Visarsin Ku-tab, 50 mg 4 pcs

Pharmacotherapeutic group: erectile dysfunction treatment – phosphodiesterase type 5 (FDE5)-inhibitor
ATX code: G04BE03

Pharmacological properties

Pharmacodynamics
Sildenafil is a potent selective inhibitor of cyclic guanosine monophosphate (cGMP), a specific FDE5.

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 the level of cGMP, the subsequent relaxation of the smooth muscle tissue of the cavernous body and an increase in blood flow.
Sildenafil has no direct relaxing effect on the isolated human cavernous body, but increases the effect of NO through inhibition of FDE5, which is responsible for cGMP breakdown.
Sildenafil is selective against FDE5 under in vitro conditions, its activity against FDE5 exceeds activity against other known phosphodiesterase isoenzymes: FDE6 – 10 times, FDE1 – more than 80 times, FDE2, FDE4, FDE7FDE11 – more than 700 times. Sildenafil is 4,000 times more selective against FDE5 compared to FDE3, which is of critical importance because FDE3 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 at doses up to 100 mg did not result in clinically significant electrocardiogram (ECG) changes in healthy volunteers. The maximum decrease in systolic blood pressure (SBP) in the supine position after sildenafil administration at a dose of 100 mg was 8.3 mm Hg, and in diastolic blood pressure (DBP), 5.3 mm Hg. A more pronounced, but also transient effect on blood pressure (BP) was noted in patients taking nitrates (see sections “Contraindications” and “Interaction with other drugs”).
In a study of the hemodynamic effects of sildenafil at a single dose of 100 mg in 14 patients with severe coronary heart disease (CHD) (more than 70% of patients had stenosis of at least one coronary artery), resting BP and BP was decreased by 7% and 6%, respectively, and pulmonary systolic pressure was decreased by 9%. Sildenafil did not affect cardiac output and did not impair blood flow in stenosed coronary arteries, and 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) performed exercise until the severity of angina symptoms decreased. Exercise duration was significantly longer (19.9 seconds, 0.9-38.9 seconds) in patients taking sildenafil in a single dose of 100 mg compared with patients receiving placebo.
A 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 hypotensive drugs. Sildenafil improved erections in 71% of men compared with 18% in the placebo group. The frequency of adverse effects was comparable to that in other patient groups, as well as in those taking more than three hypotensive drugs.
Surveillance studies
Mild and transient impairment in the ability to distinguish shades of color (blue/green) was detected in some patients 1 hour after sildenafil doses of 100 mg using the Farnsworth-Munsel 100 test. These changes were absent 2 hours after sildenafil administration. The color vision impairment is thought to be caused by inhibition of FDE6, which is involved in the transmission of light in the retina. Sildenafil had no effect on visual acuity, contrast perception, the electroretinogram, intraocular pressure, or pupil diameter.
In a placebo-controlled, cross-over study of patients with proven early-onset macular degeneration (n = 9) sildenafil in 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, Humphrey perimeter, and photostress).
Effectiveness
Efficacy and safety of sildenafil were 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 was assessed 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, was demonstrated in all studies conducted and was confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportion of patients reporting that therapy improved their erections was 62% (sildenafil 25 mg dose), 74% (sildenafil 50 mg dose), and 82% (sildenafil 100 mg dose) compared to 25% in the placebo group. Analysis of the international erectile function index showed that in addition to improved erection, sildenafil treatment also improved the quality of orgasm, allowed to achieve satisfaction of intercourse and overall satisfaction.
According to the data summarized, the patients who reported an improvement in erections with sildenafil treatment included 59% of diabetic patients, 43% of patients who had undergone radical prostatectomy, and 83% of patients with spinal cord injuries (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 is on average about 40% (25% to 63%). Under in vitro conditions sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human FDE5 activity by 50%. After a single sildenafil dose of 100 mg, the average maximum concentration (C_max) of free sildenafil in the blood plasma of men is about 18 ng/mL (38 nM). C_max when sildenafil is taken orally on an empty stomach is reached on average within 60 min (30 min to 120 min). When taken together with fatty food the absorption rate is decreased: C_max is decreased on average by 29 %, and time to maximum concentration (TC_max) is increased by 60 min, but absorption degree does not change significantly (area under the pharmacokinetic curve “concentration-time” (AUC) is reduced by 11 %).
Distribution
Distribution volume of sildenafil in equilibrium 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 sildenafil concentration. Less than 0.0002% of the sildenafil dose (188 ng on average) was detected in semen 90 min after taking the drug.
Metabolism
Sildenafil is metabolized mainly in the liver by the CYP3A4 isoenzyme (main route) and CYP2C9 isoenzyme (additional route). 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 FDE5 under in vitro conditions is about 50% of sildenafil activity. The concentration of the metabolite in plasma of healthy volunteers was about 40% of the sildenafil concentration. The N-demethyl metabolite undergoes further metabolism, its half-life (T½) is about 4 hours.
Elimation
Total clearance of sildenafil is 41 l/h and the final T½ is 3-5 hours. After oral administration as well as after intravenous administration sildenafil is excreted as metabolites mainly through the intestine (about 80 % of the oral dose) and to a lesser extent through 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 in younger patients (18-45 years of age). Age has no clinically significant effect on the incidence of side effects.
Kidney function impairment
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 failure (CKR ≤ 30 ml/min) sildenafil clearance is decreased, resulting in approximately twofold increase of AUC (100%) and Cmax (88%) compared to similar parameters in patients of the same age group with normal renal function.
Hepatic dysfunction
In patients with cirrhosis (Child-Pugh class A and B), sildenafil clearance is decreased, resulting in increased AUC (84%) and Cmax (47%) compared to those in patients in the same age group with normal hepatic function. Pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Indications

