Instructions Nebival tablets 5 mg blister No. 20
Composition
active ingredient: 1 tablet contains nebivolol hydrochloride, equivalent to nebivolol 5 mg;
Excipients: lactose monohydrate; corn starch; croscarmellose sodium; hypromellose (hydroxypropylmethylcellulose); polysorbate; microcrystalline cellulose; colloidal anhydrous silicon dioxide; magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: round tablets with a flat surface with beveled edges and two perpendicularly intersecting lines, white or almost white in color.
Pharmacotherapeutic group
Selective β-adrenergic blockers. ATC code C07A B12.
Pharmacological properties
Pharmacodynamics.
Nebivolol is a racemate consisting of two enantiomers: SRRR-nebivolol (D-nebivolol) and RSSS-nebivolol (L-nebivolol). It combines two pharmacological actions:
– it is a competitive and selective antagonist of β-receptors: this effect is explained by the SRRR-enantiomer (d-enantiomer);
– it has mild vasodilating properties due to its interaction with L-arginine/nitric oxide.
Single and repeated doses of nebivolol reduce heart rate and blood pressure at rest and during exercise in both normotensive and hypertensive subjects. The antihypertensive effect is maintained during long-term treatment. At therapeutic doses, α-adrenergic antagonism is not observed. During short-term and long-term treatment with nebivolol in hypertensive patients, systemic vascular resistance decreases. Despite the reduction in heart rate, the reduction in cardiac output at rest and during exercise is limited by the increase in stroke volume. The clinical significance of this hemodynamic difference compared with other β-adrenergic blockers is not yet fully understood. In hypertensive patients, nebivolol increases the vascular response to acetylcholine (ACh) mediated by nitric oxide; in patients with endothelial dysfunction, this response is reduced.
In mortality-morbidity studies in patients with stable chronic heart failure with reduced left ventricular ejection fraction, nebivolol as the main drug in standard therapy significantly prolonged the time to death or hospitalization for cardiovascular disease (primary efficacy endpoint) with a reduction in relative risk. This risk reduction developed after 6 months of treatment and remained so throughout the treatment period (median duration - 18 months). The effect of nebivolol does not depend on age, gender or left ventricular ejection fraction. Patients treated with nebivolol had a reduced incidence of deaths.
In vitro and in vivo animal experiments have shown that nebivolol has no intrinsic sympathomimetic activity. Nebivolol also has no membrane-stabilizing effect at pharmacological doses.
In healthy volunteers, nebivolol does not significantly affect maximal exercise tolerance or endurance.
Pharmacokinetics.
After oral administration, both enantiomers of nebivolol are rapidly absorbed. The absorption of nebivolol is not affected by food, so it can be taken with or without food.
Nebivolol is completely metabolized, partly to form active hydroxymetabolites. The metabolism of nebivolol occurs by acyclic or aromatic hydroxylation, N-dealkylation and glucuronidation; in addition, glucuronides of hydroxymetabolites are formed. The metabolism of nebivolol by hydroxylation is subject to genetic oxidative polymorphisms, which depend on CYP2D6. The bioavailability of orally administered nebivolol is 12% in extensive metabolizers and is almost complete in poor metabolizers. At steady state and at the same dose, the maximum plasma concentration of unchanged nebivolol in poor metabolizers is approximately 23 times higher than in extensive metabolizers. If unchanged nebivolol and active metabolites are taken into account, the difference in peak plasma concentrations is 1.3-1.4 times. Given the differences in metabolic rates, the dose of the drug should always be adjusted depending on the individual needs of the patient: individuals with slow metabolizers may require lower doses.
In extensive metabolizers, the half-life of the enantiomers of nebivolol is on average 10 hours. In poor metabolizers, this figure is 3–5 times higher. In extensive metabolizers, the concentration of the RSSS enantiomer is slightly higher than that of the SRRR enantiomer. In extensive metabolizers, this difference is greater.
In individuals with rapid metabolizers, the half-life values of the hydroxymetabolites of both enantiomers average 24 hours, while in individuals with slow metabolizers these values are approximately 2 times greater.
Steady-state plasma levels of nebivolol are achieved within 24 hours in most patients with rapid metabolism, and of hydroxymetabolites within several days.
In plasma, both enantiomers are predominantly bound to albumin. The plasma protein binding of SRRR-nebivolol is 98.1% and that of RSSS-nebivolol is 97.9%.
One week after administration, 38% of the dose is excreted in the urine and 48% in the feces. Renal excretion of unchanged nebivolol is less than 0.5% of the dose.
Indication
Essential hypertension.
Chronic heart failure of mild to moderate severity, as an adjunct to standard treatment methods in patients aged 70 years and older.
