Nebitens

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

Composition:

Active substance: nebivolol;

1 tablet contains 5.45 mg of nebivolol hydrochloride, corresponding to 5 mg of nebivolol;

Excipients: lactose monohydrate, macrogol 6000, sodium croscarmellose, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, biconvex tablets with a cross-score line on one side and the imprint "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 actions:

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

Single and repeated doses of nebivolol reduce 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.

In 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; in patients with endothelial dysfunction, this response is diminished.

It is known that in placebo-controlled morbidity-mortality studies in patients with stable chronic heart failure, lasting on average 20 months, nebivolol as an add-on to standard therapy significantly prolonged the time to death or hospitalization due to cardiovascular disease (primary efficacy endpoint). The effect of nebivolol was independent of age, sex, or left ventricular ejection fraction in study participants. The benefit regarding prevention of all-cause mortality compared to placebo did not reach statistical significance. In patients treated with nebivolol, a reduction in mortality rates was observed. 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 has no significant effect on maximal exercise tolerance or endurance.

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 genetic oxidative polymorphism dependent on CYP2D6. The oral bioavailability of nebivolol is 12% in individuals with rapid metabolism and is nearly complete in individuals with slow metabolism. At steady state and with 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 ranges from 1.3 to 1.4 times. Due to differences in metabolic rates, the dose of Nebitens 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 slow metabolism.

In individuals with rapid metabolism, the mean elimination half-life of the 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 concentrations ranging from 1 to 30 mg of nebivolol are proportional to the dose. 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.

Clinical characteristics.

Indications.

Essential arterial hypertension. Chronic heart failure of mild or moderate severity as an adjunct to standard treatment in patients aged 70 years and older.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition";
• hepatic insufficiency 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, Nebitens 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 phaeochromocytoma;
• metabolic acidosis;
• bradycardia (heart rate less than 60 beats/min before treatment initiation);
• arterial hypotension (systolic blood pressure less than 90 mm Hg);
• severe peripheral circulatory disorders.

Interaction with other medicinal products and other forms of interaction.

Concomitant use 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-adrenoblockers 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. Upon abrupt discontinuation, especially before stopping β-adrenoblockers, the likelihood of increased arterial pressure (withdrawal syndrome) may rise.

Caution is required 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 taking Nebitens, this should be communicated to the anesthesiologist;

c) with insulin and oral antidiabetic agents – although Nebitens does not affect blood glucose levels, it may mask symptoms of hypoglycemia such as tachycardia and palpitations; concomitant use of beta-blockers with sulfonylurea derivatives increases the risk of developing severe hypoglycemia (see section "Special precautions");

d) with baclofen (antispastic agent) and amifostine (adjunct antineoplastic agent) – concomitant use with antihypertensive agents may lead to significant reduction in arterial pressure; therefore, the dose of antihypertensive agents should be adjusted accordingly.

Concomitant use should be considered with caution:

a) digitalis glycosides (e.g., digoxin) – may slow AV conduction, although clinical studies have not provided definitive evidence 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, and in patients with heart failure, worsening of ventricular pump function may occur;

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

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

e) sympathomimetics – may counteract the antihypertensive effect of β-adrenoblockers. Agents with β-adrenergic activity may lead to unopposed α-adrenergic activity of sympathomimetics having 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 isoenzyme CYP2D6 is involved in the metabolism of nebivolol, 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 Nebitens is to be taken with food and an antacid is to be taken between meals, these drugs may be co-administered;
• combined use of nebivolol with nicardipine slightly increases plasma concentrations of both drugs without changing 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 beta-adrenergic blockers.

Anesthesia.

Continuation of beta-blockade reduces the risk of cardiac rhythm disturbances 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.

Care should be taken when using certain anesthetics that may cause myocardial depression. Vagal reactions can be prevented by intravenous administration of atropine.

Cardiovascular system.

Beta-adrenergic blockers should generally not be prescribed to patients with untreated chronic heart failure (CHF) until their condition becomes stable.

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

Beta-adrenergic blockers may cause bradycardia. If the resting heart rate decreases to 50–55 beats per minute and/or symptoms suggestive of bradycardia develop, the dose should be reduced.

Beta-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 these conditions may worsen;

b) patients with first-degree atrioventricular block due to the negative effect of beta-adrenergic blockers on cardiac conduction;

c) patients with Prinzmetal's angina due to unopposed α-adrenergic receptor-mediated coronary artery vasoconstriction: 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 generally not recommended (for detailed information, see section "Interaction with other medicinal products and other forms of interaction").

Metabolism and endocrine system.

Nebitens does not affect blood glucose levels in patients with diabetes mellitus. Nevertheless, caution is required when using it in these 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 should be advised to monitor blood glucose levels carefully (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 be aggravated.

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. For information on dosage and administration, see section "Dosage and administration".

