active ingredient: sildenafil;
1 tablet contains sildenafil citrate equivalent to sildenafil 25 mg or 50 mg, or 100 mg
Excipients: cellulose microcrystalline calcium hydrogen phosphate anhydrous aluminum hydroxide croscarmellose sodium; povidone, magnesium stearate silica colloidal anhydrous dry mixture "Opadry II white" containing titanium dioxide (E 171), talc, polyethylene glycol (macrogol), polyvinyl alcohol; Indigo I (E 132) candurin "Silver Shine".
Remedies used for erectile dysfunction. Sildenafil. ATC code G04B E03.
The drug 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.
For the effective action of the drug requires sexual arousal.
Hypersensitivity to the active substance or any of the auxiliary substances of the drug.
Concurrent use of nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated because it is known that sildenafil affects the metabolic pathways of nitric oxide/cyclic guanosine monophosphate (cGMP) and potentiates hypotensive effect of nitrates.
A condition in which is not recommended of sexual activity (e.g., severe cardiovascular disorders such as unstable angina or heart failure, severe).
Loss of vision by one eye due to nonarterial anterior ischemic neuropathy of the optic nerve, regardless of whether this pathology is associated with previous use of PDE-5 inhibitors or not.
The presence of diseases such as impaired liver function, severe hypotension (blood pressure below 90/50 mm Hg. St.), Recently moved stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a small number of these patients have genetic disorders of retinal PDE), as the safety of sildenafil has not been investigated in these subgroups of patients.
Method of application and doses
The drug is administered orally.
Adults. The recommended dose is 50 mg and is used if necessary about an hour before sexual activity. Depending on efficacy and tolerability the dose may be increased to 100 mg or reduced to 25 mg. the Maximum recommended dose of 100 mg Frequency of administration maximum recommended dose is
1 time per day. In applying the drug during eating effect of the drug may occur later than when applying it on an empty stomach.
Patients of advanced age. There is no need for dose adjustment in elderly patients (? 65 years).
Patients with renal insufficiency. For patients with mild to moderate renal insufficiency (creatinine clearance 30-80 ml/min), the recommended dose is the same as above in the Adults section.
Because in patients with severe renal insufficiency (creatinine clearance
Patients with liver failure. Because patients with hepatic insufficiency (e.g. cirrhosis), sildenafil clearance was reduced, consider using a dose of 25 mg depending on efficacy and tolerability, the dose can be increased gradually to 50 mg and 100 mg.
Patients who use other drugs. If patients are simultaneously inhibitors of CYP3A4 (see "Interactions with other medicinal products and other forms of interaction"), you should consider using an initial dose of 25 mg (with the exception of ritonavir, the use of which simultaneously sildenafilom not recommended, see Section "Peculiarities of use ").
In order to minimize the possible development of postural hypotension in patients taking blockers ?-adrenoreceptor, their condition should be stabilized with blockers ?-adrenoreceptor before use sildenafil. You should also consider the possibility of applying an initial dose of 25 mg (see section "peculiarities of application" and "Interaction with other drugs and other types of interactions").
Infectious and invasive diseases: rhinitis.
From the immune system: hypersensitivity.
From the nervous system: headache, dizziness, drowsiness, hypoesthesia, stroke, transient ischemic attack, seizures, recurrent court, syncope, ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes, anxiety , and transient global amnesia.
On the part of the organ of vision: violation of color perception (chloropeta, chromatopsia, cyanopsia, eritropenia, xanthopsia), visual disturbances, blurred vision, disorders of lacrimation (dry eyes, impaired tearing and increased lacrimation), eye pain, photophobia, photopsia, redness of the eyes , brightness of vision, conjunctivitis, occlusion of retinal vessels, retinal hemorrhage, arteriosclerotic retinopathy, disorders of the retina, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floating opacities of the vitreous body, disorders of the iris, mydriasis, the appearance of glowing circles around the light source (halo) in the field of vision, eye swelling, swelling of the eyes, eye disorders, hyperemia conjunctiva, eye irritation, abnormal sensations in the eyes, swelling of the eyelids, sclera discoloration, hemorrhage in the eyes, cataract, dry eyes, temporary loss of vision, redness of the eyes, burning in the eyes, increased intraocular pressure, retinal edema, bleeding or retinal diseases vitreous detachment.