Treatment of erectile dysfunction, characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse.
Sildenafil is effective only during sexual stimulation.

Pharmacological effect

Pharmacotherapeutic group: erectile dysfunction treatment – phosphodiesterase type 5 (PDE5) inhibitor
ATX code: G04BE03

Pharmacological properties

Pharmacodynamics
Sildenafil is a powerful selective inhibitor of cyclic guanosine monophosphate (cGMP), a specific PDE5.

Mechanism of action
The physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the corpus cavernosum and increased blood flow.
Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum, but enhances the effect of NO by inhibiting PDE5, which is responsible for the breakdown of cGMP.
Sildenafil is selective for PDE5 in vitro, its activity against PDE5 exceeds that against other known phosphodiesterase isoenzymes: PDE6 – 10 times, PDE1 – more than 80 times, PDE2, PDE4, PDE7PDE11 – more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to PDE3, which is of utmost importance since PDE3 is one of the key enzymes in the regulation of myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

Clinical data
Cardiac research
The use of sildenafil in doses up to 100 mg did not lead to clinically significant changes in the electrocardiogram (ECG) in healthy volunteers. The maximum decrease in systolic blood pressure (SBP) in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mmHg. Art., and diastolic blood pressure (DBP) – 5.3 mm Hg. Art. A more pronounced, but also transient effect on blood pressure (BP) was observed in patients taking nitrates (see sections “Contraindications” and “Interaction with other drugs”).
In a study of the hemodynamic effect of sildenafil at a single dose of 100 mg in 14 patients with severe coronary artery disease (CAD) (more than 70% of patients had stenosis of at least one coronary artery), resting SBP and DBP decreased by 7% and 6%, respectively, and pulmonary systolic pressure decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenotic coronary arteries, and also led to an increase (by approximately 13%) in adenosine-induced coronary flow in both stenotic 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 their angina symptoms improved. The duration of the exercise was significantly longer (19.9 seconds, 0.9-38.9 seconds) in patients taking sildenafil in a single dose of 100 mg compared to patients receiving placebo.
A randomized, double-blind, placebo-controlled study examined the effect of varying the dose of sildenafil (up to 100 mg) in men (n = 568) with erectile dysfunction and hypertension taking more than two antihypertensive medications. Sildenafil improved erections in 71% of men compared to 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in individuals taking more than three antihypertensive drugs.
Research on visual impairment
In some patients, 1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Munsell 100 test revealed a mild and transient impairment in the ability to distinguish shades of color (blue/green). 2 hours after taking sildenafil, these changes were absent. Color vision impairment is thought to be caused by inhibition of PDE6, which is involved in light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, intraocular pressure or pupil diameter.
In a placebo-controlled crossover study of patients with proven early-onset macular degeneration (n = 9), sildenafil in a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision assessed by specific visual tests (visual acuity, Amsler grating, color perception, color transmission simulation, Humphrey perimeter and photostress).
Efficiency
