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- Dosage mg
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- Description en
- Composition and dosage form Tablets: 28 pcs. in a pack. Nebivolol hydrochloride. . . . . . 5 mg Excipient: Lactose monohydrate. Clinical-pharmacological group Selective β1-adrenoblocker. Pharmacological properties Nebivolol is a racemate of two enantiomers, (SRRR)-nebivolol (or D-nebivolol) and (SRRR)-nebivolol (or L-nebivolol). The drug is characterized by two types of pharmacological action: - Nebivolol is a competitive and highly selective blocker of β1-receptors. This effect is due to the SRRR-enantiomer (D-enantiomer); - The drug has moderate vasodilating properties, which are due to the modulation of the release of the relaxing factor, nitric oxide (NO), from the vascular endothelium with the participation of L-arginine. Single and repeated use of nebivolol in patients with normal blood pressure and arterial hypertension reduces heart rate and blood pressure, both at rest and after physical exertion. The hypotensive effect is maintained with prolonged use of the drug. In therapeutic doses, nebivolol does not have alpha-adrenoblocking effects. In healthy volunteers, nebivolol does not significantly affect the ability and endurance for maximum physical exertion. Pharmacokinetics After oral administration, both enantiomers of nebivolol are rapidly absorbed from the gastrointestinal tract. Food intake does not affect the absorption of the drug. Nebivolol can be taken with or without food. Both enantiomers of nebivolol bind to blood plasma proteins, mainly albumin. Protein binding is 98.1% for (SRRR)-nebivolol and 97.9% for (SRRR)-nebivolol. Nebivolol is metabolized in the body to form active hydroxymetabolites. The metabolism of nebivolol occurs through alicyclic and aromatic hydroxylation, N-dealkylation, and glucuronidation. In addition, glucuronides of hydroxymetabolites are formed. In individuals with rapid metabolism, the oral bioavailability of nebivolol averages 12%. And almost complete in individuals with slow metabolism. At steady state and with equal dosing, the maximum plasma concentration of unchanged nebivolol in slow metabolizers is about 23 times higher than in rapid metabolizers. When analyzing the total content of unchanged substance and active metabolites, the difference between maximum concentrations is 1.3-1.4 times. Due to changes in metabolism, the dose of Nebet must always correspond to the patient's individual needs: therefore, slow metabolizers are prescribed relatively lower doses of the drug. In individuals with rapid metabolism, the half-life of nebivolol enantiomers averages 10 hours. In individuals with slow metabolism, this indicator increases 3-5 times. In individuals with rapid metabolism, the half-life of hydroxymetabolites of both enantiomers averages 24 hours. In individuals with slow metabolism, this indicator is approximately 2 times higher. The steady-state concentration of nebivolol in plasma is reached within 24 hours in most patients (rapid metabolizers), and for hydroxymetabolites - after several days. When using doses of nebivolol from 1 mg to 30 mg, its concentration in plasma is proportional to the dose. Age does not affect the pharmacokinetics of nebivolol. One week after administration, 38% of the dose is excreted by the kidneys and 48% by the intestines. Renal excretion of unchanged nebivolol is less than 0.5% of the dose. Indications Hypertension - Treatment of essential arterial hypertension: Ischemic heart disease; Chronic heart failure (CHF); - Treatment of mild to moderate chronic heart failure (in the compensation stage) in elderly patients (≥70 years) in combination with standard therapy. Dosage regimen Hypertension Adults: One tablet (5 mg) daily, preferably at the same time. Tablets should be taken with food. The hypotensive effect appears 1-2 weeks after the start of treatment. In some cases, optimal effect is achieved only after 4 weeks. Combination with other antihypertensive drugs Beta-blockers can be used as monotherapy or in combination with other antihypertensive agents (diuretics, dihydropyridine calcium antagonists). Patients with renal insufficiency: In case of renal insufficiency, the recommended starting dose is 2.5 mg per day. If necessary, the daily dose can be increased to 5 mg. Patients with hepatic insufficiency: Information on patients with hepatic insufficiency or impaired liver function is limited. Therefore, the use of nebivolol in this type of patient is contraindicated. Elderly patients: In patients over 65 years of age, the recommended starting dose is 2.5 mg. If necessary, the daily dose can be increased to 5 mg. Caution should be exercised in patients over 75 years of age, and they should be regularly monitored. Children