Viagra (Sildenafil Citrate)

Brand name of drug: Viagra
Generic name: Sildenafil
Dosage form: tablets, film-coated
Composition

1 tablet, film-coated, includes:

Active ingredient:

Sildenafil citrate (equivalent to 25 mg, 50 mg or 100 mg of sildenafil)
Excipients:
microcrystalline cellulose, calcium hydrogen phosphate, croscarmellose sodium. magnesium stearate, film coating: opadray blue OY-LS-20921 (contains hypromellose, lactose, triacetin, titanium dioxide (E171) and aluminum paint on indigokarmina (E132)) and opadray transparent YS -2-19114-A (contains hypromellose and triacetin)

The blue film coating can be added to 30 mg / g of vanillin and / or biotin, and the content of one or both of the components in the film coating will be up to 0.75 mg, 1.5 mg and 3.0 mg doses to 25 mg, 50 mg and 100 mg, respectively.

Description

Blue tablets, film-coated, diamond-shaped, slightly biconvex, with cut and rounded edges, engraved with �Pfizer� on one side and �VGR 25�, �VGR 50" or �VGR 100" on the other side, respectively.

Pharmacotherapeutic group: a treatment for erectile dysfunction - PDE5 inhibitor

ATH code: G04BE03

Pharmacological properties

Pharmacodynamics

Sildenafil - a powerful selective inhibitor of tsikloguanozinmonofosfat (cGMP)-specific phosphodiesterase 5-type (PDE5).

Mechanism of action

Implementation of the physiological mechanism of erection involves the release of nitric oxide (NO) in the cavernous body during sexual stimulation. This, in turn, leads to increased levels of cGMP, the subsequent relaxation of cavernous smooth muscle tissue of the body and increase blood flow.

Sildenafil has no direct relaxing effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the breakdown of cGMP.

Sildenafil is selective for PDE5 in vitro, its activity against PDE5 superior activity against other known PDE isoenzymes: FDE6 - 10 times; FDE1 - more than 80 times; FDE2, FDE4, FDE7-FDE11 - more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to FDE3, which is essential because FDE3 is a key enzyme regulating myocardial contractility.

Mandatory condition for the effectiveness of sildenafil is sexual stimulation.

Clinical data

Cardiac assessment

The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum decrease in systolic blood pressure in the supine position after taking sildenafil 100 mg was 8.3 mm Hg. Art. and diastolic blood pressure - 5.3 mm Hg. Art. More pronounced, but transient effect on blood pressure (BP) was observed in patients taking nitrates (see "Contra" and "Interaction with other drugs).

In a study of hemodynamic effects of sildenafil in 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), systolic and diastolic blood pressure at rest decreased by 7 % and 6%, respectively, and the pulmonary systolic pressure decreased by 9%. Sildenafil had no effect on cardiac output and does not impair blood flow in stenosed coronary arteries, but also led to an increase (approximately 13%) adenosine-induced coronary flow in stenosed and in intact coronary arteries.

A double-blind placebo-controlled study of 144 patients with erectile dysfunction and stable angina taking antianginal medications (except nitrates) do physical exercises to the point where symptoms of angina decreased. Duration of exercise was significantly longer (19.9 seconds, 0.9 - 38.9 seconds) in patients taking sildenafil in a single dose of 100 mg compared with patients receiving placebo.

In a randomized double-blind, placebo-controlled study examined the effects of variable doses of sildenafil (100 mg) in men (n = 568) with erectile dysfunction and hypertension, taking more than two antihypertensive drugs. Sildenafil improved erections in 71% of men compared with 18% in the placebo group. The frequency of adverse effects was comparable to that in other groups of patients, as well as persons taking more than three antihypertensive drugs.

