Sildenafil-SZ, 50mg pills, 4pcs

Composition

1 tab. sildenafil (in the form of citrate) 50 mg

Auxiliary substances:

microcrystalline cellulose – 54 mg, lactose monohydrate (milk sugar) – 74 mg,

croscarmellose sodium (primellose) – 10 mg,

povidone (polyvinylpyrrolidone medium molecular weight) – 10 mg, magnesium stearate-2 mg.

Shell composition:

Opadray II (polyvinyl alcohol, partially hydrolyzed-2.4 mg, titanium dioxide (E171) – 1.374 mg, macrogol (polyethylene glycol 3350) – 1.212 mg, talc-0.888 mg, aluminum varnish based on diamond blue-0.1152 mg, iron oxide (II) yellow (E172) – 0.0102 mg, iron oxide (II) black (E172) – 0.0006 mg).

Pharmacological action

Pharmacodynamics

Sildenafil is a potent selective inhibitor of cGMP-specific PDE5.

Mechanism of action

The realization of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the cavernous body during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the cavernous body, and increased blood flow.

Sildenafil does not have a direct relaxing effect on the isolated human cavernous body, but it 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 against PDE-5 exceeds that of other known PDE isoenzymes: PDE-6 — by 10 times; PDE-1-by more than 80 times; PDE-2, PDE-4, PDE-7 — PDE-11 — by more than 700 times. Sildenafil is 4000 times more selective for PDE-5 compared to PDE-3, which is of crucial importance, since 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 datacardiological 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 mm Hg, and dBP-5.3 mm Hg. 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 CHD (more than 70% of patients had stenosis of at least one coronary artery), sBP and dBP at rest decreased 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 approximately 13%) in adenosine-induced coronary flow in both stenosed and intact coronary arteries.

In a double-blind, placebo-controlled study,144 patients with erectile dysfunction and stable angina, taking antianginal medications (other than nitrates), performed physical exercises until the severity of angina symptoms decreased. The duration of exercise was significantly longer (19.9 seconds; 0.9-38.9 seconds) in patients taking sildenafil in a single dose of 100 mg, compared with patients receiving placebo.

A randomized, double-blind, placebo-controlled study examined the effect of varying the dose of sildenafil (up to 100 mg) in men (n=568) with erectile dysfunction and hypertension taking more than two antihypertensive medications. Sildenafil improved erections in 71% of men compared to 18% in the placebo group. The incidence of adverse events was comparable to that in other patient groups, as well as in individuals taking more than three antihypertensive medications.

Studies of visual impairments. In some patients,1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Mansel 100 test revealed a slight and transient violation of the ability to distinguish shades of color (blue/green).2 hours after taking the drug, these changes were absent. It is believed that color vision disorders are caused by inhibition of PDE-6, which is involved in the process of light transmission in the retina of the eye. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, IOP, or pupil diameter.

In a placebo-controlled cross-sectional study of patients with proven early-age macular degeneration (n=9), sildenafil at a single dose of 100 mg was well tolerated. There were no clinically significant visual changes assessed by special visual tests (visual acuity, Amsler grating, color perception, color transmission modeling, Hamuri perimeter, and photostress).

The efficacy and safety of sildenafil were evaluated in 21 randomized, double-blind, placebo-controlled trials 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 the erectile diary, the international index of erectile function (validated questionnaire on the state of sexual function) and the partner survey.

The efficacy of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all studies conducted and confirmed in long-term studies lasting 1 year. In fixed-dose studies, the ratio of patients who reported that therapy improved their erections was 62% (25 mg sildenafil),74% (50 mg sildenafil), and 82% (100 mg sildenafil versus 25% in the placebo group). Analysis of the international index of erectile function showed that in addition to improving erections, treatment with sildenafil also increased the quality of orgasm, allowed achieving satisfaction from sexual intercourse and overall satisfaction.

Overall,59% of patients with diabetes,43% of patients who underwent radical prostatectomy, and 83% of patients with spinal cord injuries reported improved erections during treatment with sildenafil (compared to 16%,15%, and 12% in the placebo group, respectively).

Pharmacokineticspharmacokinetics of sildenafil in the recommended dose range is linear. Absorption Sildenafil is rapidly absorbed after oral use. 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) suppresses the activity of human PDE-5 by 50%. After a single 100 mg dose of sildenafil, the average Cmax of free sildenafil in the blood plasma of men 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 (from 30 to 120 minutes). When taken in combination with fatty foods, the absorption rate decreases: Cmax decreases by an average of 29%, and Tmax increases by 60 minutes, but the degree of absorption does not change significantly (AUC decreases by 11%).