Contraindication
– Hypersensitivity to the active substance or to any of the excipients;
– liver failure or liver dysfunction;
– acute heart failure, cardiogenic shock or episodes of decompensated heart failure requiring intravenous administration of active substances with a positive inotropic effect;
– sick sinus syndrome, including sinoatrial block;
– atrioventricular (AV) block II–III degree (without an artificial pacemaker);
– history of bronchospasm and bronchial asthma;
– untreated pheochromocytoma;
– metabolic acidosis;
– bradycardia (before the start of treatment, the heart rate is less than 60 beats/min);
– arterial hypotension (systolic blood pressure less than 90 mm Hg);
– severe peripheral circulatory disorders.
Interaction with other medicinal products and other types of interactions
Pharmacodynamic interactions
Below is general information regarding interactions with β-adrenergic antagonists.
Concomitant use is not recommended:
Class I antiarrhythmic drugs (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): the effect on atrioventricular (AV) conduction may be potentiated and the negative inotropic effect may be increased (see section "Special warnings and precautions for use").
Calcium antagonists such as verapamil/diltiazem: negative effect on contractility and AV conduction. Intravenous administration of verapamil to patients taking β-blockers may lead to significant hypotension and atrioventricular (AV) block (see section "Special warnings and precautions for use").
Centrally acting antihypertensive drugs (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine): Concomitant use of centrally acting antihypertensive drugs may lead to worsening of heart failure due to a decrease in the tone of the central sympathetic nervous system (decrease in heart rate and stroke volume, vasodilation) (see section "Special precautions for use"). With abrupt withdrawal, in particular before the end of β-blocker use, the likelihood of an increase in blood pressure increases (withdrawal syndrome).
Caution is required when combined use:
Class III antiarrhythmic drugs (amiodarone): the effect on AV conduction may be enhanced.
Halogenated volatile anesthetics: Concomitant use of β-blockers and anesthetics may suppress reflex tachycardia and increase the risk of hypotension (see section "Special warnings and precautions for use"). Abrupt withdrawal of β-blocker treatment should be avoided. If the patient is taking Nebivolol, the anesthesiologist should be informed.
Insulin and oral antidiabetic agents: although nebivolol does not affect blood glucose levels, concomitant use may mask certain symptoms of hypoglycemia (palpitations, tachycardia).
Baclofen (antispastic agent), amifostine (adjunctive agent in the treatment of anticancer drugs): when used simultaneously with antihypertensive agents, blood pressure may decrease significantly, so the dose of antihypertensive agents should be adjusted accordingly.
When used together, the following should be considered:
Digitalis glycosides: Concomitant use may increase AV conduction time. No evidence of this interaction was observed in studies. Nebivolol does not affect the kinetics of digoxin.
Dihydropyridine-type calcium antagonists (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine): concomitant use increases the risk of hypotension, and in patients with heart failure, the risk of further deterioration of ventricular pumping function.
Antipsychotics, antidepressants (tricyclic antidepressants, barbiturates and phenothiazine derivatives): concomitant use may increase the hypotensive effect (additive effect).
Nonsteroidal anti-inflammatory drugs do not affect the antihypertensive effect of nebivolol.
Sympathomimetics: Concomitant use may counteract the antihypertensive effect of β-blockers. Active substances with β-adrenergic activity may enhance the α-adrenergic activity of sympathomimetics with both α- and β-adrenergic effects (risk of hypertension, severe bradycardia and heart block).
Pharmacokinetic interactions
Concomitant use with cimetidine increases the plasma levels of nebivolol, but does not alter the clinical efficacy of nebivolol. Concomitant use with ranitidine does not affect the pharmacokinetics of nebivolol. Provided that Nebivolol is taken with meals and the antacid is taken between meals, both drugs can be administered simultaneously.
When nebivolol was combined with nicardipine, plasma concentrations of both drugs were slightly increased without changing clinical efficacy.
Concomitant use of alcohol, furosemide or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol.
Nebivolol does not affect the pharmacokinetics and pharmacodynamics of warfarin.
Application features
The following precautions apply to β-blockers in general.
Anesthesia: Continued beta-blockade reduces the risk of cardiac arrhythmias during induction of anesthesia and intubation. If beta-blockade must be discontinued in preparation for surgery, beta-blockers should be discontinued at least 24 hours beforehand.
Caution is required with certain anesthetics that cause myocardial depression. Vagal reactions in the patient can be prevented by intravenous atropine.
Cardiovascular system: In general, patients with untreated chronic heart failure (CHF) should not be given β-adrenergic blockers until their condition is stable.
β-blocker therapy should be discontinued in patients with coronary artery disease gradually, i.e. over 1–2 weeks. If necessary, it is recommended to start replacement therapy at the same time to prevent exacerbation of angina.
