VIVAYRA - instructions for use, doses, side effects, contraindications

Excipients: calcium hydrophosphate - 118.76 / 237.52 mg, microcrystalline cellulose - 90,00 / 180,00 mg, croscarmellose sodium - 9,00 / 18,00 mg, povidone 25 - 6,00 / 12,00 mg, magnesium stearate - 6,00 / 12,00 mg; tablet shell: dryers 1047 blue (hypromellose - 55-65%, microcrystalline cellulose - 5-15%, titanium dioxide (E171) - 5-10%, dye of brilliant blue aluminum varnish (E133) - no more than 5%) - 1,025 / 2, 05 mg, sepiphilm 752 white (hypromellose 35-45%, microcrystalline cellulose 27-37%, macrogol stearate 6-10%, titanium dioxide (E171) 18-22%) 7.775 / 15.55 mg, macrogol - 0.2 / 0.4 mg.

Description:

Oval, biconvex tablets, covered with a film coating of blue color, with a risk.

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 a potent selective inhibitor of cyclic guanosine monophosphate (cGMP) - a specific type 5 phosphodiesterase (PDE-5). The physiological mechanism of erection is associated with the release of nitric oxide (NO) in the cavernous body due to sexual arousal. Nitric oxide activates the enzyme guanylate cyclase, which leads to an increase in the level of cGMP, which in turn causes a relaxation of the smooth muscle tissue of the cavernous body and an increase in blood flow.

Sildenafil does not have a direct relaxing effect on an isolated cavernous human body, but enhances the effect NO by inhibiting PDE-5, which is responsible for the degradation of cGMP.

Sildenafil is selective for PDE-5 in vitro, its activity against PDE-5 is superior to that of other known isoenzymes of phosphodiesterase: PDE-6 - 10 times, PDE-1 - more than 80 times; PDE-2 - PDE-4, PDE-7 - PDE-11 - more than 700 times. Sildenafil is 4000 times more selective with respect to PDE-5 in comparison with PDE-3, which is very important, since PDE-3 is one of the key enzymes for the regulation of myocardial contractility.

The pharmacological effect is achieved only with the presence of sexual stimulation.

Clinical data

Cardiac examinations

Sildenafil causes a slight and transient decrease in blood pressure (BP), which in most cases has no clinical manifestations. The maximum decrease in systolic blood pressure in the supine position after taking sildenafil in a dose of 100 mg averages 8.3 mm Hg, and diastolic blood pressure - 5.3 mm Hg. The decrease in blood pressure is due to the vasodilating effect of sildenafil, possibly associated with an increase in the concentration of cGMP in the smooth muscle cells of the vessels. A single dose of sildenafil in a dose up to 100 mg is not accompanied by clinically significant changes in the electrocardiogram (ECG) in healthy volunteers.

Sildenafil has no effect on cardiac output and does not change blood flow through stenosed arteries.

In patients with erectile dysfunction and stable angina, taking antianginal drugs (except nitrates),time before the onset of an attack of angina during a test with physical activity did not differ significantly after taking sildenafil in comparison with placebo.

Research of visual disorders

In some patients, an easy and transient impairment in the ability to distinguish between shades of color (blue / green) was detected 1 hour after taking 100 mg of sildenafil with the Farnsworth-Munssel test 100. After 2 hours after taking the drug, these changes were absent. It is believed that impaired color vision is caused by inhibition of PDE-6, which is involved in the process of transmitting light in the retina of the eye. Sildenafil does not affect visual acuity, perception of contrast, electroretinogram, intraocular pressure or the diameter of the pupil.

It was noted that in patients with early age macular degeneration sildenafil in a single dose 100 mg was well tolerated and did not cause clinically significant visual changes assessed by special visual tests (visual acuity, Amsler grating, color perception, color flow modeling, Humphrey perimetry and photostress).

Efficiency

A single dose of sildenafil in a dose of 100 mg did not affect the motility or morphology of spermatozoa in healthy volunteers.

In studies on fixed doses of sildenafil, of men, reported improvement of erection, was 62% (sildenafil dose - 25 mg), 74% (sildenafil dose - 50 mg) and 82% (sildenafil dose - 100 mg) compared to 25% in the placebo group. At the same time, the frequency of sildenafil withdrawal was low and comparable to that in the placebo group. Analysis of the international index of erectile function has shown that in addition to improving erectile dysfunction, sildenafil treatment also improves the quality of orgasm, allowing to achieve satisfaction from sexual intercourse and overall satisfaction. The safety and effectiveness of sildenafil persisted with prolonged use.