Abrupt discontinuation of treatment should be avoided unless clinically necessary (see section "Dosage and administration").

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

Use during pregnancy or breastfeeding.

Pregnancy

Nebivolol has pharmacological effects that may adversely affect pregnancy and/or the fetus/neonate. In general, beta-adrenergic blockers reduce placental blood flow, which has been associated with intrauterine growth retardation, intrauterine 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, β1-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 closely monitored. If harmful effects on pregnancy or the fetus are observed, alternative therapy should be considered. Newborns should be carefully 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 this substance passes into human breast milk. Most beta-blockers, particularly lipophilic compounds such as nebivolol and its active metabolites, pass into breast milk to some extent. Therefore, breastfeeding is not recommended during treatment with nebivolol.

Ability to affect 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 Nebitens at a dose of 5 mg 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

Essential Arterial Hypertension

Adults:

The recommended dose is 1 tablet (5 mg of nebivolol) once daily. It is advisable to take it at the same time each day. The antihypertensive effect becomes evident within 1–2 weeks of treatment, although optimal response may sometimes be 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. To date, an additional antihypertensive effect has been observed only when Nebiten 5 mg was 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. 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 dysfunction are limited. Therefore, the use of Nebiten in such patients is contraindicated.

Elderly Patients

For patients aged over 65 years, 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 patients aged over 75 years, caution and close monitoring are required when administering the drug to these patients.

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 only to patients who have stable 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 already 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 drugs for at least the past 2 weeks before initiating therapy with Nebiten.

Initial dose titration should follow the schedule below, with intervals of 1 to 2 weeks between dose increases, guided by patient tolerance:

• Start with 1.25 mg nebivolol once daily
• Increase to 2.5 mg nebivolol once daily
• Then to 5 mg once daily
• Then to 10 mg once daily

The maximum recommended dose is 10 mg of nebivolol once daily. At the initiation of treatment and after 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, 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 worsening of heart failure symptoms or drug intolerance occurs during the dose titration phase, it is recommended to first reduce the dose of nebivolol or, if necessary, discontinue the drug immediately (in cases of severe hypotension, worsening heart failure with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia, or atrioventricular block).

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

Nebivolol therapy 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 tapered by halving it every week.

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 level ≥ 250 μmol/L); therefore, the use of nebivolol in such patients is not recommended.

Patients with Hepatic Impairment

Data on the use of the medicinal product in patients with hepatic impairment are limited. Therefore, the use of Nebiten 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

Oral administration.

The tablets may be taken with food.

Children

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

Overdose

In cases of β-blocker overdose, the following symptoms may occur: bradycardia, arterial hypotension, bronchospasm, and acute heart failure.

Treatment of overdose: gastric lavage, administration of activated charcoal and laxatives. Mechanical ventilation may also be required. Blood glucose levels should be monitored. If necessary, intensive therapy should be administered in a hospital setting:

• For bradycardia and increased vagal tone: administration of atropine or methylatropine
• For hypotension and shock: intravenous administration of plasma expanders and catecholamines

Beta-blocking effects may be counteracted by slow intravenous infusion of isoprenaline hydrochloride, starting at a rate 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; the injection may be repeated within one hour if needed, and, if necessary, a continuous intravenous infusion of glucagon may be initiated at a rate of 70 μg/kg/hour.

In extreme cases of therapy-resistant bradycardia, cardiac pacing 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 of these conditions.

Essential arterial hypertension.

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. The most commonly reported adverse reactions in patients receiving nebivolol were bradycardia and dizziness. The following adverse reactions, which were at least potentially related to the drug and considered relevant and significant in the treatment of chronic heart failure, have been reported:

• worsening of heart failure;
• orthostatic hypotension;
• drug intolerance;
• first-degree AV block;
• lower limb edema.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. No special storage conditions required.

Keep out of the reach of children.

Packaging. 10 tablets per blister pack, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Balkanpharma - Dupnitsa AD.

Manufacturer's address and place of business.

3 Samokovsko Shose Street, Dupnitsa, 2600, Bulgaria.

INSTRUCTION

for medical use of the medicinal product

NEBITENS

(NEBITENS)

Composition:

Active substance: nebivolol;

1 tablet contains 5.45 mg of nebivolol hydrochloride, equivalent to 5 mg of nebivolol;

Excipients: lactose monohydrate, macrogol 6000, sodium croscarmellose, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, biconvex tablets with a cross-shaped notch for tablet division on one side and the marking «N5» on the other side.

Pharmacotherapeutic group. Selective β-adrenoreceptor 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 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 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.

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

During short- and long-term treatment with nebivolol in patients with arterial hypertension, systemic vascular resistance decreases. 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 reduced.