The efficacy and safety of sildenafil was assessed in 21 randomized, double-blind, placebo-controlled studies lasting up to 6 months in 3,000 patients aged 19 to 87 years with erectile dysfunction of various etiologies (organic, psychogenic or mixed). Efficacy was assessed globally using an erection diary, the International Index of Erectile Function (a validated sexual function questionnaire), and a partner interview. The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all studies conducted and was confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportions of patients who reported that therapy improved their erections were: 62% (sildenafil 25 mg dose), 74% (sildenafil 50 mg dose), and 82% (sildenafil 100 mg dose), compared with 25% in the placebo group. Analysis of the International Index of Erectile Function showed that in addition to improving erections, treatment with sildenafil also increased the quality of orgasm, achieved satisfaction from sexual intercourse and overall satisfaction.
In the pooled data, patients who reported improved erections with sildenafil included 59% of patients with diabetes, 43% of patients undergoing radical prostatectomy, and 83% of patients with spinal cord injury (versus 16%, 15%, and 12% in the placebo group, respectively).

Pharmacokinetics
The pharmacokinetics of sildenafil in the recommended dose range is linear.
Suction
After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (from 25% to 63%). In vitro, sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human PDE5 activity by 50%. After a single dose of sildenafil 100 mg, the average maximum concentration (Cmax) of free sildenafil in the blood plasma of men is about 18 ng/ml (38 nM). Cmax when taking sildenafil orally on an empty stomach is achieved on average within 60 minutes (from 30 minutes to 120 minutes). When taken simultaneously with fatty foods, the rate of absorption decreases: Cmax decreases by an average of 29%, and the time to reach maximum concentration (TCmax) increases by 60 minutes, but the degree of absorption does not significantly change (the area under the concentration-time pharmacokinetic curve (AUC) decreases by 11%).
Distribution
The volume of distribution of sildenafil at steady state averages 105 liters. The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of sildenafil. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in semen 90 minutes after taking the drug.
Metabolism
Sildenafil is metabolized mainly in the liver under the influence of the CYP3A4 isoenzyme (main route) and the CYP2C9 isoenzyme (additional route). The main circulating active metabolite, resulting from N-demethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite is further metabolized and has an elimination half-life (T½) of approximately 4 hours.
Removal
The total clearance of sildenafil is 41 l/hour, and the final half-life is 3-5 hours. After oral administration, as well as after intravenous administration, sildenafil is excreted in the form of metabolites, mainly through the intestines (about 80% of the ingested dose) and to a lesser extent by the kidneys (about 13% of the ingested dose).

Pharmacokinetics in special groups of patients
Elderly patients
In healthy elderly patients (over 65 years of age), the clearance of sildenafil is reduced, and the concentration of free sildenafil in the blood plasma is approximately 40% higher than in young patients (18-45 years of age). Age does not have a clinically significant effect on the incidence of side effects.
Renal dysfunction
In case of mild renal failure (creatinine clearance (CL) 50-80 ml/min) and moderate (CL 30-49 ml/min) severity, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (creatinine clearance ≤ 30 ml/min), the clearance of sildenafil is reduced, resulting in an approximately twofold increase in AUC (100%) and Cmax (88%) compared with those in patients of the same age group with normal renal function.
Liver dysfunction
In patients with liver cirrhosis (Child-Pugh class A and B), the clearance of sildenafil is reduced, resulting in an increase in AUC (84%) and Cmax (47%) compared with those in patients of the same age group with normal liver function. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) has not been studied.