In all studies, the proportion of patients reporting improved erections after using sildenafil, was as follows: psychogenic erectile dysfunction - 84%, mixed erectile dysfunction - 77%, organic erectile dysfunction - 68%, elderly patients - 67%, diabetes mellitus - 59%, ischemic heart disease (IHD) - 69%, arterial hypertension - 68%, transurethral resection of the prostate - 61%, radical prostatechemia - 43%, spinal cord injury - 83%, depression - 75%.

Pharmacokinetics:

Suction

After oral administration sildenafil quickly absorbed from the gastrointestinal tract (GIT). Absolute bioavailability averages 40% (25-63%). The maximum concentration in the blood plasma (C_mOh) when taken on an empty stomach is achieved on average within 60 minutes (from 30 minutes to 120 minutes). Pharmacokinetics (area under the concentration-time curve (AUC) and C_mOh) sildenafil in the recommended dosage range (25-100 mg) is linear. When taken in combination with fatty food C_mOh decreases by an average of 29%, and the time to reach the maximum concentration (T_mOh) is increased by 60 min and is achieved after 1.5-3 hours, however, the degree of absorption does not change significantly (the area under the pharmacokinetic curve of the drug concentration in the plasma versus time (AUC) is reduced by 11%).

Distribution

Volume of distribution (V_d) of sildenafil in the equilibrium state averages 105 liters. The connection between sildenafil and its main cerculating N-detyl metabolite with plasma proteins is about 96% and does not depend on the total concentration of the drug.Less than 0.0002% of the dose of sildenafil (an average of 188 ng) was found in the sperm 90 minutes after taking the drug.

Metabolism

Sildenafil is metabolized mainly in the liver under the action of microsomal isoenzymes of cytochrome P450 - CYP3A4 (main path) and CYP2C9 (additional path). The main circulating active metabolite is formed as a result of N-detylation of sildenafil. The selectivity of the metabolite to phosphodiesterases is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil. The concentration of metabolite in the blood plasma of healthy volunteers is about 40% of the concentration of sildenafil. N-detylated metabolite undergoes further metabolism, half-life (T₁_/₂) is about 4 hours.

Excretion

The total clearance of sildenafil is 41 l / h, the final half-life (T₁_/₂) - 3-5 hours. It is excreted as metabolites, mainly by the intestine (about 80% of the dose) to a lesser extent by the kidneys (about 13% of the dose).

Pharmacokinetics in specific patient groups

Elderly patients

In healthy elderly patients (65 years and older), the clearance of sildenafil is reduced, and the concentration of sildenafil and its active N-detylated metabolite in blood plasma is approximately 90% higher than in young (18-45 years). Given the age-related features of binding to plasma proteins, the concentration of free sildenafil in blood plasma increases by about 40%.

Age does not have a clinically significant effect on the incidence of side effects.

Impaired renal function

In patients with mild or moderate renal insufficiency (creatinine clearance (CK) 30-80 ml / min) the pharmacokinetics of sildenafil after single ingestion in a dose of 50 mg does not change. In patients with severe renal insufficiency (CC less than 30 ml / min), the clearance of sildenafil decreases, which leads to an approximately two-fold increase in the value of C_mOh (88%) and AUC (100%) compared with those for normal kidney function in patients of the same age group.

Impaired liver function

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 the value of C_mOh (47%) and AUC (84%) compared with those for normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe impairment of liver function (Child-Pugh Stage C) has not been studied.

Indications:

Treatment of erectile dysfunction of various etiologies (organic, psychogenic, mixed), characterized by inability to achieve or maintain an erection penis sufficient for a satisfactory sexual intercourse.

Effective only with sexual stimulation.

Contraindications:

Hypersensitivity to sildenafil or to any other component of the drug.

Simultaneous application with donators of nitric oxide (for example, amyl nitrite), organic nitrates or nitrates in any form, since sildenafil strengthens the hypotensive effect of nitrates.

The drug should not be used in men who are not recommended for sexual activity (for example, patients with severe cardiovascular diseases, such as unstable angina or severe heart failure).

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

Contraindicated simultaneous use with ritonavir.

Reduction of vision in one eye due to anterior ischemic optic neuropathy of non-arterial genesis, whether it is related or not with the use of PDE-5 inhibitors.

The use is contraindicated in: severe violations of liver function, arterial hypotension (BP less than 90/50 mm Hg), a recent stroke or myocardial infarction (MI), phenylketonuria, established hereditary degenerative diseases of the retina, including retinitis pigmentosa.