Studies of visual impairment

In some patients, after 1 hour after taking sildenafil 100 mg using the test Farnsworth-Munselya 100 revealed slight and transient impaired ability to distinguish shades of color (blue / green). 2 hours after taking the drug, these changes were absent. It is believed that a breach of color vision caused by inhibition of FDE6, which is involved in the transmission of light in the retina. Sildenafil had no effect on visual acuity, the perception of contrast, electroretinogram, the intraocular pressure or pupil diameter.
In placebo-controlled crossover study of patients with proven rannevozrastnoy-related macular degeneration (n = 9) in a single dose of sildenafil 100 mg well tolerated. There were no clinically significant changes in vision, assessed by a special visual tests (visual acuity, Amsler grid, color perception, modeling the passage of the color, the perimeter and Humphrey fotostress).

Efficiency

Efficacy and safety of sildenafil was evaluated in 21 randomized, double-blind, placebo controlled study lasting up to 6 months in 3000 patients aged 19 to 87, with erectile dysfunction of various etiologies (organic, psychogenic or mixed). Drug efficacy was evaluated globally using the diary of erections, the international index of erectile function (validated questionnaire on the status of sexual function) and survey partner. The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, was demonstrated in all the studies undertaken and has been confirmed in long-term studies lasting 1 year. In studies using a fixed dose ratio of patients who reported that treatment improved their erections, were: 62% (dose of sildenafil 25 mg), 74% (dose of sildenafil 50 mg) and 82% (dose of sildenafil 100 mg), compared with 25% in the placebo group. Analysis of the international index of erectile function showed that in addition to improving the treatment of erectile sildenafil also improved the quality of orgasm, allowed to achieve satisfaction from sexual intercourse and overall satisfaction.

According to generalized data, among the patients reported improved erections with sildenafil treatment were 59% diabetics, 43% of patients undergoing radical prostatectomy and 83% of patients with spinal cord injury (versus 16%, 15% and 12% in the placebo group, respectively ).

Pharmacokinetics

Pharmacokinetics of sildenafil in the recommended dose range is linear.

Suction

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages 40% (from 25% to 63%). In vitro sildenafil at a concentration of about 1.7 ng / ml (3.5 nM) inhibits PDE5 rights to 50%. After a single dose of sildenafil 100 mg average maximum concentration of free sildenafil citrate in blood plasma (Cmax) of men is about 18 ng / ml (38 nM). Cmax when taking sildenafil inside an empty stomach is achieved within an average of 60 minutes (from 30 min to 120 min). At a reception in conjunction with fatty food reduces the rate of absorption: Cmax decreased by an average of 29%, and the time to reach maximum concentration (Tmax) is increased by 60 minutes, but the extent of absorption was not significantly changed (the area under the pharmacokinetic concentration-time curve (AUC) is reduced 11%).

Distribution

The volume of distribution of sildenafil at steady state averaged 105 liters.
Relationship of sildenafil and its major circulating N-demetilnogo metabolite to 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 (mean 188 ng) was detected in semen after 90 minutes after ingestion.

Metabolism

Sildenafil is metabolized primarily in the liver under the action of cytochrome isoenzyme CYP3A4 (major route) and the isoenzyme cytochrome CYP2C9 (minor route). The main circulating active metabolite, formed as a result. N-demethylation of sildenafil, undergoes further metabolism. Selectivity of this metabolite with respect to the PDE is comparable to that of sildenafil and its activity against PDE5 in vitro is about 50% of the activity of sildenafil. Metabolite concentration in blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. N-demetilny metabolite undergoes further metabolism, during its half-life (T1 / 2) is about 4 hours.

Breeding

The total clearance of sildenafil is 41 l / h, and the final T 1 / 2 - 3.5 hours. After oral administration, as well as after intravenous administration of sildenafil appears in the form of metabolites, mainly the intestine (about 80% of oral dose) and to a lesser extent, the kidneys (about 13% of oral dose).

