Sildenafil-SZ, 50 mg 4 pc

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.

The clinical data
Cardiology studies. The use of sildenafil in doses up to 100 mg did not result in clinically significant ECG changes in healthy volunteers. The maximum decrease in BP at lying position after sildenafil administration at a dose of 100 mg was 8.3 mmHg, and 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 MAP 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 it 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.

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 color vision impairment 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.

As a summary of the data, the patients who reported improved erections with sildenafil treatment included 59% of diabetic patients, 43% of radical prostatectomy patients, and 83% of spinal cord injury patients (versus 16, 15, and 12% in the placebo group, respectively).

Pharmacokinetics
The pharmacokinetics of sildenafil in the recommended dose range is 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 does not change significantly (AUC is reduced by 11%).

Distribution
Vss of sildenafil is on average 105 l. 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 drug administration.

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.

Elimination
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 (over 65 years of age) have reduced sildenafil clearance and plasma free sildenafil concentrations are about 40% higher than those of younger patients (18-45 years of age). 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.

Liver function abnormalities. 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) has not been studied.

Indications

Active ingredient

Composition

1 tablet sildenafil (in the form of citrate) 50 mg

Excipients:

Microcrystalline cellulose – 54 mg, lactose monohydrate (milk sugar) – 74 mg,

croscarmellose sodium (primellose) – 10 mg,

povidone (polyvinylpyrrolidone medium molecular weight) – 10 mg, magnesium stearate – 2 mg.

Shell composition:

Opadray II (polyvinyl alcohol, partially hydrolyzed – 2.4 mg, titanium dioxide (E171) – 1.374 mg, macrogol (polyethylene glycol 3350) – 1.212 mg, talc – 0.888 mg, aluminum varnish on the basis of diamond blue – 0.1152 mg, iron oxide (II) yellow (E172) – 0.0102 mg, iron oxide (II) black (E172) – 0.0006 mg).

How to take, the dosage

Ingestion.

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 reduced to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once daily.

Renal dysfunction

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

Hepatic disorders

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

Combined use with other medicinal products

In co-administration with ritonavir, the maximum single dose of Sildenafil should not exceed 25 mg, and the frequency of use should be once every 48 hours (see section “Interaction with other medicinal products”). When concomitant use with cytochrome CYPCA4 isoenzyme inhibitors (erythromycin, saquinavir, ketoconazole, itraconazole), the initial dose of Sildenafil should be 25 mg (see section “Interaction with other medicinal products”). To minimize the risk of postural hypotension in patients taking α-adrenoblockers, Sildenafil should be started only after hemodynamic stabilization is achieved in these patients. It should also be considered to reduce the starting dose of sildenafil (see sections “Special Precautions” and “Interaction with other medicinal products”).

Elderly patients

There is no need to adjust the dose of sildenafil.

Interaction

Influence of other drugs on the pharmacokinetics of sildenafil

The 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 was 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. Erectile dysfunction treatments should be used with caution in patients with anatomic penile deformities (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see section “Caution”).

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 exam before starting any erectile dysfunction therapy. Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg), or hypotension (BP < 90/50 mm Hg) (see “Caution”). Clinical studies have shown no difference 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 treated with Sildenafil 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 (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, and hypertension and hypotension) that were temporarily associated with sildenafil use.

The majority, 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 without subsequent sexual activity. A direct relationship between these adverse events and these or other factors cannot be established.

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. However, before prescribing sildenafil, the physician should carefully evaluate 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 with the rare syndrome of multiple systemic atrophy manifested by severe disruption of BP regulation by the autonomic nervous system.

Because co-administration of sildenafil and α-adrenoblockers may lead to symptomatic hypotension in some sensitive patients, sildenafil should be used with caution in patients taking α-adrenoblockers (see section “Interaction with other drugs”).

In order to minimize the risk of postural hypotension in patients taking α-adrenoblockers, Sildenafil should be started only after hemodynamic stabilization has been achieved in these patients. It should also be considered to reduce the starting dose of Sildenafil (see section “Dosage and administration”). The physician should inform patients about what actions should be taken if symptoms of postural hypotension occur.

Visual impairment

Rare cases of development of anterior nonarteritic ischemic optic neuropathy as a cause of visual impairment or loss have been reported 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, coronary heart disease, 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 in patients with retinitis pigmentosa, so Sildenafil should be used with caution (see section “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 are no data on the safety of sildenafil in patients with a tendency to bleeding or exacerbation of peptic ulcer disease, so sildenafil should be used with caution in these patients (see “Caution” section). 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 3.0%, 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%).

Performance with other treatments for erectile dysfunction.

The safety and effectiveness of Sildenafil with other erectile dysfunction drugs have not been studied, so this combination is not recommended (see section “Contraindications”).

Influence on driving and operating ability

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

However, since taking sildenafil may result in decreased blood pressure, chromatopsia, blurred vision, and other adverse events, careful consideration should be given to the individual effect of the drug in these 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:

– anatomical deformity of the penis (angulation, cavernous fibrosis or Peyronie’s disease);

– Diseases predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia).

Diseases that cause bleeding.p> – 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 mmHgStd) or hypotension (BP <90/50 mm Hg);

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

Side effects

In the body in general: asthenia, pain, abdominal pain, back pain, infection, flu-like syndrome.

Cardiovascular system: vasodilation (side effect reported in clinical trials).
Digestive system: diarrhea, nausea.

Muscular system: joint pain, muscle pain.

CNS and peripheral nervous system disorders: dizziness (side effect reported in clinical trials), increased muscle tone, insomnia.

Respiratory system disorders: nasal congestion, pharyngitis, rhinitis (side effect reported in clinical studies), sinusitis, respiratory tract infections, respiratory disorders.

Dermatological reactions: rash.

Sensory organs: changes in vision: mild and transient, mainly changes in the color of objects, as well as increased perception of light and blurred vision (side effect reported in clinical studies), conjunctivitis.

Urinary system disorders: urinary tract infections.

Perior genital system disorders: disorders of prostate function.

When using the drug in doses higher than recommended, the side effects were similar to those noted above, but were usually more common.

The following are the adverse events reported during post-marketing use.

Cardiovascular disorders: arterial hypotension, syncope, tachycardia, palpitations.

Digestive system disorders: vomiting (side effect reported in clinical trials).

Anxiety of the sexual system: prolonged erection and/or priapism.

Sensory system disorders: pain in the eyes, redness of the eyes.

Others: allergic reactions.

The side effects were usually transient and mild to moderate.

In fixed-dose studies, the incidence of side effects increased with increasing doses.

The nature of side effects in studies in which the dose was adjusted, because such studies better reflect the recommended regimen, was comparable to that in fixed-dose studies.

Overdose

Symptoms: When taking Sildenafil-SZ in a single dose up to 800 mg, adverse events were comparable to those with lower doses, but were more frequent.

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

Pregnancy use

The drug is not intended for use in women according to its registered indication.

Similarities