Instructions Nebival tablets 5 mg blister No. 80
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 properties:
Due to the D-enantiomer, nebivolol is a competitive and selective β1-adrenoceptor blocker; due to the L-enantiomer, it has mild vasodilating properties due to metabolic interaction with L-arginine/nitric oxide (NO).
With single and repeated administration of nebivolol, the heart rate at rest and during exercise is reduced 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 is reduced. Despite the reduction in heart rate, the reduction in cardiac output at rest and during exercise is limited due to the increase in stroke volume. The clinical significance of this hemodynamic difference compared to other β-adrenergic blockers is not yet fully understood. In hypertensive patients, nebivolol increases the vascular response to acetylcholine mediated by nitric oxide; in patients with endothelial dysfunction, this response is reduced. The use of nebivolol as an adjunct to standard therapy for chronic heart failure with or without reduced left ventricular ejection fraction significantly prolonged the time to death or cardiovascular-related hospitalization. The effect of nebivolol was independent of age, gender, or left ventricular ejection fraction. A reduced incidence of sudden death was observed in patients receiving nebivolol.
Pharmacokinetics
After oral administration, both enantiomers of nebivolol are rapidly absorbed. The absorption of nebivolol is not affected by food, so it can be used regardless of food intake. Nebivolol is metabolized in the liver, in particular with the formation of active hydroxymetabolites. The metabolism of nebivolol by hydroxylation is subject to a genetic oxidative polymorphism that depends on CYP2D6. When a steady state is reached and at the same dose, the maximum plasma concentration of unchanged nebivolol in poor metabolizers is approximately 23 times higher than in extensive metabolizers. In extensive metabolizers, the half-lives of the hydroxymetabolites of both enantiomers average 24 hours, and in poor metabolizers these values are approximately 2 times higher.
The bioavailability of orally administered nebivolol is on average 12% in fast metabolisers and almost complete in slow metabolisers. Based on the difference in metabolic rates, the dosage of Nebivolol should be adjusted to the individual needs of the patient; slow metabolisers require lower doses. In fast metabolisers, the plasma half-life of the enantiomers of nebivolol is on average 10 hours, while in slow metabolisers these values are 3-5 times longer. Plasma concentrations are dose-proportional and range from 1 to 30 mg of nebivolol. Age does not affect the pharmacokinetics of nebivolol. One week after administration, 38% of the dose is excreted in the urine and 48% in the feces. Urinary excretion of unchanged nebivolol is less than 0.5% of the dose.
Indication
Essential arterial hypertension; chronic heart failure of mild or moderate severity, as an adjunct to standard treatment methods in patients aged 70 years and older.
Contraindication
Hypersensitivity to the active substance or to other components of the drug; hepatic failure or liver function impairment; 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, AV block II-III degree (without an artificial pacemaker); bronchospasm and bronchial asthma in history; 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; simultaneous use with floctafenine and sultopride.
Interaction with other medicinal products and other types of interactions
Concomitant use is not recommended:
a) with class I antiarrhythmic drugs (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone) - the effect on AV conduction may be enhanced and the negative isotropic effect may increase;
b) with calcium antagonists such as verapamil/diltiazem – negative effect on AV conduction and myocardial contractility. Intravenous administration of verapamil to patients taking β-blockers can lead to significant arterial hypotension and AV block;
c) with centrally acting antihypertensive drugs (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) - may lead to worsening of heart failure due to a decrease in heart rate, stroke volume and vasodilation. With sudden withdrawal, in particular before the end of the use of β-blockers, the likelihood of an increase in blood pressure may increase (withdrawal syndrome).
Caution should be exercised when using simultaneously:
a) with class III antiarrhythmic drugs (amiodarone) - possible increased effect on AV conduction;
b) with halogenated volatile anesthetics - may suppress reflex tachycardia and increase the risk of arterial hypotension. If the patient uses Nebival, the anesthesiologist should be informed about this;
c) with insulin and oral antidiabetic agents - although Nebival does not affect blood glucose levels, it can still mask symptoms of hypoglycemia such as tachycardia and palpitations;
d) with baclofen (antispastic agent), amifostine (additional antitumor agent) - their simultaneous use with antihypertensive agents can lead to a significant decrease in blood pressure, therefore the dose of antihypertensive agents should be adjusted accordingly).
