Description
Pharmacological action of
Sildenafil is a potent selective inhibitor of cGMP-specific PDE-5.
Mechanism of Action
The implementation of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpora cavernosa during sexual stimulation. This, in turn, leads to an increase in the level of cGMP, subsequent relaxation of the smooth muscle tissue of the corpora cavernosa and increased blood flow.
Sildenafil does not have a direct relaxing effect on an isolated human cavernous body, but enhances the effect of nitric oxide (NO) by inhibiting PDE-5, which is responsible for the breakdown of cGMP.
Sildenafil is selective for PDE-5 in vitro, its activity for PDE-5 is superior to that of other known PDE isoenzymes: PDE-6 – 10 times PDE-1 – more than 80 times PDE-2, PDE-4 , PDE-7 – PDE-11 – more than 700 times. Sildenafil is 4,000 times more selective for PDE-5 compared to PDE-3, which is crucial because PDE-3 is one of the key enzymes in the regulation of myocardial contractility.
A prerequisite for the effectiveness of sildenafil is sexual stimulation.
Clinical data
Cardiological studies. The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum decrease in sAD in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mm Hg. Art. and dad – 5.3 mm RT. Art. A more pronounced, but also transient effect on blood pressure was observed in patients taking nitrates (see “Contraindications”, “Interaction”).
In a study of the hemodynamic effect of sildenafil in a single dose of 100 mg in 14 patients with severe coronary artery disease (more than 70% of patients had stenosis of at least one coronary artery), SBP and DBP at rest were reduced by 7 and 6%, respectively, and pulmonary SBP decreased by 9%. Sildenafil did not affect cardiac output and did not impair blood flow in stenosed coronary arteries, and also led to an increase (by about 13%) in the adenosin-induced coronary flow in both stenosed and intact coronary arteries.
In a double-blind, placebo-controlled study of 144 patients with erectile dysfunction and stable angina pectoris taking antianginal drugs (except nitrates), physical exercises were performed until the severity of symptoms of angina pectoris decreased. The duration of the exercise was significantly longer (19.9 s 0.9 ² 38.9 s) in patients taking sildenafil in a single dose of 100 mg, compared with patients receiving placebo.
In a randomized, double-blind, placebo-controlled study, the effect of changing the dose of sildenafil (up to 100 mg) in men (n = 568) with erectile dysfunction and hypertension was studied. taking more than two antihypertensive drugs. Sildenafil improved erection in 71% of men compared to 18% in the placebo group. The frequency of adverse effects was comparable to that in other groups of patients, as well as in individuals taking more than three antihypertensive drugs.
Visual Impairment Research. In some patients, 1 h after taking sildenafil at a dose of 100 mg using the Farnsworth-Mansell 100 test, a mild and transient impairment of the ability to distinguish shades of color (blue / green) was detected. 2 hours after taking the drug, these changes were absent. It is believed that color vision impairment is caused by the inhibition of PDE-6, which is involved in the process of light transmission in the retina. Sildenafil did not affect visual acuity, contrast perception, electroretinogram, IOP, or pupil diameter.
In a placebo-controlled cross-sectional study of patients with proven early-stage macular degeneration (n = 9), a single dose of 100 mg sildenafil was well tolerated. No clinically significant changes in vision were assessed using special visual tests (visual acuity, Amsler lattice, color perception, color transmission modeling, Humphrey perimeter and photo stress).
Efficacy
The efficacy and safety of sildenafil was evaluated in 21 randomized, double-blind, placebo-controlled studies lasting up to 6 months in 3,000 patients aged 19 to 87 years, with erectile dysfunction of various etiologies (organic, psychogenic or mixed). The effectiveness of the drug was evaluated globally using an erection diary, international index of erectile function (a validated questionnaire on the status of sexual function) and a survey of a partner.
The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory intercourse, was demonstrated in all studies and confirmed in long-term studies lasting 1 year. In fixed-dose studies, the ratio of patients reporting that therapy improved their erection was 62% (sildenafil dose 25 mg), 74% (sildenafil 50 mg dose) and 82% (sildenafil 100 mg dose) versus 25 % in the placebo group). The analysis of the international index of erectile function showed that in addition to improving erection, treatment with sildenafil also increased the quality of orgasm, allowed to achieve satisfaction from sexual intercourse and general satisfaction.
