Silden - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate (100.275 mg / 200.550 mg), croscarmellose sodium (18,000 mg / 36,000 mg), povidone K 25 (14,800 mg / 29,600 mg), microcrystalline cellulose type 101 (48,200 mg / 96,400 mg), silicified microcrystalline cellulose (50,000 mg / 100,000 mg), sodium stearyl fumarate (4,500 mg / 9,000 mg);

film coating: (3,740 mg / 7,480 mg), titanium dioxide E 171 (2,575 mg / 5,150 mg), macrogol 6,000 (1,537 mg / 3,074 mg), talc (0.920 mg / 1.840 mg), glycerol (0.220 mg / 0.440 mg), dye diamond blue FCF (E133) (0.023 mg / 0.046 mg).

Description:

Tablets 50 mg: round, biconvex tablets, covered with a film shell of blue color, on the cross section the nucleus is white.

Tablets 100 mg: oblong, biconvex tablets, covered with a film shell of blue color, with a dividing risk on both sides,on the cross-section the nucleus is white.

Pharmacotherapeutic group:Erectile dysfunction remedy - PDE5-inhibitor

ATX: & nbsp

G.04.B.E Drugs for the treatment of erectile dysfunction

G.04.B.E.03 Sildenafil

Pharmacodynamics:

Sildenafil is intended for oral administration with erectile dysfunction. In natural conditions, i.e. with sexual stimulation, he restores impaired erectile function by increasing the flow of blood to the penis.

The physiological mechanism responsible for penile erection involves the release of nitric oxide (N0) in the cavernous body during sexual stimulation.

Nitric oxide activates the enzyme guanylate cyclase, which leads to an increase in the level of cyclic guanosine monophosphate (cGMP), resulting in a relaxation of smooth muscles and increased blood flow in the cavernous body.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which causes the disintegration of cGMP into the cavernous body of the penis. Sildenafil Has a peripheral mechanism of action in relation to erection.It does not have a direct relaxing effect on the smooth muscles of the cavernous body, but enhances the relaxing effect NO on this fabric. When the metabolic chain is activated NO/ cGMP, observed with sexual stimulation, suppression of PDE5 with sildenafil causes an increase in cGMP levels in the cavernous body. The pharmacological effect is achieved only with the presence of sexual stimulation.

Research in vitro show that sildenafil is selective for PDE5, which is involved in the process of erection. Its effect on PDE5 is more potent than for other known phosphodiesterases. It is 10 times more selective for PDE5 than PDE6, which is involved in the process of light transmission in the retina. At maximum recommended doses, its selectivity is 80 times higher for PDE5 than PDE1 and more than 700 times higher than for PDE2, 3, 4, 7, 8, 9, 10 and 11. Sildenafil has a 4,000-fold higher selectivity for PDE5 than for the PDE3 isoform of cAMP-specific phosphodiesterase involved in the regulation of myocardial contractility.

Sildenafil has a light and short-term hypotensive effect, which in most cases occurs without clinical manifestations.The average value of the maximum decrease in systolic blood pressure (BP) in the supine position after ingestion of 100 mg of sildenafil is 8.4 mm Hg. The corresponding change in diastolic blood pressure in the supine position is 5.5 mm Hg. These BP reductions confirm the vasodilating effect of sildenafil, which is probably due to an increase in the level of cGMP in the smooth muscle of blood vessels. In healthy volunteers, a single oral dose of up to 100 mg of sildenafil does not lead to clinically significant changes in the electrocardiogram.

Sildenafil has no effect on cardiac output and does not alter blood flow through stenotic coronary arteries.

One hour after taking 100 mg of sildenafil, few patients experience mild and transient impairments in the ability to distinguish between colors (blue / green), and the effect disappears completely 2 hours after the drug is applied. The likely mechanism of impaired color perception is associated with oppression of PDE6, which is involved in the transmission of light in the retina. Sildenafil does not affect visual acuity or a sense of contrast.After applying a single dose of 100 mg of sildenafil in healthy volunteers, the motility or morphology of spermatozoa does not change.

Pharmacokinetics:

Sildenafil is rapidly absorbed. After oral administration on an empty stomach, the maximum concentration in the blood plasma (C_mOh) is achieved within 30-120 minutes (mean value of 60 minutes). Absolute bioavailability (AUC) is an average of about 40% (25-63%). After oral administration of sildenafil in the recommended therapeutic doses (25-100 mg), AUC and C_mOh increase in proportion to the dose.

When taken in combination with fatty foods, FROM_mOh decreases by an average of 29%, and the time to reach the maximum concentration (T_max) increases by an average of 60 min.

