VIAGRA

Active material: Sildenafil
When ATH: G04BE03
CCF: Drug for the treatment of erectile dysfunction. PDE-5 inhibitor
ICD-10 codes (testimony): F52.2, N48.4
When CSF: 28.08.01.01.01
Manufacturer: PFIZER PGM (France)

Pharmaceutical form, composition and packaging

Pills, coated blue, diamond-shaped, slightly biconcave, with cut and rounded edges, with an inscription “Pfizer” on one side and “VGR 25” – another.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, anhydrous, sodium croscarmellose, magnesium stearate, film coating Opadry blue and Opadry transparent.

1 PC. – blisters (1) – packs cardboard.

Pills, coated blue, diamond-shaped, slightly biconcave, with cut and rounded edges, with an inscription “Pfizer” on one side and “VGR 50” – another.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, anhydrous, sodium croscarmellose, magnesium stearate, film coating Opadry blue and Opadry transparent.

1 PC. – blisters (1) – packs cardboard.
2 PC. – blisters (1) – packs cardboard.
4 PC. – blisters (1) – packs cardboard.

Pills, coated blue, diamond-shaped, slightly biconcave, with cut and rounded edges, with an inscription “Pfizer” on one side and “VGR 100” – another.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, anhydrous, sodium croscarmellose, magnesium stearate, film coating Opadry blue and Opadry transparent.

1 PC. – blisters (1) – packs cardboard.
2 PC. – blisters (1) – packs cardboard.
4 PC. – blisters (1) – packs cardboard.

* international non-proprietary name, recommended by the WHO – sildenafil.

Pharmacological action

Drug for the treatment of erectile dysfunction. Sildenafil is a potent selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5).

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

Sildenafil does not have a direct relaxing effect on the isolated corpus cavernosum in humans, but enhances the effect of NO through PDE5 inhibition, which is responsible for the breakdown of cGMP.

Sildenafil is selective for PDE5 in vitro, its activity against PDE5 is superior to that against other known phosphodiesterase isoenzymes: PDE6 – in 10 time; FDE1 – more than 80 time; FDE2, PDE4, FDE7-FDE11 – more than 700 time. Sildenafil c 4000 times more selective for PDE5 compared to PDE3, what is most important, since PDE3 is one of the key enzymes regulating myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

Clinical data

Cardiac research

Use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. Maximum reduction in systolic blood pressure in the supine position after taking sildenafil at a dose 100 mg was 8.3 mm Hg. Art., and diastolic blood pressure – 5.3 mm Hg. Article. More pronounced, but also a transient effect on blood pressure was noted in patients, who took nitrates .

In a study of the hemodynamic effect of sildenafil in a single dose 100 mg 14 patients with severe ischemic heart disease (more than 70 % patients had stenosis, at least, one coronary artery), systolic and diastolic blood pressure at rest decreased by 7% and 6% respectively, and pulmonary systolic pressure decreased by 9%. Sildenafil did not affect cardiac output and did not impair blood flow in stenotic coronary arteries, and also led to an increase (about 13%) adenosine-induced coronary blood flow as in stenotic, and in intact coronary arteries.

In a double blind, placebo-controlled study 144 patient with erectile dysfunction and stable angina, taking antianginal drugs (except nitrates), exercised up to that point, when the severity of angina symptoms has decreased. The duration of the exercise was significantly longer (19.9 sec; 0.9-38.9 sec) patients, taking sildenafil in a single dose 100 mg compared to patients, placebo.

A randomized, double-blind, placebo-controlled study examined the effect of varying the dose of sildenafil (to 100 mg) males (n =568) with erectile dysfunction and arterial hypertension, taking more than two antihypertensive drugs. Sildenafil improved erection in 71% men compared to 18% placebo. The incidence of adverse effects was comparable to that in other patient groups, just like people, taking more than three antihypertensive medications.

