Nebyar®

INSTRUCTIONS for medical use of the medicinal product NEBIAR® (NEBIAR)

Composition:

Active substance: nebivolol;

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

Excipients: colloidal anhydrous silicon dioxide (anhydrous colloidal silica); magnesium stearate; sodium croscarmellose; polyethylene glycol (PEG 6000); lactose monohydrate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored, round-shaped, biconvex tablets, 9 mm in diameter, with a cross-shaped notch on one side of the tablet and the logo "N5" on the other side.

Pharmacotherapeutic group. Selective β-adrenoreceptor blockers.

ATC code C07AB12.

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:

• it is a competitive and selective β-receptor antagonist: this effect is explained by the SRRR enantiomer (d-enantiomer);
• it has mild vasodilatory properties due to interaction with L-arginine/nitric oxide.

After single and repeated administration, nebivolol reduces heart rate and blood pressure at rest and during exercise, both in individuals with normal blood pressure and in those with arterial hypertension. The antihypertensive effect is maintained during long-term treatment.

At therapeutic doses, α-adrenergic antagonism is not observed.

During short- and long-term treatment with nebivolol in patients with arterial hypertension, systemic vascular resistance is reduced. Despite the reduction 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 to other β-adrenoceptor blockers has not yet been fully elucidated.

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

In a placebo-controlled morbidity-mortality 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%, distributed as follows: LVEF <35% in 56% of patients, LVEF 35–45% in 25%, LVEF >45% in 19%), lasting on average 20 months, nebivolol as primary medication added to standard therapy significantly prolonged the time to death or hospitalization due to cardiovascular disease (primary efficacy endpoint), reducing relative risk by 14% (absolute reduction 4.2%). This risk reduction emerged after 6 months of treatment and persisted throughout the treatment period (mean duration 18 months). The effect of nebivolol was independent of age, gender, or left ventricular ejection fraction in study participants. Benefit regarding prevention of all-cause mortality compared to placebo did not reach statistical significance (absolute reduction 2.3%).

In patients treated with nebivolol, a reduction in mortality rate was observed (4.1% vs. 6.6%, relative reduction by 38%).

In vitro and in vivo animal experiments have shown that nebivolol has no intrinsic sympathomimetic activity.

In vitro and in vivo animal experiments have shown that nebivolol, at pharmacological doses, has no membrane-stabilizing effect.

In healthy volunteers, nebivolol does not significantly affect the ability to tolerate maximal physical exertion 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. Food does not affect the absorption of nebivolol; therefore, it can be taken with or without food.

Nebivolol is completely metabolized, partly forming active hydroxymetabolites. The metabolism of nebivolol occurs via aliphatic or aromatic hydroxylation, N-dealkylation, and glucuronidation; in addition, glucuronides of hydroxymetabolites are formed. The metabolism of nebivolol via hydroxylation is subject to genetically determined oxidative polymorphism dependent on CYP2D6. The oral bioavailability of nebivolol is 12% in individuals with rapid metabolism and nearly complete in those with slow metabolism. At steady state and at the same dose, the maximum plasma concentration of unchanged nebivolol in individuals with slow metabolism is approximately 23 times higher than in those with rapid metabolism. When considering the sum of unchanged drug and its active metabolites, the difference in maximum plasma concentration is 1.3 to 1.4 times. Due to differences in metabolic rates, the dose of Nebiar® should always be adjusted according to individual patient needs; therefore, individuals with slow metabolism may require lower doses.

In individuals with rapid metabolism, the mean elimination half-life of nebivolol enantiomers is approximately 10 hours. In individuals with slow metabolism, this value is 3–5 times higher. In individuals with rapid metabolism, the concentration of the RSSS-enantiomer is slightly higher than that of the SRRR-enantiomer. This difference is greater in individuals with rapid metabolism.

In individuals with rapid metabolism, the mean elimination half-life of hydroxymetabolites of both enantiomers is approximately 24 hours, while in individuals with slow metabolism, these values are approximately twice as high.