Cases of non-arterial anterior ischemic optic neuropathy were reported, causing visual impairment, including permanent vision loss, which were associated in time with the use of PDE-5 inhibitors, including sildenafil. Many of the patients, but not all, had available anatomical or vascular risk factors for the development of non-arterial anterior ischemic neuropathy of the optic nerve, including (but not necessarily limiting) the following: low ratio of the diameter of the excavation and the optic disc (congestive optic disc), over 50 years of age, hypertension, coronary artery disease, hyperlipidemia and Smoking. It is impossible to determine whether these phenomena are directly related to the use of PDE-5 inhibitors or to existing anatomical or vascular risk factors, or a combination of these all factors, or other factors.
From the hearing and vestibular apparatus: ringing in the ears, deafness, pain in the ears.
Cases of sudden hearing loss or loss due to use of sildenafil were reported. In some cases it was reported about the presence of medical conditions and other factors that could play a role in the development of adverse reactions on the part of the ear. In many cases, information on further medical supervision is not available. It is impossible to determine whether these phenomena are directly related to the use of sildenafil, with the available risk factors for hearing loss, with a combination of these factors or with other factors.
From the heart: tachycardia, increased heartbeat, sudden cardiac death, myocardial infarction, ventricular arrhythmia, atrial fibrillation, unstable angina, angina pectoris, AV-blockade, myocardial ischemia, sudden cardiac arrest, violations of the results of ECG, cardiomyopathy.
On the part of blood vessels: blood flow, blood flow to the face, hot flashes, hypertension, hypotension, migraine, postural hypotension, thrombosis of the cerebral vessels.
Serious cardiovascular, cerebrovascular and vascular events, including cerebrovascular bleeding, subarachnoid and intra-cerebral bleeding and pulmonary bleeding, have been reported to have been associated with the use of sildenafil over time. Most patients, but not all, had existing cardiovascular risk factors. It was reported that many of these phenomena occurred during or immediately after sexual activity, and several occurrences occurred immediately when sildenafil was used without sexual activity. Other phenomena occurred within the following hours or days of the use of sildenafil and sexual activity. It is not possible to establish whether these phenomena are directly related to the use of sildenafil, to sexual activity, to existing risk factors, or to a combination of these factors, or to other factors.
From the respiratory system, chest and mediastinum: nasal congestion, nasal bleeding, nasal congestion, a feeling of compression in the throat, swelling of the nasal mucosa, dry nose, asthma, shortness of breath, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, cough.
The gastro-intestinal tract: nausea, dyspepsia, gastroesophageal reflux disease, vomiting, pain in the upper abdomen, dry mouth, hypesthesia of the mouth, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, violation of the results of liver function tests, rectal hemorrhage, gingivitis.
Skin and subcutaneous tissue: rash, Stevens-Johnson syndrome, Lyell's syndrome, urticaria, herpes, itching, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.
From the musculoskeletal system and connective tissue: myalgia, pain in the limbs, arthritis, arthrosis, tendon rupture, tenosinovitis, bone pain, myasthenia gravis, synovitis.
From urinary system: hematuria, cystitis, nocturia, increased urinary frequency, urinary incontinence.
From the reproductive system and mammary glands: bleeding from the penis, priapism, hematospermia, prolonged erection, breast enlargement, ejaculation disorders, genital edema, anorgasmia.
On the part of the blood and lymphatic systems: anemia, leukopenia.
Reported on the development of vasoocclusive crises who needed hospitalization, in the application of sildenafil to patients with pulmonary hypertension secondary to sickle cell anemia. The clinical significance of this information for patients taking the drug to treat erectile dysfunction is unknown.
Metabolic disorders and nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.
General disorders and reactions at the site of administration: chest pain, fatigue, sensation of heat, irritation, swelling of the face, photosensitization, shock, asthenia, pain, sudden drop, abdominal pain, sudden injury, back pain.
Examination increased heart rate.
A report of suspected adverse reactions . Report suspected adverse reactions after registration of the medicinal product is important. This allows continuous monitoring of the relationship between benefits and risks associated with the use of this drug. Doctors should report any suspected adverse reactions as required by law.
When applying a single dose of sildenafil to 800 mg adverse reactions were similar to those observed in the application of sildenafil at lower doses, but were more common and were heavier. The use of sildenafil at a dose of 200 mg led to increased efficiency, but caused an increase in the number of cases of adverse reactions (headache, blood spills, dizziness, dyspepsia, nasal congestion, visual impairment).
