Effex Sildenafil, 50 mg 6 pcs

Sildenafil is a potent selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

The physiological mechanism of erection is based on the release of nitric oxide (NO) in the corpora cavernosa during sexual stimulation. This in turn increases cGMP levels, which relaxes the smooth muscle tissue in the corpora cavernosa and increases blood flow in the corpora cavernosa.

Sildenafil does not have a direct relaxing effect on the isolated corpora cavernosa but enhances the relaxing effect of nitric oxide by inhibiting FDE5, which is responsible for the breakdown of cGMP in the corpora cavernosa.

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

In vitro studies have shown that sildenafil is selective against FDE5. Its activity against other known isoenzymes is much lower: FDE6 by a factor of 10, FDE1 by a factor of more than 80, FDE2, FDE4, FDE7-11 by a factor of more than 700. Sildenafil is 4,000 times more active against FDE5 as compared to FDEA, which is important because FDEA is one of the key enzymes regulating myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

The use of sildenafil in doses up to 100 mg resulted in a mild, transient decrease in blood pressure. The hypotensive effect is associated with the vasodilatory effect of sildenafil associated with an increase in cGMP levels in vascular smooth muscle cells.

In some patients, 1 hour after taking the drug at a dose of 100 mg, the Farnsworth-Munsel 100 test revealed a mild and transient impairment of the ability to distinguish shades of color (blue/green). After two hours, color perception was restored. Color vision impairment is caused by inhibition of FDE6, which is involved in the process of light transmission in the retina. Sildenafil does not affect visual acuity, contrast perception, electroretinogram values, intraocular pressure, or pupil diameter.

Intake

It is rapidly absorbed after oral administration. Maximum plasma concentration is reached within 30-120 minutes (60 minutes on average) when taken orally on an empty stomach. Bioavailability varies from 25 to 63%. In combination with fatty food it reduces absorption speed: Cmax decreases on the average by 29%, and time of reaching of maximum concentration (Tmax) is increased by 60 min, but absorption degree does not change significantly (area under the pharmacokinetic curve of concentration – time (AUC) is reduced by 11%).

Distribution

The volume of distribution of sildenafil in the equilibrium state averages 105 l. Binding to plasma proteins of sildenafil and its main circulating N-demethyl metabolite is approximately 96% and is independent of the total drug concentration. Less than 0.0002% of the dose (188 ng on average) is detected in semen 90 min after sildenafil administration.

Metabolism

Sildenafil is metabolized mainly in the liver by microsomal cytochrome P450 isoenzymes: CYP3A4 (major pathway) and CYP2C9 (minor pathway). The main circulating metabolite formed as a result of N-demethylation of sildenafil undergoes further metabolism. Selectivity of this metabolite on FDE is comparable with that of sildenafil, and its activity against FDE5 in vitro is about 50% of sildenafil activity. Plasma concentration of the metabolite is about 40% of sildenafil concentration. N-demethyl metabolite undergoes further metabolism; its final elimination half-life is about 4 hours.

Elimination

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

Pharmacokinetics in special patient groups

Elderly patients

In healthy elderly patients (65 years and older), sildenafil clearance is reduced and free sildenafil plasma concentrations are about 40% higher than in younger patients (18-45 years). Age has no clinically significant effect on the incidence of side effects.

Renal dysfunction

In mild (creatinine clearance (CK) 50-80 ml/min) and moderate (CK 30-49 ml/min) renal impairment, the pharmacokinetics of sildenafil after a single oral dose of 50 mg is unchanged. In severe renal impairment (CKR <30 ml/min) sildenafil clearance is decreased, resulting in approximately two-fold increase of area under pharmacokinetic curve of concentration-time AUC (100%) and Cmax (88%) compared to those in normal renal function patients of the same age group.

Hepatic disorders

In patients with cirrhosis (Child-Pugh stages A and B), sildenafil clearance is decreased, resulting in increased AUC (84%) AND Cmax (47%) compared to those in normal liver function in patients in the same age group. Pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh stage C) have not been studied.

To diagnose erectile dysfunction, determine its possible causes, and choose an adequate treatment, a complete medical history and a thorough physical examination must be taken.

The treatment of erectile dysfunction should be used with caution in patients with anatomic penile deformities (angulation, cavernous fibrosis, Peyronie’s disease), or those with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia).

In post-marketing studies, cases of prolonged erections and priapism have been reported. If an erection persists for more than 4 hours, immediate medical attention should be sought. If priapism is not treated immediately, it may result in damage to penile tissue and permanent loss of potency.

The drugs intended to treat erectile dysfunction should not be prescribed for men for whom sexual activity is undesirable.

Sexual activity poses some risk if you have heart disease, so your doctor should refer you for a cardiovascular physical exam before starting any erectile dysfunction therapy. Sexual activity is undesirable in patients with heart failure, unstable angina, stroke or myocardial infarction within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg) or hypotension (BP <90/50 mm Hg).