Steady-state plasma levels are achieved within 24 hours in most patients with rapid metabolism, and within several days for hydroxymetabolites.

Plasma concentration is proportional to the dose within the range of 1 to 30 mg of nebivolol. Age does not influence 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 urine and 48% in feces. Renal excretion of unchanged nebivolol is less than 0.5% of the dose.

Safety preclinical data.

Preclinical data based on standard studies of genotoxicity, reproductive toxicity, developmental toxicity, and carcinogenicity revealed no hazard to humans. Adverse effects on reproductive function were observed only at high doses several times exceeding the maximum recommended human dose (see section "Use in pregnancy or breastfeeding").

Clinical characteristics.

Indications.

Arterial hypertension

Treatment of essential arterial hypertension.

Chronic heart failure (CHF)

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

Chronic ischemic heart disease (CIHD)

Treatment of symptomatic chronic ischemic heart disease.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients;
• hepatic impairment or hepatic dysfunction;
• acute heart failure, cardiogenic shock, or episodes of heart failure decompensation requiring intravenous administration of agents with positive inotropic effect.

In addition, as with other β-blockers, Nebiar® is contraindicated in the following conditions:

• sinus node dysfunction, including sinoatrial block,
• second- or third-degree atrioventricular (AV) block (without a pacemaker);
• bronchospasm and history of bronchial asthma;
• untreated pheochromocytoma;
• metabolic acidosis;
• bradycardia (heart rate less than 60 beats per minute before treatment initiation);
• arterial hypotension (systolic blood pressure less than 90 mmHg);
• severe peripheral circulatory disorders.

Interaction with other medicinal products and other forms of interactions.

Pharmacodynamic interactions

The information below refers to general interactions associated with β-adrenoceptor blockers.

Concomitant use is not recommended:

a) with Class I antiarrhythmic agents (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone) – may enhance effects on AV conduction and increase negative inotropic effect;

b) with calcium antagonists of the verapamil/diltiazem type – negative effects on AV conduction and myocardial contractility. Intravenous administration of verapamil to patients receiving β-blockers may lead to marked arterial hypotension and AV block;

c) with centrally-acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) – may lead to worsening of heart failure due to reduced heart rate, stroke volume, and vasodilation. Abrupt withdrawal, particularly before discontinuation of β-blockers, may increase the likelihood of blood pressure elevation (withdrawal syndrome).

Use with caution when used concomitantly:

a) with Class III antiarrhythmic agents (amiodarone) – may enhance effects on AV conduction;

b) with halogenated volatile anesthetics – may suppress reflex tachycardia and increase the risk of arterial hypotension. If a patient is receiving Nebiar®, the anesthesiologist should be informed;

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

d) with baclofen (an antispastic agent) and amifostine (an adjunctive anticancer agent) – concomitant use with antihypertensive agents may lead to marked reduction in blood pressure; therefore, the dose of antihypertensive agents should be adjusted accordingly.

Consider when used concomitantly:

a) digitalis glycosides (e.g., digoxin) – AV conduction may be slowed, although clinical studies have not provided specific guidance on this interaction. Nebivolol does not affect digoxin kinetics;

b) calcium antagonists of the dihydropyridine type (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine) – increased risk of arterial hypotension; in patients with heart failure, ventricular pump function may worsen;

c) antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, phenothiazine derivatives) – antihypertensive effect may be enhanced (additive effect principle);

d) nonsteroidal anti-inflammatory drugs – do not affect the antihypertensive action of Nebiar®;

e) sympathomimetics – may counteract the antihypertensive effect of β-blockers. Substances with β-adrenergic activity may lead to unopposed α-adrenergic activity of sympathomimetics that have both α- and β-adrenergic effects (risk of arterial hypertension, severe bradycardia, and heart block).