The volume of the distribution in the equilibrium state (Vd) sildenafil is an average of 105 liters. Since the association of sildenafil and its main circulating N-desmethyl metabolite with blood plasma proteins is about 96%, the average concentration of the free fraction of sildenafil is 18 ng / ml (38 nM). Binding to proteins does not depend on the total concentration of the drug. Less than 0.0002% (an average of 188 ng) was found in semen in healthy volunteers 90 minutes after taking 100 mg of sildenafil. Sildenafil metabolized mainly in the liver under the influence of microsomal isozymes CYP3A4 (main path) and CYP2C9 (secondary path). The main circulating metabolite is formed as a result of N-Semidylation of sildenafil.

The metabolite has a phosphodiesterase selectivity similar to that of sildenafil, and in vitro its activity in relation to PDE5 is about 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma is about 40% of the concentration of sildenafil. N-demethyl-metabolite undergoes a further metabolism with a half-life (T_1/2) about 4 hours.

The total clearance of sildenafil from the body is 41 l / h, and the final T_1/2- 3-5 hours After oral administration sildenafil is excreted as metabolites, mainly by the intestine (about 80%) and to a lesser extent by the kidneys (about 13%).

Pharmacokinetics in specific patient groups

Older patients:

In elderly volunteers (over 65 years), the clearance of sildenafil is reduced, and the concentration of free active substance in the blood plasma is approximately 40% higher than in young adults (18-45 years).

Impaired renal function:

In volunteers with mild to moderate renal insufficiency (creatinine clearance 30-80 ml / min) after a single oral intake of 50 mg sildenafil,its pharmacokinetic parameters do not change. Mean values AUC and C_max N-demethylated metabolite, respectively, increased by 126% and 73% compared with those in volunteers without renal impairment. Because of the high individual variation, these differences are not statistically significant. With renal failure of severe degree (creatinine clearance ≤30 ml / min), the clearance of sildenafil decreases, which leads to approximately a twofold increase in AUC (100%) and C_max (88%) compared with those for normal kidney function in patients of the same age group. The values of AUC and C_max N-desmethylated metabolite, respectively, increased by 79% and 200%.

Dysfunction of the liver:

In patients with mild to moderate liver cirrhosis (A and B on the Child-Pugh scale), the clearance of sildenafil is reduced, the values AUC and C_max increase respectively by 84% and 47% compared with those in patients with normal liver function of the same age group. The pharmacokinetics of sildenafil in patients with severe impairment of liver function has not been studied.

Indications:

Treatment of erectile dysfunction, characterized by an inability to achieve or maintain an erection penis, sufficient for a satisfactory sexual intercourse.

Effective only with sexual stimulation.

Contraindications:

- Hypersensitivity to the active substance or any of the excipients. Sildenafil can enhance the hypotensive effect of nitrates. Its simultaneous application with donators NO (such as amyl nitrate) or nitrates in any form is contraindicated.

- Drugs for the treatment of erectile dysfunction, including sildenafil, should not be used in men who are not recommended for sexual activity (for example, patients with severe cardiovascular disorders, such as unstable angina or severe heart failure).

- Simultaneous use of sildenafil and ritonavir.

- Sildenafil is contraindicated in patients with loss of vision in one eye due to anterior ischemic optic neuropathy of non-arterial genesis (NPII), regardless of whether it is bound or not with the use of the PDE5 inhibitor.

- Chronic renal failure of severe severity.

- Severe liver function, arterial hypotension (BP <90/50 mm Hg), a recent stroke or myocardial infarction and known hereditary degenerative diseasesretina, such as retinitis pigmentosa.

- Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

- Age to 18 years.

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

Carefully:

Syndrome of multiple systemic atrophy; obstruction of the left ventricular outflow tract, including aortic stenosis, hypertrophic obstructive cardiomyopathy; anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie's disease); diseases that can lead to the development of priapism; sickle-cell anemia, multiple myeloma or leukemia; a clotting disorder or an active peptic ulcer; simultaneous administration of alpha-blockers.

Pregnancy and lactation:

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

Dosing and Administration:

Inside, about 1 hour before the planned sexual activity.

Use in adult patients

The recommended dose is 50 mg, about 1 hour before sexual activity.

Depending on the effect and tolerability, the dose can be increased to 100 mg. The maximum daily dose is 100 mg.The maximum recommended frequency of application is once a day. When using the drug with food, its effect may develop later than when it is applied on an empty stomach.

Use in elderly patients

Dose adjustments are not required.