Special instructions

To diagnose erectile dysfunction, determine its possible causes and select adequate treatment, it is necessary to collect a complete medical history and conduct a thorough physical examination. Treatments for erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie’s disease) or in patients with risk factors for the development of priapism (sickle cell anemia, multiple myeloma, leukemia) (see section “With caution”).
During post-marketing studies, cases of prolonged erection and priapism have been reported. If an erection persists for more than 4 hours, you should immediately seek medical help. If treatment for priapism is not carried out immediately, it can lead to damage to the tissue of the penis and irreversible loss of potency. Drugs intended to treat erectile dysfunction should not be used by men for whom sexual activity is not desirable.
Sexual activity poses some risks if you have heart disease, so before starting any therapy for erectile dysfunction, your doctor should refer the patient for a cardiovascular evaluation. Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke in the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg) or arterial hypotension (BP < 90/50 mm Hg). Sildenafil is contraindicated in such patients. (see section “Contraindications”). Clinical studies showed no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of cardiovascular death (0.3 per 100 people per year) in patients receiving sildenafil compared with patients receiving placebo.

Cardiovascular complications
During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension), which had a temporary association with the use of sildenafil. Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events occurred shortly after sexual activity, and some of them occurred after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the observed adverse events and these or other factors.

Arterial hypotension
Sildenafil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. However, before prescribing Visarsin® Qu-tab®, the physician must carefully assess the risk of possible undesirable manifestations of vasodilating effects in patients with relevant diseases, especially against the background of sexual activity.
Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare multiple system atrophy syndrome, which manifests itself as severe impaired regulation of blood pressure by the autonomic nervous system.
Since the simultaneous use of sildenafil and α-blockers can lead to symptomatic arterial hypotension in some sensitive patients, the drug Vizarsin® Ku-tab® should be used with caution in patients taking α-blockers (see section “Interaction with other drugs”). To minimize the risk of developing orthostatic hypotension in patients taking α-blockers, Visarsin® Qu-tab® should be started only after hemodynamic parameters have stabilized in these patients. You should also consider the advisability of reducing the initial dose of Vizarsin® Qu-tab® (see section “Method of administration and dosage”). The physician should inform patients about what actions to take if symptoms of orthostatic hypotension occur.

Visual disturbances
In rare cases, during post-marketing use of all PDE5 inhibitors, including sildenafil, NPINSID, a rare disease and cause of decreased or loss of vision, has been reported. Most of these patients had risk factors, including a decreased papilledema/disc ratio (“congestive disc”), age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study assessed whether recent use of the PDE5 inhibitor class of drugs was associated with acute onset of NPINSID. The results indicate an approximately twofold increase in the risk of developing NPINSID within 5 T1/2 after use of a PDE5 inhibitor. According to the published literature, the annual incidence of NPINSID is 2.5-11.8 cases per 100,000 men aged ≥ 50 years in the general population. In case of sudden loss of vision, patients should be advised to stop sildenafil therapy and consult a doctor immediately. Individuals who have already had a case of NPINSID are at increased risk of recurrent NPINSID. Therefore, the physician should discuss this risk with such patients, as well as discuss with them the potential for adverse effects from PDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the risk. In patients with episodes of retinitis pigmentosa with loss of vision in one eye, sildenafil is contraindicated (see section “Contraindications”).
A small number of patients with hereditary retinitis pigmentosa have genetically determined dysfunction of retinal phosphodiesterases. There is no information on the safety of sildenafil in patients with retinitis pigmentosa, therefore sildenafil should not be used in such patients (see section “Contraindications”).

