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Active ingredients
Sildenafil
Release form
Pills
Composition
Sildenafil citrate 70.24 mg,; which corresponds to the content of Sildenafil 50 mg; Excipients: mannitol - 70.76 mg, crospovidone - 6 mg, povidone - 6 mg, corn starch - 10 mg, colloidal silicon dioxide - 2 mg, sodium lauryl sulfate - 2 mg, magnesium stearate - 3 mg.; Shell composition: hypromellose - 4.13 mg, macrogol 6000 - 1.3 mg, titanium dioxide - 0.9 mg, talc - 0.43 mg, indigo carmine (E132) - 0.24 mg.
Pharmacological effect
Drug for the treatment of erectile dysfunction. Sildenafil is a potent selective cGMP-specific phosphodiesterase type 5 (PDE5) inhibitor; during sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. Sildenafil does not have a direct relaxing effect on the isolated cavernous body, but actively enhances the relaxing effect of nitric oxide (NO) due to inhibition of PDE5, which is responsible for the decay of cGMP in the cavernous body. When the NO / cGMP pathway is activated, inhibition of PDE5 under the influence of sildenafil leads to an increase in cGMP levels in the cavernous body, resulting in relaxation of smooth muscle tissue and an increase in blood flow in the cavernous body. The activity of sildenafil in relation to PDE5 is 10–10,000 times greater than the activity in relation to other PDE isoenzymes (1-11); the pharmacological effect is achieved only with sexual stimulation. In clinical studies it was shown that the average time to achieve an erection is 60% resistant ( sufficient for sexual intercourse) was 25 minutes (range from 12 to 37 minutes); In some patients, 1 hour after taking the drug in a dose of 100 mg, the Farnsworth-Munsell 100 test revealed a mild and transient violation of the ability to distinguish between ta (blue / green), 2 hours after taking the drug, these changes were absent. It is believed that the violation of color vision is caused by inhibition of PDE6, which is involved in the process of transmitting light in the retina. Sildenafil does not affect visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter. In healthy volunteers, after a single dose of sildenafil 100 mg, no effect on sperm motility or morphology was noted.
Pharmacokinetics
Absorption; After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages 41% (25-63%). After a single dose of the drug inside the fasting dose of 100 mg Cmax is 18 ng / ml (38 nM) and is reached within 30-120 min (average 60 min); When you take sildenafil in combination with fatty foods, Cmax is reduced by 20-40 % and is achieved in 1.5-3 hours; Distribution; Vd of sildenafil in the equilibrium state is on average 105 l. The binding of sildenafil and its main circulating N-desmethyl metabolite to plasma proteins is approximately 96% and does not depend on the total concentration of sildenafil.; In healthy volunteers receiving sildenafil (once in a dose of 100 mg), less than 90 minutes after oral administration in sperm 0.0002% (average 188 ng) of the administered dose.; Metabolism; Sildenafil is metabolized mainly in the liver under the action of the microsomal isoenzymes CYP3A4 (primary route) and CYP2C9 (secondary route). The main circulating metabolite is formed from sildenafil by N-desmethylation. According to the selectivity of action on PDE, the metabolite is comparable to sildenafil, its activity against PDE5 in vitro is approximately 50% of the activity of sildenafil. The concentration of the main metabolite in plasma is approximately 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism, while its T1 / 2 is about 4 hours; Excretion; The total clearance of sildenafil is 41 l / h, and the final T1 / 2 is 3-5 hours. After oral administration, sildenafil is excreted as metabolites mainly through the intestines (approximately 80% of the dose) and to a lesser extent by the kidneys (approximately 13% of the dose) .; Pharmacokinetics in special groups of patients; In elderly patients (over 65 years of age), the clearance of sildenafil is reduced, 40% more than its concentration ju in young (18–45 years) patients; in renal failure, mild (CK 50–80 ml / min) and moderate (CK 30–49 ml / min) severity pharmacokinetic parameters of sildenafil after a single dose of 50 mg orally are changing. With severe renal failure (CK ≤30 ml / min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared with those in normal renal function in patients of the same age group. ; In patients with cirrhosis of the liver of mild and moderate severity (class A and B on the Child-Pugh scale), the clearance of sildenafil decreases,which leads to an increase in AUC (84%) and Cmax (47%) compared with those in normal liver function in patients of the same age group. The pharmacokinetic parameters of sildenafil in patients with severely impaired liver function have not been studied.