In clinical trials, there have been no differences in the incidence of myocardial infarction (1.1 per 100 people per year) or cardiovascular mortality (0.3 per 100 people per year) in patients receiving sildenafil compared to patients receiving placebo.

Cardiovascular Complications

In the postmarketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as serious cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmias, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) that were temporarily associated with sildenafil use. Most, but not all, of these patients had risk factors for cardiovascular complications.

Many of these adverse events occurred shortly after sexual activity, and some occurred after sildenafil administration without subsequent sexual activity. It is not possible to establish a direct relationship between the reported adverse events and these or other factors.

Hypotension

Sildenafil has a systemic vasodilatory effect resulting in a transient decrease in BP, which is not clinically significant and has no effect in most patients. Nevertheless, before prescribing sildenafil, the physician should carefully evaluate the risk of possible adverse vasodilatory effects in patients with related conditions, especially with sexual activity.

Elevated susceptibility to vasodilators is seen in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), and with the rare multiple systemic atrophy syndrome, manifested by severe autonomic nervous system BP dysregulation. Visual Impairment

In rare cases during post-registration use of all FDE5 inhibitors, including sildenafil, nonarteritic anterior ischemic optic neuropathy (NPINZN) was reported, a rare condition and cause of decreased or lost vision. Most of these patients had risk factors, such as a decreased ratio of excavation and optic disc diameters (“stagnant disc”), age over 50 years, diabetes mellitus, hypertension, coronary heart disease, hyperlipidemia, and smoking.

The observational study evaluated whether recent use of drugs in the class of FDE5 inhibitors was associated with the acute onset of NSAIDs. The results indicated an approximately 2-fold increased risk of NPINZN within 5 half-lives of use of an FDE5 inhibitor. Published literature suggests an annual incidence of NSAIDs of 2.5-11.8 per 100,000 men aged ≥50 years in the general population.

Patients should be advised to discontinue sildenafil therapy in the event of sudden vision loss and immediately consult a physician. Individuals who have already had a history of NSAIDs have an increased risk of a recurrence of NSAIDs. Therefore, the physician should discuss this risk with such patients and also discuss with them the potential chance of adverse effects of FDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in these patients and only in situations where the expected benefits outweigh the risks.

A small number of patients with hereditary retinitis pigmentosa have genetically determined retinal phosphodiesterase dysfunction. There is no information about the safety of sildenafil use in patients with pigmentary retinitis, so the drug should be used with caution (see section “Caution”).

Hearing impairment

In some postmarketing and clinical studies, cases of sudden hearing impairment or loss have been reported associated with use of all FDE5 inhibitors, including sildenafil, most of these patients had risk factors for sudden hearing impairment or loss. A causal relationship between the use of FDE5 inhibitors and sudden hearing impairment or hearing loss has not been established. If there is sudden hearing loss or hearing loss while taking sildenafil, consult a physician immediately.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on safety of sildenafil use in patients with a tendency to bleeding or exacerbation of peptic ulcer and duodenal ulcer, so sildenafil should be used with caution in these patients.

The incidence of nasal bleeding in patients with pulmonary hypertension associated with diffuse connective tissue disease was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (sildenafil 3.0%, placebo 2.4%). Patients who received sildenafil in combination with a vitamin K antagonist had a higher rate of nasal bleeding (8.8%) than patients who did not take a vitamin K antagonist (1.7%).

Safe and effective use of sildenafil together with other sildenafil inhibitors or other drugs for treatment of pulmonary hypertension containing sildenafil (e.g., Revacio® ) or other drugs for treatment of erectile dysfunction have not been studied, therefore such combinations are not recommended.

Effect on driving ability trans. cc and mechanics:

Since taking sildenafil may cause dizziness, decreased blood pressure, chromatopsia, blurred vision, etc. side effects, caution should be exercised when driving vehicles and engaging in other potentially dangerous activities that require increased concentration and rapid psychomotor reactions. Attention should also be paid to the individual action of the drug in the above situations, especially at the beginning of treatment and when changing the dosing regimen.

Hypersensitivity to sildenafil or any other component of the drug.

Patients receiving nitric oxide donators, organic nitrates or nitrites in any form continuously or intermittently, as EFEX Sildenafil enhances the hypotensive effect of nitrates.)

Safety and efficacy of EFEX Sildenafil when used together with other means of erectile dysfunction treatment have not been studied, therefore such combinations are not recommended.

Co-administration with ritonavir.

Liver function abnormalities.

Chronic renal failure of severe severity.

Severe heart failure, unstable angina, stroke or myocardial infarction within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg) or hypotension (BP < 90/50 mm Hg).

According to the registered indication, EFEX Sildenafil is not intended for use in children under 18 years of age.

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

With caution:

Anatomical deformity of the penis (angulation, cavernous fibrosis or Peyronie’s disease).

Diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia).

Diseases accompanied by bleeding.

The exacerbation of gastric and 12 duodenal ulcers.

Hereditary retinitis pigmentosa.