Nebinorm

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEBINORM (NEBINORM)

Composition:

Active substance: nebivolol;

One tablet contains nebivolol hydrochloride equivalent to 5 mg of nebivolol;

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

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white, round, biconvex tablets.

Pharmacotherapeutic group.

Beta-adrenoreceptor blockers. Selective beta-adrenoreceptor blockers. Nebivolol. 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 actions:

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

Single and repeated doses of nebivolol reduce heart rate and arterial 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-term 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, which is reduced in patients with endothelial dysfunction.

In a placebo-controlled morbidity-mortality study involving 2128 patients aged ≥70 years (mean age 75.2 years) with stable chronic heart failure (CHF), 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% of patients, LVEF >45% in 19% of patients), lasting on average 20 months, nebivolol as an add-on therapy to standard treatment 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 developed after 6 months of treatment and persisted throughout the treatment period (mean duration – 18 months). The effect of nebivolol was independent of age, sex, or LVEF value. The benefit in preventing 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% compared to 6.6%, relative reduction by 38%).

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

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

In healthy volunteers, nebivolol had 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. Food does not affect the absorption of nebivolol; therefore, it can be taken independently of food intake.

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 genetic oxidative polymorphism dependent on CYP2D6. The oral bioavailability of nebivolol is 12% in individuals with rapid metabolism and nearly complete in individuals with slow metabolism. At steady state and with equal dosing, the maximum plasma concentration (Cmax) 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 Cmax difference is 1.3 to 1.4 times. Due to differences in metabolic rates, the dose of NEBINORM 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, and in individuals with slow metabolism, these values are about 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 concentrations of nebivolol ranging from 1 to 30 mg are dose-proportional. Age does not influence the pharmacokinetics of nebivolol.

In plasma, both enantiomers are predominantly bound to albumin. Protein binding in plasma 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 genotoxicity and carcinogenicity studies revealed no risk to humans.

Clinical characteristics.

Indications.

Arterial hypertension

Treatment of essential arterial hypertension.

Chronic heart failure

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

Treatment of symptomatic, chronic ischemic heart disease.

Contraindications.

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

In addition, as with other β-blockers, the medicinal product NEBINORM is contraindicated in:

• sick sinus syndrome, 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/min prior to treatment initiation);
• arterial hypotension (systolic blood pressure < 90 mm Hg);
• severe peripheral circulatory disorders.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

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

Concomitant use not recommended

Class I antiarrhythmic agents (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 precautions for use").

Calcium antagonists of the verapamil/diltiazem type

Negative effects on contractility and atrioventricular conduction. Intravenous administration of verapamil to patients receiving β-blockers may lead to marked arterial hypotension and atrioventricular block (see section "Special precautions for use").

Centrally-acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine)

Concomitant use of centrally-acting antihypertensive agents may lead to worsening of heart failure due to reduced central sympathetic tone (reduced heart rate and stroke volume, vasodilation) (see section "Special precautions for use"). Upon abrupt withdrawal, particularly before discontinuation of β-blockers, the risk of increased blood pressure may rise (withdrawal syndrome).

Caution required when used in combination

Class III antiarrhythmic agents (amiodarone)

The effect on atrioventricular conduction may be enhanced.

Halogenated volatile anesthetics

Concomitant use of β-blockers and anesthetics may suppress reflex tachycardia and increase the risk of hypotension (see section "Special precautions for use"). As a general rule, avoid abrupt discontinuation of β-blocker therapy. If the patient is taking NEBINORM, 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). Concomitant use of beta-blockers with sulfonylurea derivatives may increase the risk of severe hypoglycemia (see section "Special precautions for use").

Baclofen (antispastic agent), amifostine (adjunct in anticancer therapy)

When used concomitantly with antihypertensive agents, a significant decrease in blood pressure may occur; therefore, the dose of antihypertensive agents should be adjusted accordingly.