Indications
- Erectile dysfunction of various etiologies (organic, psychogenic, mixed), characterized by the inability to achieve or maintain an erection of the penis, sufficient for satisfactory sexual intercourse; Sildenafil is effective only with sexual stimulation.
Contraindications
- simultaneous use of donators of nitric oxide or nitrates in any form; - Hypersensitivity to any of the components of the drug. With caution should use the drug for anatomical deformation of the penis (including during angulation, cavernous fibrosis or Peyronie's disease); in diseases predisposing to the development of priapism (such as sickle cell anemia, multiple myeloma, leukemia, thrombocytopenia); in cases of bleeding; with the exacerbation of gastric ulcer and duodenal ulcer; hereditary pigment retinitis; heart failure, unstable stenocardia, myocardial infarction, stroke, life-threatening arrhythmias, arterial hypertension (BP more than 170/100 mm Hg) or hypotension (BP less than 90/50 mm Hg) in the last 6 months .
Use during pregnancy and lactation
Sildenafil is not intended for use in women.
Dosage and administration
The drug is taken orally, about 1 hour before the planned sexual activity. When taken simultaneously with fatty foods, the onset of action of the drug may be delayed compared to fasting. The recommended dose is 50 mg 1 time / day. Taking into account the effectiveness and tolerability of the dose can be increased to 100 mg or reduced to 25 mg. The maximum single dose is 100 mg. The maximum recommended frequency of use is 1 time / day. Elderly patients do not need dose adjustment.; Patients with severe renal insufficiency (CC less than 30 ml / min) should be reduced to 25 mg. Taking into account the effectiveness and tolerability, the dose can be increased to 50 mg and 100 mg. In patients with impaired liver function, the dose should be reduced to 25 mg.Given the efficacy and tolerability of the dose can be increased to 50 mg and 100 mg. Combined use with other drugs; In patients receiving concomitant treatment with CYP3A4 inhibitors (with the exception of ritonavir, with which simultaneous use of sildenafil is not recommended), the initial dose of sildenafil should be 25 mg. To minimize the possibility of orthostatic hypotension in patients taking alpha-blockers, treatment with sildenafil should begin after stabilization of hemodynamics. Consideration should be given to the prescription of sildenafil at an initial dose of 25 mg.
Side effects
The frequency of unwanted reactions is determined as follows: very often (> 1/10); often (> 1/100, less than 1/10); sometimes (> 1/1000, less than 1/100); rarely (> 1/10 000, less than 1/1000). Within each gradation of the frequency of occurrence, adverse events are indicated according to their severity. The side effects registered in the post-marketing period, due to the lack of accurate frequency data, are marked as “unknown.”; From the nervous system: very often - headache; often - dizziness; sometimes - drowsiness, hypesthesia; rarely - acute cerebrovascular accident, syncope; unknown - transient ischemic attack, convulsions, recurrent convulsions. On the part of the organ of vision: often - visual impairment, change in color perception; sometimes - disorders of the conjunctiva, violations of tearing, other disorders of the eyes; unknown - anterior ischemic neuropathy of the optic nerve of non-inflammatory origin (NAION), occlusion of retinal vessels, visual field defect. On the part of the organ of hearing: sometimes - ringing in the ears; rarely - deafness. On the part of the cardiovascular system: often - flushing of the face; sometimes - palpitations, tachycardia; rarely, arterial hypertension, arterial hypotension, myocardial infarction, atrial fibrillation; unknown - ventricular arrhythmia, unstable stenocardia, sudden cardiac death. From the respiratory system: often - nasal congestion; rarely - nosebleeds. From the digestive system: often - dyspepsia; sometimes - vomiting, nausea, dry mouth. From the reproductive system: unknown - priapism, prolonged erection. From the musculoskeletal system: sometimes - myalgia. From the skin and subcutaneous tissue: sometimes - skin rash .; On the part of the immune system: rarely - hypersensitivity reactions.; Other: rarely - chest pain, fatigue.
