Nebilet tablets 5 mg blister No. 28

Instructions Nebilet tablets 5 mg blister No. 28

Composition

active ingredient: nebivolol;

1 tablet contains nebivolol (as nebivolol hydrochloride) 5 mg;

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

Dosage form

Pills.

Main physicochemical properties: round biconvex tablets of almost white color with a cross-shaped notch for separation on one side.

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 patients with arterial hypertension, systemic vascular resistance decreases. Despite the decrease in heart rate, the decrease 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 with other β-adrenergic blockers is not yet fully understood.

In patients with hypertension, nebivolol increases the vascular response to acetylcholine (ACh) mediated by nitric oxide; in patients with endothelial dysfunction, this response is reduced.

In a placebo-controlled mortality-morbidity study involving 2128 patients aged ≥ 70 years (mean age 75.2 years) with stable chronic heart failure with or without reduced left ventricular ejection fraction (LVEF) (mean LVEF 36 ± 12.3% with the following distribution: LVEF less than 35% in 56% of patients, LVEF 35–45% in 25% of patients, LVEF greater than 45% in 19% of patients), lasting an average of 20 months, nebivolol as the main drug in the composition of standard therapy significantly prolonged the time to death or hospitalization due to cardiovascular pathology (primary efficacy endpoint) with a relative risk reduction of 14% (absolute reduction - 4.2%). This risk reduction developed after 6 months of treatment and was maintained throughout the treatment period (median duration 18 months). The effect of nebivolol was independent of age, gender or left ventricular ejection fraction of the study participants. The benefit in preventing all-cause mortality compared with placebo did not reach statistical significance (absolute reduction 2.3%).

In patients treated with nebivolol, there was a reduction in the incidence of sudden death (4.1% versus 6.6%, a relative reduction of 38%).

In vitro and in vivo animal experiments have shown that nebivolol does not have its own sympathomimetic activity.

In vitro and in vivo animal experiments have shown that nebivolol at pharmacological doses does not have a stabilizing effect on membranes.

In healthy volunteers, nebivolol has no significant effect on maximal exercise tolerance or endurance.

Available preclinical and clinical data have not shown that nebivolol negatively affects 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 with or without food.

In extensive metabolizers, the half-life of the enantiomers of nebivolol is on average 10 hours. In poor metabolizers, this value 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 are reached within 24 hours in most patients with rapid metabolism, and within several days for hydroxymetabolites.

Plasma concentrations, which range from 1 to 30 mg of nebivolol, are dose-proportional. Age does not affect the pharmacokinetics of nebivolol.

In plasma, both enantiomers are predominantly bound to albumin. Plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol.

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.

Preclinical safety data.

Preclinical data reveal no special hazard for humans based on conventional studies of genotoxicity, reproductive toxicity, developmental toxicity and carcinogenicity. Adverse effects on reproductive function were observed only at high doses, several times the maximum recommended human dose (see section "Use during pregnancy and lactation").

Indication

Arterial hypertension

Treatment of essential arterial hypertension.

Chronic heart failure (CHF)

Treatment of mild to moderate chronic heart failure as an adjunct to standard treatment methods in patients aged 70 years and older.

Chronic ischemic heart disease (CIHD)

Treatment of symptomatic, chronic ischemic heart disease.

Contraindication

Hypersensitivity to the active substance or to any of the excipients listed in the "Composition" section;

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.

In addition, like other β-blockers, Nebilet® is contraindicated in:

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 < 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.

Joint use is not recommended:

Class I antiarrhythmic drugs (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): the effect on atrioventricular conduction may be enhanced and the negative inotropic effect may increase (see section "Special warnings and precautions for use").

Calcium antagonists of the verapamil/diltiazem type: negative effect on contractility and atrioventricular conduction. Intravenous administration of verapamil to patients taking β-blockers may lead to significant arterial hypotension and atrioventricular block (see section "Special instructions").

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"). In case of abrupt withdrawal, in particular before the end of β-blocker use, the likelihood of an increase in blood pressure may increase (withdrawal syndrome).

Caution is required when combined use:

Class III antiarrhythmic drugs (amiodarone): the effect on atrioventricular conduction may be enhanced.

Halogenated volatile anaesthetics: Concomitant use of β-blockers and anaesthetics may suppress reflex tachycardia and increase the risk of hypotension (see section 4.4). As a general rule, avoid abrupt withdrawal of β-blocker treatment. If the patient is taking Nebilet, 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).

When used together, the following should be considered:

Digitalis glycosides: Concomitant use may increase atrioventricular conduction time. No evidence of this interaction was observed in clinical studies. Nebivolol does not affect the kinetics of digoxin.

