Sildenafil-SZ tablets coated. 50 mg, 4 pcs. (sildenafil)

Release form

Coated tablets.

Packing

In the package 4 pcs.

Pharmacological action

Pharmacodynamics

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 cGMP level, subsequent relaxation of the smooth muscle tissue of the cavernous body and an increase in 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 SBP in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mmHg and dAD was 5.3 mmHg. A more pronounced, but also transient effect on blood pressure was observed in patients taking nitrates.

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 at least one coronary artery stenosis), 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 disrupt blood flow in stenosed coronary arteries, and also led to an increase (by about 13%) in 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), performed physical exercises until the severity of symptoms of angina pectoris decreased. The duration of the exercise was significantly longer (19.9 s 0.9–38.9 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 taking more than two antihypertensive drugs was studied. 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. performed physical exercises until the severity of symptoms of angina pectoris decreased. The duration of the exercise was significantly longer (19.9 s 0.9–38.9 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 taking more than two antihypertensive drugs was studied. 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 with the help of the Farnsworth-Mansel test 100, 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. There were no clinically significant changes in vision, evaluated by special visual tests (visual acuity, Amsler lattice, color perception, modeling the passage of color, Hamuri 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, an international index of erectile function (a validated questionnaire on the state of sexual function) and a survey of a partner.

Sildenafil's effectiveness, defined as the ability to achieve and maintain an erection sufficient for satisfactory intercourse, has been demonstrated in all studies and has been confirmed in long-term studies, 1 year duration. 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, and allowed achieving 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, 43% of patients undergoing 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 the activity of human PDE-5 by 50%. After a single dose of 100 mg sildenafil, the average Cmax of free sildenafil in male blood plasma is about 18 ng / ml (38 nM) and is achieved when sildenafil is taken orally on an empty stomach for an average of 60 minutes (30 to 120 minutes). When taken in combination with fatty foods, the absorption rate decreases: Сmax decreases on average by 29%, and Tmax increases by 60 minutes, however, the degree of absorption does not change significantly (AUC decreases by 11%).

The distribution of

Vss of sildenafil averages 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 PDE-5 in vitro 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. T1 / 2 is about 4 hours.

Excretion of

The total clearance of sildenafil is 41 l / h, and the final T1 / 2 is 3-5 hours. After oral administration, as well as after iv administration, Sildenafil is excreted in the form of 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), the clearance of sildenafil is reduced, and the concentration of free sildenafil in the 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.

Impaired renal function. With mild (creatinine Cl - 50–80 ml / min) and moderate (creatinine Cl - 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 (Cl creatinine 30 ml / min), the clearance of sildenafil decreases, which leads to an approximately twofold increase in the values ​​of 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 liver cirrhosis (Child-Pugh classification of stages A and B), sildenafil clearance 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 groups. 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 an erection of the penis sufficient for satisfactory intercourse. Sildenafil is effective only with sexual stimulation.

Contraindications

- Hypersensitivity to the drug.

The drug is contraindicated in patients receiving continuously or intermittently nitric oxide donors, organic nitrates or nitrates in any form, since sildenafil enhances the hypotensive effect of nitrates taken continuously or in emergency cases.

Use during pregnancy and lactation

Sildenafil is not intended for use in women.

Adequate and strictly controlled trials during pregnancy and lactation in women have not been conducted.

Composition

active ingredients: sildenafil (as citrate) 50 mg,

excipients: microcrystalline cellulose 54 mg, lactose monohydrate 74 mg, croscarmellose sodium 10 mg, povidone 10 mg, magnesium stearate 2 mg.

film composition: Opadry II (polyvinyl alcohol, partially hydrolyzed 2.4 mg, titanium dioxide 1.374 mg, macrogol 1.212 mg, talc 0.888 mg, brilliant blue aluminum varnish 0.1152 mg, iron oxide (II) yellow 0.0102 mg, iron oxide ( Ii) black 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 combined with cytochrome CYPZA4 isoenzyme inhibitors (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? -Adrenergic blocking agents, 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 Medicinal Products”).

Elderly patients

Dose adjustment of Sildenafil is not required

Side effects of

On the part of the body as a whole: asthenia, pain, abdominal pain, back pain, infection, flu-like syndrome.