Combination use should be considered with caution

Cardiac glycosides (digitalis group)

Concomitant use may increase atrioventricular conduction time. No signs of this interaction were observed in clinical studies. Nebivolol does not affect digoxin kinetics.

Calcium antagonists of the dihydropyridine type (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 in ventricular pump function cannot be excluded.

Antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, and phenothiazine derivatives)

Concomitant use may enhance the hypotensive effect (additive effect).

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Do not affect the antihypertensive action of nebivolol.

Sympathomimetics

Concomitant use may counteract the antihypertensive effect of β-adrenoceptor blockers. Agents with β-adrenergic activity may potentiate α-adrenergic activity of sympathomimetics possessing both α- and β-adrenergic effects (risk of arterial hypertension, severe bradycardia, and heart block).

Pharmacokinetic interactions

Since the CYP2D6 isoenzyme is involved in the metabolism of nebivolol, concomitant use of medicinal products that inhibit this enzyme (e.g., paroxetine, fluoxetine, thioridazine, quinidine) may increase plasma levels of nebivolol and thereby increase the risk of pronounced bradycardia and adverse reactions.

Concomitant use with cimetidine increases plasma levels of nebivolol but does not alter its clinical efficacy. Concomitant use with ranitidine does not affect the pharmacokinetics of nebivolodol. Provided NEBINORM is taken with food and antacids are taken between meals, both medicinal products can be administered simultaneously.

When nebivolol is used concomitantly with nicardipine, plasma concentrations of both drugs are slightly increased, without changes in clinical efficacy.

Concomitant use of alcohol, furosemide, or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol. Nebivolol does not affect the pharmacokinetics or pharmacodynamics of warfarin.

Special precautions for use.

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

Anesthesia

Continuation of beta-blockade reduces the risk of cardiac arrhythmias during induction of anesthesia and intubation. If beta-blockade needs to be discontinued prior to surgery, beta-adrenergic blockers should be withdrawn at least 24 hours beforehand.

Extreme caution is required when using anesthetics that cause myocardial depression. Vagal reactions in the patient can be prevented by intravenous administration of atropine.

Cardiovascular system

Beta-adrenergic blockers are generally not prescribed to patients with untreated chronic heart failure until their condition becomes stable.

Beta-adrenergic blocker therapy should be discontinued gradually over 1–2 weeks in patients with ischemic heart disease. If necessary, replacement therapy should be initiated simultaneously to prevent exacerbation of angina.

Beta-adrenergic blockers may cause bradycardia. If resting heart rate decreases to 50–55 beats per minute and/or symptoms indicative of bradycardia develop, dose reduction is recommended.

Beta-adrenergic blockers should be used with caution in the treatment of:

• Patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as exacerbation of these conditions may occur;
• Patients with first-degree atrioventricular block due to the negative effect of beta-adrenergic blockers on conduction;
• Patients with Prinzmetal's angina, due to unopposed α-adrenergic receptor-mediated vasoconstriction of coronary arteries: beta-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 not recommended (for detailed information, see section "Interaction with other medicinal products and other forms of interaction").

Metabolism and endocrine system

The medicinal product NEBINORM does not affect blood glucose levels in patients with diabetes mellitus. Nevertheless, caution is required when administering it to such patients, as nebivolol may mask certain symptoms of hypoglycemia (tachycardia, palpitations). Beta-blockers may additionally increase the risk of severe hypoglycemia when used concomitantly with sulfonylurea derivatives. Patients with diabetes mellitus should be advised to closely monitor their blood glucose levels (see section "Interaction with other medicinal products and other forms of interaction").

Beta-adrenergic blockers may mask symptoms of tachycardia associated with hyperthyroidism. Abrupt discontinuation of therapy may exacerbate these symptoms.

Respiratory system

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

Other

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

Beta-adrenergic blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.

Regular monitoring of the patient's condition is required at the beginning of chronic heart failure treatment with nebivolol. Information on dosage and administration is provided in the section "Dosage and administration".