Use in patients with impaired renal function

For patients with mild and moderate renal impairment (creatinine clearance - 30-80 ml / min), dose adjustment is not required.

Use in patients with impaired liver function

In patients with impaired liver (for example, cirrhosis), the clearance of sildenafil is reduced. In this case, patients should consult a physician to determine the dose. Depending on the effect and tolerability, the dose can be increased to 50 mg or 100 mg.

Application in humans, taking other medications

With the exception of ritonavir, for which simultaneous use with sildenafil is not recommended (see section "Interaction with other drugs"), patients taking inhibitors CYP3A4, a lower dose is recommended. In this case, patients should consult a physician to determine the dose.

To reduce the risk of development of orthostatic (postural) hypotension, before beginning the use of sildenafil in patients taking alpha-blockers, it is necessary to achieve stabilization of hemodynamics, and to clarify the initial dose with the attending physician.

Side effects:

Side effects are classified according to the WHO recommendation: very often (≥ 1/10), often (≥ 1/100 and <1/10) infrequently (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), very rarely (<1/10 000), with an unknown frequency (based on existing data, it is impossible to make an estimate).

In addition, the frequency of clinically important side effects reported during the postmarketing period is included as an unknown.

Immune system disorders

Rarely hypersensitivity reactions.

Disturbances from the nervous system

Often - headache;

Often - dizziness;

Infrequently - drowsiness, hypoesthesia;

Rarely - Stroke, fainting;

With an unknown frequency - transient ischemic attack, convulsions, including recurrent.

Disturbances on the part of the organ of sight

Often - impaired vision, violation of color perception;

Infrequently - defeat of the conjunctiva, violation of lacrimation, increased perception of light, impaired vision;

With an unknown frequency - anterior ischemic optic neuropathy (NPION), occlusion of retinal vessels, narrowing of the visual fields.

Hearing disorders and labyrinthine disorders

Infrequently - Vertigo, noise in the ears;

Rarely - deafness. *

Disorders from the cardiovascular system

Often - "tides" of blood to the skin of the face;

Infrequently - palpitation, tachycardia;

Rarely - increased or decreased blood pressure, myocardial infarction, atrial fibrillation;

With an unknown frequency - ventricular arrhythmia, unstable angina, sudden coronary death.

Disturbances from the respiratory organs

Often - nasal congestion;

Rarely - nose bleed.

Disorders from the gastrointestinal tract

Often - dyspepsia;

Infrequently - vomiting, nausea, dryness of the oral mucosa.

Allergic reactions

Infrequently - skin rash;

With unknown frequency - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Disturbances from musculoskeletal system and connective tissue

Infrequently - myalgia.

Disorders from the kidneys and urinary tract

Infrequently - Hematuria.

Violations of the genitals and mammary gland

Infrequently - Hematospermia, hemorrhage in the penis;

With an unknown frequency - priapism, prolonged erection.

Other

Infrequently - pain in the chest, fatigue.

* Hearing impairment: sudden deafness, sudden decline or loss of hearing is reported in a small number of cases in post-marketing and clinical trials with all PDE 5 inhibitors, including sildenafil.

Overdose:

With a single application of the drug at a dose of up to 800 mg, side effects are similar to those observed with therapeutic doses, but have a higher frequency and are more pronounced. Doses up to 200 mg do not increase efficacy, but increase the incidence of side effects (headache, flushing of the blood to the skin of the face, dizziness, dyspepsia, nasal congestion, impaired vision).

Treatment: symptomatic therapy. Hemodialysis is ineffective.

Interaction:

Actions of other drugs on sildenafil

Research in vitro:

Metabolism of sildenafil is carried out with the help of isoenzymes 3A4 (the main pathway) and 2C9 (a secondary pathway) of cytochrome P450 (CYP), therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil.

Research in vivo:

Inhibitor inhibitors CYP3A4 and CYP2C9 (such as ketoconazole, erythromycin, cimetidine) reduce metabolism and increase the concentration of sildenafil in the blood.

In this case, the dose needs to be clarified with the attending physician.

Simultaneous use of the protease inhibitor HIV ritonavir and sildenafil (100 mg single dose) causes a 300% increase in C_max and 1000% - AUC sildenafil and remains after a day after taking sildenafil. Because of this, simultaneous use of sildenafil and ritonavir is not recommended (see section "Contraindications").

