.
Method of administration and doses
The tablets are intended for oral administration. Sexual arousal is necessary for sildenafil to exert its effect.
The recommended dose of Erosil is 50 mg and is used if necessary approximately 1 hour before sexual intercourse. Depending on the effectiveness and tolerability of the drug, the dose can be increased to 100 mg or reduced to 25 mg. (tablets in the appropriate dosage are used). The maximum recommended dose is 100 mg. The maximum recommended frequency of use is 1 time per day. When using the drug Erosil during meals, its effect may occur later than when used on an empty stomach.
Elderly patients.
There is no need for dose adjustment for elderly patients.
Patients with renal failure.
For patients with mild to moderate renal impairment (creatinine clearance 30 to 80 ml/min), the recommended dose is similar to the dose given above.
Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 ml/min), the recommended dose is 25 mg (tablets of the appropriate dosage are used). Depending on the efficacy and tolerability of the drug, the dose can be increased to 50 mg and 100 mg.
Patients with liver failure.
Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis), the recommended dose is 25 mg (tablets of the appropriate dosage are used). Depending on the efficacy and tolerability of the drug, the dose may be increased to 50 mg or 100 mg.
Patients taking other medications.
The recommended starting dose for patients taking CYP3A4 inhibitors, except ritonavir, is 25 mg (tablets of the appropriate dosage are used).
In order to reduce the risk of orthostatic hypotension, the condition of patients taking α-adrenergic blockers should be stabilized before starting sildenafil. The recommended starting dose of sildenafil is 25 mg (tablets of the appropriate dosage are used).
Children
The drug is not used in children.
Overdose
Symptoms. When using a single dose of sildenafil up to 800 mg, adverse reactions were similar to those observed with the use of sildenafil in lower doses, but their frequency and severity increased. Taking 200 mg of sildenafil does not lead to increased efficacy, but causes an increase in the number of cases of adverse reactions (headache, hot flashes, dizziness, dyspepsia, nasal congestion, visual disturbances).
Treatment: In case of overdose, symptomatic therapy should be applied if necessary. Since sildenafil is extensively bound to plasma proteins and is not excreted in the urine, there is no reason to expect that renal dialysis will accelerate the clearance of the drug.
Adverse reactions
The most common side effects are headache, hot flashes, dyspepsia, visual disturbances, nasal congestion, dizziness, and color vision disturbances.
Immune system disorders: hypersensitivity reactions.
From the nervous system: headache, dizziness, drowsiness, hypoesthesia, stroke, transient ischemic attack, seizures, recurrent seizures, fainting.
From the cardiovascular system: flushing, palpitations, tachycardia, hypertension, hypotension, myocardial infarction, atrial fibrillation, ventricular arrhythmia, unstable angina, sudden cardiac death.
From the organs of vision: visual disorders; color perception disorders; conjunctival disorders; lacrimation disorders; other visual disorders; non-arteritic anterior ischemic optic neuropathy; retinal vascular occlusion, visual field defects.
From the auditory system: vertigo, tinnitus, deafness.
Respiratory system: nasal congestion, nosebleeds.
On the part of the digestive tract: dyspepsia, vomiting, nausea, dry mouth.
Skin: skin rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal system: myalgia.
From the urinary system: hematuria.
General disorders: chest pain, fatigue.
Examination: increased heart rate.
From the reproductive system: hematospermia, bleeding from the penis, priapism, prolonged erection.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
1 or 2 or 4 tablets in a blister; 1 blister No. 1 or No. 2 or No. 4 in a cardboard box.
Vacation category
According to the recipe.
Producer
"ASTRAPHARM" LLC.
Location of the manufacturer and address of its place of business
Ukraine, 08132, Kyiv region, Kyiv-Svyatoshynskyi district, Vyshneve, Kyivska st., 6.
