Viatail 100 mg, 4 pcs.

Pharmacotherapeutic group:

A treatment for erectile dysfunction FDE5 inhibitor

ICD-10:

V.F50-F59.F52.2 Genital Insufficiency

XIV.N40-N51.N48.4 Impotence of organic origin

ATC:

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

G.04.B.E.03 Sildenafil

Pharmacodynamics:

Sildenafil is a potent selective inhibitor of cycloguanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

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. The subsequent relaxation of the smooth muscle tissue of the corpora cavernosa and an increase in blood flow.

Sildenafil has no direct relaxant effect on the isolated human cavernous body, but it enhances the effect of nitric oxide (NO) by inhibiting FDE5, which is responsible for the breakdown of cGMP.

Sildenafil is selective against FDE5 in vitro, its activity against FDE5 is superior to other known phosphodiesterase isoenzymes: FDE6, 10 times; FDE1, more than 80 times; FDE2, FDE4, FDE7-FDE11, more than 700 times. Sildenafil is 4,000 times more selective against FDE5 compared to FDE3, which is of critical importance because FDE3 is one of the key enzymes regulating myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

The use of sildenafil in doses up to 100 mg did not result in clinically significant electrocardiogram (ECG) changes in healthy volunteers. The maximum decrease in systolic blood pressure in the supine position after sildenafil administration at a dose of 100 mg was 8.3 mm Hg, and in diastolic blood pressure, 5.3 mm Hg. A more pronounced but also transient effect on blood pressure (BP) was noted in patients taking nitrates.

In a study of the hemodynamic effects of sildenafil at a single dose of 100 mg in 14 patients with severe coronary heart disease (CHD) (more than 70% of patients had stenosis of at least one coronary artery), resting systolic and diastolic BP decreased by 7% and 6%. respectively, and systolic pulmonary artery pressure decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenosed coronary arteries, and it also resulted in an increase (by approximately 13%) in adenosine-induced coronary flow in both stenosed and intact coronary arteries.

The endurance to exercise in patients with erectile dysfunction and stable angina pectoris taking antianginal drugs (except nitrates) is significantly higher when taking sildenafil.

Sildenafil improves erection in men with erectile dysfunction and arterial hypertension taking more than two antihypertensive drugs. The incidence of adverse effects is comparable to that in other patient groups, as well as in those taking more than three antihypertensive drugs.

In some patients, 1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Mansell 100 test reveals mild and transient impairment in the ability to distinguish shades of color (blue/green). Two hours after taking the drug, these changes disappear. It is believed that color vision impairment is caused by inhibition of FDE6, which is involved in the transmission of light in the retina. Sildenafil has no effect on visual acuity, contrast perception, the electroretinogram, intraocular pressure, or pupil diameter.

In patients with proven early-onset macular degeneration (n = 9), sildenafil at a single dose of 100 mg was well tolerated with no significant visual changes. Efficacy of sildenafil is defined as the ability to achieve and maintain an erection sufficient for satisfactory intercourse.

The fixed dose improved erections in 62% (sildenafil 25 mg dose), 74% (sildenafil 50 mg dose), and 82% (sildenafil 100 mg dose) of cases. Analysis of the international erectile function index shows that in addition to improvement of erection with sildenafil treatment, the quality of orgasm, satisfaction of sexual intercourse and overall satisfaction are also improved.

Allocated data shows that among the patients who reported improved erections with sildenafil treatment, 59% had diabetes, 43% had a radical prostatectomy, and 83% had a spinal cord injury.

Pharmacokinetics:

The pharmacokinetics of sildenafil in the recommended dose range is linear.

Intake

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (25% to 63%). In vitro sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human FDE5 activity by 50%. After a single sildenafil dose of 100mg, the average maximum plasma concentration (cmax) of free sildenafil in men is about 18 ng/ml (38 nM). Cmax when sildenafil is taken orally on an empty stomach is reached within an average of 60 minutes (30 minutes to 120 minutes). When taken in combination with a fatty food the speed of absorption is decreased: Cmax is decreased by 29% on average, and time to maximum concentration (Tmax) is increased by 60 minutes, but the degree of absorption is not significantly changed (area under the pharmacokinetic curve of concentration-time (AUC) is decreased by 11%).

Distribution

The volume of distribution of sildenafil in the equilibrium state averages 105 liters. The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and is independent of the total drug concentration. Less than 0.0002% of the sildenafil dose (188 ng on average) is detected in semen 90 minutes after taking the drug.