The distribution of VSS sildenafil is an average of 105 liters. The association 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 sildenafil dose (average 188 ng) was detected in semen 90 minutes after taking the drug.

Metabolism Sildenafil is primarily metabolized in the liver by the cytochrome SURZA isoenzyme 4 (major pathway) and the cytochrome SURZA 2C9 isoenzyme (minor pathway). The main circulating active metabolite formed as a result of N-demethylation of sildenafil undergoes further metabolism. The selectivity of this metabolite against PDE is comparable to that of sildenafil, and its activity against PDE-5 in vitro is about 50% of that of sildenafil.

The concentration of the 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.

Elimination The total clearance of sildenafil is 41 l / h, and the final T1/2 is 3-5 hours. After oral use, as well as after intravenous use, 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 (older than 65 years), the clearance of sildenafil is reduced, and the concentration of free sildenafil in blood plasma is approximately 40% higher than in young (18-45 years). Age does not have a clinically significant effect on the incidence of side effects.

Impaired renal function. In mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal insufficiency, the pharmacokinetics of sildenafil do not change after a single oral dose of 50 mg. In severe renal insufficiency (creatinine clearance < 30 ml/min), sildenafil clearance decreases, resulting in approximately a twofold increase in AUC (100%) and Cmax (88%) compared to those with normal renal function in patients of the same age group.

Liver function disorders. In patients with cirrhosis of the liver (stages A and B according to the Child-Pugh classification), the clearance of sildenafil decreases, which leads to an increase in AUC (84%) and Cmax (47%) compared to those with normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh stage C) have not been studied.

Indications

Treatment of erectile dysfunction characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse.Sildenafil is only effective with sexual stimulation.

Use during pregnancy and lactation

According to the registered indication, the drug is not intended for use in women.

Contraindications

— application in patients receiving constantly or intermittently donators of nitric oxide, organic nitrates or nitrites in any form, as sildenafil enhances the hypotensive effect of nitrates;

— the registered indication, the drug sildenafil-Sz is not intended for use in children and adolescents under the age of 18 years;

— the registered indication, the drug sildenafil-Sz is not intended for use in women;

— lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

— it is not recommended simultaneous use of sildenafil with ritonavir;

— hypersensitivity to sildenafil or to any other component of the drug.

The safety and efficacy of Sildenafil-SZ in combination with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended.

With caution:

anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie’s disease);

— diseases of, predisposing to the development of priapism (sickle-cell anemia, multiple myeloma, leukemia, thrombocythemia);

diseases accompanied by haemorrhage;

— exacerbation of gastric ulcer and duodenal ulcer;

— hereditary retinitis pigmentosa;

— heart failure, unstable angina, moved in last 6 months, myocardial infarction, stroke or life-threatening arrhythmias, hypertension (BP >170/100 mm Hg. St. ) or hypotension (blood pressure <90/50 mm Hg. St. )

— in patients with episodes of development partizanai anterior ischemic neuropathy of the optic nerve (history).

Side effects

From the body as a whole: asthenia, aches, abdominal pain, back pain, infection, flu-like syndrome.

From the cardiovascular system: vasodilation (a side effect reported in clinical trials). From the digestive system: diarrhea, nausea.

Musculoskeletal disorders: joint pain, muscle pain.

From the central nervous system and peripheral nervous system: dizziness (side effect reported in clinical studies), increased muscle tone, insomnia.

Respiratory system disorders: nasal congestion, pharyngitis, rhinitis (a side effect reported in clinical studies), sinusitis, respiratory tract infections, respiratory dysfunction.

Dermatological reactions: a rash.

From the side of the senses: visual changes: mild and transient, mainly changes in the color of objects, as well as increased light perception and blurred vision (a side effect reported in clinical studies), conjunctivitis.

From the urinary system: urinary tract infections.

From the side of the reproductive system: impaired prostate function.

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

The following lists the adverse events reported during the post-marketing application process.

From the cardiovascular system: hypotension, syncope, tachycardia, palpitations.

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

From the side of the reproductive system: prolonged erections and / or priapism.

From the side of the senses: pain in the eyes, redness of the eyes.

Other services: allergic reactions.

Side effects were usually transient and mild to moderate.

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

The nature of side effects in studies where the dose was selected, since such studies better reflect the recommended regimen, was comparable to those in studies with fixed doses.