When used together, the following should be considered:
a) digitalis glycosides – AV conduction is slowed down, but there are no indications of this interaction among the available data. Nebivolol does not affect the kinetics of digoxin;
b) dihydropyridine-type calcium antagonists (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine) - the risk of arterial hypotension increases, and in patients with heart failure, deterioration of ventricular pumping function is possible;
c) antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, phenothiazine derivatives) – antihypertensive effect may increase (principle of additive effects);
d) nonsteroidal anti-inflammatory drugs - do not affect the antihypertensive effect of the drug Nebival;
e) sympathomimetics – may counteract the antihypertensive effect of β-blockers. Active substances with β-adrenergic action may lead to unhindered α-adrenergic activity of sympathomimetics with the presence of both α- and β-adrenergic effects (risk of developing arterial hypertension, severe bradycardia and heart block).
Interactions due to the pharmacokinetics of the drug:
Since the CYP2D6 isoenzyme is involved in the metabolism of nebivolol, the concomitant use of drugs that inhibit this enzyme (paroxetine, fluoxetine, thioridazine, quinidine) increases the level of nebivolol in the blood plasma and thus increases the risk of excessive bradycardia and other adverse reactions; cimetidine increases the level of nebivolol in the blood plasma, but without changing the clinical efficacy. Ranitidine does not affect the pharmacokinetics of nebivolol; provided that Nebivolol is taken during meals, and the antacid is taken between meals, these drugs can be prescribed together; with the concomitant use of nebivolol and nicardipine, the concentrations of both substances in the blood plasma increased slightly without changing the clinical efficacy;
e) simultaneous use of alcohol, furosemide or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol;
Nebivolol does not affect the pharmacodynamics and pharmacokinetics of warfarin.
Application features
Maintenance of β-blockade reduces the risk of cardiac arrhythmias during induction of anesthesia and intubation. In preparation for surgery, β-blockers should be discontinued for at least 24 hours. Caution is required when using certain anesthetics that cause myocardial depression, such as cyclopropane, ether, or trichloroethylene. Vagal reactions in the patient can be prevented by intravenous atropine.
As a rule, patients with untreated chronic heart failure should not be prescribed β-blockers until their condition is stable. β-blocker therapy should be discontinued in patients with ischemic heart disease gradually, i.e. over 1-2 weeks. If necessary, to prevent exacerbation of the disease, it is recommended to start treatment with a replacement drug at the same time. β-blockers can cause bradycardia. If the resting heart rate decreases to 50-55 beats per minute and/or the patient develops symptoms indicating bradycardia, it is recommended to reduce the dose. β-blockers should be used with caution in the treatment of: a) patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as exacerbation of these diseases may develop; b) patients with first-degree atrioventricular block due to the negative effect of β-adrenergic blockers on conduction; c) patients with Prinzmetal's angina due to unobstructed vasoconstriction of the coronary arteries mediated through α-adrenergic blockers: β-adrenergic 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 antiarrhythmic drugs, as well as with centrally acting antihypertensive drugs is not recommended.
Nebivolol does not affect the blood glucose levels of patients with diabetes. However, caution should be exercised when using it to treat patients in this category, as nebivolol may mask some signs of hypoglycemia, such as tachycardia and palpitations. β-adrenergic blockers may mask the symptoms of tachycardia in hyperthyroidism. These symptoms may worsen if therapy is abruptly discontinued.
In patients with obstructive airway diseases, β-adrenergic blockers should be used with caution as airway constriction may be exacerbated.
At the beginning of treatment with nebivolol for chronic heart failure, regular monitoring of the patient is necessary. Treatment should not be stopped abruptly unless absolutely necessary.
Patients with a history of psoriasis should be prescribed β-blockers only after careful consideration. β-blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.
The medicinal product contains lactose, therefore it should not be used in patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.
Ability to influence reaction speed when driving vehicles or other mechanisms
No relevant studies have been conducted. Available data suggest that nebivolol does not affect psychomotor function. However, it should be noted that dizziness and fatigue may occasionally occur.
Use during pregnancy or breastfeeding
The pharmacological effects of nebivolol may adversely affect the course of pregnancy, the fetus and the infant, so it should be used only when the benefit of use outweighs the potential risk to the fetus. If treatment with nebivolol is necessary, monitoring of uteroplacental blood flow and fetal growth should be carried out. If negative effects are confirmed, treatment with alternative drugs should be considered. The infant should be carefully monitored and it should be borne in mind that symptoms such as hypoglycemia and bradycardia can be expected during the first 3 days. Breastfeeding is not recommended during treatment with nebivolol.