and adolescents: No studies have been conducted in children and adolescents. The use of the drug in this age group is not recommended. Ischemic heart disease Adults: Half a tablet or one tablet (2.5 mg – 5 mg) daily, preferably at the same time. Tablets should be taken with food. Chronic heart failure Treatment of chronic heart failure (in the compensation stage) should begin with gradual dose titration until the optimal individual maintenance dose is reached. Patients with chronic heart failure should not have had an episode of acute heart failure in the last 6 weeks. It is recommended that the treating physician be experienced in treating this pathology. For patients taking cardiovascular drugs, including diuretics and/or digoxin and/or angiotensin-converting enzyme inhibitors and/or angiotensin II antagonists, the final doses of these drugs should be selected 2 weeks before starting nebivolol treatment. Dose titration should be carried out stepwise, at 1-2 week intervals, depending on patient tolerance: starting dose – 1.25 mg nebivolol, then it can be increased to 2.5 mg once daily, then 5 mg once daily, and then 10 mg once daily. The maximum recommended dose is 10 mg of nebivolol once daily. The initiation of treatment and dose increase should be carried out under the supervision of an experienced physician for at least 2 hours to ensure stability of condition (special attention should be paid to blood pressure, heart rate, conduction disturbances, signs of worsening heart failure). Treatment with maximum recommended doses may not be possible due to the development of side effects. If necessary, the achieved dose can be gradually reduced and re-prescribed. During the titration phase, in case of worsening heart failure or intolerance, it is recommended to initially reduce the dose of nebivolol or discontinue it immediately if necessary (in case of severe hypotension, worsening heart failure with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia or atrioventricular block). Treatment of chronic heart failure with Nebet (in the compensation stage) is a long-term process. Abrupt discontinuation of nebivolol treatment is not recommended, as it may lead to a transient worsening of heart failure. The drug should be withdrawn gradually, halving the dose weekly. Tablets can be taken with food. Side effects The list of side effects varies for hypertension/ischemic heart disease and chronic heart failure. Hypertension and ischemic heart disease Most common side effects: headache, dizziness, paresthesia, shortness of breath, constipation, nausea, diarrhea, fatigue, edema. Other less common side effects include: nightmares, depression, visual disturbances, bradycardia, heart failure, slowed AV conduction/AV block, hypotension, intermittent claudication, bronchospasm, dyspepsia, flatulence, vomiting, itching, erythematous rash. The following side effects have been observed with some beta-blockers: hallucinations, psychoses, confusion, cold/cyanotic extremities, Raynaud's phenomenon, dry eyes. Chronic heart failure Data on side effects in patients with chronic heart failure were obtained from one placebo-controlled clinical trial. 1067 patients received nebivolol and 1061 patients received placebo. In this study, 449 patients (42.1%) reported a nebivolol-related side effect, compared to 334 patients (31.5%) who received placebo. The most common side effects in nebivolol patients were bradycardia and dizziness, both occurring in approximately 11% of patients. The incidence of these events among patients in the placebo group was approximately 2% and 7%, respectively. Side effects (possibly drug-related) that are particularly important in the treatment of chronic heart failure: - Worsening of heart failure, observed in 5.8% of patients in the nebivolol group, compared to 5.2% in the placebo group. - Orthostatic hypotension: Nebivolol - 2.1%, placebo - 1.0%. - Drug intolerance: Nebivolol - 1.6%, placebo - 0.8%. - First-degree atrioventricular block: Nebivolol - 1.4%, placebo - 0.9%. - Lower limb edema: Nebivolol - 1.05%, placebo - 0.2%. In case of adverse events, consult your doctor. Patients with renal insufficiency: No special dose adjustment is required for mild and moderate renal insufficiency. There is no data on patients with severe renal insufficiency (serum creatinine ≥250 µmol/l). Therefore, the use of nebivolol in this case is not recommended. Patients with hepatic insufficiency: Data on patients with hepatic insufficiency are limited. Therefore, the use of nebivolol in this type of patient is contraindicated. Elderly: No dose adjustment is required, as the maximum tolerated dose is selected individually. Children and adolescents: No studies have been conducted in children and adolescents. Therefore, the use of this drug in children and