Sildenafil-SZ, 100 mg 14 pcs

Pharmacodynamics

Sildenafil is a potent selective inhibitor of cGMP-specific FDE-5.

The mechanism of action

The realization of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the cavernous body during sexual stimulation. This in turn leads to an increase in cGMP levels, a subsequent relaxation of the smooth muscle tissue of the corpora cavernosa and an increase in blood flow.

Sildenafil does not have a direct relaxing effect on the isolated human cavernous body, but it enhances the effect of nitric oxide (NO) by inhibiting FDE-5, which is responsible for the breakdown of cGMP.

Sildenafil is selective against FDE-5 in vitro, its activity against FDE-5 is superior to other known FDE isoenzymes: FDE-6 – 10 times; FDE-1 – more than 80 times; FDE-2, FDE-4, FDE-7 – FDE-11 – more than 700 times. Sildenafil is 4,000 times more selective against FDE-5 compared to FDE-3, which is of critical importance because FDE-3 is one of the key enzymes regulating myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

Clinical data

Cardiology studies. Use of sildenafil in doses up to 100 mg did not result in clinically significant ECG changes in healthy volunteers. The maximum decrease in supine BP after sildenafil 100 mg was 8.3 mmHg, and the maximum decrease in BP was 5.3 mmHg. A more pronounced but also transient effect on BP was noted in patients taking nitrates.
In a study of the hemodynamic effects of sildenafil in a single dose of 100 mg in 14 patients with severe CHD (more than 70% of patients had stenosis of at least one coronary artery), resting BP and BP decreased by 7% and 6% respectively, and pulmonary BP decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenosed coronary arteries, and also resulted in an increase (by approximately 13%) in adenosine-induced coronary flow in both stenosed and intact coronary arteries.

In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until the severity of angina symptoms decreased. Exercise duration was significantly longer (19.9 s; 0.9-38.9 s) in patients taking sildenafil in a single dose of 100 mg compared with patients receiving placebo.

The randomized, double-blind, placebo-controlled study examined the effect of a variable dose of sildenafil (up to 100 mg) in men (n=568) with erectile dysfunction and arterial hypertension who were taking more than two antihypertensive drugs. Sildenafil improved erections in 71% of men compared with 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in those taking more than three antihypertensive drugs.

The studies on visual impairment. Mild and transient impairment in the ability to distinguish shades of color (blue/green) was detected in some patients 1 h after taking sildenafil at a dose of 100 mg using the Farnsworth-Mansel 100 test. These changes were absent 2 h after drug administration. It is believed that impairment of color vision is caused by inhibition of FDE-6, which is involved in the process of light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, IOP, or pupil diameter.

In a placebo-controlled, cross-over study of patients with proven early-onset macular degeneration (n=9), sildenafil at a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision as assessed by specific visual tests (visual acuity, Amsler grid, color perception, color passage simulation, Hamouri perimeter, and photostress). The effectiveness and safety of sildenafil have been evaluated in 21 randomized, double-blind, placebo-controlled trials lasting up to 6 months in 3000 patients aged 19 to 87 years, with erectile dysfunction of various etiologies (organic, psychogenic or mixed). Efficacy of the drug was evaluated globally using an erection diary, the International Erectile Function Index (a validated sexual function questionnaire), and a partner survey.

The efficacy of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory intercourse, has been demonstrated in all studies conducted and confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportion of patients who reported that therapy improved their erections was 62% (sildenafil dose – 25 mg), 74% (sildenafil dose – 50 mg) and 82% (sildenafil dose – 100 mg) versus 25% in the placebo group). Analysis of the International Index of Erectile Function showed that in addition to improved erections, sildenafil treatment also improved the quality of orgasm, allowed to achieve satisfaction of sexual intercourse and overall satisfaction.

The data summarized showed that among the patients who reported improved erections with sildenafil treatment, 59% had diabetes, 43% had radical prostatectomy, and 83% had spinal cord injury (versus 16%, 15%, and 12% in the placebo group, respectively).

Pharmacokinetics

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

Absorption

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (25 to 63%). In vitro sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human FDE-5 activity by 50%. After a single sildenafil dose of 100 mg, the average Cmax of free sildenafil in plasma of men is about 18 ng/ml (38 nM) and is reached when sildenafil is taken orally on an empty stomach within an average of 60 minutes (30 to 120 minutes). When taken in combination with fatty food the absorption rate is reduced: Cmax is reduced by 29% on average, and Tmax is increased by 60 min, but the degree of absorption is not significantly changed (AUC is reduced by 11%).

Distribution

The Vss of sildenafil averages 105 L. The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and is independent of the total drug concentration. Less than 0.0002% of the sildenafil dose (188 ng on average) is detected in semen 90 min after taking the drug.