Treatment should not be abruptly discontinued without urgent need (see section "Dosage and administration"). For additional information, refer to the section "Dosage and administration".

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

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Nebivolol has pharmacological effects that may adversely affect pregnancy and/or the fetus/newborn. In general, beta-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 beta-blockers is necessary, beta1-selective beta-adrenergic blockers are preferred.

Nebivolol must not be used during pregnancy unless clearly necessary. If treatment with nebivolol is considered essential, uteroplacental blood flow and fetal growth should be monitored. If harmful effects on pregnancy or the fetus are observed, alternative therapy should be considered. Newborns should be closely monitored. Hypoglycemia and bradycardia are generally expected within the first three days of life.

Breastfeeding period

Animal studies have shown that nebivolol passes into breast milk. It is unknown whether it passes into human breast milk. Most beta-blockers, particularly lipophilic compounds such as nebivolol and its active metabolites, pass into breast milk to varying degrees. Therefore, breastfeeding during nebivolol treatment is not recommended.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of nebivolol on the ability to drive or operate machinery have not been conducted. Pharmacodynamic studies have shown that nebivolol does not affect psychomotor function. However, dizziness and fatigue may occasionally occur, which should be taken into account when driving or operating machinery.

Method of Administration and Dosage

Dosage Regimen

Arterial Hypertension

Adults

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

Combination with other antihypertensive agents

Beta-blockers may be used as monotherapy or in combination with other antihypertensive drugs. To date, an additional antihypertensive effect has been observed only when nebivolol is combined with 12.5–25 mg of hydrochlorothiazide.

Patients with renal impairment

For patients with renal impairment, the recommended initial dose is 2.5 mg once daily (use another medicinal product containing nebivolol in the appropriate dosage). 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 liver function disorders are limited. Therefore, the use of NEBINORM in such patients is contraindicated.

Elderly patients

For patients aged 65 years and older, the recommended initial dose is 2.5 mg once daily (use another medicinal product containing nebivolol in the appropriate dosage). If necessary, the dose may be increased to 5 mg. However, due to insufficient experience with patients aged 75 years and older, use in this population requires caution and careful monitoring.

Chronic Heart Failure

Treatment of chronic heart failure should begin with gradual dose titration to reach the individual optimal maintenance dose. This medicinal product should be prescribed to patients who have stable chronic heart failure without episodes of acute decompensation within the last 6 weeks. It is recommended that the prescribing physician has experience in managing chronic heart failure. Patients already receiving 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 NEBINORM.

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 of nebivolol once daily (use another medicinal product containing nebivolol in the appropriate dosage), increase to 2.5 mg of nebivolol once daily (use another medicinal product containing nebivolol in the appropriate dosage), then to 5 mg once daily, and subsequently to 10 mg (2 tablets of nebivolol 5 mg) once daily. The maximum recommended dose is 10 mg (2 tablets of nebivolol 5 mg) once daily. At the start 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 heart failure symptoms). Adverse reactions may prevent all patients from reaching the maximum recommended dose. If necessary, a previously achieved dose may be reduced stepwise or readjusted.

If heart failure symptoms worsen or if the medicinal product is not tolerated during the titration phase, the dose of nebivolol should be reduced initially 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).

Treatment of stable chronic heart failure with nebivolol is generally long-term.

Nebivolol therapy should not be stopped abruptly, as this may lead to a temporary worsening of heart failure. If discontinuation is necessary, the dose should be tapered gradually, reducing it by half 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 of nebivolol (use another medicinal product containing nebivolol in the appropriate dosage) to 2.5 mg of nebivolol (use another medicinal product containing nebivolol in the appropriate dosage) once daily, then to 5 mg once daily, and subsequently to 10 mg (2 tablets of nebivolol 5 mg) once daily. The maximum recommended dose is 10 mg of nebivolol (2 tablets of nebivolol 5 mg) once daily. Data for special patient groups apply to both patients with chronic heart failure and those with chronic ischemic heart disease.