Simultaneous use of an HIV protease inhibitor and an inhibitor CYP3A4 saquinavir, after achieving a constant concentration of saquinavir (1200 mg 3 times a day) and sildenafil (100 mg single dose), leads to an increase of 140% C_max and by 210% - AUC sildenafil. Sildenafil does not affect the pharmacokinetics of ritonavir and saquinavir. More powerful inhibitors CYP3A4, such as ketoconazole and itraconazole, may cause, presumably, a more pronounced change in the pharmacokinetics of sildenafil.

With the simultaneous use of sildenafil in a single dose of 100 mg and a specific inhibitor CYP3A4 erythromycin, after reaching equilibrium concentrations (500 mg twice a day / day for 5 days), leads to an increase AUC sildenafil by 182%.

In healthy volunteers there was no effect of azithromycin (500 mg per day for 3 days) on AUC, FROM_max, T_max, rate of elimination rate constant or half-life of sildenafil or its circulating metabolites.

Cimetidine (800 mg), which is an inhibitor of cytochrome P450 and a nonspecific inhibitor CYP3A4, causes an increase in the concentration of sildenafil in blood plasma by 56% with simultaneous application with sildenafil (50 mg) in healthy volunteers.

Grapefruit juice is a weak inhibitor CYP3A4 and may lead to a moderate increase in the concentrations of sildenafil in blood plasma.

Single doses of antacids (magnesium hydroxide / aluminum hydroxide) do not affect the bioavailability of sildenafil.

Despite the fact that no specific pharmacokinetic studies of interactions with all drugs have been conducted, population pharmacokinetic analysis revealed no changes in the pharmacokinetics of sildenafil when used simultaneously with such drugs from the group of inhibitors CYP2C9, as tolbutamide, warfarin, phenytoin, inhibitors of isoenzyme CYP2D6 (selective serotonin reuptake inhibitors,tricyclic antidepressants), and similar thiazide diuretics, potassium-sparing diuretics and loop, angiotensin-converting enzyme inhibitors, calcium antagonists, beta-adrenoceptor antagonists or isoenzyme inducers CYP450 (such as rifampicin, barbiturates).

With the simultaneous use of sildenafil with bosentan (inductor of isoenzymes CYP3A4, CYP2C9) there was a decrease AUC and C_max sildenafil by 62.6% and 55.4% respectively.

Nicorandil is a hybrid of nitrate and potassium channel activator. Because of the nitrate component in the composition, there is a possibility of serious interaction with sildenafil (development of severe arterial hypotension).

Effect of sildenafil on other drugs

Research in vitro:

Sildenafil is a weak inhibitor of isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 cytochrome P450 (IC50> 150 μM). When using sildenafil in recommended doses, its C_max in the blood plasma is about 1 μM, so there is little chance that it will affect the clearance of the substrates of these isoenzymes.

There are no data on the interaction between sildenafil and nonspecific inhibitors of phosphodiesterases, such as theophylline or dipyridamole.

Research in vivo:

Sildenafil potentiates hypotensive effects of nitrates. Its simultaneous use with donators of nitric oxide or nitrates in any form is contraindicated.

Simultaneous use of sildenafil with alpha-blockers can cause symptomatic hypotension in a few susceptible patients. Arterial hypotension usually develops within the first 4 hours after application of the drug. In three special studies of drug interaction in patients with benign prostatic hyperplasia (BPH) and stable hemodynamics, an alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg or 100 mg). In these groups of patients, there is an average additional decrease in arterial pressure in the prone position by 7/7 mm Hg, respectively. st., 9/5 mm Hg. Art. and 8/4 mm Hg. and in the standing position - 6/6 mm Hg. st., 11/4 mm Hg. Art. and 4/5 mm Hg. Art.

With the simultaneous use of sildenafil and doxazosin, in rare cases, the development of symptomatic orthostatic hypotension was reported (dizziness and sensations of "lightness" appeared, but without the development of syncope).

With the simultaneous use of sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), which are metabolized with participation CYP2C9, significant interaction is not established.

Sildenafil (50 mg) does not potentiate the prolongation of bleeding time caused by acetylsalicylic acid (150 mg).

Sildenafil increased AUC and C_max bosentan by 49.8% and 42% respectively.

Sildenafil (50 mg) does not potentiate hypotensive effects of alcohol in healthy volunteers with average maximum blood alcohol concentrations of 80 mg / dl.

In general, antihypertensive drugs (diuretics, beta-blockers, ACE inhibitors, angiotensin II receptor antagonists, vasodilators and central action), adrenergic blockers, calcium antagonists and alpha-adrenoreceptor blockers, did not reveal differences in the side-effect profile in patients receiving sildenafil in comparison with placebo.