Visual impairment studies

In some patients, after 1 h after taking sildenafil dose 100 mg using Farnsworth-Munsel test 100 Mild and transient impairment of the ability to distinguish shades of color was detected (blue/green). Through 2 hours after taking the drug, these changes were absent. It is believed, that color vision impairment is caused by PDE6 inhibition, which is involved in the process of light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, jelektroretinogrammu, intraocular pressure or pupil diameter.

In a placebo-controlled crossover study of patients with proven early-onset macular degeneration (n =9) sildenafil single dose 100 mg was well tolerated. There were no clinically significant changes in vision, assessed by special visual tests (visual acuity, Amsler grid, color perception, color flow simulation, Humphrey's perimeter and photostress).

Effectiveness

The effectiveness and safety of sildenafil was assessed in 21 randomized, double-blind, placebo-controlled study lasting up to 6 months 3000 patients aged 19 to 87 with erectile dysfunction of various etiologies (organic, psychogenic or mixed). The effectiveness of the drug was assessed globally using an erection diary, international index of erectile function (validated questionnaire on the state of sexual function) and partner survey. 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 has been confirmed in long-term studies of 1 year. In fixed-dose studies, the patient ratio, who reported, that the therapy improved their erections, was: 62% (dose of sildenafil 25 mg), 74 % (dose of sildenafil 50 mg) and 82 % (dose of sildenafil 100 mg), compared with 25 % placebo. Analysis of the international index of erectile function showed, that in addition to improving erection, treatment with sildenafil also increased the quality of orgasm, allowed to achieve satisfaction from sexual intercourse and general satisfaction.

According to summarized data, among patients, who reported improved erections when treated with sildenafil were 59% diabetic patients, 43% patients, who have undergone radical prostatectomy and 83% patients with spinal cord injuries (compared with 16%, 15% and 12% in the placebo group, respectively).

Pharmacokinetics

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

Absorption

After taking the drug orally, sildenafil is rapidly absorbed. The average absolute bioavailability is 40% (25-63%). In vitro sildenafil at a concentration of approximately 1.7 ng / ml (3.5 nM) suppresses human PDE5 50%. After a single dose 100 mg of the drug orally C_max is 18 ng / ml (38nM) and is achieved when taken on an empty stomach for an average of 60 m (30-120 m).

When taken in combination with fatty foods, the rate of absorption is reduced; T_max increases by 60 m, a C_max decreases on average by 29%. However, the degree of absorption does not change significantly ( AUC reduced by 11%).

Distribution

V_d sildenafil at steady state averages 105 l.

Sildenafil and its main circulating N-desmethyl metabolite are approximately 96% binds to plasma proteins. Protein binding is independent of total sildenafil concentration. Less 0.0002% dose (average 188 ng) found in sperm through 90 min then take sildenafil.

Metabolism

Sildenafil is metabolized, mainly, in the liver under the influence of CYP3A4 isoenzymes (the basic way) and CYP2C9 (minor path).

Major circulating metabolite, which is formed as a result of N-demethylation of sildenafil, undergoes further metabolism.

In terms of selectivity of action on PDE, the metabolite is comparable to sildenafil, and its activity against PDE5 in vitro is approximately 50% activities sildenafil.

The metabolite concentration in blood plasma is approximately 40% from that of sildenafil.

N-demethyl metabolite undergoes further metabolism; his T_1/2 is about 4 no.

Deduction

The total clearance of sildenafil from the body is 41 l /, and the final T_1/2 – 3-5 no. After oral administration, sildenafil is excreted as metabolites, primarily, with feces (about 80% dose) and to a lesser extent – urine (about 13% dose).

Pharmacokinetics in special clinical situations

Elderly (65 and older) patients, the clearance of sildenafil is reduced, and the concentration of free active substance in plasma is approximately 40% exceeds its concentration in young people (18-45 years) patients.

For mild renal failure (CC 50-80 ml / min) and secondary (CC 30-49 ml / min) severity, pharmacokinetic parameters of sildenafil after single oral administration (50 mg) not changed.