Overdose
Symptoms: with a single dose of the drug in a dose of up to 800 mg in studies in healthy volunteers, adverse events were comparable to those in the administration of sildenafil in lower doses, but their frequency and severity increased. The use of the drug at a dose of 200 mg did not lead to an increase in efficacy, but the incidence of adverse events (headache, flushing, dizziness, dyspepsia, nasal congestion, impaired vision) was increased; Treatment: symptomatic therapy. Sildenafil is not excreted by hemodialysis.
Interaction with other drugs
The influence of other drugs on the metabolism of sildenafil; Sildenafil metabolism occurs mainly in the liver under the influence of CYP3A4 isoenzymes (primary pathway) and CYP2C9 (secondary pathway), therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil. If used simultaneously with CYP3A4 inhibitors as ketoconazole, erythromycin, cimetidine) marked decrease in the clearance of sildenafil.; A single dose of sildenafil 100 mg together with erythromycin, a specific CYP3A4 inhibitor (when taking erythromycin 500 mg 2 times a / day for 5 days), against the background of achieving a constant concentration of erythromycin in the blood leads to an increase in AUC of sildenafil by 182%; Cimetidine (at a dose of 800 mg), which is a nonspecific CYP3A4 inhibitor, when used together with sildenafil (at 50 mg ) in healthy volunteers caused an increase in plasma concentration of sildenafil by 56%; simultaneous use of sildenafil (once in a dose of 100 mg) and HIV protease inhibitor ritonavir (500 mg 2 times / day), which is a powerful inhibitor of cytochrome P450 isoenzymes, is not background reaching ritonavir constant concentration in the blood leads to an increase in Cmax of sildenafil 300% (4 times), a AUC sildenafil - 1000% (11 times). After 24 h, the plasma concentration of sildenafil was approximately 200 ng / ml (when using only sildenafil - approximately 5 ng / ml); Simultaneous use of sildenafil (once in a dose of 100 mg) and HIV protease inhibitor saquinavir (at a dose of 1200 mg 3 times / day), which is an inhibitor of CYP3A4, against the background of achieving a constant concentration of saquinavir in the blood led to an increase in Cmax of sildenafil by 140%, and AUC of sildenafil by 210%. Sildenafil had no effect on the pharmacokinetics of saquinavir.; More potent CYP3A4 inhibitors, such as ketoconazole and itraconazole, may cause more pronounced changes in the pharmacokinetics of sildenafil.; CYP2C9 inhibitors (such as tolbutamide, warfarin, phenytoin),inhibitors of CYP2D (for example, selective serotonin reuptake inhibitors, tricyclic antidepressants), tacas and thiazide-like diuretics, loop and potassium-sparing diuretics, ACE inhibitors, beta-adrenoblockers, calcium antagonists, and isoenzymes inducers, cytochemistry inducers, cytoprotein inducers, calcium antagonists, and inducers of cyanogenic acid inhibitors, beta-adrenergic blockers, calcium antagonists, and isoenzymes inducers, cytoprotein inhibitors, beta-blockers, calcium antagonists, and inducers of cytoprotein diuretics, ace inhibitors, beta-adrenoblockers, calcium antagonists, and inducers of cytoprotein diuretics; have an effect on the pharmacokinetics of sildenafil.; A single dose of an antacid (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability of sildenafil.; In healthy male volunteers, at the same time Taking azithromycin (500 mg / day for 3 days) has no effect on AUC, Сmax, Tmax, elimination rate constant and T1 / 2 of sildenafil or its main circulating metabolite. Grapefruit juice is a weak CYP3A4 inhibitor and can cause a moderate increase in plasma sildenafil; Effect of sildenafil on other drugs; Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes - 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50150 µmol). It is unlikely that sildenafil can affect the substrate clearance of these isoenzymes. Sildenafil enhances the hypotensive effect of nitrates, so its combined use with nitric oxide donators or nitrates in any form is contraindicated.; Separate sensitive patients receiving alpha-adrenergic blockers may simultaneously use sildenafil to symptomatic hypotension. With simultaneous use of alpha-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional decrease in systolic / diastolic blood pressure in the supine position was 7 / 7 mm Hg, 9/5 mm Hg and 8/4 mm Hg, respectively, and in the standing position - 6/6 mm Hg, 11/4 mm Hg. and 4/5 