Vizarsin

The influence of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the influence of cytochrome P450 isoenzymes - CYP3A4 (main pathway) and CYP2C9 (minor pathway), therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers, accordingly, increase the clearance of sildenafil.

Concomitant use of CYP3A4 isoenzyme inhibitors (such as ketoconazole, erythromycin, pimetidine) and sildenafil reduces its clearance.

Ritonavir increases the AUC of sildenafil by 11 times; simultaneous use of these drugs is not recommended. If simultaneous use with ritonavir is necessary, the maximum single dose of Vizarsin® should not exceed 25 mg, and the frequency of use should be 1 time every 48 hours.

With the simultaneous use of sildenafil (100 mg 1 time / day) and the HIV protease inhibitor and inhibitor of the CYP3A4 isoenzyme saquinavir, while achieving a constant concentration of saquinavir in the blood (1200 mg 3 times / day), Cmax of sildenafil increases by 140%, and AUC - by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir. Stronger inhibitors of the CYP3A4 isoenzyme, such as ketoconazole and itraconazole, presumably may cause more pronounced changes in the pharmacokinetics of sildenafil.

The use of sildenafil at a dose of 100 mg 1 time / day simultaneously with erythromycin, a specific CYP3A4 inhibitor, against the background of achieving a constant concentration of erythromycin in the blood (500 mg 2 times / day for 5 days), leads to an increase in the AUC of sildenafil by 182%. In healthy male volunteers, azithromycin (500 mg/day for 3 days) did not affect the AUC, Cmax, Tmax, elimination rate constant, and T1/2 of sildenafil or its main circulating metabolite. Cimetidine (800 mg), a nonspecific inhibitor of CYP3A4, when coadministered with sildenafil (50 mg) to healthy volunteers caused an increase in plasma sildenafil concentrations by 56%.

Grapefruit juice, a weak inhibitor of CYP3A4, may moderately increase plasma concentrations of sildenafil.

Single use of antacids (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

Although special pharmacokinetic studies have not been conducted with all drugs, a population pharmacokinetic analysis did not reveal changes in the pharmacokinetics of sildenafil when used simultaneously with such inhibitors of the CYP2C9 isoenzyme as tolbutamide, warfarin, phenytoin, with inhibitors of the CYP2D6 isoenzyme (selective serotonin reuptake inhibitors and tricyclic antidepressants), thiazide and similar diuretics, loop and potassium-sparing diuretics, ACE inhibitors, calcium channel blockers, beta-blockers or CYP450 inducers (such as rifampicin, barbiturates).

Nicorandil is a hybrid of a nitrate and a potassium channel activator. Due to the presence of a nitrate component, it may interact undesirably with sildenafil.

Effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µmol). When sildenafil is used in recommended doses, its Cmax in blood plasma is about 1 µmol, so it is unlikely that Vizarsin® can affect the clearance of substrates of these isoenzymes.

There is no data on the interaction of sildenafil with nonspecific phosphodiesterase inhibitors such as theophylline or dipyridamole.

Given the known effect of sildenafil on NO/cGMP, it may enhance the hypotensive effect of nitrates, therefore its simultaneous use with nitric oxide donors or nitrates in any dosage form is contraindicated.

Concomitant use of sildenafil and alpha-blockers may lead to symptomatic hypotension in selected susceptible patients. Arterial hypotension most often develops 4 hours after taking sildenafil. In three specific drug interaction studies, hemodynamically stable benign prostatic hyperplasia (BPH) patients receiving doxazosin (4 mg and 8 mg) were co-administered sildenafil (25 mg, 50 mg, or 100 mg). In all three studies, there were mean additional reductions in supine BP of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg. and an additional reduction in blood pressure in the standing position by 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. With the simultaneous use of sildenafil and doxazosin in patients with stable hemodynamics while taking doxazosin, rare cases of the development of symptomatic postural hypotension have been observed. In these described cases, dizziness or a feeling of lightness developed, but without the development of fainting conditions. To reduce the likelihood of developing orthostatic hypotension, it is necessary to achieve a stable state on alpha-blocker therapy before starting the use of sildenafil.

No significant interaction was observed with simultaneous use of sildenafil (at a dose of 50 mg) and tolbutamide (at a dose of 250 mg) or warfarin (at a dose of 40 mg), which are metabolized with the participation of CYP2C9.

Sildenafil (at a dose of 50 mg) does not potentiate the increase in bleeding time caused by acetylsalicylic acid (at a dose of 150 mg).

Sildenafil (at a dose of 50 mg) does not potentiate the hypotensive effect of ethanol in healthy volunteers at a maximum ethanol blood level of 80 mg/dL.

A synthesis of available data on the following drugs: diuretics, beta-blockers, ACE inhibitors, angiotensin II receptor blockers, vasodilators and centrally acting antihypertensives, adrenergic neuron blockers, calcium channel blockers and alpha-adrenergic blockers, did not reveal differences in the profile of adverse reactions among patients taking sildenafil or placebo concomitantly. In a special study, sildenafil (at a dose of 100 mg) was used simultaneously with amlodipine in patients with arterial hypertension, and additionally reduced systolic blood pressure in the supine position by an average of 8 mm Hg, and diastolic blood pressure by 7 mm Hg. Art. This additional reduction in blood pressure was the same as that observed with sildenafil alone in healthy volunteers.