Beta-blockers can cause bradycardia. If the resting heart rate decreases to 50–55 beats per minute and/or the patient develops symptoms suggestive of bradycardia, a dose reduction is recommended.
β-adrenergic blockers should be used with caution in the treatment of:
- patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as exacerbation of these diseases may develop;
- patients with first-degree atrioventricular block due to the negative effect of β-adrenergic blockers on conduction;
- patients with Prinzmetal's angina due to unobstructed vasoconstriction of the coronary arteries mediated through α-adrenergic receptors: β-adrenergic receptor blockers may increase the frequency and duration of angina attacks.
The combination of nebivolol with calcium antagonists such as verapamil and diltiazem, with group I antiarrhythmics, as well as with centrally acting hypotensive agents is not recommended at all (for details, see the section "Interaction with other medicinal products and other types of interactions").
Metabolism and endocrine system. Nebivolol does not affect blood glucose levels in patients with diabetes mellitus. Despite this, caution should be exercised when using it in patients of this category, since nebivolol may mask some symptoms of hypoglycemia (tachycardia, palpitations). β-adrenergic blockers may mask the symptoms of tachycardia in hyperthyroidism. Abrupt discontinuation of therapy may exacerbate these symptoms.
Respiratory system: β-blockers should be used with caution in patients with chronic obstructive airway diseases, as airway narrowing may be exacerbated.
Other: Patients with a history of psoriasis should be prescribed β-blockers only after careful assessment of the appropriateness of such treatment.
Beta-adrenergic blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.
At the beginning of treatment of chronic heart failure with nebivolol, monitoring of the patient's condition is necessary (see also the section "Method of administration and dosage").
Treatment should not be stopped abruptly unless absolutely necessary (see also section “Method of administration and dosage”).
The medicinal product contains lactose, therefore it should not be used in patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.
Use during pregnancy or breastfeeding
Pregnancy. Nebivolol has pharmacological effects that may have adverse effects on pregnancy and/or the fetus/infant. In general, β-blockers reduce placental blood flow, which has been associated with growth retardation, intrauterine death, miscarriage and premature birth. Adverse effects (e.g. hypoglycemia and bradycardia) may occur in the fetus and newborn. If treatment with β-blockers is necessary, β1-selective β-blockers are preferable.
Breast-feeding. Animal studies have shown that nebivolol passes into breast milk. It is not known whether this substance passes into human breast milk. Most β-blockers, namely lipophilic compounds - such as nebivolol and its active metabolites - pass into breast milk, although to varying degrees. Therefore, breastfeeding is not recommended during the use of nebivolol.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect on the reaction rate when driving vehicles or using other mechanisms have not been conducted. Available data indicate that nebivolol does not affect psychomotor function. However, when driving vehicles or using other mechanisms, it should be taken into account that dizziness and fatigue may occasionally occur.
Method of administration and doses
For oral administration. Tablets can be taken with food.
Arterial hypertension.
Adult patients should take 1 tablet of Nebival (5 mg nebivolol) per day; it is advisable to always take it at the same time of day. The hypotensive effect becomes apparent after 1–2 weeks of treatment, but sometimes the optimal effect is observed only after 4 weeks.
Combination with other antihypertensive agents.
β-blockers can be used both as monotherapy and in combination with other antihypertensive drugs. Until now, an additional antihypertensive effect has only been observed with the combination of the drug Nebival (5 mg nebivolol) with 12.5–25 mg hydrochlorothiazide.
Patients with renal failure.
For patients with renal insufficiency, the recommended initial dose is 2.5 mg per day. If necessary, the daily dose can be increased to 5 mg.
Patients with liver failure.
Data on the use of the drug in patients with hepatic insufficiency or impaired liver function are limited. Therefore, the use of Nebival in such patients is contraindicated.
Elderly patients.
For patients over 65 years of age, the recommended starting dose is 2.5 mg per day. If necessary, it can be increased to 5 mg. However, due to insufficient experience with the drug in patients over 75 years of age, its use requires caution and close monitoring of such patients.
Chronic heart failure.
Treatment of chronic heart failure should begin with slow titration of the dose until the individual optimal maintenance dose is achieved. Such patients should be prescribed the drug if they have chronic heart failure without episodes of its acute decompensation within the last 6 weeks. It is recommended that the doctor has experience in the treatment of chronic heart failure. Patients using other cardiovascular drugs, including diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, should have already adjusted the dose of these drugs during the last 2 weeks before starting therapy with Nebival.