Dihydropyridine-type calcium antagonists (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine): concomitant use may increase the risk of hypotension, and in patients with heart failure an increased risk of further deterioration of ventricular pumping function cannot be excluded.

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 developing arterial hypertension, severe bradycardia and heart block).

Pharmacokinetic interactions.

Since the CYP2D6 isoenzyme is involved in the metabolism of nebivolol, the combined use of drugs that inhibit this enzyme (namely paroxetine, fluoxetine, thioridazine, quinidine) may increase the level of nebivolol in the blood plasma and, thus, increase the risk of severe bradycardia and adverse reactions.

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 warnings and precautions are common to β-blockers.

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.

As a rule, 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:

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 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 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 patients with diabetes. However, caution should be exercised when using it in this category of patients, as 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.

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

Other.

Patients with a history of psoriasis should be prescribed β-blockers only after careful consideration.

At the beginning of treatment with nebivolol for chronic heart failure, regular monitoring of the patient's condition is necessary. For information on the method of administration and dosage, see the section "Method of administration and dosage".

Treatment should not be stopped abruptly unless absolutely necessary (see section 4.2). For further information, see section 4.2.

The medicinal product contains lactose. Nebilet® should not be used in patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

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 harmful 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 generally be expected within the first three days.

Breastfeeding period.

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. A risk to the newborn/infants cannot be excluded. Therefore, mothers receiving nebivolol should not breast-feed.

Fertility

Nebivolol did not affect fertility in rats, except at doses several times the maximum recommended human dose, when adverse effects were observed on the reproductive organs of male and female rats and mice. The effect of nebivolol on human fertility is unknown.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect on the reaction rate when driving vehicles or other mechanisms have not been conducted. Pharmacodynamic studies have shown that Nebilet 5 mg does not affect psychomotor function. However, the possibility of dizziness and fatigue should be taken into account when driving vehicles or other mechanisms.

Method of administration and doses

Dosage regimen

Arterial hypertension.

Adults:

The dose is 1 tablet (5 mg nebivolol) per day; it is advisable to take it at the same time each day. The antihypertensive 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 Nebilet® 5 mg with 12.5–25 mg of 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 Nebilet® 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 use of the drug in patients over 75 years of age, its use requires caution and close supervision of such patients.

Chronic heart failure.

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 of heart failure symptoms). The appearance of side effects may prevent treatment with the maximum recommended dose in all patients. 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 atrioventricular 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.

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 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.

Patients with liver failure.

There are only limited data on the use of the drug in patients with hepatic insufficiency. Therefore, the use of Nebilet® in these patients is contraindicated.

Elderly patients.

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

Method of application.

Oral use.

The tablets can be taken with food.

Children

The efficacy and safety of Nebilet® 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

There are no data regarding overdose of the drug Nebilet®.

Symptoms.

Symptoms of β-blocker overdose: 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 lead to 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.

Side effects

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.

Adverse reactions, which were mostly mild to moderate in severity, are listed in the table below; they are classified according to organ system and frequency of occurrence:

Often

(≥ 1/100 to <1/10)

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.

Adverse reactions in heart failure patients were reported in placebo-controlled clinical trials in which 1067 patients received nebivolol and 1061 patients received placebo. In this study, a total of 449 patients (42.1%) on nebivolol and 334 (31.5%) on placebo reported adverse reactions that were possibly related to the drug. The most common adverse reactions reported by patients on nebivolol were bradycardia and dizziness, which occurred in approximately 11% of patients. The corresponding incidences among patients on placebo were approximately 2% and 7%, respectively.

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

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

Orthostatic hypotension was observed in 2.1% of patients taking nebivolol, and in

1% of patients receiving placebo;

Drug intolerance was observed in 1.6% of patients taking nebivolol and in 0.8% of patients taking placebo;

First-degree AV block was observed in 1.4% of patients receiving nebivolol, and in

0.9% of patients receiving placebo;

Lower limb edema was reported in 1.0% 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 of suspected adverse reactions

Reporting suspected adverse reactions during the post-marketing period of a medicinal product is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Expiration date

3 years.

Do not use the medicine after the expiry date stated on the packaging.

Storage conditions

No special storage conditions are required. Keep the medicine out of the reach of children.

Packaging

7 tablets in a blister, 1 blister in a cardboard box; 14 tablets in a blister, 1 or 2 blisters in a cardboard box; 10 tablets in a blister, 9 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

BERLIN-CHEMIE AG / BERLIN-CHEMIE AG.

Location of the manufacturer and address of its place of business

Glienicker Weg 125, 12489 Berlin, Germany.

Applicant

Menarini International Operations Luxembourg SA / Menarini International Operations Luxembourg SA

Applicant's location

1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg/1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.