In case of overdose, if necessary, resort to the usual supportive measures. Acceleration of clearance of sildenafil in hemodialysis is unlikely due to the high degree of binding of the drug with plasma proteins and the lack of elimination of sildenafil with urine.
Pregnancy and breast-feeding
The drug is not intended for use by women.
The drug is indicated for use by persons under the age of 18 years.
Prior to therapy, it is necessary to collect the medical history of the patient and conduct a physical examination to diagnose erectile dysfunction and determine its possible causes.
Risk factors for cardiovascular disease. Since sexual activity is accompanied by a certain risk from the heart, before any treatment of erectile dysfunction, the doctor should assess the state of the cardiovascular system of the patient. Sildenafil has a vasodilating effect, manifested by a slight and short-term decrease in blood pressure. Prior to sildenafil's appointment, the physician should carefully consider whether such an effect can adversely affect patients with certain major diseases, especially in combination with sexual activity. To patients with hypersensitivity to vasodilators include patients with obstruction of the excretory tract of the left ventricle (eg aortic stenosis, hypertrophic obstructive cardiomyopathy), or patients with a rare syndrome, Multisystem atrophy, one manifestation of which is severe dysregulation of blood pressure the autonomic nervous system.
The drug potentiates the hypotensive effect of nitrates (see section"Contraindications").
Reported serious adverse reactions from the cardiovascular system, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, arterial hypertension and arterial hypotension, which coincided with the use of sildenafil. In most patients, but not all, there was the risk factors of cardiovascular diseases. Many of these adverse reactions were observed during or immediately after sexual intercourse and only a few occurred shortly after the use of sildenafil without sexual activity. Therefore, it is impossible to determine whether the development of such adverse reactions is directly related to risk factors, or their development is due to other factors.
Priapism. Funds for the treatment of erectile dysfunction, including sildenafil, should be administered with caution in patients with anatomical deformities of the penis (such as angulation, cavernous fibrosis or Peyronie's disease) or patients with conditions that contribute to the development of priapism (such as sickle cell anemia, multiple myeloma or leukemia).
Cases of prolonged erection and priapism were reported. If an erection lasts more than 4:00, patients should immediately seek medical help. In the absence of immediate treatment, priapism can lead to damage to the tissues of the penis and to persistent loss of potency.
The simultaneous use with other inhibitors of PDE5 or to other drugs for the treatment of erectile dysfunction. The safety and efficacy of the simultaneous application of sildenafil with other inhibitors of PDE5 or to other drugs used to treat hypertension of the pulmonary artery that contains sildenafil or other drugs for the treatment of erectile dysfunction were studied. Therefore, the use of such combinations is not recommended.
Effect on vision. Spontaneous reports on the occurrence of visual defects have been associated with the use of sildenafil and other inhibitors of PDE-5 (see "Adverse reactions"). Cases of non-arterial anterior ischemic optic neuropathy are rare, spontaneous reports have been reported and reported to be associated with the use of sildenafil and other PDE-5 inhibitors (see "Adverse reactions"). Patients should be warned that in case of sudden visual impairment of the drug should be stopped and immediately consult a doctor (see. Section "Contraindications").
Concurrent use with ritonavir. The simultaneous use of sildenafil and ritonavir is not recommended (see "Interaction with other medicinal products and other forms of interaction").
The simultaneous use of blockers ?-adrenergic receptors. Patients receiving blockers ?-adrenergic receptors, sildenafil should be used with caution as this combination may lead to symptomatic hypotension in some predisposed patients. Symptomatic hypotension usually occurs within 4: 00 after the use of sildenafil. In order to minimize the possible development of postural hypotension in patients taking blockers ?-adrenoreceptor, their condition should be stabilized with blockers ?-adrenoreceptor before use sildenafil. You should also consider using an initial dose of 25 mg (see Section "Method of application and dosage"). In addition, patients should be informed how to act in case of symptoms of orthostatic hypotension.
Effect on bleeding. In vitro sildenafil potentiates the antiplatelet effects of sodium nitroprusside. There is no information about the safety of the use of sildenafil in patients with coagulation disorders or acute ulcer disease. Thus, the use of sildenafil in patients of this group is possible only after a thorough assessment of the ratio of benefit and risk.