According to the registered indication, the drug is not intended for use in children under 18 years of age and in women.

Carefully:

Anatomic deformation of the penis (angulation, cavernous fibrosis or Peyronie's disease); diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocytopenia); diseases accompanied by bleeding; exacerbation of peptic ulcer of the stomach and duodenum; heart failure (CH); unstable angina; transferred for the last 6 months myocardial infarction, stroke, or life-threatening arrhythmia; Arterial hypertension (AH) (blood pressure more than 170/100 mm Hg.item); episodes of development in patients with anterior non-artery ischemic neuropathy of the optic nerve in anamnesis; simultaneous administration with alpha-blockers due to the risk of postural hypotension.

Pregnancy and lactation:

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

Dosing and Administration:

Inside.

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

With regard to 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 the drug - 1 once a day.

Special patient groups

Elderly patients

For elderly patients, dose adjustment is not required.

Impaired renal function

For patients with mild or moderate renal failure (CK 30-80 ml / min) dose adjustment is not required, in severe renal failure (QC less than 30 ml / min), the dose of sildenafil should be reduced to 25 mg. With good tolerability, the dose can be increased to 50 or 100 mg.

Impaired liver function

For patients with mild or compensated liver failure, the first dose is 25 mg. With good tolerability, the dose can be increased to 50 mg or 100 mg.

Simultaneous use with other medicinal products

It is not recommended simultaneous use with ritonavir. When combined with ritonavir, the maximum single dose of sildenafil should not exceed 25 mg, and the frequency of application is 1 time in 48 hours.

With simultaneous application with inhibitors of isoenzyme CYP3A4 (erythromycin, saquinavir, ketoconazole, itraconazole) the initial dose of the drug Vivira® should not exceed 25 mg.

For patients taking alpha-adrenoblockers, the first dose is 25 mg. With good tolerability, the dose can be increased to 50 mg or 100 mg. To minimize the risk of postural hypotension in patients taking alpha-adrenergic blockers, sildenafil should be taken only after hemodynamic stabilization has been achieved in these patients.

Side effects:

Usually the side effects of sildenafil are weak or moderate and are transient. In studies using a fixed dose, it has been shown that the incidence of certain adverse events increases with increasing doses.

The incidence of side effects is classified according to the recommendations of the World Health Organization (WHO): very often (> 1/10), often (> 1/100 and < 1/10), infrequently (> 1/1000 and < 1/100), rarely (> 1/10000 and < 1/1000), very rarely (< 1/10000), the frequency is unknown (can not be calculated from available data).

From the central nervous system: very often - headache; often - dizziness; infrequently - drowsiness, hypoesthesia; rarely - a stroke, a faint; frequency unknown - transient ischemic attack, convulsions, recurrence of convulsions.

From the cardiovascular system: often - vasodilation ("tides" of blood to the skin of the face); infrequently - arrhythmia, tachycardia; rarely - increased or decreased blood pressure, myocardial infarction, atrial fibrillation; frequency unknown - ventricular arrhythmia, unstable angina, sudden cardiac arrest.

From the side of the organ of vision: often - a change in vision (blurred vision, changes in sensitivity to light), chromatopsy (light and transient, mainly changing the perception of color shades), infrequently - conjunctival damage, dysentery; rarely - pain in the eyeballs, redness of the sclera; frequency unknown - anterior ischemic optic neuropathy, retinal vascular occlusion, visual field defect.

From the organ of hearing: often - vertigo, noise in the ears; rarely - deafness.

On the part of the respiratory system: often - nasal congestion; rarely - epistaxis.

From the gastrointestinal tract: often - indigestion; infrequently - vomiting, nausea, dryness of the oral mucosa.

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

On the part of the reproductive system: infrequently - hematospermia, bleeding from the penis; frequency unknown - priapism, prolonged erection.

From the side of the musculoskeletal and connective tissue: infrequently - myalgia.

General disorders: infrequently - pain in the chest, increased fatigue.

Overdose:

Symptoms: with a single dose of the drug in a dose of up to 800 mg, the frequency and severity of adverse reactions (headache, "hot flashes", dizziness, dyspepsia, nasal congestion, impaired vision) increased.

Treatment: symptomatic therapy. Hemodialysis is ineffective.