Patients with renal impairment

Since dose titration to the maximally tolerated dose is individual, dose adjustment is not required in patients with mild to moderate renal impairment. There is no experience with the use of the medicinal product 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

Only limited data are available on the use of the medicinal product in patients with hepatic impairment. Therefore, the use of NEBINORM in these patients is contraindicated.

Elderly patients

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

Method of Administration

The medicinal product is intended for oral use. Tablets may be taken with or without food.

Children

The efficacy and safety of nebivolol in children and adolescents (under 18 years of age) have not been established. Data are unavailable. Therefore, the use of the medicinal product in children and adolescents (under 18 years of age) is not recommended.

Overdose

Data regarding nebivolol overdose are lacking.

Symptoms

Symptoms of beta-blocker overdose include bradycardia, hypotension, bronchospasm, and 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. Gastric lavage, activated charcoal, and laxatives may be used to prevent further absorption of any medicinal product remaining in the gastrointestinal tract. Mechanical ventilation may also be necessary. For treatment of bradycardia or increased vagal tone, administration of atropine or methylatropine is recommended. Hypotension and shock should be managed with plasma/plasma substitutes and, if necessary, catecholamines.

Beta-blocking effects can be counteracted by slow intravenous infusion of isoprenaline hydrochloride, starting at 5 μg/min, or dobutamine, starting at 2.5 μg/min, titrated to achieve the desired effect. In case of resistance, isoprenaline may be combined with dopamine. If this fails to produce the desired effect, intravenous glucagon may be administered at a dose of 50–100 μg/kg. Repeat injections may be necessary within the first hour, followed, if needed, by continuous intravenous glucagon infusion at 70 μg/kg/h. In extreme cases of therapy-resistant bradycardia, a temporary pacemaker may be required.

Adverse reactions.

Adverse reactions are listed separately for arterial hypertension and chronic heart failure due to differences in the underlying pathophysiological processes of these conditions.

Arterial hypertension

The adverse reactions, which in most cases were of mild to moderate severity, are presented in the table below and are classified according to system organ classes and frequency of occurrence.

In addition, the following adverse reactions have been reported with some β-blockers: hallucinations, psychosis, confusion, cold extremities/cyanosis, Raynaud's syndrome, dry eyes, and ocular-mucocutaneous toxicity of the propranolol 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 (42.1%) taking nebivolol and 334 patients (31.5%) taking placebo reported adverse reactions possibly related to the drug. The most commonly reported adverse reactions in patients treated with nebivolol were bradycardia and dizziness, occurring in approximately 11% of patients. The corresponding incidence in the placebo group was approximately 2% and 7%, respectively.

The following adverse reactions, at least potentially related to drug administration and considered relevant and significant in the treatment of chronic heart failure, have been reported:

• Worsening of heart failure was observed 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% of patients receiving placebo;
• Drug intolerance occurred in 1.6% of patients receiving nebivolol and in 0.8% of patients receiving placebo;
• First-degree AV block occurred in 1.4% of patients receiving nebivolol and in 0.9% of patients receiving placebo;
• Peripheral edema occurred in 1% of patients receiving nebivolol and in 0.2% of patients receiving placebo.

Chronic ischemic heart disease

Data on adverse reactions in patients with chronic ischemic heart disease were obtained from a specific analysis of the same clinical trial described for chronic heart failure. It is reasonable to assume that the safety and tolerability results observed in patients with chronic heart failure are also applicable to patients with chronic ischemic heart disease.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack, 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM PHARMACEUTICAL COMPANY LTD. (responsible for batch release, excluding batch control/testing).

Manufacturer's address and location of operations.

5 Budynsturii Street, Kyiv, 01013, Ukraine.

Marketing Authorization Holder.