Metabolism

Sildenafil is metabolized primarily in the liver by the cytochrome isoenzyme CYP3A4 (main pathway) and the cytochrome isoenzyme CYP2C9 (additional pathway). The main circulating active metabolite formed as a result of N-demethylation of sildenafil undergoes further metabolism. Selectivity of this metabolite against FDE is comparable with that of sildenafil, and its activity against FDE5 in vitro is about 50% of sildenafil activity. Concentration of the metabolite in blood plasma of healthy volunteers is about 40% of sildenafil concentration. The N-demethyl metabolite is further metabolized; its half-life (T1/2) is about 4 hours.

The total clearance of sildenafil is 41 l/hour and the T1/2 is 3-5 hours. After oral administration as well as after intravenous administration sildenafil is excreted as metabolites mainly by the intestine (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

Healthy elderly patients (over 65 years of age) have reduced sildenafil clearance and plasma free sildenafil concentrations are about 40% higher than those of younger patients (18-45 years of age). Age has no clinically significant effect on the incidence of side effects.

Renal impairment

In mild (creatinine clearance (CK) 50-80 ml/min) and moderate (CK 30-49 ml/min) renal impairment, the pharmacokinetics of sildenafil after a single oral dose of 50 mg is unchanged. In severe renal impairment (CKD 30 ml/min), sildenafil clearance is decreased, resulting in approximately twofold increase in AUC (100%) and Cmax (88%) compared to normal renal function in patients of the same age group.

Hepatic disorders

In patients with cirrhosis (Child-Pugh grades A and B), sildenafil clearance is decreased, resulting in increased AUC (84%) and Cmax (47%) compared to normal hepatic function in patients in the same age group. Pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) has not been studied.

Indications

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

Active ingredient

Composition

film-coated tablets.

Active ingredient:

sildenafil citrate 140.48 mg, equivalent to sildenafil 100 mg.

Associates:

microcrystalline cellulose* – 337.52 mg,

calcium hydrophosphate anhydrous – 100.00 mg,

croscarmellose sodium – 12.00 mg,

magnesium stearate – 10.0 mg,

opadray red (06B 55000) – 18.00 mg.

How to take, the dosage

Ingestion.

The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of administration is once daily.

Renal dysfunction

In mild to moderate renal impairment (CK 30-80 ml/min), no dose adjustment is necessary; in severe renal impairment (CK < 30 ml/min), the sildenafil dose should be reduced to 25 mg.

Hepatic disorders

Because sildenafil excretion is impaired in patients with liver damage (particularly in cirrhosis), the dose of Viatail should be reduced to 25 mg.

Combined use with other medications

When used together with ritonavir, the maximum single dose of Viatail should not exceed 25 mg and the frequency of administration should be once in 48 hours.

In co-administration with cytochrome CYP3A4 isoenzyme inhibitors (erythromycin, saquinavir, ketoconazole, itraconazole) the starting dose of Vital should be 25 mg.

In order to minimize the risk of postural hypotension in patients taking α-adrenoblockers, Vyatail should be started only after hemodynamic stabilization has been achieved in these patients. A reduction in the starting dose of sildenafil should also be considered.

Elderly patients

In elderly patients, the starting dose is 25 mg. If tolerated well, the dose may be increased to 50 mg or 100 mg.

Interaction

Influence of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome CYP3A4 isoenzymes (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers, respectively, increase sildenafil clearance. There is a decrease in sildenafil clearance with concomitant use of inhibitors of cytochrome CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine).

Cimetidine (800 mg), a non-specific inhibitor of cytochrome CYP3A4, when taken with sildenafil (50 mg) increases sildenafil plasma concentrations by 56%.

Single use of sildenafil 100 mg together with erythromycin (250 mg twice daily for 5 days), a specific inhibitor of cytochrome CYP3A4, on the background of achieving a steady concentration of erythromycin in blood, leads to an increase of AUC sildenafil by 182%. When taking sildenafil (single dose 100 mg) and saquinavir (400 mg/day 3 times a day), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme, together against reaching a steady concentration of saquinavir in blood Cmax of sildenafil was increased by 140%, and AUC was increased by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir. Stronger inhibitors of CYP3A4 cytochrome isoenzyme, such as ketoconazole and itraconazole, may cause greater changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg twice daily), an HIV protease inhibitor and a strong cytochrome P450 inhibitor, against the background of achieving a steady blood concentration of ritonavir leads to an increase in Cmax of sildenafil by 300% (4 times) and AUC by 1000% (11 times). After 24 hours the plasma concentration of sildenafil is about 200 ng/ml (after a single use of sildenafil – 5 ng/ml).

If sildenafil at recommended doses is taken by patients receiving concomitant strong CYP3A4 cytochrome isoenzyme inhibitors, the Cmax of free sildenafil is less than 200 nM and the drug is well tolerated.