Interactions due to the pharmacokinetics of the drug:

• since the CYP2D6 isoenzyme is involved in nebivolol metabolism, concomitant use of drugs that inhibit this enzyme (paroxetine, fluoxetine, thioridazine, quinidine) increases plasma levels of nebivolol, thereby increasing the risk of excessive bradycardia and other adverse reactions;
• cimetidine increases plasma levels of nebivolol without altering clinical efficacy. Ranitidine does not affect the pharmacokinetics of nebivolol;
• if Nebiar® is taken with food and antacids are taken between meals, these drugs can be co-administered;
• concomitant administration of nebivolol and nicardipine slightly increases plasma concentrations of both substances without affecting clinical efficacy;
• concomitant use of alcohol, furosemide, or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol;
• nebivolol does not affect the pharmacodynamics or pharmacokinetics of warfarin.

Special precautions for use.

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

Anesthesia.

Maintaining β-adrenergic blockade reduces the risk of cardiac rhythm disturbances during induction of anesthesia and intubation. When preparing for surgery, β-adrenergic blockers should be discontinued at least 24 hours prior. Caution is required when using certain anesthetics that may depress myocardial function, such as cyclopropane, ether, or trichloroethylene. Vagal reactions in patients can be prevented by intravenous administration of atropine.

Cardiovascular system.

In general, β-adrenergic blockers should not be administered to patients with untreated chronic heart failure until their condition becomes stable. Discontinuation of β-adrenergic blocker therapy in patients with ischemic heart disease should be gradual, over a period of 1–2 weeks. If necessary, to prevent disease exacerbation, concomitant initiation of treatment with a substitute medication is recommended. β-Adrenergic blockers may cause bradycardia. If resting pulse rate decreases to 50–55 beats per minute and/or symptoms indicative of bradycardia develop, the dose should be reduced. β-Adrenergic blockers should be used with caution in treating: a) patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as these conditions may worsen; 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 unopposed α-adrenergic-mediated coronary artery vasoconstriction: β-adrenergic blockers may increase the frequency and duration of angina attacks.

Combination of nebivolol with calcium antagonists of the verapamil and diltiazem type, antiarrhythmic agents of Class I, and centrally acting antihypertensive agents is generally not recommended.

Metabolism and endocrine system.

Nebiar® does not affect blood glucose levels in patients with diabetes mellitus. Nevertheless, caution is required when administering it to patients in this category, as nebivolol may mask certain signs of hypoglycemia, such as tachycardia and palpitations. β-Adrenergic blockers may mask symptoms of tachycardia in hyperthyroidism. Upon abrupt discontinuation of therapy, these symptoms may intensify.

Respiratory system.

β-Adrenergic blockers should be used with caution in patients with chronic obstructive airway diseases, as bronchoconstriction may worsen.

Other.

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

β-Adrenergic blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.

Regular monitoring of the patient is required at the beginning of chronic heart failure treatment with nebivolol. Therapy should not be abruptly discontinued unless absolutely necessary.

The product contains lactose monohydrate and therefore should not be administered to patients with hereditary galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

The pharmacological effects of nebivolol may adversely affect pregnancy, the fetus, and the newborn.

In general, β-adrenergic blockers reduce placental blood flow, which has been associated with intrauterine growth retardation, fetal death, abortion, and premature delivery. Adverse effects (e.g., hypoglycemia and bradycardia) may occur in the fetus and newborn. If treatment with β-blockers is necessary, β1-selective β-adrenergic blockers are preferred.

Nebivolol should not be used during pregnancy unless there is a clear and compelling need.

If treatment with nebivolol is necessary, monitoring of uteroplacental circulation and fetal growth should be performed. If adverse effects are confirmed, alternative treatment should be considered. Close monitoring of the fetus is required, and it should be noted that symptoms such as hypoglycemia and bradycardia may be expected during the first 3 days of life.