Hearing impairment
Some post-marketing studies have reported cases of sudden deterioration or loss of hearing associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or loss of hearing. A cause-and-effect relationship between the use of PDE5 inhibitors and sudden hearing loss or deterioration has not been established. In case of sudden deterioration in hearing or hearing loss while taking Visarsin® Qu-tab®, you should immediately consult your doctor.

Bleeding
Sildenafil enhances the antiplatelet effect of sodium nitroprusside, an NO 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 gastric and duodenal ulcers, therefore Vizarsin® Ku-tab® should be used with caution in such patients (see section “With caution”). The incidence of epistaxis in patients with pulmonary hypertension associated with diffuse connective tissue diseases was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (sildenafil 3.0%, placebo 2.4%). In patients receiving sildenafil in combination with a vitamin K antagonist, the incidence of epistaxis was higher (8.8%) than in patients not taking a vitamin K antagonist (1.7%).
Concomitant use with other drugs for the treatment of erectile dysfunction
Safety and effectiveness of Visarsin® Qu-tab® concomitantly with other PDE5 inhibitors or other drugs for the treatment of pulmonary hypertension containing sildenafil or other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended (see section “Contraindications”).
Special information on excipients
Patients with congenital fructose intolerance should not take Vizarsin® Qu-tab®, since it contains sorbitol.
Vizarsin® Qu-tab® contains aspartame, which is a source phenylalanine, and may be dangerous for patients with phenylketonuria.

Influence on the ability to drive vehicles and machinery

Since when taking sildenafil, dizziness, a decrease in blood pressure, the development of chromatopsia, blurred vision, and other side effects are possible, caution should be exercised when driving vehicles, operating machinery, and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. You should also be careful about the individual effect of the drug Vizarsin® Qu-tab® in these situations, especially at the beginning of treatment and when changing the dosage regimen.

Active ingredient

Sildenafil

Composition

per tablet, dispersible in the oral cavity, 50 mg/100 mg
Active ingredient: sildenafil 50.00 mg/100.00 mg
Excipients: hyprolose, mannitol, aspartame, neohesperidin dihydrochalcone, mint flavor, *peppermint flavor, crospovidone type A, calcium silicate FM1000, magnesium stearate
*Peppermint flavoring: maltodextrin, acacia gum, sorbitol, mint oil, levomenthol and water.

Pregnancy

According to its registered indication, Vizarsin® Ku-tab® is not intended for use in women.

Contraindications

Hypersensitivity to sildenafil or any other component of the drug.
Use in patients receiving nitric oxide donors continuously or intermittently, organic nitrates or nitrites in any form, since sildenafil enhances the hypotensive effect of nitrates (see section “Interaction with other drugs”).
Concomitant use of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated, as this may lead to symptomatic hypotension (see section “Interactions with other drugs”).
The safety and effectiveness of Vizarsin® Qu-tab® when used simultaneously with other drugs for the treatment of erectile dysfunction has not been studied, therefore simultaneous use is contraindicated (see section “Special instructions”).
Severe liver failure (class C according to the Child-Pugh classification).
Concomitant use of ritonavir.
Severe cardiovascular diseases (severe heart failure, unstable angina, stroke or myocardial infarction in the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg) or arterial hypotension (BP < 90/50 mm Hg)) (see section "Special instructions"). Patients with episodes of nonarteritic anterior ischemic optic neuropathy (NAIOPN) with vision loss in one eye. Hereditary retinitis pigmentosa (see section "Special instructions"). According to its registered indication, Vizarsin® Ku-tab® is not intended for use in children under 18 years of age. According to its registered indication, Vizarsin® Ku-tab® is not intended for use in women. Patients with congenital fructose intolerance should not take Vizarsin® Qu-tab®, as it contains sorbitol. Vizarsin® Qu-tab® contains aspartame, which is a source of phenylalanine and may be dangerous for patients with phenylketonuria.