. CYP2C9 isoenzyme inhibitors (tolbutamide, warfarin), CYP2D6 isoenzyme inhibitors (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists, have no effect on sildenafil pharmacokinetics. Azithromycin (500 mg daily for 3 days) has no effect on the AUC, Cmax, Tmax. elimination rate constant and T1/2 of sildenafil or its main circulating metabolite.

Concomitant use of sildenafil and bosentan, an inducer of CYP3A4 and CYP2C9 isoenzymes, results in a 62.6% and 52.4% decrease in AUC and Cmax of sildenafil, respectively.

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

The effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes – 1A2, 2C9,

209, 2D6, 2E1 and 3A4 (IR 50> 150 μmol). When sildenafil is taken at the recommended doses, its Cmax 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 when prescribed for acute indications. Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

When the α-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were taken concomitantly in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional decrease in systolic/diastolic BP in the supine position was 7/7 mm Hg, 9/5 mmHg and 8/4 mmHg, respectively, and in the standing position were 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively. Rare cases of symptomatic postural hypotension, manifested as dizziness (without fainting), have been reported in these patients. In some sensitive patients receiving α-adrenoblockers, concomitant use of sildenafil may lead to symptomatic hypotension.

The concomitant use of sildenafil and bozentan increases AUC and Cmaxbozentan by 49.8% and 42%, respectively.

There is no evidence of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome isoenzyme CYP2C9. Sildenafil (100 mg) has no effect on the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir. which are substrates of cytochrome CYP3A4 isoenzyme, when their blood levels are constant.

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

Sildenafil (50 mg) does not increase the hypotensive effects of alcohol in healthy volunteers at a maximum blood alcohol concentration of 0.08% (80 mg/dL) on average.

In patients with arterial hypertension, there is no evidence of interaction of sildenafil (100 mg) with amlodipine. Mean additional BP reduction 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.

Special Instructions

The diagnosis of erectile dysfunction, the determination of its possible causes, and the choice of appropriate treatment require a complete medical history and a thorough physical examination.

Sexual activity poses some risk if you have heart disease, so your doctor should refer you for a cardiovascular exam before starting any therapy for erectile dysfunction. Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg) or hypotension (BP < 90/50 mm Hg). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or cardiovascular mortality rate (0.3 per 100 people per year) in patients receiving sildenafil compared to patients receiving placebo.

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

The drug Viathail has a systemic vasodilatory effect resulting in a transient decrease in BP, which is not clinically significant and has no effect in most patients. Nevertheless, before prescribing sildenafil, the physician should carefully evaluate the risk of possible adverse vasodilatory effects in patients with related conditions, especially with sexual activity.

Elevated susceptibility to vasodilators is seen in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), and with rare multiple systemic atrophy syndrome, manifested by severe autonomic nervous system BP dysregulation.

There have been rare cases of anterior ischemic optical neuropathy unrelated to arteritis as a cause of visual impairment or loss with all FDE5 inhibitors, including sildenafil. Most of these patients had risk factors such as optic nerve head excavation (deepening), age over 50 years, diabetes mellitus, arterial hypertension, coronary heart disease (CHD), hyperlipidemia, and smoking. No causal relationship between the intake of FDE5 inhibitors and the development of anterior ischemic optical neuropathy unrelated to arteritis has been identified.

The physician should inform the patient of an increased risk of developing anterior ischemic optic neuropathy unrelated to arteritis if this condition has previously occurred.

Because co-administration of sildenafil and α-adrenoblockers may result in symptomatic hypotension in some sensitive patients, sildenafil should be prescribed with caution in patients taking α-adrenoblockers. To minimize the risk of postural hypotension in patients taking α-adrenoblockers, sildenafil should be started only after hemodynamic stabilization is achieved in these patients. It should also be considered whether it is reasonable to reduce the initial dose of sildenafil. The physician should inform patients as to what action to take if symptoms of postural hypotension occur.

A small number of patients with hereditary retinitis pigmentosa have genetically determined retinal phosphodiesterase dysfunction. There is no information about the safety of sildenafil use in patients with pigmentary retinitis, so sildenafil should be used with caution.

Sildenafil increases the anti-aggregation effect of sodium nitroprusside (a nitric oxide donor) on human platelets in vitro.

There is no information about the safety of sildenafil in patients with internal bleeding or active peptic ulcer, so it should be used with caution.

The treatment of erectile dysfunction should be used with caution in patients with anatomical malformation of the penis (penile curvature, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia).

Cases of priapism have been reported with sildenafil. If an erection persists for more than 4 hours, medical attention should be sought. If priapism is not treated promptly, it may result in damage to penile tissue and permanent loss of potency.