mm Hg, respectively. Rare cases of symptomatic orthostatic hypotension, manifested as dizziness (without fainting), have been reported in these patients. Signs of significant interaction of sildenafil (50 mg) with tolbutamide (250 mg) or warfarin (40 mg) metabolized by CYP2C9 have not been identified. ; Sildenafil at a dose of 100 mg does not affect the pharmacokinetic parameters of HIV protease inhibitors at their constant concentration in the blood, such as saquinavir and ritonavir, which are also CYP3A4 substrates.; Sildenafil at a dose of 50 mg does not cause a further increase of bleeding time,caused by taking acetylsalicylic acid in a dose of 150 mg; Sildenafil at a dose of 50 mg does not enhance the hypotensive effect of ethanol in healthy volunteers at a maximum blood ethanol concentration of 80 mg / dl on average. In patients with arterial hypertension signs of sildenafil interaction (at a dose of 100 mg ) with amlodipine not identified. The average additional decrease in blood pressure in the supine position is 8 mm Hg. (systolic) and 7 mm Hg. (diastolic); The use of sildenafil in combination with antihypertensive drugs does not lead to additional side effects.
special instructions
Before prescribing the drug, it is necessary to collect a medical history and conduct a physical examination to diagnose erectile dysfunction and determine the possible causes of its development. Since sexual activity poses a certain risk in heart disease, before starting any therapy for erectile dysfunction, the doctor should examine the state of the cardiovascular disease patient's system.; Sildenafil has the properties of a vasodilator, which leads to a slight and transient decrease in blood pressure. Before prescribing sildenafil, the risk of undesirable effects of the vasodilating action in patients with certain concomitant diseases, especially in combination with sexual activity, should be carefully weighed. Increased susceptibility to vasodilators is observed in patients with obstruction of the excretory tract of the left ventricle (for example, aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as rarely encountered multiple systemic atrophy syndrome, manifested by a severe dysregulation of the regulation of blood pressure in the autonomic nervous system. The use of sildenafil and other PDE5 inhibitors has been associated with visual impairment and cases of anterior ischemic optic neuropathy. evospalitelnogo genesis. In the case of a sudden visual impairment, the patient should stop taking sildenafil and consult a doctor immediately.; Sildenafil should be prescribed with caution to patients taking alpha blockers, since their combined use can lead to clinically pronounced hypotension in certain sensitive patients.This effect is most likely to develop within 4 hours after taking sildenafil. To minimize the possibility of orthostatic hypotension in patients taking alpha blockers, treatment with sildenafil should be started after stabilization of hemodynamics in these patients. Consideration should be given to the prescription of sildenafil at an initial dose of 25 mg. In addition, patients should be informed what actions should be taken in case of symptoms of orthostatic hypotension. Sildenafil enhances the antiplatelet effect of sodium nitroprusside on human platelets in vitro.; Clinical studies have shown no differences in the incidence of myocardial infarction (1.1 per 100 people per year ) or mortality rates from cardiovascular diseases (0.3 per 100 people per year) in patients who received sildenafil, compared with patients who received placebo. ie for the treatment of erectile dysfunction, should not be given to men for whom sexual activity is undesirable;. Studies of safety and efficacy of combined use of sildenafil with other drugs have not been conducted for the treatment of erectile dysfunction. Therefore, the use of such combinations is not recommended.; Use in pediatrics; Sildenafil is not intended for use in children and adolescents under the age of 18.; Effect on ability to drive vehicles and control mechanisms; Effect of sildenafil on the ability to drive vehicles and perform work requiring enhanced attention has not been studied. However, during the period of use of the drug, care must be taken when driving vehicles and engaging in potentially hazardous activities that require increased concentration and psychomotor speed, because dizziness and visual disturbances are possible.