Interaction

Effect of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome CYP3A4 (main pathway) and CYP2C9 isoenzymes, so inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers, respectively, increase the clearance of sildenafil. A decrease in the clearance of sildenafil was observed with the simultaneous use of inhibitors of the cytochrome CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a non-specific inhibitor of the cytochrome CYP3A4 isoenzyme, when co-administered with sildenafil (50 mg) causes an increase in the concentration of sildenafil in plasma by 56%. A single dose of 100 mg of sildenafil in combination with erythromycin (500 mg 2 times / day for 5 days), a specific inhibitor of the cytochrome CYP3A4 isoenzyme, against the background of achieving a constant concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%.

When co-administered with sildenafil (100 mg once) and saquinavir (1200 mg / day 3 times / day), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme, while achieving a constant concentration of saquinavir in the blood, the Cmax of sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil does not affect the pharmacokinetics of saquinavir.

Stronger inhibitors of the cytochrome CYP3A4 isoenzyme, such as ketoconazole and itraconazole, can also cause stronger changes in the pharmacokinetics of sildenafil.

Simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg twice daily), 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 sildenafil Cmax by 300% (4 times), and AUC by 1000% (11 times). After 24 hours, the concentration of sildenafil in blood plasma is about 200 ng / ml (after a single application of sildenafil alone-5 ng / ml), which is consistent with the information about the pronounced effect of ritonavir on the pharmacokinetics of various cytochrome P 450 substrates. Sildenafil has no effect on the pharmacokinetics of ritonavir. Concomitant use of sildenafil with ritonavir is not recommended.

If sildenafil is taken at the recommended doses in patients receiving simultaneously strong inhibitors of the cytochrome CYP3A4 isoenzyme, the Cmax of Free sildenafil does not exceed 200 nM, and the drug is well tolerated.

A single antacid dose (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

Inhibitors of the cytochrome CYP2C9 isoenzyme (tolbutamide, warfarin), 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 the AUC, Cmax, Tmax, elimination rate constant and T 1/2 of sildenafil or its main circulating metabolite.

Effect of sildenafil on other medications

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2,2C9,2C19,2D6,2E1AND 3A4 (IR 50>150 mmol). When taking sildenafil at the recommended doses, its Cmax is about 1 mmol, 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 when they are prescribed for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

When the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg,50 mg and 100 mg) were co – administered in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional reduction 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. st. and 4/5 mmHg, respectively. Rare cases of symptomatic postural hypotension, which manifested itself in the form of dizziness (without fainting), have been reported in such patients. In some sensitive patients receiving alpha-blockers, concomitant use of sildenafil may lead to symptomatic hypotension.

There were no signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome CYP2C9 isoenzyme.

Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the cytochrome CYP3A4 isoenzyme, at constant blood levels.

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 ethanol in healthy volunteers with a maximum blood ethanol concentration of 0.08% (80 mg/dl) on average.

In patients with arterial hypertension, there were no signs of interaction between sildenafil (100 mg) and amlodipine. The average additional reduction in blood pressure in the supine position is 8 mmHg (systolic) and 7 mmHg (diastolic).

The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.

How to take it, course of administration and dosage

Inside.

The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity.Depending on the efficacy 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.

Impaired renal function

In mild to moderate renal insufficiency (creatinine clearance 30-80 ml/min), no dose adjustment is required, in severe renal insufficiency (creatinine clearance < 30 ml/min), the dose of sildenafil should be reduced to 25 mg.

Liver function disorders

Since the elimination of sildenafil is impaired in patients with liver damage (in particular, cirrhosis), the dose of Sildenafil should be reduced to 25 mg.

Co-use with other medicinal products

When co-administered with ritonavir, the maximum single dose of Sildenafil should not exceed 25 mg, and the frequency of use should be 1 time in 48 hours (see the section “Interaction with other medications”). When co-administered with inhibitors of the cytochrome SURZA 4 isoenzyme (erythromycin, saquinavir, ketoconazole, itraconazole), the initial dose of Sildenafil should be 25 mg (see the section “Interaction with other drugs”). To minimize the risk of postural hypotension in patients taking alpha-blockers, Sildenafil should be started only after hemodynamic stabilization has been achieved in these patients. Consideration should also be given to reducing the initial dose of sildenafil (see sections “Special instructions” and “Interactions with other medicinal products”).

Elderly patients

No dose adjustment of Sildenafil is required

Overdose

Symptoms: with a single dose of Sildenafil-SZ up to 800 mg, adverse events were comparable to those with lower doses, but were more common.