The safety and effectiveness of sildenafil combined with other treatments for erectile dysfunction have not been studied, so these combinations are not recommended.

Some post-marketing and clinical studies using all FDE5 inhibitors, including sildenafil, have reported a sudden reduction or loss of hearing in patients. However, most of these patients had risk factors for this pathology, and no correlation was found between the use of FDE5 inhibitors and sudden hearing loss or reduction. In case of sudden hearing loss or decline, sildenafil therapy should be discontinued and a physician should be consulted immediately.

Impact on the ability to drive:

Because taking sildenafil may result in decreased BP, development of chromatopsia, blurred vision, and other adverse effects, care should be taken with the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosing regimen. In case of adverse reactions of nervous system and sensory organs patients are advised to refrain from driving a vehicle and operating mechanisms as well as to be cautious while performing activities requiring concentration and quick psychomotor reactions.

Contraindications

Hypersensitivity to sildenafil or any other component of the drug; use in patients receiving, continuously or intermittently, nitric oxide donators, organic nitrates or nitrites in any dosage form, since sildenafil increases the hypotensive effect of nitrates; concomitant use of ritonavir: Patients for whom sexual activity is undesirable, including those with severe cardiovascular disease such as unstable angina, severe heart failure, life-threatening arrhythmias; unstable angina, myocardial infarction, stroke or life-threatening arrhythmias in the past 6 months, arterial hypertension (BP > 170/100 mm Hg Hg) or arterial hypotension (BP < 90/50 mm Hg).); patients with vision loss in one eye due to anterior ischemic optical neuropathy unrelated to arteritis (whether or not this occurred due to taking an FDE5 inhibitor); hereditary degenerative retinal diseases, including retinitis pigmentosa (a smaller proportion of these patients have a genetic retinal FDE disease); severe liver failure; severe chronic renal failure.

Simultaneous use with cytochrome CYP3A4 isoenzyme inhibitors is contraindicated.

When using sildenafil with other drugs for treatment of erectile dysfunction, there are no data on safety and effectiveness, so the use of such combinations is not recommended.

It is not intended for use in children under 18 years of age.

It is not intended for use in women.

With caution:

The anatomical deformity of the penis (curvature of the penis, cavernous fibrosis or Peyronie’s disease).

Diseases that predispose to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia).

Diseases accompanied by bleeding.

The exacerbation of peptic ulcer disease.

Hereditary retinitis pigmentosa.

Heart failure.

Periods of history of anterior nonarteritic ischemic optic neuropathy.

Rarely, multiple systemic atrophy syndrome manifesting severe impairment of blood pressure regulation; left ventricular exit tract obstruction, including aortic stenosis; concomitant use of α-adrenoblockers.

Side effects

In general, the side effects of Viatail are mild to moderate and transient. When a fixed dose is used, the frequency of some adverse events increases with increasing dose.

In terms of frequency, adverse effects were divided according to WHO criteria into the following categories: very frequent (≥ 1: 10); frequent (≥ 1: 100 and < 1: 10); infrequent (≥ 1: 1000 and < 1: 100); rare (≥ 1: 10000 and < 1: 1000); very rare (< 1: 10000).

Immune system disorders: rare – hypersensitivity.

Nervous system: very common – headache; common – dizziness; infrequent – somnolence, hypoesthesia; rare – stroke, fainting; frequency unknown – transient ischemic attack, seizures, including recurrent.

An organ of vision: often – changes in vision (blurred vision, changes in sensitivity to light), chromatopsia (mild and transient, mainly changes in perception of color shades); infrequent – visual organ damage, including conjunctival damage, lacrimation disorders; frequency unknown – anterior ischemic optical neuropathy, retinal vessel occlusion, narrowing of the visual fields.

Hearing organs: infrequent – vertigo, tinnitus; rarely – deafness.

The cardiovascular system: frequently – vasodilation (“rush” of blood to the skin); infrequent – palpitation, tachycardia, increased heart rate; rarely – increase or decrease of BP, myocardial infarction, atrial fibrillation; frequency unknown – ventricular arrhythmias, unstable angina, sudden cardiac death.

Respiratory system disorders: frequently – nasal congestion, rhinitis; rarely – nasal bleeding.

The digestive system: frequent – dyspepsia; infrequent – vomiting, nausea, dry mouth.

Allergic reactions: infrequent – skin rash, frequency unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

Musculoskeletal system: infrequent – myalgia.

Reproductive system disorders: infrequent hematospermia and bleeding from the penis, frequency unknown – priapism, prolonged erection.

Others: infrequent – chest pain, fatigue.

Overdose

Single administration of sildenafil in doses up to 800 mg resulted in adverse events comparable to, but more frequent than, those associated with lower doses.

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

Similarities