adolescents is not recommended. Contraindications - Hypersensitivity to the active substance or any of the excipients.; - Hepatic insufficiency or impaired liver function; - Acute heart failure, cardiogenic shock, or chronic heart failure in the decompensation stage requiring intravenous inotropic treatment; - Pregnancy and lactation. In addition, as with other beta-blockers, nebivolol is contraindicated in the following cases: - Sick sinus syndrome, including sinoatrial block; - Second and third-degree AV block (without a pacemaker); - Bronchospasm or bronchial asthma in history; - Untreated pheochromocytoma; - Metabolic acidosis; - Bradycardia (heart rate - Hypotension (systolic blood pressure < 90 mm Hg); - Severe peripheral circulatory disorders. Pregnancy and lactation Nebivolol can cause adverse effects on the course of pregnancy and/or the fetus/newborn. In general, beta-blockers reduce placental blood supply, leading to fetal growth retardation, abortion, or premature birth. In addition, adverse events may develop in the fetus and newborn, such as hypoglycemia or bradycardia. In pregnant women and during lactation, selective beta1-adrenoblockers are preferred when beta-blockers are necessary. Nebivolol use during pregnancy is possible only if strictly indicated. Continuous monitoring of uteroplacental blood flow and fetal growth and development is required. If the mother received beta-blockers, the newborn requires detailed monitoring. Typically, symptoms of hypoglycemia and bradycardia are expected within the first 3 days. Animal studies have shown that nebivolol is excreted in breast milk. Most beta-blockers, especially lipophilic substances like nebivolol and its active metabolites, pass into breast milk in varying amounts. Therefore, prescribing the drug during lactation is not recommended. Special instructions The following precautions should be observed when using beta-blockers: General anesthesia Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation. Beta-blocker treatment should be discontinued 24 hours before surgery. Caution should be exercised with certain types of anesthetics that cause increased cardiodepressive effects. Atropine may be used for premedication to prevent vagal reactions. Heart and blood vessels In general, the use of beta-blockers in patients with congestive heart failure is not recommended until the condition is stabilized. In patients with ischemic heart disease, beta-blocker treatment should be gradually discontinued over 1-2 weeks. If necessary, concomitant therapy with beta-blocker substitutes should be initiated to prevent angina. Beta-blockers cause bradycardia: if the resting pulse rate decreases to 50-55 beats per minute and/or the patient has symptoms characteristic of bradycardia, the dose should be reduced. Beta-blockers should be prescribed with caution in patients with: - Peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as the disease may worsen; - First-degree atrioventricular block, due to the negative effect of beta-blockers on conduction time; - Prinzmetal's angina due to the risk of coronary artery spasm: beta-blockers can increase the frequency and duration of angina attacks. Combination of nebivolol with calcium antagonists (verapamil and diltiazem), class I antiarrhythmics, and centrally acting antihypertensives is not recommended. Metabolism and endocrine system Nebet does not affect glucose levels in diabetic patients. However, caution is advised, as nebivolol can mask certain symptoms of hypoglycemia (tachycardia, tremor, sweating). Beta-blockers mask symptoms of tachycardia in hyperthyroidism. Abrupt discontinuation of the drug may exacerbate these symptoms. Respiratory system Beta-blockers should be prescribed with caution in chronic obstructive pulmonary disease and bronchial asthma, as bronchoconstriction may be exacerbated. Miscellaneous Caution is required when prescribing beta-blockers in patients with psoriasis. Beta-blockers can increase sensitivity to allergens and the severity of anaphylactic reactions. Initiation of treatment for chronic heart failure with nebivolol requires regular monitoring. This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Effect of the drug on the ability to drive and operate machinery: No studies have been conducted on the effects of Nebet on driving and operating other machinery. Pharmacodynamic studies have shown that 5 mg of Nebet does not impair psychomotor function. When driving or operating machinery, it should be borne in mind that taking the drug can sometimes cause dizziness and fatigue. Overdose Symptoms: Bradycardia, hypotension, bronchospasm, and acute heart failure. Treatment: In case of overdose or hypersensitivity, regular monitoring of the patient and treatment in an intensive care unit are necessary. Blood glucose