MICROCHEM PHARMACEUTICAL COMPANY LTD.

Address of the Marketing Authorization Holder.

5 Budynsturii Street, Kyiv, 01013, Ukraine.

INSTRUCTION

for medical use of the medicinal product

NEBINORM

(NEBINORM)

Composition:

Active substance: nebivolol;

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

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets.

Pharmacotherapeutic group.

β-adrenoreceptor blockers. Selective β-adrenoreceptor blockers. Nebivolol. 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 actions:

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

Single and repeated doses of nebivolol reduce heart rate and arterial pressure at rest and during exercise, both in individuals with normal blood pressure and in those with arterial hypertension. The antihypertensive effect persists 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, which is reduced in patients with endothelial dysfunction.

In a placebo-controlled morbidity-mortality study involving 2128 patients aged ≥70 years (mean age 75.2 years) with stable chronic heart failure (CHF), 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% of patients, LVEF >45% in 19% of patients), lasting on average 20 months, nebivolol as an add-on therapy to standard treatment significantly prolonged the time to death or hospitalization due to cardiovascular disease (primary efficacy endpoint), reducing the relative risk by 14% (absolute reduction – 4.2%). This risk reduction developed 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 LVEF value. The benefit in preventing 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 showed that nebivolol has no intrinsic sympathomimetic activity.

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

In healthy volunteers, nebivolol had 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. Food does not affect the absorption of nebivolol; therefore, it can be taken independently of food intake.

Nebivolol is completely metabolized, partially 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 genetic 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 with equal dosing, the maximum plasma concentration (C_max) of unchanged nebivolol in slow metabolizers is approximately 23 times higher than in rapid metabolizers. When considering the sum of unchanged drug and its active metabolites, the C_max difference is 1.3 to 1.4 times. Due to differences in metabolic rates, the dose of NEBINORM should always be adjusted according to individual patient needs; thus, 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 slow metabolizers, this value is 3–5 times higher. In rapid metabolizers, 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; in slow metabolizers, these values are about twice as high.

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

Plasma concentration is proportional to the dose over 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 genotoxicity and carcinogenicity studies revealed no hazard to humans.

Clinical characteristics.

Indications.

Arterial hypertension

Treatment of essential arterial hypertension.

Chronic heart failure

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

Treatment of symptomatic, chronic ischemic heart disease.

Contraindications.

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

In addition, as with other β-blockers, the medicinal product NEBINORM is CONTRAINDICATED in:

• 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 prior to initiation of treatment);
• arterial hypotension (systolic blood pressure < 90 mm Hg);
• 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-adrenoreceptor antagonists.

Co-administration not recommended

Class I antiarrhythmic agents (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 precautions").

Calcium antagonists of the verapamil/diltiazem type

Negative effects on contractility and atrioventricular conduction. Intravenous administration of verapamil to patients receiving β-blockers may lead to severe arterial hypotension and atrioventricular block (see section "Special precautions").

Centrally-acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine)

Concomitant use of centrally-acting antihypertensive agents may exacerbate heart failure due to reduced central sympathetic tone (decreased heart rate and stroke volume, vasodilation) (see section "Special precautions"). Upon abrupt discontinuation, especially before stopping β-blocker therapy, the risk of increased blood pressure may rise (withdrawal syndrome).

Caution required when used in combination

Class III antiarrhythmic agents (amiodarone)

The effect on atrioventricular conduction may be enhanced.

Halogenated volatile anesthetics

Concomitant use of β-blockers and anesthetics may suppress reflex tachycardia and increase the risk of hypotension (see section "Special precautions"). As a general rule, avoid abrupt withdrawal of β-blocker therapy. If the patient is taking NEBINORM, 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). Concurrent use of beta-blockers with sulfonylurea derivatives may increase the risk of severe hypoglycemia (see section "Special precautions").