In renal failure, severe (CC ≤ 30 ml / min) Sildenafil clearance decreases, resulting in an approximately twofold increase in AUC (100%) and C_max (88%) compared with those with normal renal function in patients of the same age group.

In patients with liver cirrhosis (class a and b on a scale Child-Pugh) Sildenafil clearance decreases, which leads to an increase in AUC (84%) and C_max (47%) compared with those with normal liver function in patients of the same age group.

Pharmacokinetics of sildenafil in patients with severe liver dysfunction (class C Child-Pugh) I have not been studied.

Testimony

- erectile dysfunction, characterized by the inability to achieve or maintain penile erection, sufficient for satisfactory sexual intercourse.

Sildenafil is effective only in the presence of sexual stimulation.

Dosage regimen

The drug is taken orally.

For most patients, the recommended dose is 50 mg approximately for 1 hours before sexual activity. Taking into account efficiency and endurance dose can be increased to 100 mg or decreased to 25 mg.

The maximum recommended dose is 100 mg. Maximum recommended frequency of use- 1 time / day.

In elderly patients dose adjustment is required.

At renal insufficiency of mild to moderate severity (CC 30-80 ml / min) dose adjustment is required, at severe renal insufficiency (CC<30 ml / min) reduce the dose 25 mg.

At hepatic dysfunction the dose of the drug can be reduced to 25 mg.

When used together with ritonavir, the maximum single dose of Viagra^® should be 25 mg, multiplicity of application – 1 once every 48 no.

When used together with inhibitors of the CYP3A4 isoenzyme (Erythromycin, saquinavir, ketoconazole, itraconazole) initial dose of Viagra^® should be 25 mg.

To minimize the risk of postural hypotension in patients, taking alpha-blockers, You should start taking sildenafil only after, How will hemodynamic stabilization be achieved in these patients?. The advisability of reducing the initial dose of Viagra should be considered.^®.

Side effect

Side effects are usually transient and mild or moderate.

The frequency of adverse events increases with increasing dose and is practically independent of age.

When using the drug in doses, exceeds the recommended, side effects were similar to those noted above, but usually met more often.

Allergic reactions: hypersensitivity reactions (incl. skin rash).

CNS: convulsions.

Cardio-vascular system: tachycardia, decrease in blood pressure, swoon, nose bleed.

From the digestive system: vomiting.

On the part of the organ of vision: sore eyes, red eyes/scleral injections.

On the part of the reproductive system: prolonged erection and / or priapism.

Contraindications

- Hypersensitivity to the drug;

- The application of patients, receiving nitric oxide donors continuously or intermittently, organic nitrates or nitrates in any forms (since sildenafil enhances the hypotensive effect of nitrates).

It is not recommended to use the drug in combination with other drugs for the treatment of erectile dysfunction. (the safety and effectiveness of combination therapy have not been studied).

The drug is not intended for use in children and adolescents aged 18 years, female.

FROM caution the drug should be used for anatomical deformation of the penis (incl. during angulation, cavernous fibrosis or Peyronie's disease); for diseases, predisposing to the development of priapism (such as sickle cell anemia, mnozhestvennaya myeloma, leukemia, thrombocytopenia); for diseases, accompanied by bleeding; with exacerbation of peptic ulcer of the stomach and duodenum; hereditary retinitis pigmentosa; Heart Failure, unstable angina, transferred to recent 6 months of myocardial infarction, stroke, heavy, life-threatening arrhythmias, hypertension (HELL more 170/100 mmHg.) or hypotension (BP less 90/50 mmHg.).

Pregnancy and lactation

Registered indication the product is not intended for use in women.

Cautions

To diagnose erectile dysfunction, To determine their possible causes and select adequate treatment, it is necessary to obtain a complete medical history and conduct a thorough physical examination.