levels should be monitored. Absorption of the active substance still present in the gastrointestinal tract can be stopped by gastric lavage and administration of activated charcoal and a laxative. Artificial lung ventilation may be necessary. To prevent bradycardia or increased vagotonia, administration of atropine or methylatropine is recommended. Hypotension and shock should be treated with plasma and plasma substitutes, and if necessary, catecholamines. Beta-blockade can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting dose 5 mcg/min, or dobutamine, starting dose 2.5 mcg/min, until the desired effect is achieved. In case of incompatibility, isoprenaline can be combined with dopamine. In case of adverse effects, 50-100 mcg/kg intravenous glucagon can be used. If necessary, the injection can be repeated within an hour, and then, if necessary, with intravenous infusion of 70 mcg/kg/hour glucagon. In extreme cases, for treatment-resistant bradycardia, a pacemaker may be used. Drug interactions Pharmacodynamic interactions The following forms of interaction are common to beta-blockers. Combinations with the following drugs are not recommended: - Class I antiarrhythmics (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): may increase the effect on atrioventricular conduction and increase the negative inotropic effect. - Calcium channel blockers: verapamil, diltiazem: increased negative effect on contractility and atrioventricular conduction. Intravenous administration of verapamil during nebivolol treatment can cause severe hypotension and atrioventricular block. - Centrally acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine): concomitant use with centrally acting antihypertensive agents can deepen heart failure by reducing central sympathetic tone (reduced heart rate and cardiac output, vasodilation). Abrupt discontinuation of treatment, especially before withdrawal of the beta-blocker, increases the risk of "rebound hypertension". Combinations that should be used with caution: - Class III antiarrhythmics (amiodarone): may increase the effect on atrioventricular conduction. - General anesthetics: Combined use of beta-blockers and inhaled general anesthetics can suppress reflex tachycardia and increase the risk of arterial hypotension. As a rule, abrupt discontinuation of beta-blocker treatment is not possible. The anesthesiologist should be informed that the patient is taking Nebet. - Insulin and oral antidiabetic agents: Although nebivolol does not affect glucose levels, concomitant use may mask some symptoms of developing hypoglycemia (palpitations, tachycardia). Combinations that should be considered Digoxin: Concomitant use may increase atrioventricular conduction time. Clinical trials have not revealed any interactions between nebivolol and drugs in this group. Nebivolol does not affect the pharmacokinetics of digoxin. Dihydropyridine calcium antagonists (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, minodipine, nitrendipine): concomitant use may increase the risk of hypotension, and in patients with heart failure, the risk of further deterioration of ventricular ejection function. Antipsychotics, antidepressants (tricyclic drugs, barbiturates, and phenothiazines): concomitant use may enhance the hypotensive effect of beta-blockers (additive effect). Non-steroidal anti-inflammatory drugs: reduce the hypotensive effect of nebivolol. Sympathomimetic substances: concomitant use may reduce beta-blocker activity. Beta-adrenergic substances may increase the alpha-adrenergic activity of sympathomimetic substances, enhancing both alpha- and beta-adrenergic effects (risk of hypertension, severe bradycardia, and AV block). Pharmacokinetic interactions Metabolism of nebivolol is carried out by the CYP2D6 isoenzyme, and combination with inhibitors of this enzyme, especially paroxetine, fluoxetine, thioridazine, and quinidine, can lead to an increase in plasma levels of nebivolol and an increased risk of bradycardia and other side effects. Concomitant administration of cimetidine increases the concentration of nebivolol in blood plasma without changing the clinical effect. Combination with ranitidine does not affect the pharmacokinetics of nebivolol and can be prescribed concurrently. In combination of nebivolol with nicardipine, a slight increase in the concentrations of both drugs in plasma is observed without changing the clinical activity. Intake with alcohol, furosemide, or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol. The drug does not affect the pharmacokinetics and pharmacodynamics of warfarin. Storage conditions and shelf life The drug should be stored at a temperature not exceeding 25°C, in a dry, protected from light, and inaccessible to children place. Shelf life - 2 years. Conditions of dispensing from pharmacies: The drug is dispensed by prescription.