Breastfeeding period

Animal studies have shown that nebivolol passes into breast milk. It is unknown whether nebivolol passes into human breast milk. Studies in animals have demonstrated that nebivolol is excreted in breast milk. Most beta-blockers, particularly lipophilic compounds such as nebivolol, pass into breast milk to varying degrees. Therefore, breastfeeding is not recommended during treatment with nebivolol.

Fertility

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

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect on reaction speed when driving or operating machinery have not been conducted. Pharmacodynamic studies have shown that Nebiar® 5 mg does not affect psychomotor function. However, the possibility of dizziness and fatigue should be taken into account when driving or operating machinery.

Method of Administration and Dosage.

Dosing Regimen

Arterial Hypertension.

Adults. The dose is 1 tablet of Nebiar® (5 mg nebivolol) once daily, preferably taken at the same time each day. The antihypertensive effect becomes evident within 1–2 weeks of treatment, but in some cases optimal effect may be observed only after 4 weeks.

Combination with other antihypertensive agents.

Nebiar® can be used both as monotherapy and in combination with other antihypertensive medicinal products. To date, an additional antihypertensive effect has been observed only when combined with 12.5–25 mg hydrochlorothiazide.

Patients with renal impairment.

For patients with renal impairment, the recommended initial dose is 2.5 mg once daily. If necessary, the daily dose may be increased to 5 mg.

Patients with hepatic impairment.

Data on the use of the medicinal product in patients with hepatic impairment or impaired liver function are limited. Therefore, the use of the medicinal product in such patients is contraindicated.

Elderly patients (aged 65 years and older).

For this patient group, the recommended initial dose is 2.5 mg once daily. If necessary, the dose may be increased to 5 mg. However, due to limited experience with use in patients aged 75 years and older, administration requires caution and careful monitoring of these patients.

Chronic Heart Failure.

Treatment of chronic heart failure should begin with gradual dose titration to achieve the individual optimal maintenance dose. This medicinal product should be prescribed to patients who have chronic heart failure without episodes of acute decompensation during the preceding 6 weeks. It is recommended that the prescribing physician has experience in managing chronic heart failure. Patients receiving other cardiovascular medications, including diuretics and/or digoxin and/or angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists, should have been on stable doses of these medications for at least the previous 2 weeks before initiating therapy with Nebiar®.

Initial dose titration should follow the schedule below, with intervals of 1 to 2 weeks between dose increases, based on patient tolerance: start with 1.25 mg nebivolol once daily, increase to 2.5 mg nebivolol once daily, then to 5 mg once daily, and subsequently to 10 mg once daily. The maximum recommended dose is 10 mg nebivolol once daily. At the beginning of treatment and with each dose increase, the patient should remain under the supervision of an experienced physician for at least 2 hours to ensure clinical stability (particularly regarding blood pressure, heart rate, myocardial conduction disturbances, and worsening of heart failure symptoms). The occurrence of adverse reactions may prevent all patients from reaching the maximum recommended dose. If necessary, the achieved dose can be gradually reduced or readjusted.

In case of worsening heart failure symptoms or intolerance to the medicinal product during dose titration, the dose of nebivolol should first be reduced or, if necessary, the medicinal product should be discontinued immediately (in case of severe hypotension, worsening heart failure symptoms with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia, or atrioventricular block).

Generally, treatment of stable chronic heart failure with nebivolol is long-term.

Nebivolol treatment should not be discontinued abruptly, as this may lead to a temporary worsening of heart failure. If discontinuation is necessary, the dose should be gradually reduced by halving it every week.

Chronic Ischemic Heart Disease.

Adults. Treatment of chronic ischemic heart disease should begin with gradual dose escalation to determine the optimal maintenance dose for each patient.

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

Patients with renal impairment.

Since dose titration to the maximally tolerated dose is individualized, dose adjustment is not required in patients with mild to moderate renal impairment. There is no experience with use in patients with severe renal impairment (serum creatinine level ≥ 250 µmol/L); therefore, the use of nebivolol in such patients is not recommended.

Patients with hepatic impairment.