Sexual activity poses some risk for heart disease; in this regard, before starting any therapy for erectile dysfunction, the doctor may consider it necessary to examine the cardiovascular system. Sexual activity is not advisable in patients with heart failure, unstable angina, moved to recent 6 months of myocardial infarction or strokes, life-threatening arrhythmias, hypertension (FROM>170/100 mmHg.) or hypotension (FROM<90/50 mmHg.). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 on 100 person per year) or mortality rate from cardiovascular diseases (0.3 on 100 person per year) patients, receiving the drug Viagra^®, compared to patients, placebo.

Viagra^® has a systemic vasodilating effect, which leads to a transient decrease in blood pressure. This effect is not clinically significant and does not lead to any consequences in most patients. However, before prescribing Viagra^® the physician should carefully weigh the risk of adverse effects of vasodilating effects in patients with certain concomitant diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with left ventricular outflow tract obstruction (eg, aortalnыy stenosis, gipertroficheskaya obstruktivnaya cardiomyopathy), as well as the rare multiple system atrophy syndrome, manifested by severe dysregulation of blood pressure on the part of the autonomic nervous system.

Rare cases of anterior ischemic optic neuropathy of non-arterial origin have been reported as a cause of deterioration or loss of vision, against the background of the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors, such as excavation (deepening) optic nerve heads, over age 50 years, diabetes, arterial hypertension, CHD, hyperlipidemia, smoking. No cause-and-effect relationship has been identified between the use of PDE5 inhibitors and anterior ischemic optic neuropathy of non-arterial origin.. The physician should inform the patient about the increased risk of developing anterior ischemic optic neuropathy of non-arterial origin., if this condition has already been noted in him before.

Since concomitant use of sildenafil and alpha-blockers may lead to symptomatic hypotension in selected sensitive patients, sildenafil should be prescribed with caution to patients, taking alpha-blockers. To minimize the risk of postural hypotension in patients, taking alpha-blockers, You should start taking sildenafil only after, How will hemodynamic stabilization be achieved in these patients?. The advisability of reducing the initial dose of sildenafil should be considered.. Besides, The doctor must inform patients about, what actions should be taken if symptoms of postural hypotension occur.

Sildenafil enhances the antiplatelet effect of sodium nitroprusside (of nitrogen oxide donors) on human platelets in vitro. Information about the safety of using Viagra^® patients with internal bleeding or active peptic ulcers are absent, therefore, in such cases the drug should be used with caution.

A small number of patients with hereditary retinitis pigmentosa have hereditary disorders of retinal phosphodiesterases. There is no information on the safety of sildenafil in patients with retinitis pigmentosa.; in this regard, in such patients the drug Viagra^® should be used with caution.

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

Safety and effectiveness of sildenafil when used in combination with other drugs, intended for the treatment of erectile dysfunction, We have not been studied, therefore, the use of such combinations is not recommended.

In some post-marketing and clinical studies using all PDE5 inhibitors, including sildenafil, Sudden decrease or loss of hearing has been reported in patients. However, in most cases, these patients had risk factors for the development of this pathology, and there was no correlation between the use of PDE5 inhibitors and sudden decrease or loss of hearing. Patients should be warned about, that in case of sudden decrease or loss of hearing, sildenafil therapy should be discontinued, and consult your doctor immediately.

Effects on ability to drive vehicles and management mechanisms

While taking Viagra^® any negative impact on the ability to drive a car or other technical means were observed. However, since taking the drug may reduce blood pressure, development of chromatopsia, blurred vision, you should be careful about the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosing.

Overdose

With a single dose of the drug up to 800 mg adverse events were comparable to those when taking sildenafil at lower doses, but they were more frequent.

Treatment: if necessary, symptomatic therapy. Hemodialysis does not accelerate the clearance of sildenafil, tk. the latter actively binds to plasma proteins and is not excreted in the urine.