Metabolism

Sildenafil is metabolized primarily in the liver by the cytochrome CYPCA4 isoenzyme (major pathway) and cytochrome CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite formed as a result of N-demethylation of sildenafil undergoes further metabolism. The selectivity of this metabolite against FDE is comparable with that of sildenafil, and its activity against FDE-5 in vitro is about 50% of sildenafil activity.

The plasma concentration of this metabolite in healthy volunteers was about 40% of that of sildenafil. The N-demethyl metabolite undergoes further metabolism; T1/2 is about 4 h.

The total clearance of sildenafil is 41 l/h, and the final T1/2 is 3-5 h. After oral administration, as well as after IUI, 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. Healthy elderly patients (older than 65 years) have decreased sildenafil clearance and plasma free sildenafil concentrations are about 40% higher than those of younger patients (18-45 years). Age has no clinically significant effect on the incidence of side effects.

Kidney function abnormalities. In mild (creatinine Cl 50-80 ml/min) and moderate (creatinine Cl 30-49 ml/min) degree of renal failure, sildenafil pharmacokinetics does not change after a single oral dose of 50 mg. In severe renal failure (creatinine Cl≤30 mL/min), sildenafil clearance is decreased, resulting in approximately two-fold increase of AUC (100%) and Cmax (88%) compared to normal renal function in patients of the same age group.

Hepatic disorders. Sildenafil clearance is decreased in patients with cirrhosis (Child-Pugh stages A and B), resulting in higher AUC (84%) and Cmax (47%) than in normal hepatic 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.

Indications

– treatment of erectile dysfunction characterized by the inability to achieve or maintain an erection of the penis sufficient for satisfactory intercourse.

Sildenafil is effective only with sexual stimulation.

Active ingredient

Composition

1 tabletcasildenafil (in the form of citrate)100 mg

Associated substances:

Microcrystalline cellulose – 83.5 mg,

Lactose monohydrate (milk sugar) – 83.5 mg,

croscarmellose sodium (primellose) – 15 mg,

povidone (polyvinylpyrrolidone medium molecular weight) – 15 mg,

magnesium stearate – 3 mg.

Shell contents:

Opadray II (polyvinyl alcohol, partially hydrolyzed – 3.6 mg, titanium dioxide (E171) – 2.061 mg, macrogol (polyethylene glycol 3350) – 1.818 mg, talc – 1.332 mg, aluminum varnish based on diamond blue – 0.1728 mg, iron oxide (II) yellow (E172) – 0.0153 mg, iron oxide (II) black (E172) – 0.0009 mg).

How to take, the dosage

The drug is taken orally.

The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Depending on 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 frequency of use is once daily.

In mild to moderate renal failure (CKR 30-80 ml/min), no dose adjustment is required; in severe renal failure (CKR <30 ml/min), the sildenafil dose should be reduced to 25 mg.

Because sildenafil excretion is impaired in patients with liver damage (particularly in cirrhosis), the dose of sildenafil-SZ should be reduced to 25 mg.

There is no need to adjust the dose of sildenafil-SZ in elderly patients.

Combined use with other drugs

In co-administration with ritonavir, the maximum single dose of Sildenafil-SZ should not exceed 25 mg and the frequency of use should be once every 48 hours.

When used together with CYP3A4 isoenzyme inhibitors (erythromycin, saquinavir, ketoconazole, itraconazole), the starting dose of Sildenafil-SZ should be 25 mg.

In order to minimize the risk of postural hypotension in patients taking alpha-adrenoblockers, Sildenafil-SZ should be started only after hemodynamic stabilization has been achieved in these patients. A reduction in the starting dose of sildenafil should also be considered.

Interaction

Influence of other drugs on the pharmacokinetics of sildenafil

. Metabolism of sildenafil occurs mainly under the action of cytochrome CYP3A4 isoenzymes (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers, respectively, increase sildenafil clearance. There has been noted a decrease in sildenafil clearance when concomitant use of inhibitors of CYP3A4 cytochrome isoenzyme (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a non-specific inhibitor of cytochrome CYP3A4 isoenzyme, when taken together with sildenafil (50 mg) increases sildenafil concentration in plasma by 56%. A single use of sildenafil at a dose of 100 mg in combination with erythromycin (500 mg 2 times per day for 5 days), a specific inhibitor of cytochrome CYP3A4 enzyme, on the background of achieving a constant concentration of erythromycin in blood, leads to an increase in sildenafil AUC by 182%.