In a special study sildenafil (100 mg) was used concomitantly with amlodipine in individuals with hypertension, with an additional decrease in systolic blood pressure in the supine position of 8 mm Hg. Art.The corresponding additional decrease in diastolic blood pressure in the supine position was 7 mm Hg. Art. This additional decrease in blood pressure was the same as with the use of only sildenafil in healthy volunteers.

Special instructions:

- Before using sildenafil it is necessary to collect anamnesis and conduct a clinical examination to diagnose erectile dysfunction and determine its possible causes.

- Before beginning any therapy for erectile dysfunction, you need to assess the cardiovascular status of the patient, because there is a degree of cardiac risk associated with sexual activity. Sildenafil has a vasodilating effect, leading to a small and transient lowering of blood pressure. Before the appointment of sildenafil, the risk of possible undesirable manifestations of vasodilating effects in patients with certain concomitant diseases, especially in combination with sexual activity, should be carefully assessed. Increased sensitivity to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (eg, aortic stenosis,hypertrophic obstructive cardiomyopathy) and syndrome rarely encountered multiple system atrophy, manifesting severe impairment of the autonomous regulation of blood pressure by the autonomic nervous system.

- Sildenafil potentiates the hypotensive effect of nitrates. In postmarketing research, there is evidence of serious cardiovascular events such as myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension, coinciding with the use of sildenafil. Most patients had data in the history of cardiovascular risk factors. Events that are reported, have evolved over the short period of time after the application of sildenafil even in the absence of sexual activity. It is impossible to determine whether these incidents directly to the above or other factors.

- Drugs for the treatment of erectile dysfunction, including sildenafilShould be used with caution in patients with anatomical deformation of the penis (angulation,cavernous fibrosis or Peyronie's disease) or patients with conditions predisposing to priapism (sickle-cell anemia, multiple myeloma or leukemia).

- If the erection persists for more than 4 hours, seek medical attention. If priapism therapy is not performed in a timely manner, it can lead to damage to the penile tissue and an irreversible loss of potency.

- The safety and effectiveness of combinations of sildenafil with other drugs for the treatment of erectile dysfunction have not been studied, so the use of such combinations is not recommended.

- There are data on visual impairment and cases of anterior ischemic optic neuropathy of non-arterial genesis in connection with the use of sildenafil and other PDE5 inhibitors. The patient should be informed that in case of sudden appearance of visual disturbances (loss of vision or sudden deterioration), it is necessary to stop using the drug and immediately consult a doctor.

- Caution should be exercised for individual susceptible patients taking both alpha-blockers and sildenafil, because of the possible development of symptomatic hypotension.Arterial hypotension most often develops 4 hours after the application of sildenafil. To reduce the possibility of developing orthostatic hypotension, it is necessary that such patients have stable hemodynamics before starting treatment with sildenafil (see section "Dosing and Administration"). In addition, the doctor should explain to the patient what to do in case of symptoms of orthostatic hypotension.

- Studies with human platelets show that sildenafil potentiates in vitro antiaggregant properties of sodium nitroprusside.

- There is no information on the safe use of sildenafil in patients with coagulation disorders or active peptic ulcers, so sildenafil It should be used in such patients only after a thorough assessment of the benefit / risk ratio.

- The composition of the drug includes lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, Lappease lactase deficiency, or glucose-galactose malabsorption should not be used Silden®.

Effect on the ability to drive transp. cf. and fur:

Since it is possible to reduce blood pressure, the development of chromatopsy, blurred vision,should carefully consider the individual effect of the drug, especially at the beginning of treatment and when changing the dosage regimen, and to be careful when driving vehicles and engage in potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 50 mg and 100 mg.

Packaging:

For 1 or 4 tablets in a contour mesh box made of a solid, colorless, transparent PVC film and aluminum foil.

Tablets 100 mg: 1 circuit cell pack (1 or 4 tablets) together with the instructions for use are put in a pack of cardboard.

50 mg tablets: 1 circuit cell pack (1 tablet) or 1 or 2 contour cell packs (4 tablets each) together with instructions for use are put in a pack of cardboard.

Storage conditions:

In a dry, dark place, at a temperature of no higher than 25 FROM.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004009

Date of registration:07.12.2016

Expiration Date:07.12.2021

The owner of the registration certificate:Sopharma, AOSopharma, AO Bulgaria

Manufacturer: & nbsp

UNIPHARM, AD Bulgaria

Representation: & nbspSOFARMA SA SOFARMA SA Bulgaria

Information update date: & nbsp16.01.2017

Illustrated instructions

Instructions

Silden® (Silden)