After taking 100 mg there is no effect on the morphology or mobility of sperm.
Hearing loss. Physicians should advise patients to stop use of inhibitors of PDE5, including sildenafil, and seek immediate medical assistance in cases of sudden decrease or loss of hearing. These phenomena, which may also be accompanied by tinnitus and dizziness, have been reported to the timing Association with the use of PDE-5 inhibitors, including sildenafil. To determine these effects directly associated with the use of inhibitors of PDE5 or to other factors.
The simultaneous use of antihypertensive drugs. Sildenafil has systemic vasodilatory effect and may further reduce blood pressure in patients using antihypertensive drugs. With simultaneous use of amlodipine (5 mg or
10 mg) and sildenafil (100 mg) orally observed an average additional reduction in systolic pressure by 8 mm Hg. art. and diastolic-7 mm Hg. art.
Sexually transmitted diseases. The use of the drug 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 human immunodeficiency virus.
The ability to influence the reaction rate when driving motor transport or operating other mechanisms
Studies of the effect of the drug on the ability to drive vehicles and work with other mechanisms were not carried out. Since the use of sildenafil reported cases of dizziness and visual impairment, before you get behind the wheel of a vehicle or work with mechanisms, patients need to find out what their individual reaction to the use of the drug.
Interaction with other medicinal products and other forms of interaction.
Effects of other medicinal products on sildenafil. Metabolism of sildenafil occurs mainly with the participation of the ZA4 isoforms (major route) and 2C9 isoforms (minor route) cytochrome
450 (CYP). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.
There is evidence of a decrease in clearance of sildenafil while the use of inhibitors CYP3A4 (such as ketoconazole, erythromycin, cimetidine). Although the simultaneous use of sildenafil and CYP3A4 inhibitors, the increase in the frequency of adverse events was not observed, it should be considered to use the initial dose of sildenafil 25 mg.
The simultaneous use of HIV protease inhibitor, a very powerful CYP inhibitor, in a state of equilibrium concentration (500 mg 1 time per day) and sildenafil (a single dose of 100 mg) led to an increase in C max sildenafil 300% (4 times) and increase in plasma sildenafil AUC 1000% (11-fold). After 24 hours, plasma levels of sildenafil were still approximately 200 ng/ml compared to about 5 ng/ml typical of sildenafil alone, corresponding to the significant effect of ritonavir on a wide range of CYP substrates.
Sildenafil does not affect the pharmacokinetics of ritonavir. Taking into account these pharmacokinetic data, the simultaneous use of sildenafil and ritonavir is not recommended (see section "features of application"); in any case, the maximum dose of sildenafil under what circumstances should not exceed 25 mg for 48 hours.
Coadministration of protease inhibitors HIV of saquinavir, a CYP3A4 inhibitor, at a dose that provides the equilibrium concentration (1200 mg three times daily) and sildenafil (100 mg dose) led to an increase in sildenafil C max 140% and an increase in systemic exposure (AUC) to sildenafil by 210%. Is not revealed the influence of sildenafil on the pharmacokinetics of saquinavir (see Section "Method of application and dosage"). It is assumed that more potent CYP3A4 inhibitors such as ketoconazole and Itraconazole will have a more pronounced effect.
In the application of sildenafil (100 mg dose) and erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice a day for 5 days) was observed increase in systemic exposure to sildenafil 182% (AIS). There was no effect of azithromycin (500 mg/day for 3 days) on AUC, with max , t max , elimination rate constant and further t ? sildenafil or its main circulating metabolite. Cimetidine (cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg, while the use of sildenafil at a dose of 50 mg led to an increase in plasma concentrations of sildenafil by 56%.
Grapefruit juice is a weak inhibitor of CYP3A4 in the intestinal wall and can cause a moderate increase in the level of sildenafil in blood plasma.
Single use of antacids (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.
Pharmacokinetics of sildenafil did not change with the simultaneous use of drugs belonging to the group of inhibitors CYP2C9 (tolbutamide, warfarin, phenytoin), group of inhibitors CYP2D6 (such as selective serotonin reuptake inhibitors, tricyclic antidepressants) , groups of thiazide-like and thiazide-like diuretics, loop and potassium-sparing diuretics, inhibitors, calcium antagonists, ?-adrenoreceptor antagonists or CYP metabolism inducers (such as rifampicin, barbiturates).