- Active
- nebivolol
What is it?
Composition and dosage form Tablets: 28 pcs. in a pack. Nebivolol hydrochloride. . . . . . 5 mg Excipient: Lactose monohydrate. Clinical-pharmacological group Selective β1-adrenoblocker. Pharmacological properties Nebivolol is a racemate of two enantiomers, (SRRR)-nebivolol (or D-nebivolol) and (SRRR)-nebivolol (or L-nebivolol). The drug is characterized by two types of pharmacological action: - Nebivolol is a competitive and highly selective blocker of β1-receptors. This effect is due to the SRRR-enantiomer (D-enantiomer); - The drug has moderate vasodilating properties, which are due to the modulation of the release of the relaxing factor, nitric oxide (NO), from the vascular endothelium with the participation of L-arginine. Single and repeated use of nebivolol in patients with normal blood pressure and arterial hypertension reduces heart rate and blood pressure, both at rest and after physical exertion. The hypotensive effect is maintained with prolonged use of the drug. In therapeutic doses, nebivolol does not have alpha-adrenoblocking effects. In healthy volunteers, nebivolol does not significantly affect the ability and endurance for maximum physical exertion. Pharmacokinetics After oral administration, both enantiomers of nebivolol are rapidly absorbed from the gastrointestinal tract. Food intake does not affect the absorption of the drug. Nebivolol can be taken with or without food. Both enantiomers of nebivolol bind to blood plasma proteins, mainly albumin. Protein binding is 98.1% for (SRRR)-nebivolol and 97.9% for (SRRR)-nebivolol. Nebivolol is metabolized in the body to form active hydroxymetabolites. The metabolism of nebivolol occurs through alicyclic and aromatic hydroxylation, N-dealkylation, and glucuronidation. In addition, glucuronides of hydroxymetabolites are formed. In individuals with rapid metabolism, the oral bioavailability of nebivolol averages 12%. And almost complete in individuals with slow metabolism. At steady state and with equal dosing, the maximum plasma concentration of unchanged nebivolol in slow metabolizers is about 23 times higher than in rapid metabolizers. When analyzing the total content of unchanged substance and active metabolites, the difference between maximum concentrations is 1.3-1.4 times. Due to changes in metabolism, the dose of Nebet must always correspond to the patient's individual needs: therefore, slow metabolizers are prescribed relatively lower doses of the drug. In individuals with rapid metabolism, the half-life of nebivolol enantiomers averages 10 hours. In individuals with slow metabolism, this indicator increases 3-5 times. In individuals with rapid metabolism, the half-life of hydroxymetabolites of both enantiomers averages 24 hours. In individuals with slow metabolism, this indicator is approximately 2 times higher. The steady-state concentration of nebivolol in plasma is reached within 24 hours in most patients (rapid metabolizers), and for hydroxymetabolites - after several days. When using doses of nebivolol from 1 mg to 30 mg, its concentration in plasma is proportional to the dose. Age does not affect the pharmacokinetics of nebivolol. One week after administration, 38% of the dose is excreted by the kidneys and 48% by the intestines. Renal excretion of unchanged nebivolol is less than 0.5% of the dose. Indications Hypertension - Treatment of essential arterial hypertension: Ischemic heart disease; Chronic heart failure (CHF); - Treatment of mild to moderate chronic heart failure (in the compensation stage) in elderly patients (≥70 years) in combination with standard therapy. Dosage regimen Hypertension Adults: One tablet (5 mg) daily, preferably at the same time. Tablets should be taken with food. The hypotensive effect appears 1-2 weeks after the start of treatment. In some cases, optimal effect is achieved only after 4 weeks. Combination with other antihypertensive drugs Beta-blockers can be used as monotherapy or in combination with other antihypertensive agents (diuretics, dihydropyridine calcium antagonists). Patients with renal insufficiency: In case of renal insufficiency, the recommended starting dose is 2.5 mg per day. If necessary, the daily dose can be increased to 5 mg. Patients with hepatic insufficiency: Information on patients with hepatic insufficiency or impaired liver function is limited. Therefore, the use of nebivolol in this type of patient is contraindicated. Elderly patients: In patients over 65 years of age, the recommended starting dose is 2.5 mg. If necessary, the daily dose can be increased to 5 mg. Caution should be exercised in patients over 75 years of age, and they should be regularly monitored. Children and adolescents: No studies have been conducted in