Initial dose titration should be carried out according to the following scheme, maintaining intervals of 1 to 2 weeks and focusing on the patient's tolerability of the dose: 1.25 mg nebivolol per day can be increased to 2.5 mg nebivolol per day, and then to 5 mg 1 time per day, and then to 10 mg 1 time per day. The maximum recommended dose is 10 mg nebivolol 1 time per day. At the beginning of treatment and with each dose increase, the patient should be under the supervision of an experienced physician for at least 2 hours to ensure that the clinical condition remains stable (especially blood pressure, heart rate, myocardial conduction disorders, as well as worsening symptoms of heart failure). The appearance of side effects may prevent the use of the maximum recommended dose. If necessary, the dose already reached can be gradually reduced again or returned to it again.
If symptoms of heart failure worsen or if the drug is not tolerated during the titration phase, it is recommended to first reduce the dose of nebivolol or, if necessary, immediately discontinue the drug (if severe hypotension occurs, symptoms of heart failure worsen with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia or AV block occur).
As a rule, treatment of stable chronic heart failure with nebivolol is long-term.
Nebivolol treatment should not be stopped abruptly, as this may lead to temporary worsening of heart failure. If discontinuation of the drug is necessary, the dose should be reduced gradually, reducing it by half at intervals of 1 week.
Patients with renal failure.
Since the dose is titrated to the maximum tolerated dose on an individual basis, no dose adjustment is required in mild to moderate renal impairment. There is no experience in patients with severe renal impairment (serum creatinine ≥ 250 μmol/l), therefore the use of nebivolol in such patients is not recommended.
There are only limited data on the use of the drug in patients with hepatic insufficiency. Therefore, the use of Nebivolol in these patients is contraindicated.
Elderly patients.
Since dose titration to the maximum tolerated dose is performed individually, dose adjustment is not required.
Children
The efficacy and safety of the medicinal product in children and adolescents (under 18 years of age) have not been studied. Data are not available. Therefore, use in children and adolescents (under 18 years of age) is not recommended.
Overdose
Symptoms: Symptoms of overdose with β-blockers include bradycardia, hypotension, bronchospasm and acute heart failure.
Treatment. In case of overdose or hypersensitivity reactions, the patient should be closely monitored and treated in an intensive care unit. Blood glucose levels should be monitored. Gastric lavage, activated charcoal and laxatives may prevent absorption of any drug still in the gastrointestinal tract. Mechanical ventilation may also be required. Atropine or methyltropine is recommended to reverse bradycardia or increased vagotonia. Hypotension and shock should be treated with plasma/plasma substitutes and, if necessary, catecholamines.
The β-blocking effect can be reversed by slow intravenous administration of isoprenaline hydrochloride, starting at a dose of 5 μg/min, or dobutamine, starting at a dose of 2.5 μg/min, until the desired effect is achieved. In case of resistance, isoprenaline can be combined with dopamine. If this does not give the desired effect, glucagon can be administered intravenously at a rate of 50–100 μg/kg. If necessary, the injection should be repeated within an hour and then, if necessary, an intravenous infusion of glucagon at a rate of 70 μg/kg/h. In extreme cases of bradycardia resistant to therapy, an artificial pacemaker can be connected.
Adverse reactions
Side effects in arterial hypertension and chronic heart failure are listed separately due to the differences in the pathological processes underlying these diseases.
Arterial hypertension.
Immune system disorders: angioedema, hypersensitivity.
Psychiatric: nightmares, depression.
From the nervous system: headache, dizziness, paresthesia; syncope.
On the part of the organs of vision: visual impairment.
Cardiovascular system: bradycardia, heart failure, AV conduction delay/AV block; hypotension, increased intermittent claudication.
Respiratory, thoracic and mediastinal disorders: shortness of breath; bronchospasm.
Gastrointestinal: constipation, nausea, diarrhea; dyspepsia, flatulence, vomiting.
Skin and subcutaneous tissue disorders: itching, erythematous skin rash; exacerbation of psoriasis, urticaria.
From the genitals and mammary glands: impotence.
General disorders and administration site conditions: fatigue, edema.
In addition, the following adverse reactions have been reported with some β-blockers: hallucinations, psychosis, confusion, coldness/cyanosis of the extremities, Raynaud's syndrome, dry eyes, and practolol-type ocular-mucocutaneous toxicity.
Chronic heart failure.
The most common adverse reactions reported by patients taking nebivolol were bradycardia and dizziness.
Adverse reactions that were at least potentially related to the use of the drug and were considered characteristic and significant in the treatment of chronic heart failure: worsening heart failure, orthostatic hypotension, intolerance to nebivolol, first-degree AV block, edema of the lower extremities.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister; 2 blisters in a pack.
10 tablets in a blister; 3 blisters in a pack
10 tablets in a blister; 8 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "KYIV VITAMIN FACTORY".
Location of the manufacturer and address of its place of business
04073, Ukraine, Kyiv, Kopylivska St., 38.
Website: www.vitamin.com.ua
