Composition:

1 extended-release tablet contains:

Active substance:

Sildenafil citrate equivalent to sildenafil 100 mg

Excipients:

Silicified microcrystalline cellulose, maltodextrin, hypromellose, povidone, polyethylene glycol 400, colloidal silicon dioxide, magnesium stearate, Opadry White YS-1-7006, Opadry 03B 28796 White

Description:

Tablets are white, oval-shaped, film-coated, smooth on both sides.

Indications for use

Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for successful intercourse.

Sildenafil is effective only in the presence of sexual arousal!

Dosage and administration

The drug is taken orally. For most patients, the recommended dose is 50 mg, taken if necessary, approximately 1 hour before sexual activity, and after a fatty meal, 1.5-2 hours before sexual activity. Based on efficacy and tolerability, the dose may be increased to 100 mg or reduced to 25 mg. The maximum recommended frequency of use is 1 time/day.

You should consult your physician if the following occurs:

Adverse events are usually transient and are mild or moderate in severity. The nature of adverse events in studies related to the selection of doses was comparable to those in studies with fixed doses since such studies better reflect the recommended regimen.

From the side of the cardiovascular system:

Symptoms of vasodilation.

From the gastrointestinal tract:

Diarrhea, abdominal pain, nausea.

From the musculoskeletal system:

Back pain, arthralgia, myalgia.

From the nervous system:

Dizziness, increased muscle tone, insomnia.

Side effects

Adverse events are usually transient and are mild or moderate in severity. The nature of adverse events in studies related to the selection of doses was comparable to those in studies with fixed doses, since such studies better reflect the recommended regimen.

From the side of the cardiovascular system:

Symptoms of vasodilation.

From the gastrointestinal tract:

Diarrhea, abdominal pain, nausea.

From the musculoskeletal system:

Back pain, arthralgia, myalgia.

From the nervous system:

Dizziness, increased muscle tone, insomnia.

From the respiratory system:

Nasal congestion, pharyngitis, rhinitis, sinusitis, respiratory infections, respiratory failure.

Dermatological reactions:

Rash.

From the sense organs:

Changes in vision (mild and transient, mainly a change in the color rendering of objects, as well as the increased perception of light and blurred vision), conjunctivitis.

From the genitourinary system:

urinary tract infections, prostate dysfunction.

In post-marketing observations, there have been reports of cases of prolonged erection and/or priapism.

Drug Interactions

Effect of other drugs on sildenafil:

Cimetidine (800 mg), which is a non-specific inhibitor of cytochrome P450 3A4, in in vivo studies, when taken with sildenafil, caused an increase in the concentration the latter in plasma by 56% in healthy volunteers. A single dose of sildenafil at a dose of 100 mg simultaneously with erythromycin, a specific inhibitor of cytochrome P450 3A4 (when taking erythromycin 2 times / day, 500 mg for 5 days) against the background of achieving a constant level of erythromycin in blood, contributed to an increase in the AUC of sildenafil by 182%. Also, while taking sildenafil at a dose of 100 mg and saquinavir, which is both an inhibitor of HIV protease and an inhibitor of cytochrome P450 3A4 (when taking saquinavir 3 times / day at a dose of 1200 mg) against the background of achieving a constant level of saquinavir in the blood, the maximum concentration of sildenafil in the blood increased by 140%, and AUC increased by 210%. Sildenafil had no effect on pharmacokinetic parameters saquinavir.

Simultaneous use of sildenafil (once at a dose of 100 mg) and ritonavir, which is an inhibitor of HIV protease and a fairly strong inhibitor of cytochrome P450 (at a dose of 500 mg 2 times / day) against the background of achieving a constant level of ritonavir in the blood, Cmax increased by 300% ( 4-fold), and AUC by 1000% (11-fold). After 24 hours, the level of sildenafil in the blood plasma was 200 ng / ml (comparative concentration with a single application of one sildenafil after 24 hours was 5 ng / ml). This is consistent with the effect of ritonavir on a number of drugs that are substrates of cytochrome P450. Sildenafil did not affect the pharmacokinetic parameters of ritonavir.