When taking sildenafil (100 mg single dose) and saquinavir (1200 mg/day 3 times/day), an HIV protease inhibitor and CYP3A4 cytochrome isoenzyme, together, against achieving a steady concentration of saquinavir in the blood Cmax of sildenafil was increased by 140% and AUC was increased by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir.

Special Instructions

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. Treatment of erectile dysfunction should be used with caution in patients with anatomical deformities of the penis (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia).

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 physician 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, myocardial infarction or stroke in last 6 months, life-threatening arrhythmias, arterial hypertension (BP >170/100 mm Hg) or hypotension (BP <90/50 mm Hg). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 patient-years) or cardiovascular mortality (0.3 per 100 patient-years) in patients treated with Sildenafil-SZ compared to patients treated with placebo.

Cardiovascular Complications

In the postmarketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as serious cardiovascular complications (includingincluding myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, 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 were observed shortly after sexual activity, and some were noted 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 vasodilator effect resulting in a transient decrease in BP, which is not clinically significant and has no effect in most patients. Nevertheless, before prescribing Sildenafil-SZ, the physician should carefully assess the risk of possible adverse vasodilatory effects in patients with related conditions, especially during sexual activity. Increased susceptibility to vasodilators is seen in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy) and also with rare multiple systemic atrophy syndrome manifested by severe impairment of BP regulation by the autonomic nervous system.

Because co-administration of sildenafil and alpha-adrenoblockers may lead to symptomatic hypotension in some sensitive patients, Sildenafil-SZ should be used with caution in patients taking alpha-adrenoblockers. To minimize the risk of postural hypotension in patients taking alpha-adrenoblockers, Sildenafil-SZ should be started only after hemodynamic stabilization is achieved in these patients. A reduction in the starting dose of Sildenafil-SZ should also be considered. The physician should inform patients what actions should be taken if symptoms of postural hypotension occur.

Visual Impairment

Rare cases of anterior nonarteritic ischemic optic neuropathy have been reported as a cause of visual impairment or loss with all FDE5 inhibitors, including sildenafil. Most of these patients had risk factors such as optic disc excavation (deepening), age over 50 years, diabetes mellitus, arterial hypertension, CHD, hyperlipidemia, and smoking. No causal relationship between the intake of FDE5 inhibitors and the development of anterior nonarteritic ischemic optic neuropathy has been identified. The physician should inform the patient about the increased risk of anterior nonarteritic ischemic optic neuropathy if this condition has already been reported. In case of sudden loss of vision, patients should be treated immediately. A small number of patients with hereditary retinitis pigmentosa have genetically determined disorders of retinal phosphodiesterase functions. There is no information about the safety of Sildenafil-SZ in patients with pigmentary retinitis, so sildenafil should be used with caution.

Hearing impairment

Some postmarketing and clinical studies have reported cases of sudden hearing impairment or loss associated with use of all FDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or hearing 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 is no data on safety of sildenafil use in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcer, therefore Sildenafil-SZ should be used with caution in these patients. The incidence of nasal bleeding in patients with LH associated with diffuse connective tissue disease was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (sildenafil 3%, 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%).

Combination with other erectile dysfunction drugs

The safety and effectiveness of Sildenafil-SZ with other erectile dysfunction drugs have not been studied, so such combinations are not recommended.

Influence on driving and operating ability

There have been no adverse effects on the ability to drive or operate machinery while taking sildenafil.

But because sildenafil may decrease BP, develop chromatopsia, blurred vision, and other adverse events, careful consideration should be given to the individual effect of the drug in the above situations, especially at the beginning of treatment and when changing the dosing regimen.

Contraindications

– use in patients receiving nitric oxide donators, organic nitrates or nitrites in any form continuously or intermittently, since sildenafil increases the hypotensive effect of nitrates;

Sildenafil-SZ is not indicated for use in children and adolescents under the age of 18 years;

– Sildenafil-SZ is not indicated for use in women;

Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

– Simultaneous use of sildenafil with ritonavir is not recommended;

– Hypersensitivity to sildenafil or any other component of the drug.

The safety and effectiveness of sildenafil-SZ when used together with other treatments for erectile dysfunction has not been studied, so these combinations are not recommended.

With caution:

– anatomic 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;

– exacerbation of gastric and duodenal ulcer disease;

– hereditary retinitis pigmentosa;

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

– in patients with episodes of anterior nonarteritic ischemic optic neuropathy (history).

Overdose

Symptoms:Single administration of Sildenafil-SZ in doses up to 800 mg had similar adverse events to those of lower doses, but were more frequent.

Treatment:Conducting symptomatic therapy. Hemodialysis does not accelerate the clearance of sildenafil, because the latter is actively bound to plasma proteins and is not excreted by the kidneys.

Similarities