Pharmacokinetics in special patient groups

Elderly patients
In healthy elderly patients (over 65), sildenafil clearance was reduced, and the concentration of free sildenafil citrate in plasma by approximately 40% higher than in young (18-45 years). Age has no clinically significant effect on the incidence of side effects.

Renal dysfunction
In mild (creatinine clearance (CC) 50-80 ml / min) and moderate (creatinine clearance 30-49 ml / min) the degree of renal failure Pharmacokinetics of sildenafil after single oral dose of 50 mg did not change. In severe renal insufficiency (creatinine clearance (30 ml / min), sildenafil clearance is reduced, resulting in approximately a twofold increase in the values ??of AUC (100%) and Cmax (88%) compared with those with normal indices of renal function in patients of the same age group.

Liver function

In patients with liver cirrhosis (stages A and B on the classification of Child-Pugh), sildenafil clearance is reduced, which leads to increased values ??of AUC (84%) and Cmax (47%) compared with those with normal indices of liver function in patients of the same age group. Pharmacokinetics of sildenafil in patients with severe liver dysfunction (stage C by Child-Pugh classification) has not been studied.

Indications for Use

Treatment of erectile dysfunction, characterized by an inability to achieve or preserve penile erection sufficient for satisfactory sexual intercourse. Sildenafil is effective only with sexual stimulation.

Contraindications

Hypersensitivity to sildenafil or any other component of the drug.
Application in patients receiving constant or intermittent donator of nitric oxide, organic nitrates or nitrites in any form, as sildenafil enhances the hypotensive effect of nitrates (see "Interactions with other drugs)
Safety and efficacy of Viagra � in a joint application with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended (see "Special Instructions")
On the registered indication the drug Viagra � is not intended for use in children under 18 years
On the registered indication the drug Viagra � is not intended for use in women

Precautions

- Anatomical deformity of the penis (angulation, cavernous fibrosis or Peyronie's disease) (see "Special Instructions")
- Diseases predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia) (see "Special Instructions")
- Disease, accompanied by bleeding
- Aggravation of peptic ulcer
- Hereditary retinitis pigmentosa (see "Special Instructions")
- Congestive heart failure, unstable angina, migrated in the last 6 months, myocardial infarction, stroke or life-threatening arrhythmia, hypertension (blood pressure> 170/100 mmHg. Cent.) Or hypotension (BP <90/50 mmHg. Cent.) (Cm . section "Cautions")

Pregnancy and Lactation

On the registered indication the drug is not intended for use in women

Dosing and Administration
Inside.

The recommended dose for most adults is 50 mg approximately 1 hour before sexual activity. Given the efficacy and tolerability the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended multiplicity of application - once a day.

Renal dysfunction

In mild to moderate degree of renal insufficiency (creatinine clearance 30-80 ml / min), dosage adjustment is required in severe renal insufficiency (creatinine clearance <30 ml / min) - a dose of sildenafil should be reduced to 25 mg.

Liver function

Since the withdrawal of sildenafil is disturbed in patients with liver damage (including cirrhosis), the dose of the drug Viagra � should be reduced to 25 mg.

Joint application with other drugs

In a joint application with ritonavir maximum single dose of Viagra � should not exceed 25 mg, and the multiplicity of applications - 1 per 48 hr (see "Interactions with other drugs).
In a joint application with inhibitors of cytochrome isoenzyme CYP3A4 (erythromycin, saquinavir, ketoconazole, itraconazole), the initial dose of the drug Viagra � should be 25 mg (see "Interactions with other drugs).
To minimize the risk of postural hypotension in patients taking?-Blockers, the drug Viagra � should be initiated only after stabilization of hemodynamics in these patients. It should also consider reducing the initial dose of sildenafil (see "Cautions" and "Interaction with other drugs).

Elderly patients
Adjusting the dose of Viagra � is not required.

Side effect

Common side effects of Viagra � is weakly or moderately expressed and are transient in nature.
In studies using a fixed dose is shown that the incidence of some adverse events increased with increasing dose.