Treatment: conducting symptomatic therapy. Hemodialysis does not accelerate the clearance of sildenafil, since the latter is actively bound to plasma proteins and is not excreted by the kidneys.

Special instructions

To diagnose erectile dysfunction, determine their possible causes, and choose appropriate treatment, it is necessary to collect a complete medical history and conduct a thorough physical examination. Treatment of erectile dysfunction should be used with caution in patients with anatomical deformity of the penis (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with

risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see the section “With caution”).

Drugs intended for the treatment of erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable.

Sexual activity poses a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for a cardiovascular examination. Sexual activity is undesirable in patients with heart failure, unstable angina, a history of myocardial infarction or stroke in the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg) or hypotension (BP > Clinical

studies have shown no differences in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of cardiovascular mortality (0.3 per 100 people per year) in patients treated with Sildenafil compared to patients treated with placebo.

Cardiovascular complications

Adverse events such as serious cardiovascular events (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack,

hypertension, and hypotension) that were temporarily associated with the use of sildenafil have been reported during post-marketing use of sildenafil for the treatment of erectile dysfunction.

Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some of them were observed after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct link between the observed adverse events and these or other factors.

Hypotension

Sildenafil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. However, before prescribing the drug

Sildenafil the doctor should carefully assess the risk of possible undesirable manifestations of vasodilating effects in patients with the corresponding diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular exit tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with a rare syndrome of multiple systemic atrophy, manifested by a severe violation of blood pressure regulation by the autonomic nervous system.

Since the combined use of sildenafil and alpha-blockers can lead to symptomatic hypotension in some sensitive patients, the drug

Sildenafil should be used with caution in patients taking alpha-blockers (see section “Interactions with other medicinal products”).

To minimize the risk of postural hypotension in patients taking alpha-blockers, Sildenafil should be started only after the hemodynamic parameters have stabilized in these patients. Consideration should also be given to reducing the initial dose of Sildenafil (see section “Dosage and use”). The doctor should inform patients about what actions should be taken in case of symptoms of postural hypotension.

Visual impairments

Rare cases of anterior non-arteritic ischemic optic neuropathy have been reported as a cause of visual impairment or loss with all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors such as an excavated optic disc, age over 50 years, diabetes mellitus, hypertension, coronary heart disease, hyperlipidemia, and smoking. No causal relationship was found between the use of PDE5 inhibitors and the development of anterior non-arteritic ischemic optic neuropathy. The doctor should inform the patient about the increased risk of developing anterior non-arteritic ischemic neuropathy of the optic nerve, if this condition has already been noted. In case of sudden loss of vision, patients should immediately receive the necessary medical care. A small number of patients with hereditary retinitis pigmentosa have genetically determined disorders of retinal phosphodiesterase functions. There is no information on the safety of Sildenafil in patients with retinitis pigmentosa, so sildenafil should be used with caution (see the section “With caution”).

Hearing disorders

Some post-marketing and clinical studies have reported cases of sudden hearing impairment or loss associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or loss of hearing. No causal relationship has been established between the use of PDE5 inhibitors and sudden hearing impairment or hearing loss. In case of sudden hearing loss or loss of hearing while taking sildenafil, you should immediately consult your doctor.

Bleeding issues

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of using sildenafil in patients with a tendency to bleeding or exacerbation of gastric and

duodenal ulcers, so Sildenafil should

be used with caution in these patients (see the section “With caution”). The incidence of nosebleeds in patients with PH associated with diffuse connective tissue diseases was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (sildenafil 3.0%, placebo 2.4%). In patients treated with sildenafil in combination with a vitamin K antagonist, the incidence of nosebleeds was higher (8.8%) than in patients who did not take a vitamin K antagonist (1.7%).

Use in conjunction with other means of treating erectile dysfunction.

The safety and efficacy of Sildenafil in combination with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended (see the section “Contraindications”).

Influence on the ability to drive motor vehicles and manage mechanisms

While taking sildenafil, no negative effects on the ability to drive a car or other technical means were observed.

However, since taking sildenafil may reduce blood pressure, develop chromatopsia, blurred vision, etc. side effects, you should carefully consider the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosage regimen.

Form of production

Film-coated tablets of blue color, round, biconvex; on the break – white or almost white color.

Storage conditions

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

Shelf

life is 3 years.

Active ingredient

Sildenafil

Conditions of release from pharmacies

By prescription

Dosage form

Tablets