active ingredient: sildenafil;
- 1 tablet contains 35.112 mg of sildenafil citrate, which is equivalent to 25 mg of sildenafil, or
- 1 tablet contains 70.225 mg of sildenafil citrate, which is equivalent to 50 mg of sildenafil, or
- 1 tablet contains 140,450 mg of sildenafil citrate, which is equivalent to 100 mg of sildenafil;
excipients: microcrystalline cellulose; anhydrous calcium hydrophosphate; sodium croscarmelose; magnesium stearate; Opadry® blue (OY-LS-20921): hypromelose; lactose, monohydrate; glycerol triacetate; titanium dioxide (E 171); indigocarmine aluminum varnish (E 132); Opadry® transparent (YS-2-19114-A): hypromelose; glycerol triacetate.
Basic physico-chemical properties: tablets coated with a blue film, in the shape of a diamond, with rounded edges, embossed with "Pfizer" on one side and, according to the dosage, "VGR 25" or "VGR 50" or "VGR 100" on the other.
Mechanism of action. Sildenafil is an oral medication intended for the treatment of erectile dysfunction. During sexual arousal, the drug restores decreased erectile function by increasing blood flow to the penis.
The physiological mechanism that determines erection involves the release of nitric oxide (NO) in the cavernous bodies during sexual arousal. The released nitric oxide activates the enzyme guanylate cyclase, which stimulates an increase in the level of cyclic guanosine monophosphate (cGMP), which, in turn, causes relaxation of the smooth muscles of the cavernous bodies, promoting blood flow.
Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase 5 (PDE5) in cavernous bodies, where PDE5 is responsible for the breakdown of cGMP. The effect of sildenafil on erection is peripheral. Sildenafil does not have a direct relaxing effect on isolated human cavernous bodies, but greatly enhances the relaxing effect of NO on this tissue. When the NO/cGMP metabolic pathway is activated during sexual stimulation, sildenafil inhibition of PDE5 leads to an increase in cGMP levels in the cavernous bodies. Thus, in order for sildenafil to cause the desired pharmacological effect, sexual arousal is necessary.
Effects on pharmacodynamics. In vitro studies have demonstrated that sildenafil is selective to PDE5, actively participating in the erection process. The effect of sildenafil on PDE5 is more powerful than on other known phosphodiesterases. This effect is 10 times more powerful than the effect on PDE6, which is involved in the processes of phototransformation in the retina. When using the maximum recommended doses, the selectivity of sildenafil to PDE5 is 80 times higher than its selectivity to PDE1, 700 times higher than to PDE2, PDE4, PDE4, PDE7, PDE8, PDE9, PDE10 and PDE1. In particular, the selectivity of sildenafil to PDE5 is 4000 times higher than its selectivity to the PDEZ – cAMP-specific isoform of phosphodiesterase involved in the regulation of cardiac contractility.
Absorption. Sildenafil is rapidly absorbed. The maximum plasma concentration of the drug is reached within 30-120 minutes (with a median of 60 minutes) after its oral administration on an empty stomach. The average absolute bioavailability after oral use is 41% (with a range of values from 25 to 63%). In the recommended dose range (from 25 to 100 mg), the AUC and Cmax of sildenafil after oral administration increase proportionally to the dose.
When using sildenafil during meals, the degree of absorption decreases with an average lengthening of Tmax to 60 minutes and an average decrease in Cmax by 29%.
Distribution. The average equilibrium volume of distribution (Vd) is 105 liters, which indicates the distribution of the drug in the tissues of the body. After a single oral administration of sildenafil at a dose of 100 mg, the average maximum total plasma concentration of sildenafil is about 440 ng / ml (the coefficient of variation is 40%). Since the binding of sildenafil and its main N-desmethylmethabolite to plasma proteins reaches 96%, the average maximum plasma concentration of free sildenafil reaches 18 ng/ml (38 nmol). The degree of binding to plasma proteins does not depend on the total concentrations of sildenafil.