From the cardiovascular system: vasodilation (a side effect recorded in clinical trials).

From the digestive system: diarrhea, nausea.

From the musculoskeletal system: joint pain, muscle pain.

From the side of the central nervous system and peripheral nervous system: dizziness (a side effect recorded in clinical trials), increased muscle tone, insomnia.

From the respiratory system: nasal congestion, pharyngitis, rhinitis (a side effect recorded in clinical trials), sinusitis, respiratory tract infections, respiratory failure.

Dermatological reactions: rash.

On the part of the sensory organs: change in vision: slight and transient, mainly a change in the color of objects, as well as increased perception of light and blurred vision (a side effect recorded in clinical studies), conjunctivitis.

From the urinary system: urinary tract infections.

From the reproductive system: impaired prostate function.

When using the drug in doses higher than recommended, side effects were similar to those noted above, but were usually more common.

The following are adverse events, registered in the process of post-marketing application.

From the cardiovascular system: arterial hypotension, fainting, tachycardia, palpitations.

From the digestive system: vomiting (a side effect reported in clinical studies).

From the reproductive system: prolonged erection and / or priapism.

From the sensory organs: pain in the eyes, redness of the eyes.

Other: allergic reactions.

Side effects were usually transient and mild or moderate.

In fixed-dose studies, the incidence of side effects increased with increasing doses.

The nature of the side effects in the studies in which the dose was selected, since such studies better reflect the recommended regimen, was comparable to that in fixed-dose studies.

Drug Interaction

Single administration of antacids (magnesium hydroxide / aluminum hydroxide) with sildenafil does not affect its bioavailability. Increases the antihypertensive effect of nitrates (simultaneous intake is contraindicated) and the anti-aggregation effect of sodium nitroprusside. When taken with acetylsalicylic acid (150 mg), it does not increase bleeding time. CYP3A4 inhibitors (cimetidine, ketoconazole, itraconazole, erythromycin, etc. ) increase the concentration of sildenafil in plasma (in particular, cimetidine at a dose of 800 mg - by 56%, when taking sildenafil at a dose of 50 mg) and reduce its excretion. With single administration of 100 mg of sildenafil on an equilibrium erythromycin concentration (500 mg twice daily intake for 5 days), sildenafil AUC increases 182%, on equilibrium saquinavir (1200 mg 3 times daily) Sildenafil Cmax increases by 140% , AUC by 210%. A single intake of 100 mg of sildenafil amid the equilibrium concentration of ritonavir, a potent cytochrome P450 inhibitor (400 mg twice daily), results in a 4-fold (300%) increase in Cmax and an 11-fold (1000%) increase in sildenafil AUC. Sildenafil has no effect on the pharmacokinetics of ritonavir and saquinavir. CYP2C9 inhibitors (tolbutamide, warfarin), CYP2D6 (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, ACE inhibitors, calcium antagonists, beta-blockers, and cytokines It is assumed that when sildenafil is administered concomitantly with CYP3A4 inducers (rifampicin, etc.), its plasma concentration will decrease. The AUC of the active metabolite of sildenafil is increased by 62% with loop and potassium-sparing diuretics and 102% with non-specific beta-blockers (the clinical significance of these effects has not been determined). No signs of interaction with amlodipine (5 and 10 mg) were found: mean additional BP decrease in supine position (SAD by 8 mm Hg, dAD by 7 mm Hg ) is comparable to that of healthy volunteers when taking one sildenafil. Does not enhance the antihypertensive effect of alcohol in healthy volunteers at a blood alcohol concentration of up to 80 mg / dl.

overdose

Symptoms: Increased severity of adverse events was observed in studies in healthy volunteers with single administration of up to 800 mg of sildenafil.

Treatment: symptomatic. Dialysis is ineffective because of the high degree of binding of sildenafil and its metabolite to blood plasma proteins.

Storage conditions

The drug should be stored at room temperature (15 ° to 30 ° C).

Expiration

3 years.

Active substance

Silden fil

Terms of delivery from

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dosage form

dosage form

tablets

Northern Star, Russia



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