Sildenafil Citrate

Kamagra tablets of 100 mg, 4 pcs. - Instructions for use
Composition
active ingredient: sildenafil;

1 tablet contains sildenafil citrate listed on sildenafil 100 mg;

excipients: microcrystalline cellulose, magnesium stearate, sodium starch glycolate (type A), povidone, talc, hypromelose, Instacoat Sol IC-S-3788 coating (green)*, titanium dioxide (E 171); *Instacoat Sol IC-S-3788 (green): talc, hypromelose, polyethylene glycol, titanium dioxide (E 171), quinoline yellow (E 104), diamond blue (E 133).

Dosage form
Coated tablets.

Basic physico-chemical properties: diamond–shaped tablets, coated, green, embossed with "ar" on one side and "KGR 100" on the other.

Pharmacotherapeutic group
Remedies used for erectile dysfunction. Sildenafil. ATX code G04B E03.

Pharmacodynamics
Sildenafil is an oral medication intended for the treatment of erectile dysfunction. During sexual arousal, the drug sildenafil citrate 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, leads to 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 tadalafil 5mg is responsible for the breakdown of cGMP. The effects of sildenafil on erection are peripheral in nature. 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 necessary pharmacological effect, sexual arousal is necessary.

In vitro studies have shown the selectivity of the effect of sildenafil on PDE5, which is actively involved 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, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10 and PDE1. In particular, the selectivity of sildenafil to PDE5 is 4000 times higher than its selectivity to PDE3 – cGMP-specific isoform of phosphodiesterase involved in the regulation of cardiac contractility.

Pharmacokinetics

Absorption. Sildenafil is rapidly absorbed. The maximum plasma concentrations of the drug are 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 area under the concentration-time curve (AUC) and the maximum concentration (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 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. Plasma concentrations of this metabolite account for approximately 40% of sildenafil concentrations 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 l / h, causing a half-life of 3-5 hours. Both after oral and after intravenous administration, the excretion of sildenafil in the form of metabolites is carried out mainly with feces (approximately 80% of the administered oral dose) and to a lesser extent with urine (approximately 13% of the administered oral dose).

Elderly patients. In healthy elderly volunteers (aged over 65 years) 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%.

Renal insufficiency In volunteers with mild to moderate renal impairment (creatinine clearance from 30 to 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 increased by 126% and 73% compared to 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 by 100% and 88% compared with volunteers of the same age without renal impairment. In addition, the AUC and Cmax of the N-demethylated metabolite increased by 79% and 200%, respectively.

Liver failure. In volunteers with mild to 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 volunteers of the same age without disorders. The pharmacokinetics of sildenafil in patients with severe hepatic impairment has not been studied.

Indications

The drug is recommended for men with erectile dysfunction, which is defined as the inability to achieve or maintain an erection of the penis necessary for successful sexual intercourse.

Sexual arousal is required for the effective action of the drug.

Contraindications
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.
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 one 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. genetic disorders of retinal phosphodiesterases), since the safety of sildenafil has not been studied in such subgroups of patients.
Interaction with other drugs and other types of interactions
Effects of other drugs on sildenafil.

In vitro research.

Sildenafil metabolism occurs mainly with the participation of isoform 3A4 (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.

In vivo research

A population pharmacokinetic analysis of clinical trial data showed a decrease in the clearance of sildenafil when used concomitantly with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although no increase in the frequency of side effects was observed with the simultaneous use of sildenafil and CYP3A4 inhibitors, the recommended initial dose of sildenafil is 25 mg.