Baclofen (antispastic agent), amifostine (adjunct in anticancer therapy)

When used concomitantly with antihypertensive agents, a significant decrease in blood pressure may occur; therefore, the dose of antihypertensive agents should be adjusted accordingly.

Consideration required when used in combination

Cardiac glycosides (digitalis group)

Concomitant use may increase atrioventricular conduction time. However, clinical studies have not shown evidence of this interaction. Nebivolol does not affect digoxin kinetics.

Calcium antagonists of the dihydropyridine type (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine)

Concomitant use may increase the risk of hypotension, and in patients with heart failure, a worsening of ventricular pump function cannot be excluded.

Antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, and phenothiazine derivatives)

Concomitant use may enhance hypotensive effects (additive effect).

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Do not affect the antihypertensive action of nebivolol.

Sympathomimetics

Concomitant use may counteract the antihypertensive effects of β-adrenoblockers. Active substances with β-adrenergic activity may promote α-adrenergic activity of sympathomimetics possessing both α- and β-adrenergic effects (risk of arterial hypertension, severe bradycardia, and heart block).

Pharmacokinetic interactions

Since the CYP2D6 isoenzyme is involved in the metabolism of nebivolol, concomitant use of medicinal products that inhibit this enzyme (e.g., paroxetine, fluoxetine, thioridazine, quinidine) may increase plasma levels of nebivolol and thereby increase the risk of pronounced bradycardia and adverse reactions.

Concomitant use with cimetidine increases plasma levels of nebivolol but does not alter its clinical efficacy. Concomitant use with ranitidine does not affect the pharmacokinetics of nebivolol. If NEBINORM is taken with food and an antacid is taken between meals, both medicinal products may be administered simultaneously.

When nebivolol is used concomitantly with nicardipine, plasma concentrations of both drugs are slightly increased, without changes in clinical efficacy.

Concomitant intake of alcohol, furosemide, or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol. Nebivolol does not affect the pharmacokinetics or pharmacodynamics of warfarin.

Special precautions.

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

Anesthesia

Continuation of β-blockade reduces the risk of cardiac arrhythmias during induction of anesthesia and intubation. If β-blockade needs to be discontinued prior to surgery, β-adrenergic receptor blockers should be withdrawn at least 24 hours beforehand.

Caution is required when using anesthetics that cause myocardial depression. Vagal reactions in the patient can be prevented by intravenous administration of atropine.

Cardiovascular system

β-adrenergic blockers are generally not prescribed 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, replacement therapy should be initiated simultaneously to prevent exacerbation of angina.

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 the treatment of:

• patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as these conditions may worsen;
• patients with first-degree atrioventricular block due to the negative effect of β-adrenergic blockers on conduction;
• patients with Prinzmetal's angina due to unopposed α-adrenergic receptor-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 (see section "Interaction with other medicinal products and other forms of interaction" for detailed information).

Metabolism and endocrine system

The medicinal product NEBINORM 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 symptoms of hypoglycemia (tachycardia, palpitations). β-blockers may additionally increase the risk of severe hypoglycemia when used concomitantly with sulfonylurea derivatives. Patients with diabetes mellitus should be advised to closely monitor their blood glucose levels (see section "Interaction with other medicinal products and other forms of interaction"). β-adrenergic blockers may mask symptoms of tachycardia in hyperthyroidism. Abrupt discontinuation of therapy may exacerbate these symptoms.

Respiratory system

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

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's condition is required at the beginning of treatment with nebivolol for chronic heart failure. Information on method and dosage can be found in the section "Dosage and administration".

Treatment should not be abruptly discontinued without urgent need (see section "Dosage and administration"). For additional information, see section "Dosage and administration".

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

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Nebivolol has pharmacological effects that may adversely affect pregnancy and/or the fetus/neonate. In general, β-adrenergic blockers reduce placental blood flow, which has been associated with intrauterine growth retardation, intrauterine death, miscarriage, 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 clearly necessary. If treatment with nebivolol is considered essential, uteroplacental blood flow and fetal growth should be monitored. If harmful effects on pregnancy or the fetus are observed, alternative therapy should be considered. Newborns should be closely monitored. Hypoglycemia and bradycardia are generally expected within the first three days of life.