A population pharmacokinetic analysis of the results of a clinical study demonstrated a decrease in the clearance of sildenafil with the simultaneous use of inhibitors of cytochrome P450 3A4 (such as ketoconazole, itraconazole, erythromycin).

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

The results of pharmacokinetic studies of patients participating in clinical trials of sildenafil showed that inhibitors of cytochrome P450 2C9 (such as tolbutamide, warfarin), cytochrome P450 2D6 (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, loop and potassium-sparing diuretics, ACE inhibitors and calcium antagonists did not affect the pharmacokinetic parameters of sildenafil.

The effect of sildenafil on other drugs:

In patients with arterial hypertension, there were no signs of the interaction of sildenafil (100 mg) with amlodipine.

Sildenafil (50 mg) did not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not enhance the hypotensive effect of ethanol in healthy volunteers with a maximum blood ethanol level of 80 mg/ml on average.

Special Precautions

Sexual activity poses a certain risk in heart disease; in this regard, before starting therapy with sildenafil, an examination of the cardiovascular system should be carried out.

In clinical studies, sildenafil had a systemic vasodilatory effect, which leads to a transient decrease in blood pressure. Before prescribing the drug, the physician should carefully weigh the risk of adverse manifestations of the vasodilating effect in patients with various concomitant diseases, especially on background of sexual activity. Increased susceptibility to vasodilators is observed in patients with left ventricular obstruction (eg, aortic stenosis, hypertrophic cardiomyopathy), as well as rare multiple atrophy of various systems, manifested by severe impairment of autonomic BP control.

Due to the lack of data on the safety of sildenafil, the drug should be used with caution in the following groups of patients:

– survivors of myocardial infarction, suffering from cerebrovascular accident, as well as life-threatening arrhythmia during the last 6 months;

– suffering from orthostatic hypotension (BP 90/50) or hypertension (BP 170/110);

– suffering from heart failure or coronary heart disease due to unstable angina.

– with hereditary pigment retinin, having hereditary disorders associated with the synthesis of retinal phosphodiesterase;

– in patients with anatomical deformity of the penis (for example, angulation, cavernous fibrosis or Peyronie’s disease) and in patients with diseases that predispose to the development of priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Drugs intended for the treatment of erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable. In addition, the safety and efficacy of sildenafil when used in combination with other drugs intended for the treatment of erectile dysfunction have not been studied, so the use of such combinations is not recommended.

When using the drug in patients over 65 years of age, patients with impaired liver function, patients with severe renal insufficiency, as well as in patients receiving concomitant drugs – inhibitors of cytochrome P450 3A4 (for example, erythromycin, saquinavir), there is an increase in the level of sildenafil in plasma. This can affect both the increase in the effectiveness of the drug and the possibility of side effects. For such groups of patients, it is advisable to prescribe the drug at a dose of 25 mg/day.

Influence on the ability to drive vehicles and control mechanisms:

The drug can cause dizziness and blurred vision, so patients should assess their reaction to the drug before driving a car or using machinery.

The drug should be stored out of the reach of children and should not be used after the expiration date.

Overdose

In studies in healthy volunteers with a single dose of the drug in doses up to 800 mg, adverse events were comparable to those when taking sildenafil at lower doses, but were more common.

Treatment:

If necessary, carry out symptomatic therapy. Dialysis does not accelerate the clearance of sildenafil, since the latter is actively bound to plasma proteins and is not excreted in the urine.

Contraindications

Hypersensitivity to the components of the drug.

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

The drug is not intended for use in women and children. There are no adequate and well-controlled trials in pregnancy and lactation in women.

Pharmacological properties

Sildenafil citrate is a potent and selective inhibitor of specific phosphodiesterase type 5 (PDE5).

The physiological mechanism of penile erection involves the release of nitric oxide (NO) 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) and, accordingly, relaxation of the smooth muscles of the cavernous body, resulting in increased blood flow in the penis.

Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum, but actively enhances the relaxing effect of NO on this tissue by inhibiting PDE5, which is responsible for the breakdown of cGMP in the corpus cavernosum.

This leads to an increase in cGMP levels, resulting in smooth muscle relaxation and increased blood flow in the cavernous body.

Therefore, the use of sildenafil in the recommended doses is ineffective in the absence of sexual stimulation.

Pharmacodynamics

The effect of sildenafil on erectile dysfunction:

In a double-blind, placebo-controlled crossover study of patients with erectile dysfunction of various etiologies (organic, psychogenic, mixed), the result of sexual stimulation was the onset of a prolonged erection sufficient for sexual intercourse after the appointment of sildenafil compared with placebo.

The effect of sildenafil on blood pressure:

When using the drug orally at a dose of 100 mg, the maximum decrease in systolic blood pressure (BP) in the supine position averaged 8.4 mm Hg, and diastolic blood pressure in the prone position was 5.5 mm Hg. Art. A more pronounced, but similarly transient effect on blood pressure was observed in patients receiving concomitant nitrates.

The effect of sildenafil on hemodynamics:

A single dose of sildenafil at a dose of 100 mg did not cause clinically significant changes in the ECG in healthy volunteers.

The effect of sildenafil on vision:

In some patients, 1 hour after taking the drug at a dose of 100 and 200 mg, a slight and transient impairment in color discrimination (blue/green) was detected, 2 hours after taking these changes, these changes were not observed. The established mechanism of color vision impairment is the inhibition of PDE 6, which is involved in the process of light transmission to the retina.

Sildenafil does not affect visual acuity, contrast sensitivity, and intraocular pressure, or pupil diameter.

Pharmacokinetics

The pharmacokinetics of sildenafil depends on the dose ranges used orally. Metabolism of the drug is carried out mainly in the liver (mainly by cytochrome P450 3A4 isoenzyme) with the formation of an active metabolite, similar in properties to sildenafil.

Suction and distribution:

The drug is rapidly absorbed through the gastrointestinal tract. After taking it inside on an empty stomach, Cmax is achieved within 30-120 minutes (60 minutes on average). Absolute bioavailability averages 41% (25-63%). When taking sildenafil in combination with fatty foods, the rate of absorption decreases; Tmax increases by 60 minutes, and Cmax decreases by an average of 29%.

The volume of distribution (Vd) of sildenafil at steady state averages 105 L, indicating its tissue distribution. Sildenafil and its main circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Protein binding is independent of the total concentration of sildenafil. In healthy volunteers treated with sildenafil, less than 0.0002% (mean 188 ng) of the dose was detected in semen 90 minutes after administration.

Sildenafil is metabolized mainly by the action of P450 3A4 (main route) and P450 2C9 (additional route) of hepatic microsomal isoenzymes. The main circulating metabolite, which is formed as a result of N-desmethylation of sildenafil, undergoes further metabolism. The metabolite is comparable in selectivity to PDE with sildenafil, and its activity against PDE5 in vitro is approximately 50% of the activity of sildenafil itself. Plasma metabolite concentrations are approximately 40% of those of sildenafil. The total clearance of sildenafil from the body is 41 l / h, and the half-life (T1 / 2) in the terminal phase is 3-5 hours. Excreted as metabolites mainly with feces (approximately 80% of the dose administered orally) and to a lesser extent with urine (approximately 13% administered orally).

Pharmacokinetics in special clinical situations:

Metabolism and excretion:

The following factors influence the increase in the level of sildenafil in blood plasma (AUC):

– age over 65 years (40% increase in AUC);

– insufficiency of liver function (for example, cirrhosis of the liver, 84%);

– severe renal failure (CC <30 ml / min, 100%);

– concomitant use of drugs – inhibitors of cytochrome P450 3A4 (for example, erythromycin, 182%, saquinavir, 210%).

Storage conditions

Store at a temperature not exceeding 25°C in a dry, dark place.

Best before date

2 years.

Release form

1 or 4 tablets in a blister, each blister in a carton.