children and adolescents. The use of the drug in this age group is not recommended. Ischemic heart disease Adults: Half a tablet or one tablet (2.5 mg – 5 mg) daily, preferably at the same time. Tablets should be taken with food. Chronic heart failure Treatment of chronic heart failure (in the compensation stage) should begin with gradual dose titration until the optimal individual maintenance dose is reached. Patients with chronic heart failure should not have had an episode of acute heart failure in the last 6 weeks. It is recommended that the treating physician be experienced in treating this pathology. For patients taking cardiovascular drugs, including diuretics and/or digoxin and/or angiotensin-converting enzyme inhibitors and/or angiotensin II antagonists, the final doses of these drugs should be selected 2 weeks before starting nebivolol treatment. Dose titration should be carried out stepwise, at 1-2 week intervals, depending on patient tolerance: starting dose – 1.25 mg nebivolol, then it can be increased to 2.5 mg once daily, then 5 mg once daily, and then 10 mg once daily. The maximum recommended dose is 10 mg of nebivolol once daily. The initiation of treatment and dose increase should be carried out under the supervision of an experienced physician for at least 2 hours to ensure stability of condition (special attention should be paid to blood pressure, heart rate, conduction disturbances, signs of worsening heart failure). Treatment with maximum recommended doses may not be possible due to the development of side effects. If necessary, the achieved dose can be gradually reduced and re-prescribed. During the titration phase, in case of worsening heart failure or intolerance, it is recommended to initially reduce the dose of nebivolol or discontinue it immediately if necessary (in case of severe hypotension, worsening heart failure with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia or atrioventricular block). Treatment of chronic heart failure with Nebet (in the compensation stage) is a long-term process. Abrupt discontinuation of nebivolol treatment is not recommended, as it may lead to a transient worsening of heart failure. The drug should be withdrawn gradually, halving the dose weekly. Tablets can be taken with food. Side effects The list of side effects varies for hypertension/ischemic heart disease and chronic heart failure. Hypertension and ischemic heart disease Most common side effects: headache, dizziness, paresthesia, shortness of breath, constipation, nausea, diarrhea, fatigue, edema. Other less common side effects include: nightmares, depression, visual disturbances, bradycardia, heart failure, slowed AV conduction/AV block, hypotension, intermittent claudication, bronchospasm, dyspepsia, flatulence, vomiting, itching, erythematous rash. The following side effects have been observed with some beta-blockers: hallucinations, psychoses, confusion, cold/cyanotic extremities, Raynaud's phenomenon, dry eyes. Chronic heart failure Data on side effects in patients with chronic heart failure were obtained from one placebo-controlled clinical trial. 1067 patients received nebivolol and 1061 patients received placebo. In this study, 449 patients (42.1%) reported a nebivolol-related side effect, compared to 334 patients (31.5%) who received placebo. The most common side effects in nebivolol patients were bradycardia and dizziness, both occurring in approximately 11% of patients. The incidence of these events among patients in the placebo group was approximately 2% and 7%, respectively. Side effects (possibly drug-related) that are particularly important in the treatment of chronic heart failure: - Worsening of heart failure, observed in 5.8% of patients in the nebivolol group, compared to 5.2% in the placebo group. - Orthostatic hypotension: Nebivolol - 2.1%, placebo - 1.0%. - Drug intolerance: Nebivolol - 1.6%, placebo - 0.8%. - First-degree atrioventricular block: Nebivolol - 1.4%, placebo - 0.9%. - Lower limb edema: Nebivolol - 1.05%, placebo - 0.2%. In case of adverse events, consult your doctor. Patients with renal insufficiency: No special dose adjustment is required for mild and moderate renal insufficiency. There is no data on patients with severe renal insufficiency (serum creatinine ≥250 µmol/l). Therefore, the use of nebivolol in this case is not recommended. Patients with hepatic insufficiency: Data on patients with hepatic insufficiency are limited. Therefore, the use of nebivolol in this type of patient is contraindicated. Elderly: No dose adjustment is required, as the maximum tolerated dose is selected individually. Children and adolescents: No studies have been conducted in children and adolescents. Therefore, the use of this drug in children and adolescents is not recommended. Contraindications - Hypersensitivity to the active substance or any of the excipients.; - Hepatic insufficiency or impaired liver function; - Acute heart failure, cardiogenic shock, or chronic heart failure in the decompensation stage requiring intravenous inotropic treatment; - Pregnancy and lactation. In addition, as with other beta-blockers, nebivolol is contraindicated in the following cases: - Sick sinus syndrome, including sinoatrial block; - Second and third-degree AV block (without a pacemaker); - Bronchospasm or bronchial asthma in history; - Untreated pheochromocytoma; - Metabolic acidosis; - Bradycardia (heart rate - Hypotension (systolic blood pressure < 90 mm Hg); - Severe peripheral circulatory disorders. Pregnancy and lactation Nebivolol can cause adverse effects on the course of pregnancy and/or the fetus/newborn. In general, beta-blockers reduce placental blood supply, leading to fetal growth retardation, abortion, or premature birth. In addition, adverse events may develop in the fetus and newborn, such as hypoglycemia or bradycardia. In pregnant women and during lactation, selective beta1-adrenoblockers are preferred when beta-blockers are necessary. Nebivolol use during pregnancy is possible only if strictly indicated. Continuous monitoring of uteroplacental blood flow and fetal growth and development is required. If the mother received beta-blockers, the newborn requires detailed monitoring. Typically, symptoms of hypoglycemia and bradycardia are expected within the first 3 days. Animal studies have shown that nebivolol is excreted in breast milk. Most beta-blockers, especially lipophilic substances like nebivolol and its active metabolites, pass into breast milk in varying amounts. Therefore, prescribing the drug during lactation is not recommended. Special instructions The following precautions should be observed when using beta-blockers: General anesthesia Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation. Beta-blocker treatment should be discontinued 24 hours before surgery. Caution should be exercised with certain types of anesthetics that cause increased cardiodepressive effects. Atropine may be used for premedication to prevent vagal reactions. Heart and blood vessels In general, the use of beta-blockers in patients with congestive heart failure is not recommended until the condition is stabilized. In patients with ischemic heart disease, beta-blocker treatment should be gradually discontinued over 1-2 weeks. If necessary, concomitant therapy with beta-blocker substitutes should be initiated to prevent angina. Beta-blockers cause bradycardia: if the resting pulse rate decreases to 50-55 beats per minute and/or the patient has symptoms characteristic of bradycardia, the dose should be reduced. Beta-blockers should be prescribed with caution in patients with: - Peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as the disease may worsen; - First-degree atrioventricular block, due to the negative effect of beta-blockers on conduction time; - Prinzmetal's angina due to the risk of coronary artery spasm: beta-blockers can increase the frequency and duration of angina attacks. Combination of nebivolol with calcium antagonists (verapamil and diltiazem), class I antiarrhythmics, and centrally acting antihypertensives is not recommended. Metabolism and endocrine system Nebet does not affect glucose levels in diabetic patients. However, caution is advised, as nebivolol can mask certain symptoms of hypoglycemia (tachycardia, tremor, sweating). Beta-blockers mask symptoms of tachycardia in hyperthyroidism. Abrupt discontinuation of the drug may exacerbate these symptoms. Respiratory system Beta-blockers should be prescribed with caution in chronic obstructive pulmonary disease and bronchial asthma, as bronchoconstriction may be exacerbated. Miscellaneous Caution is required when prescribing beta-blockers in patients with psoriasis. Beta-blockers can increase sensitivity to allergens and the severity of anaphylactic reactions. Initiation of treatment for chronic heart failure with nebivolol requires regular monitoring. This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Effect of the drug on the ability to drive and operate machinery: No studies have been conducted on the effects of Nebet on driving and operating other machinery. Pharmacodynamic studies have shown that 5 mg of Nebet does not impair psychomotor function. When driving or operating machinery, it should be borne in mind that taking the drug can sometimes cause dizziness and fatigue. Overdose Symptoms: Bradycardia, hypotension, bronchospasm, and acute heart failure. Treatment: In case of overdose or hypersensitivity, regular monitoring of the patient and treatment in an intensive care unit are necessary. Blood glucose levels should be monitored. Absorption of the active