With caution
Anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie’s disease) (see section “Special instructions”), diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia) (see section “Special instructions”), diseases accompanied by bleeding, peptic ulcer of the stomach and duodenum in the stage exacerbations, impaired liver function, severe renal failure (creatinine clearance < 30 ml/min), patients with a history of an episode of NPINS development (see section “Special Instructions”), simultaneous use of α-blockers.

Side Effects

The most common side effects were headache and flushing.
Typically, the side effects of sildenafil are mild or moderate and transient.
Fixed-dose studies have shown that the incidence of some adverse events increases with increasing dose.
World Health Organization (WHO) side effect frequency classification:
very often ≥ 1/10
often from ≥ 1/100 to < 1/10
uncommon ≥ 1/1000 to < 1/100
rarely from ≥ 1/10000 to < 1/1000
very rare from <1/10000
frequency unknown cannot be estimated from available data.
Immune system disorders:
uncommon: hypersensitivity reactions (including skin rash), allergic reactions.
Visual disorders:
often: blurred vision, blurred vision, cyanopsia;
uncommon: eye pain, photophobia, photopsia, chromatopsia, redness of the eyes/scleral injections, changes in the brightness of light perception, mydriasis, conjunctivitis, hemorrhage in the eye tissue, cataracts, disruption of the lacrimal apparatus;
rarely: swelling of the eyelids and adjacent tissues, a feeling of dryness in the eyes, the presence of rainbow circles in the field of vision around the light source, increased eye fatigue, seeing objects in yellow (xanthopsia), seeing objects in red (erythropsia), conjunctival hyperemia, irritation of the mucous membrane of the eyes, discomfort in the eyes;
frequency unknown – NPINS, retinal vein occlusion, visual field defect, diplopia*, temporary loss of vision or decreased visual acuity, increased intraocular pressure, retinal edema, retinal vascular disease, vitreous detachment/vitreal traction.
Hearing and labyrinthine disorders:
uncommon: sudden decrease or loss of hearing, tinnitus, ear pain.
Disorders of the heart and blood vessels:
often: “hot flashes”;
uncommon: tachycardia, palpitations, decreased blood pressure, increased heart rate, unstable angina, atrioventricular block, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal ECG readings, cardiomyopathy;
rare: atrial fibrillation, sudden cardiac death⃰, ventricular arrhythmia⃰.
Blood and lymphatic system disorders:
uncommon: anemia, leukopenia.
Metabolic and nutritional disorders:
uncommon: feeling of thirst, edema, gout, uncompensated diabetes mellitus, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.
Disorders of the respiratory system, chest and mediastinal organs:
often: nasal congestion;
uncommon: nosebleeds, rhinitis, asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased volume of sputum, increased cough;
rarely: a feeling of tightness in the throat, dryness of the nasal mucosa, swelling of the nasal mucosa.
Gastrointestinal disorders:
often: nausea, dyspepsia;
uncommon: gastroesophageal reflux disease, vomiting, abdominal pain, dry oral mucosa, glossitis, gingivitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding;
rarely: hypoesthesia of the oral mucosa.
Musculoskeletal and connective tissue disorders:
often: back pain;
uncommon: myalgia, pain in the limbs, arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia gravis, synovitis.
Renal and urinary tract disorders:
uncommon: cystitis, nocturia, urinary incontinence, hematuria.
Disorders of the genital organs and breast:
uncommon: enlarged mammary glands, impaired ejaculation, swelling of the genitals, anorgasmia, hematospermia, damage to penile tissue;
rare: prolonged erection and/or priapism.
Nervous system and mental disorders:
very often: headache;
often: dizziness;
uncommon: drowsiness, migraine, ataxia, muscle hypertonicity, neuralgia, neuropathy, paresthesia, tremor, vertigo, symptoms of depression, insomnia, unusual dreams, increased reflexes, hypoesthesia;
rarely: convulsions*, repeated convulsions*, fainting.
Skin and subcutaneous tissue disorders:
uncommon: skin rash, urticaria, herpes simplex, pruritus, increased sweating, skin ulceration, contact dermatitis, exfoliative dermatitis;
frequency unknown: Stevens-Johnson syndrome, toxic epidermal necrolysis.
General disorders and disorders at the injection site:
infrequently – feeling of heat, swelling of the face, photosensitivity reaction, shock, asthenia, increased fatigue, pain of various localizations, chills, accidental falls, pain in the chest, accidental injuries;
rarely – irritability.
*Side effects identified during post-registration studies.
Cardiovascular complications
During the post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, arterial hypertension and hypotension) were reported, which were temporally related to the use sildenafil. Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events occurred shortly after sexual activity, and some of them occurred after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the observed adverse events and these or other factors.
Visual impairment
In rare cases, during post-marketing use of all PDE5 inhibitors, including sildenafil, NPINSID, a rare disease and cause of decreased or loss of vision, has been reported. Most of these patients had risk factors, including a decreased papilledema/disc ratio (“congestive disc”), age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study assessed whether recent use of the PDE5 inhibitor class of drugs was associated with acute onset of NPINSID. The results indicate an approximately two-fold increase in the risk of NPINI within 5 T½ after use of a PDE5 inhibitor. According to the published literature, the annual incidence of NPINSID is 2.5-11.8 cases per 100,000 men aged ≥ 50 years in the general population. In case of sudden loss of vision, patients should be advised to stop sildenafil therapy and consult a doctor immediately. Individuals who have already had a case of NPINSID are at increased risk of recurrent NPINSID. Therefore, the physician should discuss this risk with such patients, as well as discuss with them the potential risk of adverse effects from PDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the risk.
When using the drug Vizarsin® Ku-tab® in doses exceeding the recommended ones, adverse events were similar to those noted above, but usually occurred more often.