According to generalized data, among patients reporting improved erections during treatment with sildenafil were 59% of patients with diabetes mellitus, 43% of patients who underwent radical prostatectomy and 83% of patients with spinal cord injuries (versus 16, 15 and 12% in the placebo group, respectively) .
Pharmacokinetics:
The pharmacokinetics of sildenafil in the recommended dose range is linear.
Absorption
After oral administration, sildenafil is rapidly absorbed. The absolute bioavailability is on average about 40% (from 25% to 63%). In vitro, sildenafil at a concentration of about 1.7 ng / ml (3.5 nM) inhibits human PDE5 activity by 50%. After a single dose of 100 mg sildenafil, the average maximum concentration of free sildenafil in the blood plasma (Cmax) of men is about 18 ng / ml (38 nM). Cmax when taking sildenafil inside an empty stomach is achieved on average within 60 minutes (from 30 minutes to 120 minutes). When taken in combination with fatty foods, the absorption rate decreases: Cmax decreases on average by 29%, and the time to reach the maximum concentration (Tmax) increases by 60 minutes, however, the degree of absorption does not significantly change (the area under the concentration-time pharmacokinetic curve (AUC) decreases by 11%).
Distribution
The volume of distribution of sildenafil in equilibrium is an average of 105 liters. The connection of sildenafil and its main circulating N-demethyl metabolite with plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the dose of sildenafil (an average of 188 ng) was found in semen 90 minutes after taking the drug.
Metabolism
Sildenafil is metabolized mainly in the liver by the action of the cytochrome CYPZA4 isoenzyme (main pathway) and the cytochrome CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite formed as a result of N-demethylation of sildenafil undergoes further metabolism. The selectivity of the action of this metabolite in relation to PDE is comparable to that of sildenafil, and its activity against PDE5 invitro is about 50% of the activity of sildenafil.
The concentration of metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism its half-life (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, as after intravenous administration, sildenafil is excreted as metabolites, mainly by the intestines (about 80% of the oral dose) and, to a lesser extent, by the kidneys (about 13% of the oral dose).
Pharmacokinetics in special patient groups
Elderly patients
In healthy elderly patients (over 65 years of age), sildenafil clearance is reduced, and the concentration of free sildenafil in blood plasma is approximately 40% higher than in young patients (18-45 years old). Age does not have a clinically significant effect on the incidence of side effects.
Renal dysfunction
With mild (creatinine clearance (CC) 50-80 ml / min) and moderate (CC 30-49 ml / min) renal failure, the pharmacokinetics of sildenafil does not change after a single oral dose of 50 mg. In severe renal failure (CC ² °Ò 30 ml / min), the clearance of sildenafil decreases, which leads to an approximately twofold increase in the values ² ¹ ² ¹of AUC (100%) and Cmax (88%) compared with those in normal renal function in patients of the same age group.
Impaired liver function
In patients with cirrhosis of the liver (stages A and B according to the Child-Pugh classification), the clearance of sildenafil is reduced, which leads to an increase in the values ² ¹ ² ¹of AUC (84%) and Cmax (47%) compared with those with normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severely impaired liver function (Child-Pugh classification C stage) has not been studied.
Indications
Treatment of erectile dysfunction characterized by an inability to achieve or maintain a penile erection, sufficient for satisfactory sexual intercourse.
Sildenafil is effective only with sexual stimulation.
Contraindications
Hypersensitivity to sildenafil or to any other component of the
preparation Use in patients receiving nitric oxide donors, organic nitrates or nitrites in any form, continuously or intermittently, since sildenafil enhances the hypotensive effect of nitrates (see section Interaction with other drugs )
The safety and effectiveness of the drug sildenafil when used together with other treatments for erectile dysfunction have not been studied, therefore, the use of such combinations is not recommended (see section Special instructions )
According to the registered indication, Sildenafil is not intended for use in children under 18
According to the registered indication, Sildenafil is not intended for use in women
lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
The simultaneous use of sildenafil with ritonavir is not recommended.
Precautions:
Anatomical deformation of the penis (angulation, cavernous fibrosis, or Peyronie’s disease) (see section “Special instructions”).
Diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia)
(see section “Special instructions”).
Diseases accompanied by bleeding.
Exacerbation of gastric ulcer and 12 duodenal ulcer.
Hereditary retinitis pigmentosa (see Special Instructions).