Drug Interactions

Effect of other drugs on the metabolism of sildenafil

The metabolism of sildenafil occurs, primarily, in the liver under the influence of CYP3A4 isoenzymes (the basic way) and CYP2C9, therefore, inhibitors of these isoenzymes may reduce the clearance of sildenafil, and inductors, respectively, increase the clearance of sildenafil.

With simultaneous use of CYP3A4 inhibitors (such as ketoconazole, Erythromycin, cimetidine) a decrease in the clearance of sildenafil was noted.

Cimetidine (800 mg), being a nonspecific inhibitor of CYP3A4, when taken simultaneously with sildenafil (50 mg) causes an increase in the concentration of sildenafil in plasma by 56%.

Single dose of sildenafil 100 mg simultaneously with erythromycin, specific inhibitor of CYP3A4 (while taking erythromycin 2 times / day for 500 mg for 5 days), against the background of achieving a constant level of erythromycin in the blood leads to an increase in the AUC of sildenafil by 182%.

With simultaneous use of sildenafil (one dose of 100 mg) and saquinavir, acting as an inhibitor of HIV protease, and a CYP3A4 inhibitor (while taking saquinavir 3 times/day in dose 1200 mg), against the background of achieving a constant level of saquinavir in the blood, C_max sildenafil in the blood increased by 140%, and AUC increased by 210%. Sildenafil had no effect on the pharmacokinetic parameters of saquinavir.

Stronger CYP3A4 inhibitors, such as ketoconazole or itraconazole, may cause more pronounced changes in the pharmacokinetics of sildenafil.

Concomitant use of sildenafil (one dose of 100 mg) and ritonavir, which is an inhibitor of HIV protease and a strong inhibitor of isoenzymes of the cytochrome P450 system (when taking ritonavir po 500 mg 2 times / day), against the background of achieving a constant level of ritonavir in the blood, C_max sildenafil increased by 300% (in 4 times), and AUC by 1000% (in 11 time). Through 24 h the concentration of sildenafil in blood plasma was approximately 200 ng / ml (with a single use of sildenafil alone – 5 ng / ml).

If sildenafil is taken in recommended doses by patients, concomitantly receiving strong CYP3A4 inhibitors, then C_max free sildenafil does not exceed 200 nM, and the drug is well tolerated.

One-time dose of antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide diuretics, ACE inhibitors and calcium antagonists do not affect the pharmacokinetic parameters of sildenafil.

Concomitant use of azithromycin (500 mg / day for 3 days) no effect on AUC, C_max, T_max, elimination rate constant and T_1/2 sildenafil or its main circulating metabolite.

Effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes – 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IK₅₀ >150 mmol). Unlikely, that sildenafil may affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates as with long-term use, and when used for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

When taking the alpha-blocker doxazosin simultaneously (4 mg 8 mg) sildenafil and (25 mg, 50 mg 100 mg) 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 mmHg, 9/5 mmHg. and 8/4 mmHg. respectively, and in a standing position – 6/6 mmHg, 11/4 mmHg. and 4/5 mmHg. respectively. Rare cases of symptomatic postural hypotension have been reported in such patients., manifested as dizziness (without fainting). In selected sensitive patients, receiving alpha-blockers, concomitant use of sildenafil may lead to symptomatic hypotension.

Signs of a significant interaction between sildenafil and tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP2C9, not found.

Sildenafil in dose 100 mg does not affect the pharmacokinetic parameters of HIV protease inhibitors at constant concentrations in the blood, such as saquinavir and ritonavir, simultaneously being substrates of CYP3A4.

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 at the average maximum level of ethanol in the blood 80 mg / dL.

In patients with arterial hypertension, signs of interaction with sildenafil (100 mg) not detected with amlodipine. The average additional reduction in blood pressure in the supine position is: systolic - on 8 mmHg., diastolic-on 7 mmHg.

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

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored out of reach of children, dry place at temperatures no higher than 30 ° C. Shelf life - 5 years.