Simultaneous application of the antagonist of endothelin bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg twice a day) and sildenafil at steady state (80 mg three times daily) resulted in a decrease in AUC and C max sildenafil 62, 6% and 55.4%, respectively. Therefore, the simultaneous use of such powerful inductors CYP3A4, as rifampicin, can lead to a more pronounced decrease in the concentration of sildenafil in blood plasma.
Nicorandil is a hybrid of calcium channel activator and nitrate. Nitrate component determines the possibility of its serious interaction with sildenafil.
The effects of sildenafil on other drugs. Sildenafil is a weak inhibitor isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and ZA4 cytochrome P450 (IC 50 > 150 µmol). Since the peak plasma concentrations of sildenafil are approximately 1 µmol, the effect of the drug on the clearance of substrates of these isoferments is unlikely.
There is no evidence of the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.
Since it is known that sildenafil affects the metabolism of nitric oxide/cyclic guanosine monophosphate (cGMP), it was found that sildenafil potentiates the hypotensive effect of nitrates, so its simultaneous use with nitric oxide donors or nitrates in any form is contraindicated (see section " Contraindications ").
Simultaneous use of sildenafil and ?-adrenoreceptor blockers can lead to the development of symptomatic hypotension in some predisposed patients. This reaction often occurred within 4: 00 after the use of sildenafil (see section" dosage and Administration "and"features"). When you apply a blocker of ?-adrenergic receptors doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) simultaneously to patients with benign hyperplasia of the prostate, stabilization of a condition which was achieved with the use of doxazosin, observed average additional reduction in blood pressure in the supine position on a 7/7 mm Hg. art., 9/5 mm Hg. article and 8/4 mm Hg. C. the average reduction of blood pressure in the standing position on 6/6 mm Hg. art., 11/4 mm Hg. art., 4/5 mm Hg. the article under. With the simultaneous use of sildenafil and doxazosin in patients, the stabilization of which was achieved by the use of doxazosin, sometimes reported the development of symptomatic orthostatic hypotension, namely, cases of dizziness and condition before fainting, but without syncope.
No significant interactions were observed with simultaneous use of sildenafil (50 mg) and tolbutamide (250 mg) and warfarin (40 mg), which were metabolized by CYP2C9.
Sildenafil (50 mg) did not lead to an increase in bleeding time caused by acetylsalicylic acid (150 mg).
Sildenafil (50 mg) potentiual hypotensive effect of alcohol with average maximum levels of ethanol in blood is 80 mg/DL.
Patients receiving sildenafil, there was no difference in side-effect profile, while the use of such classes of antihypertensive drugs, like diuretics, ?-adrenergic blocker, ACE inhibitors, angiotensin II antagonists, antihypertensive medicinal products (vasodilator and centrally acting), adrenergic neuron blockers, calcium channel blockers, and blockers of ?-adrenergic receptors. While the use of sildenafil (100 mg) and amlodipine in patients with hypertension, there was an additional decrease in systolic blood pressure in the lying position of 8 mm Hg. reduction of diastolic blood pressure was 7 mm Hg. art. the magnitude of these additional decrease in blood pressure were comparable to those observed in the application of sildenafil only.
Sildenafil at a dose of 100 mg did not affect the pharmacokinetic parameters of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of CYP3A4.
The use of sildenafil in equilibrium (80 mg three times a day) led to an increase in AUC and C max bosentan (125 mg twice a day) by 49.8% and 42% respectively.
Mechanism of action. Sildenafil is an oral drug intended for the treatment of erectile dysfunction. In sexual arousal drug restores reduced erectile function by increasing blood flow to the penis.
The physiological mechanism that leads to erection, including the release of nitric oxide (NO) in cavernous bodies during sexual arousal. The released nitric oxide activates the enzyme guanylate cyclase, which stimulates an increase in the level of cyclic guanosine monophosphate (cGMP), which, in turn, causes relaxation of the smooth muscles of cavernous bodies, contributing to blood flow.
Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase 5 (PDE-5) in cavernous bodies, where PDE-5 is responsible for the breakdown of cGMP. The effects of sildenafil on erection are peripheral character. Sildenafil does not have a direct relaxing effect on isolated human cavernous bodies, but powerfully enhances the relaxing effect of NO on this tissue. When you activate a metabolic pathway NO/cGMP, what happens when sexual stimulation, inhibition of PDE5 sildenafilom leads to increased levels of cGMP in the cavernous bodies. Thus, in order for sildenafil to cause a pharmacological effect, sexual arousal is necessary.