Method of administration and doses
Essential hypertension
Adult patients should take 1 tablet of the drug Nebival (5 mg nebivolol) per day, if possible at the same time. The drug can be taken with meals. 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. Nebival can be used both as monotherapy and in combination with other antihypertensive agents. To date, an additional hypotensive effect has only been observed when it is combined with 12.5-25 mg of hydrochlorothiazide.
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.
Elderly patients (aged 65 years and over). For this group of patients, the recommended initial dose is 2.5 mg per day, which can be increased to 5 mg if necessary. Due to insufficient experience with the drug in patients aged 75 years and over, its use requires caution and close monitoring.
Chronic heart failure
Treatment of chronic heart failure should be initiated by slow titration of the dose until the individual optimal maintenance dose is achieved. Such patients should be prescribed the drug if chronic heart failure is observed without episodes of its acute decompensation within the last 6 weeks. The physician should have experience in the treatment of heart failure. Patients using other cardiovascular drugs (diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) should have already had their dose of these drugs adjusted during the last 2 weeks before starting treatment with Nebivolol. The 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 of nebivolol per day can be increased to 5 mg per day, and subsequently to 10 mg 1 time per day. The maximum recommended dose is 10 mg per day. At the beginning of treatment and at 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 disturbances, and worsening of heart failure symptoms). The occurrence of adverse reactions may mean that not all patients can be treated with the highest recommended doses. If necessary, the dose already reached can be gradually reduced again or returned to it again. If the symptoms of heart failure worsen or the drug is not tolerated during the titration phase, it is recommended to first reduce the dose of nebivolol or, if necessary, immediately cancel the drug (if severe hypotension occurs, worsening of heart failure symptoms with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia or AV block occurs). Nebivolol treatment should not be stopped abruptly, as this may lead to worsening of heart failure symptoms. If discontinuation of the drug is necessary, the frequency of administration should be gradually reduced to 2 times a week. As a rule, treatment of chronic heart failure with nebivolol is long-term.
Patients with renal insufficiency. Since the dose is titrated to the maximum tolerated dose on an individual basis, no dose adjustment is required in mild to moderate renal insufficiency. There is no experience in patients with severe renal insufficiency (serum creatinine ≥ 250 μmol/l), therefore the use of nebivolol in such patients is not recommended.
Patients with hepatic impairment: Nebivolol is contraindicated in patients with hepatic impairment due to limited experience.
Children
No studies have been conducted on the use of the drug in children and adolescents, therefore the drug is not recommended for this age group.
Overdose
Symptoms: Overdose of β-blockers may cause: bradycardia, hypotension, bronchospasm, acute heart failure.
Treatment. Gastric lavage, administration of activated charcoal and laxatives. Artificial ventilation of the lungs may also be necessary. Monitoring of blood glucose levels is recommended. If necessary, intensive therapy is performed in a hospital setting: for bradycardia and increased vagotonia - administration of atropine or methylatropine, for hypotension and shock - intravenous administration of plasma substitutes and catecholamines. The beta-blocking effect can be stopped 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 expected effect is achieved. In resistant cases, isoprenaline can be combined with dopamine. If the above measures do not help, glucagon should be administered at a rate of 50-100 mcg/kg, if necessary - the injection can be repeated within an hour and, if necessary, an intravenous infusion of glucagon at a rate of 70 mcg/kg/h should be performed. In extreme cases, artificial ventilation of the lungs should be performed and an artificial pacemaker should be connected.
Adverse reactions
Adverse reactions in essential hypertension and chronic heart failure are listed separately due to the differences in the pathological processes underlying these diseases.
Essential 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.
Gastrointestinal: constipation, nausea, diarrhea; dyspepsia, flatulence, vomiting.
Skin: itching, erythematous skin rash; exacerbation of psoriasis.
From the genitals: impotence.
General disorders: increased 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 propranolol-like toxicity.
Chronic heart failure
The most common adverse reactions reported by patients receiving nebivolol were bradycardia and dizziness.
Adverse reactions that are at least potentially related to the use of the drug and that 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; 8 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "KYIV VITAMIN FACTORY".
Location of the manufacturer and its business address
04073, Ukraine, Kyiv, Kopylivska St., 38.