substance still present in the gastrointestinal tract can be stopped by gastric lavage and administration of activated charcoal and a laxative. Artificial lung ventilation may be necessary. To prevent bradycardia or increased vagotonia, administration of atropine or methylatropine is recommended. Hypotension and shock should be treated with plasma and plasma substitutes, and if necessary, catecholamines. Beta-blockade can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting dose 5 mcg/min, or dobutamine, starting dose 2.5 mcg/min, until the desired effect is achieved. In case of incompatibility, isoprenaline can be combined with dopamine. In case of adverse effects, 50-100 mcg/kg intravenous glucagon can be used. If necessary, the injection can be repeated within an hour, and then, if necessary, with intravenous infusion of 70 mcg/kg/hour glucagon. In extreme cases, for treatment-resistant bradycardia, a pacemaker may be used. Drug interactions Pharmacodynamic interactions The following forms of interaction are common to beta-blockers. Combinations with the following drugs are not recommended: - Class I antiarrhythmics (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): may increase the effect on atrioventricular conduction and increase the negative inotropic effect. - Calcium channel blockers: verapamil, diltiazem: increased negative effect on contractility and atrioventricular conduction. Intravenous administration of verapamil during nebivolol treatment can cause severe hypotension and atrioventricular block. - Centrally acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine): concomitant use with centrally acting antihypertensive agents can deepen heart failure by reducing central sympathetic tone (reduced heart rate and cardiac output, vasodilation). Abrupt discontinuation of treatment, especially before withdrawal of the beta-blocker, increases the risk of "rebound hypertension". Combinations that should be used with caution: - Class III antiarrhythmics (amiodarone): may increase the effect on atrioventricular conduction. - General anesthetics: Combined use of beta-blockers and inhaled general anesthetics can suppress reflex tachycardia and increase the risk of arterial hypotension. As a rule, abrupt discontinuation of beta-blocker treatment is not possible. The anesthesiologist should be informed that the patient is taking Nebet. - Insulin and oral antidiabetic agents: Although nebivolol does not affect glucose levels, concomitant use may mask some symptoms of developing hypoglycemia (palpitations, tachycardia). Combinations that should be considered Digoxin: Concomitant use may increase atrioventricular conduction time. Clinical trials have not revealed any interactions between nebivolol and drugs in this group. Nebivolol does not affect the pharmacokinetics of digoxin. Dihydropyridine calcium antagonists (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, minodipine, nitrendipine): concomitant use may increase the risk of hypotension, and in patients with heart failure, the risk of further deterioration of ventricular ejection function. Antipsychotics, antidepressants (tricyclic drugs, barbiturates, and phenothiazines): concomitant use may enhance the hypotensive effect of beta-blockers (additive effect). Non-steroidal anti-inflammatory drugs: reduce the hypotensive effect of nebivolol. Sympathomimetic substances: concomitant use may reduce beta-blocker activity. Beta-adrenergic substances may increase the alpha-adrenergic activity of sympathomimetic substances, enhancing both alpha- and beta-adrenergic effects (risk of hypertension, severe bradycardia, and AV block). Pharmacokinetic interactions Metabolism of nebivolol is carried out by the CYP2D6 isoenzyme, and combination with inhibitors of this enzyme, especially paroxetine, fluoxetine, thioridazine, and quinidine, can lead to an increase in plasma levels of nebivolol and an increased risk of bradycardia and other side effects. Concomitant administration of cimetidine increases the concentration of nebivolol in blood plasma without changing the clinical effect. Combination with ranitidine does not affect the pharmacokinetics of nebivolol and can be prescribed concurrently. In combination of nebivolol with nicardipine, a slight increase in the concentrations of both drugs in plasma is observed without changing the clinical activity. Intake with alcohol, furosemide, or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol. The drug does not affect the pharmacokinetics and pharmacodynamics of warfarin. Storage conditions and shelf life The drug should be stored at a temperature not exceeding 25°C, in a dry, protected from light, and inaccessible to children place. Shelf life - 2 years. Conditions of dispensing from pharmacies: The drug is dispensed by prescription.