Nebivolol-Darnitsa tablets 5 mg No. 28

Instructions for Nebivolol-Darnitsa tablets 5 mg No. 28

Composition

active ingredient: nebivolol;

1 tablet contains nebivolol hydrochloride, equivalent to nebivolol 5 mg;

Excipients: hypromellose, polysorbate 80; lactose monohydrate; microcrystalline cellulose; corn starch; croscarmellose sodium; colloidal anhydrous silicon dioxide; magnesium stearate.

Dosage form

Pills.

Main physicochemical properties: white or almost white tablets, biconvex, with two perpendicular dividing lines.

Pharmacotherapeutic group

Selective β-adrenergic blockers.

ATX 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:

– thanks to the D-enantiomer, nebivolol is a competitive and selective blocker of β1-adrenoreceptors;

– due to the L-enantiomer, it has mild vasodilating properties due to metabolic interaction with L-arginine/nitric oxide (NO).

With single and repeated use of nebivolol, heart rate and blood pressure at rest and during exercise are 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 or long-term treatment with nebivolol in patients with hypertension, systemic vascular resistance is reduced. Despite the decrease in heart rate, the decrease in cardiac output at rest and during exercise is limited due to an increase in stroke volume. The clinical significance of this hemodynamic difference, compared with other β-adrenergic blockers, is not yet sufficiently studied. In patients with hypertension, nebivolol increases the vascular response to acetylcholine, mediated by nitric oxide; in patients with endothelial dysfunction, this response is reduced.

In a placebo-controlled study of 2128 patients ≥70 years of age (mean age 75.2 years) with stable chronic heart failure with or without reduced left ventricular ejection fraction, nebivolol as an add-on to standard therapy significantly prolonged the time to death or cardiovascular-related hospitalization. The effect of nebivolol was independent of age, gender, or left ventricular ejection fraction in the study participants. A reduction in the incidence of sudden death was observed in patients receiving nebivolol.

According to available preclinical and clinical data, nebivolol does not have a negative effect on erectile function in patients with hypertension.

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 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-life of the hydroxymetabolites of both enantiomers is on 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 extensive metabolisers and almost complete in poor metabolisers. Plasma concentrations, which range from 1 to 30 mg of nebivolol, are dose-proportional. 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 faeces. Urinary 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.

Treatment of symptomatic, chronic ischemic heart disease.

Contraindication

– Hypersensitivity to the active substance or to other components of the medicinal product;

– liver 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.

In addition, like other β-blockers, the drug is contraindicated in the following diseases:

– sick sinus syndrome, including sinoatrial block, atrioventricular block (AV block) of the II-III degree (without an artificial pacemaker);

– history of bronchospasm and bronchial asthma;

– untreated pheochromocytoma;

– metabolic acidosis;

– arterial hypotension (systolic blood pressure (BP) – less than 90 mm Hg);

– severe peripheral circulatory disorders.

Interaction with other medicinal products and other types of interactions

Pharmacodynamic interactions

Concomitant use is not recommended:

– with class I antiarrhythmic drugs (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone), as the effect on AV conduction may be enhanced and the negative inotropic effect may increase;

– 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;

– 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 (withdrawal syndrome) may increase.

Caution should be exercised when using the following medicines at the same time:

– with class III antiarrhythmic drugs (amiodarone) – the effect on

AV conduction;

– with halogenated volatile anesthetics – may suppress reflex tachycardia and increase the risk of arterial hypotension. According to general recommendations, sudden withdrawal of β-blocker treatment should be avoided. If the patient is using nebivolol, the anesthesiologist should be informed;

– with insulin and oral antidiabetic agents – although nebivolol does not affect blood glucose levels, it may mask symptoms of hypoglycemia such as tachycardia and palpitations;

– with baclofen (antispastic agent), amifostine (additional antitumor agent) – their simultaneous use with antihypertensive agents can lead to a significant decrease in blood pressure, so the dose of antihypertensive agents must be adjusted.

When used together, the following should be considered:

– digitalis glycosides – AV conduction is slowed down, however, during clinical studies there were no indications of this interaction; nebivolol does not affect the kinetics of digoxin;

– dihydropyridine-type calcium antagonists (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine) – the risk of arterial hypotension increases, and in patients with heart failure, ventricular pumping function may deteriorate;

– antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, phenothiazine derivatives) – antihypertensive effect may be increased (principle of additive effects);

– nonsteroidal anti-inflammatory drugs – do not affect the antihypertensive effect of nebivolol;

– 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 joint 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 blood plasma, but without changing the clinical efficacy;

– ranitidine does not affect the pharmacokinetics of nebivolol;

– provided that nebivolol is taken with meals and the antacid is taken between meals, these medicines can be prescribed together;

– with simultaneous use of nebivolol and nicardipine, the concentrations of both drugs in the blood plasma slightly increased without changing the clinical efficacy;

– simultaneous use of alcohol and furosemide or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol;

– nebivolol does not affect the pharmacodynamics and pharmacokinetics of warfarin.

Application features

The following warnings and precautions are common to β-adrenergic blockers.

Anesthesia.

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.

In general, patients with untreated chronic heart failure should not be given 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 angina, 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 suggestive of bradycardia, the dose should be reduced.

β-adrenergic 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 AV 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 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 antihypertensives, is not recommended at all (for detailed information, 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 diabetic patients. However, caution should be exercised when using it in this category of patients, 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.

Respiratory system.

In patients with obstructive airway diseases, β-adrenergic blockers should be used with caution as airway constriction may be exacerbated.

Other.

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.

Excipients.

The medicine contains lactose monohydrate, so it should not be taken by patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

For information on the method of administration and dosage, see the section “Method of administration and dosage”.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.

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.