Heart failure, unstable angina pectoris, myocardial infarction, stroke or life-threatening arrhythmias, arterial hypertension (BP> 170/100 mm Hg) or hypotension (BP <90/50 mm Hg) (see . Section "Special Instructions"). In patients with episodes of development of anterior non-arteritic ischemic optic neuropathy (a history of). Use during pregnancy and lactation According to the registered indication, Sildenafil-SZ is not intended for use in women. Composition active substance: sildenafil citrate in terms of sildenafil – 50 mg excipients (core): microcrystalline cellulose – 54.0 mg lactose monohydrate (milk sugar) – 74.0 mg croscarmellose sodium (primrose) – 10.0 mg povidone (polyvinylpyrrolidone mid-molecular ) – 10.0 mg of magnesium stearate – 2.0 mg of excipients (coating): Opadry II (polyvinyl alcohol, partially hydrolyzed – 2.4 mg of titanium dioxide E 171 – 1.374 mg macrogol (polyethylene glycol 3350) – 1.212 mg of talc – 0.888 mg brilliant blue aluminum varnish – 0.1152 mg iron oxide (II) yellow E 172 – 0.0102 mg iron oxide (II) black E 172 – 0.0006 mg). Dosage and Administration Inside. The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Given the effectiveness and tolerability, the dose can be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once a day. Renal dysfunction In case of mild to moderate degree of renal failure (KK 30-80 ml / min) dose adjustment is not required, in severe renal failure (KK <30 ml / min) - the dose of sildenafil should be reduced to 25 mg. Impaired liver function Since excretion of sildenafil is impaired in patients with liver damage (in particular, cirrhosis), the dose of sildenafil should be reduced to 25 mg. Combined use with other medicines When combined with ritonavir, the maximum single dose of Sildenafil should not exceed 25 mg, and the frequency of use should be 1 time per 48 hours (see the section “Interaction with other medicines”). When used together with inhibitors of the cytochrome CYPZA4 isoenzyme (erythromycin, saquinavir, ketoconazole, itraconazole), the initial dose of Sildenafil should be 25 mg (see section “Interaction with other drugs”). To minimize the risk of developing postural hypotension in patients taking -blockers, Sildenafil should be started only after hemodynamic stabilization is achieved in these patients. The feasibility of lowering the initial dose of sildenafil should also be considered (see sections “Special Instructions” and “Interaction with Other Medicines”). Elderly patients Dosage adjustment of Sildenafil is not required. Side effects of Usually, the side effects of Sildenafil are mild or moderate and are transient. In studies using a fixed dose, it has been shown that the frequency of some adverse events increases with increasing dose. When using the drug Sildenafil in doses exceeding the recommended, adverse events were similar to those noted above, but were usually more common. General disorders: facial swelling, photosensitivity reactions, shock, asthenia, pain, chills, abdominal pain, chest pain. Allergic reactions: hypersensitivity reactions (including skin rash), Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome). Disorders from the central and peripheral nervous system: drowsiness, insomnia, hypesthesia, paresthesia, ataxia, neuralgia, neuropathy, tremor, depression, unusual dreams, decreased reflexes, stroke, transient ischemic attack, convulsions, incl. recurrent. Disorders from the cardiovascular system: tachycardia, increase or decrease in blood pressure, myocardial infarction, atrial fibrillation, atrial fibrillation, unstable angina pectoris, AV block, cerebral vascular thrombosis, heart failure, ECG disturbances, cardiomyopathy, sudden death, fainting. Respiratory disorders: nosebleeds, asthma, shortness of breath, laryngitis, pharyngitis, sinusitis, bronchitis, increased sputum production, increased coughing. Gastrointestinal disorders: vomiting, nausea, dry oral mucosa, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, rectal bleeding, gingivitis. Disorders of the organ of vision: eye pain, redness of the eyes / injection of the sclera, lesion of the conjunctiva, violation of lacrimation, anterior ischemic optic neuropathy, retinal vascular occlusion, visual field defects, mydriasis, cataracts, eye pain. Hearing impairment: vertigo, tinnitus, earache, deafness. Disorders from the blood and lymphatic system: anemia, leukopenia. Metabolic and nutritional disorders: thirst, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia. Disorders of the musculoskeletal system: arthritis, arthrosis, myalgia, tendon rupture, tendovaginitis, bone pain, myasthenia gravis, synovitis. Disorders of the skin and subcutaneous tissues: urticaria, herpes simplex, itching, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis. Disorders from the genitourinary system: cystitis, nocturia, frequent urination, gynecomastia, urinary incontinence, impaired ejaculation, genital edema, anorgasmia. Reproductive system disorders: prolonged erection and / or priapism. Drug interaction Effect of other drugs on the