Interaction:

The effect of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome P450 isoenzymes - CYP3A4 (main path) and CYP2C9 (additional path).Consequently, inhibitors of these isoenzymes can reduce the clearance of sildenafil. There was a decrease in clearance of sildenafil with simultaneous application of inhibitors of isoenzyme CYP3A4 (ketoconazole, erythromycin, cimetidine, saquinavir). An increase in the incidence of adverse events in these patients was not observed. Patients taking isoenzyme inhibitors CYP3A4, treatment with sildenafil should be started with a dose of 25 mg.

Simultaneous use of sildenafil (once 100 mg) with an HIV protease inhibitor and potent inhibitor of cytochrome P450 ritonavir (500 mg twice daily) increases C_max and AUC of sildenafil in blood plasma by 300% (4 times) and 1000% (11 times), respectively. After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng / ml (with the intake of only sildenafil - 5 ng / ml). Given the results of the pharmacokinetic study, the simultaneous use of sildenafil with ritonavir is contraindicated.

The simultaneous use of the HIV protease inhibitor-saquinavir (isoenzyme inhibitor CYP3A4) in an equilibrium state (1200 mg 3 times daily) with sildenafil (100 mg once a day) increases C_mOh and AUC sildenafil by 140% and 210%, respectively. Sildenafil does not affect the pharmacokinetics of saquinavir.

More potent inhibitors of cytochrome isoenzyme CYP3A4 (ketoconazole and itraconazole) can cause a more pronounced effect on the pharmacokinetics of sildenafil.

With the simultaneous use of sildenafil (100 mg once) with erythromycin, a specific inhibitor of the cytochrome isoenzyme CYP3A4, in an equilibrium state (500 mg twice a day for 5 days) AUC sildenafil increases by 182%.

Azithromycin (500 mg per day for 3 days) does not cause changes in pharmacokinetic parameters (AUC, FROM_mOh, TS_mOh, the elimination rate or T1/2) sildenafil or its main circulating metabolite.

Cimetidine (800 mg), a nonspecific inhibitor of the isoenzyme CYP3A4, increases the concentration of sildenafil (50 mg) in blood plasma by 56%.

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

Grapefruit juice, a weak isoenzyme inhibitor CYP3A4 in the intestinal wall, may slightly increase the concentration of sildenafil in blood plasma.

Population pharmacokinetic analysis revealed no changes in the pharmacokinetics of sildenafil when applied simultaneously with: isoenzyme inhibitors CYP2C9 (tolbutamide, warfarin, phenytoin), inhibitors of isoenzyme CYP2D6 (selective serotonin reuptake inhibitors and tricyclic antidepressants), thiazides and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, beta adrenoblockers or isoenzyme inducers CYP450 (rifampicin and barbiturates).

With the simultaneous use of sildenafil with bosentan (inductor of isoenzymes CYP3A4, CYP2C9) there was a decrease AUC and C_ma_x sildenafil by 62.6% and 55.4% respectively. Sildenafil increased AUC and C_mOh bosentan by 49.8% and 42% respectively.

Nicorandil is a hybrid of the activator of potassium channels and nitrate. Due to the presence of nitrate in the drug, serious interaction with sildenafil is possible.

Effect of sildenafil on the pharmacokinetics of other drugs

Sildenafil is a weak inhibitor of cytochrome P450 - 1A2, 2C9, 2C19, 2 isoenzymesD6, 2E1 and 3A4 (IC₅₀ > 150 μmol). FROM_max sildenafil after taking the recommended dose is about 1 μmol, so it is unlikely that sildenafil affects the clearance of the substrates of these isoenzymes. Data on the interaction of sildenafil with nonspecific inhibitors of phosphodiesterase (theophylline or dipyridamole) are absent.

Sildenafil has an effect on the system NO/ cGMP, so it increases the hypotensive effect of nitrates. In this regard, the simultaneous use with donors of nitric oxide, such as amyl nitrite, or nitrates in any form is contraindicated.

Simultaneous use of sildenafil with alpha-adrenoblockers can lead to the development of symptomatic arterial hypotension, which most often develops within the first 4 hours after taking sildenafil. In clinical studies, the use of sildenafil (25 mg, 50 mg or 100 mg) was studied with the use of alpha-adrenoblocker doxazosin in doses of 4 mg or 8 mg in patients with benign prostatic hyperplasia and stable hemodynamics. There was an additional decrease in blood pressure in the horizontal position of the patient, on average, by 7/7, 9/5 and 8/4 mm Hg, respectively, and in an upright position, on average, 6/6, 11/4 and 4/5 mm Hg. There are rare cases of development in these patients of symptomatic postural hypotension, clinically manifested as dizziness (without syncope).