Interaction

The influence of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the influence of the isoenzymes CYP3A4 (the main pathway) and CYP2C9, therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers, accordingly, increase the clearance of sildenafil. A decrease in the clearance of sildenafil was noted with simultaneous use of inhibitors of the CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a nonspecific inhibitor of the CYP3A4 isoenzyme, when taken simultaneously with sildenafil (50 mg), causes an increase in the concentration of sildenafil in the blood plasma by 56%. A single dose of 100 mg of sildenafil simultaneously with erythromycin (500 mg/day 2 times a day for 5 days), a moderate inhibitor of the CYP3A4 isoenzyme, while achieving a constant concentration of erythromycin in the blood plasma leads to an increase in the AUC of sildenafil by 182%. With simultaneous administration of sildenafil (100 mg once) and saquinavir (1200 mg/day 3 times a day), an inhibitor of HIV protease and the CYP3A4 isoenzyme, while achieving a constant concentration of saquinavir in the blood plasma, the Cmax of sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir. More potent inhibitors of the CYP3A4 isoenzyme, such as ketoconazole and itraconazole, may cause more pronounced changes in the pharmacokinetics of sildenafil.
The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg 2 times a day), an HIV protease inhibitor and a powerful inhibitor of the cytochrome P450 system, while achieving a constant concentration of ritonavir in the blood plasma leads to an increase in Cmax of sildenafil by 300% (4 times), and AUC by 1000% (11 times). After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng/ml (after a single use of sildenafil alone – 5 ng/ml). This is consistent with the effect of ritonavir on a wide range of cytochrome P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Given these data, simultaneous use of ritonavir and sildenafil is not recommended. In any case, the maximum dose of sildenafil should under no circumstances exceed 25 mg in 48 hours.