The use of the medicinal product in patients with hepatic impairment is contraindicated due to limited experience.

Elderly patients (aged 65 years and older).

Since dose titration to the maximally tolerated dose is individualized, dose adjustment is not required.

Method of Administration.

Oral use.

Tablets may be taken with food.

Children.

The efficacy and safety of Nebiar® in children and adolescents (under 18 years of age) have not been studied. Data are unavailable. Therefore, use in children and adolescents (under 18 years of age) is not recommended.

Overdose.

There are no reported cases of nebivolol overdose.

Symptoms.

In overdose of beta-blockers, the following symptoms may occur: bradycardia, arterial hypotension, bronchospasm, acute heart failure.

Treatment.

In case of overdose or development of hypersensitivity reactions, continuous patient monitoring and treatment in an intensive care unit are required. Blood glucose levels should be monitored. Absorption of any remaining drug in the gastrointestinal tract can be prevented by gastric lavage, administration of activated charcoal, and laxatives. Mechanical ventilation may also be necessary. For treatment of bradycardia or increased vagal tone, administration of atropine or methylatropine is recommended. Treatment of hypotension and shock should be managed with plasma/plasma substitutes and, if necessary, catecholamines.

Beta-blocking effects can be reversed by slow intravenous infusion of isoprenaline hydrochloride, starting at a dose of 5 µg/min, or dobutamine, starting at 2.5 µg/min, titrated to achieve the desired effect. In resistant cases, isoprenaline may be combined with dopamine. If the above measures are ineffective, glucagon should be administered at a dose of 50–100 µg/kg; if needed, the injection may be repeated within one hour, and, if necessary, a continuous intravenous infusion of glucagon at 70 µg/kg/hour may be initiated. In extreme cases of therapy-resistant bradycardia, a temporary pacemaker may be required.

Adverse reactions.

Adverse reactions in essential arterial hypertension and chronic heart failure are listed separately due to differences in the underlying pathological processes associated with these conditions.

Essential arterial hypertension.

In addition, the following adverse reactions have been reported with some β-adrenoblockers: hallucinations, psychoses, confusion, cold extremities/cyanosis, Raynaud's syndrome, dry eyes, and ocular-mucocutaneous toxicity of the practolol type.

Chronic heart failure.

Information on adverse reactions in patients with heart failure was obtained from placebo-controlled clinical trials in which 1067 patients received nebivolol and 1061 patients received placebo. In this study, a total of 449 patients taking nebivolol (42.1%) and 334 patients (31.5%) taking placebo reported adverse reactions possibly related to the study drug. The most commonly reported adverse reactions in patients receiving nebivolol were bradycardia and dizziness, occurring in approximately 11% of patients. The corresponding incidence in patients receiving placebo was approximately 2% and 7%, respectively.

Adverse reactions at least potentially related to the study drug and considered characteristic and significant in the treatment of chronic heart failure:

• Worsening of heart failure occurred in 5.8% of patients receiving nebivolol and in 5.2% of patients receiving placebo;
• Orthostatic hypotension occurred in 2.1% of patients receiving nebivolol and in 1.0% 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;
• Lower limb edema occurred in 1.0% of patients receiving nebivolol and in 0.2% of patients receiving placebo.

Chronic ischemic heart disease.

Data on adverse reactions in patients with IHD were obtained through a specific analysis of data from the same clinical trial described for CHF. It is reasonable to assume that the safety and tolerability results obtained in patients with CHF are also applicable to patients with IHD.

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years from the date of manufacture of the bulk product.

Storage conditions.

In the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets in a blister. 3 blisters containing 10 tablets each, together with the instruction for medical use, are packed in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat" (processing of bulk product manufactured by Actavis Limited, Malta, and by Balkanpharma-Dupnitsa AD, Bulgaria).

Manufacturer's address and location of its operations.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.

Marketing Authorization Holder. ARTIUM LTD LLC.

Address of the Marketing Authorization Holder and/or its representative.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.