In healthy volunteers who used sildenafil once at a dose of 100 mg, after 90 minutes, less than 0.0002% (on average 188 ng) of the dose was determined in the ejaculate.
Biotransformation. Sildenafil metabolism is carried out mainly with the participation of microsomal liver isoenzymes CYP3A4 (main pathway) and CYP2C9 (secondary pathway). The main circulating metabolite is formed by N-demethylation of sildenafil. The selectivity of the metabolite with respect to PDE5 is comparable to the selectivity of sildenafil, and the activity of the metabolite with respect to PDE5 is approximately 50% of the activity of the starting substance. The plasma concentration of this metabolite is about 40% of the concentration of sildenafil in blood plasma. The N-demethylated metabolite undergoes further metabolism, and its half-life is approximately 4 hours.
Elimination. The total clearance of sildenafil is 41 liters / hour, causing a half-life of 3-5 hours. Both after oral and intravenous administration, the excretion of sildenafil in the form of metabolites is carried out mainly with feces (about 80% of the administered oral dose) and to a lesser extent with urine (about 13% of the administered oral dose).
Pharmacokinetics in special groups of patients.
Elderly patients. In healthy elderly volunteers (age 65+) there was a decrease in the clearance of sildenafil, which led to an increase in plasma concentrations of sildenafil and its active N-demethylated metabolite by about 90% compared with the corresponding concentrations in healthy young volunteers (18-45 years). Due to age differences in binding to plasma proteins, the corresponding increase in the plasma concentration of free sildenafil was approximately 40%.
Kidney failure. In volunteers with mild to moderate renal impairment (creatinine clearance 30-80 ml / min), the pharmacokinetics of sildenafil remained unchanged after a single oral dose of 50 mg. The average AUC and Cmax of the N-demethylated metabolite, respectively, increased by a maximum of 126 and 73% compared with such indicators in volunteers of the same age without impaired renal function. However, due to the high individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance below 30 ml/min), sildenafil clearance decreased, which led to average increases in AUC and Cmax, respectively, by 100% and 88% compared with volunteers of the same age without renal impairment. In addition, the AUC and Cmax values of the N-demethylated metabolite were significantly increased by 200% and 79%, respectively.
Liver failure. In volunteers with mild and moderate cirrhosis of the liver (classes A and B according to the Child–Pugh classification), the clearance of sildenafil decreased, which led to an increase in AUC (84%) and Cmax (47%) compared with the corresponding indicators in volunteers of the same age without liver dysfunction. The pharmacokinetics of sildenafil in patients with severe hepatic impairment has not been studied.
Hypersensitivity to the active substance or any of the excipients of the drug.
Simultaneous use with nitric oxide donors (for example, amyl nitrite) or nitrates in any form is contraindicated, since it is known that sildenafil affects the pathways of nitric oxide / cyclic guanosine monophosphate (cGMP) metabolism and potentiates the hypotensive effect of nitrates.
Simultaneous use of PDE5 inhibitors (including sildenafil) it is contraindicated with guanylate cyclase stimulants, such as riociguate, because it can lead to symptomatic hypotension (see the section "Interaction with other drugs and other types of interactions").
Conditions in which sexual activity is not recommended (for example, severe cardiovascular disorders, such as unstable angina or severe heart failure).
Loss of vision in the eye due to non-arterial anterior ischemic optic neuropathy, regardless of whether this pathology is associated with the preliminary use of PDE5 inhibitors or not.
The presence of diseases such as severe liver dysfunction, arterial hypotension (blood pressure below 90/50 mmHg), a recent stroke or myocardial infarction and known hereditary degenerative diseases of the retina, such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterase), since the safety of sildenafil has not been investigated in such cases subgroups of patients.
In vitro research. Sildenafil metabolism occurs mainly with the participation of isoform ZA4 (main pathway) and isoform 2C9 (secondary pathway) of cytochrome P450 (CYP). Therefore, inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers of these isoenzymes can increase the clearance of sildenafil.