Influence on pharmacodynamics. Sildenafil is selective to PDE-5, which is actively involved in the erection process. The effect of sildenafil on PDE5 is more powerful than on other known phosphodiesterases. This effect is 10 times more powerful than the effect on PDE6, which is involved in the processes of photo-rotation in the retina. When using the maximum recommended doses of selectivity of sildenafil in PDE-5 to 80 times greater than its selectivity for ФДЕ1, 700 times higher than in ФДЕ2, PDAS, ФДЕ4, ФДЕ7, ФДЕ8, ФДЕ9, ФДЕ10 and ФДЕ11. In particular, the selectivity of sildenafil in PDE5 4000 times greater than its selectivity for FDEZ - camp-specific PDE isoforms involved in the regulation of cardiac contractility.
Absorption. Sildenafil is rapidly absorbed. The maximum plasma concentration of the drug is achieved within 30-120 minutes (with a median of 60 minutes) after its oral administration on an empty stomach. The average bioavailability after oral administration is 41% (with a range of values from 25 to 63%). In the recommended dose range (25 to 100 mg), AUC and max sildenafil after oral administration are increased in proportion to the dose.
In the application of sildenafil during meals extent of absorption is reduced, with an average lengthening of the T max of 60 minutes and an average reduction in C max of 29%.
Distribution. The average equilibrium volume of distribution (V d ) is 105 liters, which indicates the distribution of the drug in the body tissues. After a single oral administration of sildenafil at a dose of 100 mg, the average maximum total plasma concentration of sildenafil is approximately 440 ng/ml (coefficient of variation is 40%). Since the binding of sildenafil and its main N-desmetil metabolite with plasma proteins 96%, the average maximum plasma concentration of free sildenafil reaches 18 ng/ml (38 nmol). The degree of binding with plasma proteins does not depend on the total concentrations of sildenafil.
In persons who took sildenafil once at a dose of 100 mg, after 90 minutes in the ejaculate was determined less than 0.0002% (average 188 ng) dose.
Metabolism. Sildenafil metabolism is carried out mainly with the participation of microsomal liver isoenzymes CYP3A4 (the main path) and CYP2C9 (minor route). The main circulating metabolite is formed by n-demethylation of sildenafil. The selectivity of the metabolite relative to PDE - 5 is comparable to the selectivity of sildenafil, and the activity of the metabolite relative to PDE-5 is about 50% of the activity of the starting substance. Plasma concentrations of this metabolite are approximately 40% of the concentration of sildenafil in plasma. N-demethylated metabolite undergoes further metabolism, and the T ? is approximately 4:00.
Breeding. The total clearance of sildenafil is 41 l/h, causing t ? duration
3-5 hours. Both after administration and after administration sildenafil excretion in the form of metabolites is carried out mainly with feces (about 80% of the administered dose) and to a lesser extent with urine (about 13% of the administered dose).
Pharmacokinetics in special groups of patients.
Patients of advanced age. In the elderly (over 65 years) there was a decrease in clearance of sildenafil, which led to an increase in plasma concentrations of sildenafil and its active N-demetilirovannogo metabolite by about 90% compared with the corresponding concentrations in young people (18-45 years). Due to age differences in plasma protein binding, the corresponding increase in the plasma concentration of free sildenafil was approximately 40%.
Renal failure. In patients with impaired renal function or moderate (creatinine clearance 30-80 ml/min) the pharmacokinetics of sildenafil was unchanged after a single oral dose of 50 mg. Average AUC and C max of the N-demethylated metabolite increased 126% and 73% respectively in comparison with these indicators in individuals of the same age without renal impairment. However, due to the high individual variability, these differences were not statistically significant. In persons with severe renal impairment (creatinine clearance below 30 ml/min), sildenafil clearance decreased, resulting in average increases of AUC and C max of 100% and 88%, respectively, compared to persons of the same age without renal impairment. In addition, the AUC and C max of the N-demethylated metabolite significantly increased 79% and 200%, respectively.
Liver failure. In persons with cirrhosis of the liver or moderate (class A and b according to the classification of child-Pugh), sildenafil clearance was reduced, resulting in increase in AUC (84%) and C ma