pharmacokinetics of sildenafil Sildenafil metabolism occurs mainly under the influence of cytochrome CYPZA4 isoenzymes (main pathway) and CYP2C9, therefore, inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inductors, respectively, increase the clearance of sildenafil. A marked decrease in clearance of sildenafil with the simultaneous use of inhibitors of the cytochrome CYPZA4 isoenzyme (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a non-specific inhibitor of the cytochrome CYPZA4 isoenzyme, when taken together with sildenafil (50 mg) causes an increase in plasma concentration of sildenafil by 56%. A single dose of 100 mg of sildenafil together with erythromycin (500 mg / day 2 times a day for 5 days), a specific inhibitor of the cytochrome CYPZA4 isoenzyme, against the background of achieving a constant concentration of erythromycin in the blood, leads to an increase in AUC of sildenafil by 182%. When combined with sildenafil (once 100 mg) and saquinavir (1200 mg / day 3 times a day), HIV protease inhibitor and cytochrome CYP3A4 isoenzyme, against the background of achieving a constant concentration of saquinavir in the blood, C max of sildenafil increased by 140%, and AUC increased by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir. Stronger inhibitors of the CYPZA4 cytochrome isoenzyme, such as ketoconazole and itraconazole, can also cause stronger changes in the pharmacokinetics of sildenafil. The simultaneous use of sildenafil (once 100 mg) and ritonavir (500 mg 2 times a day), an HIV protease inhibitor and a strong cytochrome P450 inhibitor, while achieving a constant concentration of ritonavir in the blood leads to an increase in Cmax of sildenafil by 300% (in 4 times), and AUC by 1000% (11 times). After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng / ml (after a single use of one sildenafil – 5 ng / ml), which is consistent with information about the pronounced effect of ritonavir on the pharmacokinetics of various substrates of cytochrome P450. Sildenafil does not affect the pharmacokinetics of ritonavir. The combined use of sildenafil with ritonavir is not recommended. If sildenafil is taken in recommended doses by patients receiving at the same time strong inhibitors of the cytochrome CYPZA4 isoenzyme, then Cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated. A single dose of antacid (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability of sildenafil. Inhibitors of the cytochrome CYP2C9 isoenzyme (tolbutamide, warfarin), the cytochrome CYP2D6 isoenzyme (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists do not affect the pharmacokinetics of sildenafil. Azithromycin (500 mg / day for 3 days) has no effect on AUC, Cmax, Tmax, excretion rate constant, and T1 / 2 of sildenafil or its main circulating metabolite. Effect of sildenafil on other drugs Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and ZA4 (IC50> 150 μmol). When taking sildenafil in recommended doses, its C max is about 1 μmol, so it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.
Sildenafil enhances the hypotensive effect of nitrates both with prolonged use of the latter, and with their appointment for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.
With the simultaneous administration of? -adrenoblocker 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 mmHg Art., 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 the development of symptomatic postural hypotension in such patients, manifested in the form of dizziness (without fainting), have been reported. In some sensitive patients receiving? -Adrenergic blockers, the simultaneous use of sildenafil can lead to symptomatic hypotension.
Signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome CYP2C9 isoenzyme, were not detected.
Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the cytochrome CYPZA4 isoenzyme, at their constant blood level.
Sildenafil (50 mg) does not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg).
Sildenafil (50 mg) does not enhance the hypotensive effect of alcohol in healthy volunteers with a maximum blood alcohol concentration of an average of 0, 08% (80 mg / dl)
In patients with arterial hypertension, no signs of interaction of sildenafil (100 mg) with amlodipine were detected. The average additional decrease in blood pressure in the supine position is 8 mm Hg. (systolic) and 7 mmHg (diastolic).
The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.
Overdose of
With a single dose of Sildenafil at a dose of up to 800 mg, adverse events were comparable to those when taking the drug at lower doses, but were more common.
Symptomatic treatment. Hemodialysis does not accelerate the clearance of sildenafil, since the latter actively binds to plasma proteins and is not excreted by the kidneys.
Storage conditions
In a dry, dark place at a temperature of no higher than 25 ° C.
Keep out of the reach of children.
The Expiration of
is 3 years.
Deystvuyuschee substances
sildenafil
Conditions of supply of pharmacies
prescription
Form of Treatment
tablets
Northern Star, Russia