Vizarsin, 12 pcs., 100 mg, film-coated tablets

To diagnose erectile dysfunction, determine its possible causes and select adequate treatment, it is necessary to obtain 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 priapism (sickle cell anemia, multiple myeloma, leukemia) (see 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. Medicines intended to treat erectile dysfunction should not be used by men for whom sexual activity is undesirable.

Sexual activity poses a certain risk in the presence of heart disease, therefore, before starting any therapy for erectile dysfunction, the doctor should refer the patient to an examination of the cardiovascular system. 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 . Art.) (see With caution

). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of cardiovascular mortality (0.3 per 100 people per year) in patients treated with sildenafil compared with patients treated with sildenafil. those 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) have been reported ), 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 Vizarsin®, the physician must carefully assess the risk of possible undesirable manifestations of the vasodilating effect 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 the rare multiple system atrophy syndrome, manifested by severe dysregulation of blood pressure from the autonomic nervous system.

Since the simultaneous use of sildenafil and α-blockers can lead to symptomatic arterial hypotension in some sensitive patients, Vizarsin® should be used with caution in patients taking α-blockers (see “Interactions”).

To minimize the risk of developing orthostatic hypotension in patients taking α-blockers, Vizarsin® 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® (see “Dosage and Administration”). The physician should inform patients about what actions to take if symptoms of orthostatic hypotension occur.

Visual impairment.

In rare cases, during post-registration use of all PDE-5 inhibitors, incl. sildenafil, reported NPINSID, a rare disease and cause of decreased or loss of vision. 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 T1/2 after use of a PDE5 inhibitor. Published literature estimates the annual incidence of NPINSID to be 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 NPIND have an increased risk of recurrent NPIND. Therefore, the physician should discuss this risk with such patients, as well as the potential for adverse effects from PDE5 inhibitors. PDE-5 inhibitors, incl. sildenafil should be used with caution in such patients and only in situations where the expected benefit outweighs the risk.

A small number of patients with hereditary retinitis pigmentosa have genetically determined dysfunction of the retinal PDE. There is no information on the safety of using sildenafil in patients with retinitis pigmentosa, so Vizarsin® should be used with caution (see Precautions

Hearing impairment.

Some post-marketing studies have reported cases of sudden deterioration or loss of hearing associated with 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. If there is a sudden deterioration in hearing or hearing loss while taking Vizarsin®, 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, so Vizarsin should be used with caution in such patients (see 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, placebo 2.4%). Patients receiving sildenafil in combination with a vitamin K antagonist had a higher incidence of epistaxis (8.8%) than patients not taking a vitamin K antagonist (1.7%).

Simultaneous use with other drugs for the treatment of erectile dysfunction. The safety and effectiveness of Vizarsin® concomitantly with other PDE5 inhibitors or other drugs for the treatment of pulmonary hypertension containing sildenafil, or other drugs for the treatment of erectile dysfunction, therefore the use of such combinations is not recommended (see “Contraindications”).

Impact on the ability to perform potentially hazardous activities that require special attention and quick reactions (for example, driving, working with moving mechanisms).

Since when taking sildenafil, it is possible to develop dizziness, decrease in blood pressure, develop chromatopsia, blurred vision, etc. side effects, caution should be exercised when driving vehicles 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 Vizarsin® in these situations, especially at the beginning of treatment and when changing the dosage regimen.

Vizarsin Qu-tab tablets, dispersible in the oral cavity 50 mg 4 pcs. in Krasnoyarsk

Sexual activity poses a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for an examination of the condition of the cardiovascular system. Sexual activity is not advisable 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) . Art.) Taking sildenafil in such patients is contraindicated (see section “Contraindications”). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of cardiovascular mortality (0.3 per 100 people per year) in patients treated with sildenafil compared with patients treated with sildenafil. those receiving placebo.

Cardiovascular complications

During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular events (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) have been reported. ), 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 the vasodilating effect 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 syndrome of multiple system atrophy, manifested by severe dysregulation of blood pressure from the autonomic nervous system.

Since the simultaneous use of sildenafil and α-blockers can lead to symptomatic arterial hypotension in some sensitive patients, Visarsin® 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 impairment

In rare cases, non-arteritic anterior ischemic optic neuropathy, a rare disease and cause of vision reduction or loss, has been reported during post-marketing use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors, including 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 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 NPIND have an increased risk of recurrent NPIND. 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 NPINS development 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 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%) . Patients receiving sildenafil in combination with a vitamin K antagonist had a higher incidence of epistaxis (8.8%) than patients not receiving a vitamin K antagonist (1.7%).

Simultaneous use with other drugs for the treatment of erectile dysfunction

The safety and effectiveness of Vizarsin® Qu-tab® concomitantly with other PDE5 inhibitors or other drugs for the treatment of pulmonary hypertension containing sildenafil or other drugs for the treatment of erectile dysfunction have not been studied, therefore 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.

Visarsin® Qu-tab® contains aspartame, which is a source of phenylalanine and may be harmful to patients with phenylketonuria.

Impact on driving vehicles and machinery

Since dizziness, a decrease in blood pressure, the development of chromatopsia, blurred vision, and other side effects are possible when taking sildenafil, caution should be exercised when driving vehicles 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.