If sildenafil is taken in recommended doses by patients simultaneously receiving potent inhibitors of the CYP3A4 isoenzyme, then the Cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated.
A single dose of antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.
In studies involving healthy volunteers, with simultaneous use of the endothelin receptor antagonist, bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19 isoenzymes) at steady state concentration (125 mg 2 times daily) and sildenafil at steady state concentration (80 mg 3 times daily), a decrease in AUC and Cmax of sildenafil by 62.6% and 52.4% was observed. respectively. The use of sildenafil increased the AUC and Cmax of bosentan by 49.8% and 42%, respectively. It is assumed that the simultaneous use of sildenafil with strong inducers of the CYP3A4 isoenzyme, such as rifampicin, may lead to a greater decrease in the concentration of sildenafil in the blood plasma.
Inhibitors of the CYP2C9 isoenzyme (tolbutamide, warfarin), the CYP2D6 isoenzyme (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists do not affect the pharmacokinetics of sildenafil.

Azithromycin (500 mg/day for 3 days) has no effect on the AUC, Cmax, TCmax, elimination rate constant and T½ of sildenafil or its main circulating metabolite.
Effect of sildenafil on other drugs
Sildenafil is a weak inhibitor of the isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 (IC50 > 150 µmol). When sildenafil is taken at recommended doses, its Cmax is approximately 1 µmol, so it is unlikely that sildenafil could affect the clearance of substrates of these isoenzymes.
Sildenafil enhances the hypotensive effect of nitrates both with long-term use of the latter and when used for acute indications. In this regard, the use of sildenafil simultaneously with nitrates or NO donors is contraindicated.
Riociguat
In preclinical studies, an additive effect in the form of a decrease in systemic blood pressure was noted when using PDE5 inhibitors in combination with riociguat. In clinical studies, riociguat has been shown to enhance the hypotensive effects of PDE5 inhibitors. There was no evidence of a beneficial clinical effect of the combination in the populations studied. Concomitant use of riociguat and PDE5 inhibitors, including sildenafil, is contraindicated (see section “Contraindications”).
When taking the α-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) simultaneously in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional reduction in SBP/DBP in the supine position was 7/7 mm Hg. Art., 9/5 mm Hg. Art. and 8/4 mm Hg. Art., respectively, and in the “standing” position – 6/6 mm Hg. Art., 11/4 mm Hg. Art. and 4/5 mm Hg. Art., respectively. Rare cases of symptomatic orthostatic hypotension, manifested in the form of dizziness (without fainting), have been reported in such patients. In selected sensitive patients receiving α-blockers, concomitant use of sildenafil may lead to symptomatic hypotension.
There were no signs of significant interactions with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the CYP2C9 isoenzyme.
Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the CYP3A4 isoenzyme, at constant plasma concentrations.
Co-administration of sildenafil at steady state (80 mg 3 times daily) leads to an increase in the AUC and Cmax of bosentan (125 mg 2 times daily) by 49.8% and 42%, respectively.
Sildenafil (50 mg) does not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg).
Sildenafil (50 mg) does not enhance the hypotensive effect of alcohol in healthy volunteers with a maximum plasma alcohol concentration of 0.08% (80 mg/dL) on average.
In patients with arterial hypertension, no signs of interaction between sildenafil (100 mg) and amlodipine were detected.
The average additional decrease in blood pressure in the supine position is 8 mmHg. Art. (SBP) and 7 mm Hg. Art. (DAD).
The use of sildenafil simultaneously with antihypertensive drugs does not lead to additional side effects.

Overdose

Symptoms: with a single dose of sildenafil in doses up to 800 mg, adverse reactions are similar to those when taking the drug in lower doses, while the severity and frequency increased. Taking sildenafil at a dose of 200 mg did not lead to an increase in effectiveness, but the frequency of adverse reactions (headache, hot flashes, dizziness, dyspepsia, nasal congestion, visual impairment) increased.
Treatment: symptomatic. Hemodialysis is ineffective because sildenafil binds tightly to plasma proteins and is not excreted by the kidneys.

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging.
Keep out of the reach of children.

Shelf life

3 years.
Do not use the drug after the expiration date.

Manufacturer

KRKA dd Novo Mesto, Slovenia