Breastfeeding period

Animal studies have shown that nebivolol passes into breast milk. It is unknown whether it passes into human breast milk. Most β-blockers, particularly lipophilic compounds such as nebivolol and its active metabolites, pass into breast milk to varying degrees. Therefore, breastfeeding during nebivolol treatment is not recommended.

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 nebivolol does not affect psychomotor function. However, dizziness and fatigue may occasionally occur, which should be taken into account when driving or operating machinery.

Method of Administration and Dosage

Dosage Regimen

Arterial Hypertension

Adults

The dose is 1 tablet (5 mg of nebivolol) once daily, preferably taken at the same time each day. The antihypertensive effect becomes evident within 1–2 weeks of treatment, although optimal response may sometimes only be achieved after 4 weeks.

Combination with Other Antihypertensive Agents

Beta-blockers can be used as monotherapy or in combination with other antihypertensive medicinal products. To date, an additional antihypertensive effect has been observed only when nebivolol is combined with 12.5–25 mg of hydrochlorothiazide.

Patients with Renal Impairment

For patients with renal impairment, the recommended initial dose is 2.5 mg once daily (use another medicinal product containing nebivolol in the appropriate dosage). 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 liver function disorders are limited. Therefore, the use of NEBINORM in such patients is contraindicated.

Elderly Patients

For patients aged 65 years and older, the recommended initial dose is 2.5 mg once daily (use another medicinal product containing nebivolol in the appropriate dosage). 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.

Chronic Heart Failure

Treatment of chronic heart failure should begin with gradual dose titration until the individual optimal maintenance dose is reached. This medicinal product should be prescribed to patients who have stable chronic heart failure without episodes of acute decompensation in the past 6 weeks. It is recommended that the prescribing physician has experience in managing chronic heart failure. Patients already receiving other cardiovascular medicinal products, 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 agents for at least the previous 2 weeks before initiating therapy with NEBINORM.

Initial dose titration should follow the schedule below, with intervals of 1 to 2 weeks between dose increases, based on patient tolerability: start with 1.25 mg nebivolol once daily (use another medicinal product containing nebivolol in the appropriate dosage), increase to 2.5 mg nebivolol once daily (use another medicinal product containing nebivolol in the appropriate dosage), then to 5 mg once daily, and subsequently to 10 mg (2 nebivolol 5 mg tablets) once daily. The maximum recommended dose is 10 mg (2 nebivolol 5 mg tablets) of nebivolol once daily. At the start of treatment and with each dose increase, the patient should be monitored by an experienced physician for at least 2 hours to ensure clinical stability (particularly 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, a previously achieved dose may be reduced stepwise or readjusted.

If heart failure symptoms worsen or the medicinal product is not tolerated during the titration phase, the dose of nebivolol should be reduced initially or, if necessary, discontinued immediately (in cases of severe hypotension, worsening heart failure symptoms with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia, or atrioventricular block).

Treatment of stable chronic heart failure with nebivolol is generally long-term.

Nebivolol treatment should not be stopped 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 tolerability, starting from 1.25 mg nebivolol (use another medicinal product containing nebivolol in the appropriate dosage) to 2.5 mg nebivolol (use another medicinal product containing nebivolol in the appropriate dosage) once daily, then to 5 mg once daily, and subsequently to 10 mg (2 nebivolol 5 mg tablets) once daily. The maximum recommended dose is 10 mg nebivolol (2 nebivolol 5 mg tablets) once daily. Data for special patient groups apply to both patients with chronic heart failure and those with chronic ischemic heart disease.