Nebivolol should not be used during pregnancy unless clearly necessary. If treatment with nebivolol is considered necessary, uteroplacental circulation and foetal growth should be monitored. If adverse effects on pregnancy or foetus are observed, alternative treatment should be considered. The newborn infant should be closely monitored. Symptoms of hypoglycaemia and bradycardia can be expected during the first

3 days.

Breastfeeding period.

Animal studies have shown that nebivolol passes into animal 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

No relevant studies have been conducted. Pharmacokinetic studies have shown that nebivolol does not affect psychomotor function. However, it should be noted that dizziness and fatigue may occasionally occur.

Method of administration and doses

Dosage regimen

For oral administration. Swallow the tablets with sufficient liquid (e.g. 1 glass of water). Take regardless of meals.

Essential hypertension

Combination with other antihypertensive agents.

Nebivolol can be used as monotherapy or 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 failure.

The recommended starting dose is 2.5 mg per day. If necessary, the daily dose can be increased to 5 mg.

Patients with liver failure.

Experience with the drug in such patients is limited, therefore nebivolol is contraindicated.

Elderly patients (aged 65 and over).

For this group of patients, the recommended initial dose is 2.5 mg per day, if necessary it can be increased to 5 mg. Due to insufficient experience with the use of the drug in patients over 75 years of age, its use requires caution and close supervision of such patients.

Chronic heart failure

Treatment of chronic heart failure should be initiated with slow titration of the dose until the individual optimal maintenance dose is reached. Such patients should be prescribed the drug if chronic heart failure is observed without episodes of its acute decompensation within the last 6 weeks. It is recommended that the physician has experience in the treatment of heart failure. Patients taking other cardiovascular drugs (diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) should have already had the dose of this drug adjusted for the last 2 weeks before starting treatment with nebivolol. The initial dose should be administered 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, which can be increased to 2.5 mg per day, then to 5 mg per day, and subsequently to 10 mg once a day. The maximum recommended dose is 10 mg 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, and worsening of heart failure symptoms). The appearance of adverse reactions in the patient indicates that they cannot be treated with the highest recommended doses. 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). Usually, treatment of 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 2 times with an interval of 1 week.

Chronic ischemic heart disease.

Adults

Treatment of chronic coronary heart disease should begin with a gradual increase in dose until the optimal maintenance dose is determined for each patient.

The initial dose should be increased every 1–2 weeks, depending on tolerability, from 1.25 mg nebivolol to 2.5 mg nebivolol once daily, then to 5 mg once daily, and then to 10 mg once daily. The maximum recommended dose is 10 mg nebivolol once daily. Data for special patient groups apply to patients with both CHF and CKD.

Patients with renal failure.

Since the dose is titrated to the maximum tolerated dose, no dose adjustment is required in patients with 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.

Patients with liver failure.

There are limited data on the use of nebivolol in patients with hepatic impairment, therefore the use of this drug in these patients is contraindicated.

Elderly patients.

Since dose titration to the maximum tolerated dose is performed individually, dose adjustment is not required.

Children

Studies on the efficacy and safety of nebivolol in children have not been conducted, therefore the use of the drug is not recommended for this age group.

Overdose

No data are available regarding overdose with nebivolol.

Treatment of overdose. Gastric lavage, administration of activated charcoal and laxatives are necessary. Artificial ventilation of the lungs may also be required. Monitoring of blood glucose levels is recommended. In case of overdose or hypersensitivity, careful medical supervision of the patient is necessary and intensive therapy should be carried out in a hospital setting: for bradycardia and increased vagotonia - administration of atropine or methylatropine, for arterial hypotension and shock - intravenous administration of plasma substitutes and catecholamines. The β-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 refractory 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/hour. In extreme cases, when bradycardia is not amenable to treatment, it may be necessary to connect an artificial pacemaker.

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

Adverse reactions were mostly mild to moderate in severity (listed in the table below); they are classified according to system organ class and frequency of occurrence.

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 oculomucocutaneous toxicity.

Chronic heart failure

Information on adverse reactions in patients with heart failure was obtained during placebo-controlled clinical trials in which 1067 patients received nebivolol and

1061 patients - placebo. In this study, a total of 449 patients taking nebivolol (42.1%) and 334 (31.5%) patients taking placebo reported adverse reactions that were possibly related to the drug. The most common adverse reactions reported by patients taking nebivolol were bradycardia and dizziness (occurring in approximately 11% of patients). The corresponding incidence among patients taking placebo was approximately 2% and 7%, respectively.

The following adverse reactions have been reported, which were at least potentially related to the use of nebivolol and which were considered characteristic and significant in the treatment of chronic heart failure:

– worsening of heart failure was observed in 5.8% of patients receiving nebivolol and in 5.2% of patients receiving placebo;

– orthostatic hypotension – in 2.1% of patients receiving nebivolol and in 1% of patients receiving placebo;

– drug intolerance was observed in 1.6% of patients receiving nebivolol and in 0.8% of patients receiving placebo;

– First-degree AV block was observed in 1.4% of patients receiving nebivolol and in 0.9% of patients receiving placebo;

– edema of the lower extremities – in 1% of patients receiving nebivolol and in 0.2% of patients receiving placebo.

Chronic ischemic heart disease.

The adverse reaction data in patients with CHF were obtained by a special analysis of data from the same clinical study as described for CHF. It can be reasonably assumed that the safety and tolerability results of nebivolol obtained in patients with CHF are also applicable to patients with CHF.

Reporting suspected adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at https://aisf.dec.gov.ua.

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

14 tablets in a contour blister pack; 2 contour blister packs in a pack.

Vacation category

According to the recipe.

Producer

PrJSC "Pharmaceutical Company "Darnitsa".

Location of the manufacturer and address of its place of business.

Ukraine, 02093, Kyiv, Boryspilska St., 13.