The interaction of sildenafil (50 mg) with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by isoenzyme CYP2C9, it is not revealed.

Sildenafil (50 mg) does not cause an additional increase in bleeding time with simultaneous use with acetylsalicylic acid (150 mg).

Sildenafil (50 mg) does not potentiate the hypotensive effect of ethanol in healthy volunteers (C_mOh ethanol in the blood serum was, on average, 80 mg / dL).

The undesirable effects of antihypertensive drugs, including diuretics, beta-blockers, ACE inhibitors, angiotensin II receptor antagonists, vasodilators, central action drugs, adrenergic neuron blockers, slow calcium channel blockers and alpha-blockers, did not differ in patients who used sildenafil or placebo.

Sildenafil (100 mg) in equilibrium does not affect the pharmacokinetic indices of HIV protease inhibitors (saquinavir and ritonavir), which are substrates of the isoenzyme CYP3A4.

With the simultaneous use of sildenafil (100 mg) with amlodipine in patients with AH, there was an additional decrease in the horizontal position of the systolic blood pressure by 8 mm Hg. and diastolic blood pressure by 7 mm Hg. The additional reduction in blood pressure is comparable to that of sildenafil in healthy individualsvolunteers.

Sildenafil enhances the anti-aggregation effect of sodium nitroprusside (donator N0) in vitro.

Special instructions:

Before using sildenafil, a thorough examination of the patient should be performed to diagnose erectile dysfunction and to determine the causes of its occurrence.

Drugs for the treatment of sexual dysfunction, including sildenafil, should be used with caution in patients with anatomical deformities of the penis, such as angulation, cavernous fibrosis or Peyronie's disease, as well as in patients with conditions predisposing to priapism, such as 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.

Before the beginning of the treatment of erectile dysfunction, it is necessary to assess the risk of developing cardiovascular complications associated with sexual activity. Sexual activity is undesirable in patients with heart failure, unstable angina,suffered in the last 6 months myocardial infarction or stroke, life-threatening arrhythmias, arterial hypertension (BP> 170/100 mmHg) or hypotension (BP <90/50 mmHg). Sildenafil has a vasodilating action that causes a short-term decrease in blood pressure. Before you start using Vivaira®, you must exclude the risk of an adverse effect of sildenafil on the background of sexual activity. Patients with obstruction of the left ventricular outflow tract (for example, aortic stenosis, hypertrophic obstructive cardiomyopathy) or with a rarely occurring syndrome of multiple systemic atrophy, manifested in impaired regulation of arterial pressure from the autonomic nervous system, are most prone to the hypotensive effect of vasodilators.

Most side effects from the cardiovascular system develop in patients with already existing heart and vascular diseases. Most often, such complications developed either immediately after intercourse, or a short time after it, in some cases - after taking sildenafil without a subsequent sexual intercourse.The relationship between these side effects and the described phenomena is not established.

In the joint use of sildenafil and other PDE5 inhibitors, visual disturbances and cases of development of anterior ischemic optic neuropathy of non-arterial genesis were rare in rare cases. In case of sudden visual impairment, patients are advised to stop taking sildenafil and immediately consult a doctor.

Doses of more than 200 mg do not increase the effectiveness of the drug, but increase the incidence and severity of side effects.

The preparation Vivara® is not intended for use in women.

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

Since visual and color perception disorders are possible while taking the drug, reducing blood pressure and developing dizziness, especially at the beginning of treatment and changing the dosage regimen, you should carefully consider the individual effect of the drug.

Form release / dosage:

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

Packaging:

1 tablet in PVC / PE / PVDC / / Al blister. One or two blisters together with instructions for use are placed in a cardboard box.

For 4 tablets in PVC / PE / PVDC / / Al blister.One blister, along with instructions for use, is placed in a cardboard box.

Storage conditions:At a temperature of no higher than 25 ° C, in the original packaging, protected from light.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004045

Date of registration:27.12.2016

Expiration Date:27.12.2021

The owner of the registration certificate:Beluga, medicines and cosmetics.Beluga, medicines and cosmetics. Croatia

Manufacturer: & nbsp

HBM PHARMA, s.r.o. The Slovak Republic

BELUPO, Pharmaceuticals & Cosmetics, d.d. Croatia

Representation: & nbspBeluga, medicines and cosmetics. Beluga, medicines and cosmetics. Croatia

Information update date: & nbsp26.01.2017

Illustrated instructions

Instructions

VIVAYRA® (Vivayra)