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 the use of the medicinal product in patients with severe renal impairment (serum creatinine ≥ 250 μmol/L); therefore, the use of nebivolol in such patients is not recommended.

Patients with Hepatic Impairment

Only limited data are available regarding the use of the medicinal product in patients with hepatic impairment. Therefore, the use of NEBINORM in these patients is contraindicated.

Elderly Patients

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

Method of Administration

The medicinal product is intended for oral administration. Tablets may be taken with or without food.

Children

The efficacy and safety of nebivolol in children and adolescents (under 18 years of age) have not been established. Data are unavailable. Therefore, the use of the medicinal product in children and adolescents (under 18 years of age) is not recommended.

Overdose.

Data regarding nebivolol overdose are lacking.

Symptoms

Symptoms of beta-blocker overdose include bradycardia, hypotension, bronchospasm, and 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. Gastric lavage, activated charcoal, and laxatives may be used to prevent absorption of any remaining medicinal product in the gastrointestinal tract. Mechanical ventilation may also be necessary. For treatment of bradycardia or increased vagal tone, administration of atropine or methylatropine is recommended. Hypotension and shock should be managed with plasma/plasma substitutes and, if necessary, catecholamines.

Beta-blocking effects may be reversed by slow intravenous infusion of isoprenaline hydrochloride, starting at 5 μg/min, or dobutamine, starting at 2.5 μg/min, titrated to desired effect. In case of resistance, isoprenaline may be combined with dopamine. If this fails to produce the desired effect, intravenous glucagon may be administered at a dose of 50–100 μg/kg. Repeat injections may be necessary within one hour, followed, if needed, by continuous intravenous glucagon infusion at 70 μg/kg/hour. In extreme cases of therapy-resistant bradycardia, a temporary pacemaker may be required.

Adverse reactions.

Adverse reactions are presented separately for arterial hypertension and chronic heart failure due to differences in the underlying pathophysiological processes of these conditions.

Arterial hypertension

The adverse reactions, which in most cases were of mild to moderate severity, are listed in the table below and are classified according to system organ classes and frequency of occurrence.

In addition, the following adverse reactions have been reported with some β-blockers: 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 (42.1%) taking nebivolol and 334 patients (31.5%) taking placebo reported adverse reactions possibly related to the study drug. The most commonly reported adverse reactions in patients treated with nebivolol were bradycardia and dizziness, occurring in approximately 11% of patients. The corresponding incidence in placebo-treated patients was approximately 2% and 7%, respectively.

The following adverse reactions, considered at least potentially related to the drug and deemed relevant and significant in the treatment of chronic heart failure, have been reported:

• Worsening of heart failure was observed in 5.8% of patients treated with nebivolol and in 5.2% of patients receiving placebo;
• Orthostatic hypotension occurred in 2.1% of patients treated with nebivolol and in 1% of patients receiving placebo;
• Drug intolerance was observed in 1.6% of patients treated with nebivolol and in 0.8% of patients receiving placebo;
• First-degree AV block occurred in 1.4% of patients treated with nebivolol and in 0.9% of patients receiving placebo;
• Lower limb edema occurred in 1% of patients treated with nebivolol and in 0.2% of patients receiving placebo.

Chronic ischemic heart disease

Data on adverse reactions in patients with chronic ischemic heart disease were obtained from a specific analysis of the same clinical trial described for chronic heart failure. It is reasonable to assume that the safety and tolerability results observed in patients with chronic heart failure also apply to patients with chronic ischemic heart disease.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25°C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack, 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM PHARMACEUTICAL COMPANY LTD (production unit (all stages of the manufacturing process)).

Manufacturer's address and location of operations.

24-V Promyslova Street, Severodonetsk, Luhansk Oblast, 93400, Ukraine.

Marketing Authorization Holder.

MICROCHEM PHARMACEUTICAL COMPANY LTD.

Address of the Marketing Authorization Holder.

5 Budynsturiyi Street, Kyiv, 01013, Ukraine