It is known that in placebo-controlled morbidity-mortality studies in patients with stable chronic heart failure, lasting on average 20 months, nebivolol as an additional agent to standard therapy significantly prolonged the time to death or hospitalization due to cardiovascular disease (primary efficacy endpoint). The effect of nebivolol was independent of age, sex, or left ventricular ejection fraction in study participants. The benefit regarding prevention of all-cause mortality compared to placebo did not reach statistical significance. However, a reduction in cardiovascular mortality was observed in patients treated with nebivolol. 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 has no significant effect on tolerance to maximal exercise or endurance.

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 with the same dose, the maximum plasma concentration 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 difference in maximum plasma concentration is 1.3 to 1.4 times. Due to differences in metabolic rates, the dose of Nebitens should always be adjusted according to individual patient needs; therefore, lower doses may be required in slow metabolizers.

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 enanti游戏副本. This difference is greater in slow metabolizers.

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 concentrations ranging from 1 to 30 mg of nebivolol are proportional to the dose. 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 urine and 48% in feces. Renal excretion of unchanged nebivolol is less than 0.5% of the dose.

Clinical characteristics.

Indications.

Essential arterial hypertension. Chronic heart failure of mild or moderate severity as an adjunct to standard treatment in patients aged 70 years and older.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition";
• hepatic insufficiency or hepatic dysfunction;
• acute heart failure, cardiogenic shock, or episodes of heart failure decompensation requiring intravenous administration of active substances with positive inotropic effect.

In addition, as with other β-blockers, Nebivolol 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 phaeochromocytoma;
• metabolic acidosis;
• bradycardia (heart rate less than 60 beats/min prior to initiation of treatment);
• arterial hypotension (systolic blood pressure less than 90 mm Hg);
• severe peripheral circulatory disorders.

Interaction with other medicinal products and other forms of interaction.

Concomitant use 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. Upon abrupt discontinuation, especially before stopping β-blockers, the likelihood of increased blood pressure (withdrawal syndrome) may rise.

Caution is required 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 the patient is taking Nebivolol, the anesthesiologist should be informed;

c) with insulin and oral antidiabetic agents – although Nebivolol does not affect blood glucose levels, it may mask symptoms of hypoglycemia such as tachycardia and palpitations; concomitant use of beta-blockers with sulfonylurea derivatives increases the risk of severe hypoglycemia (see section "Special precautions for use");

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

Concomitant use should be considered with caution:

a) cardiac glycosides of the digitalis group – AV conduction may be slowed, although clinical studies have not provided clear evidence of 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, and in patients with heart failure, ventricular pump function may deteriorate;

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 Nebivolol;

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

Interactions due to pharmacokinetic properties 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 Nebivolol is to be taken with food and antacids are to be taken between meals, these drugs may be co-administered;
• concomitant administration of nebivolol and nicardipine slightly increases plasma concentrations of both drugs without altering 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 beta-adrenergic blockers.

Anesthesia.

Continuation of beta-blockade reduces the risk of cardiac rhythm disturbances during induction of anesthesia and intubation. If beta-blockade must be discontinued prior to surgery, beta-adrenergic blockers should be withdrawn at least 24 hours before the procedure.

Use of certain anesthetics that cause myocardial depression requires caution. Vagal reactions may be prevented by intravenous administration of atropine.

Cardiovascular system.

Beta-adrenergic blockers should generally not be administered to patients with untreated chronic heart failure (CHF) until their condition becomes stable.

Beta-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 suggestive of bradycardia develop, the dose should be reduced.

Beta-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 conditions may occur;

b) patients with first-degree atrioventricular block due to the negative effect of beta-adrenergic blockers on cardiac conduction;

c) patients with Prinzmetal’s (vasospastic) angina due to unopposed α-adrenergic receptor-mediated coronary artery vasoconstriction: beta-adrenergic blockers may increase the frequency and duration of angina attacks.

Combination of nebivolol with calcium antagonists of the verapamil and diltiazem type, with class I antiarrhythmic agents, and with 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.

Nebivolol does not affect blood glucose levels in patients with diabetes mellitus. Nevertheless, caution is required when using it in these patients, as nebivolol may mask some symptoms of hypoglycemia (tachycardia, palpitations). Beta-blockers may additionally increase the risk of severe hypoglycemia when used concomitantly with sulfonylurea derivatives. Patients with diabetes 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 in 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 be intensified.

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 is required at the beginning of chronic heart failure treatment with nebivolol. For information on dosage and administration, see section "Dosage and administration".

Treatment should not be abruptly discontinued unless clinically necessary (see section "Dosage and administration").

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

Use during pregnancy or breastfeeding.

Pregnancy

Nebivolol has pharmacological effects that may adversely affect pregnancy and/or the fetus/neonate. 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, β1-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 detected, alternative therapy should be considered. Newborns should be closely observed. 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 this substance 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 is not recommended during treatment with nebivolol.

Ability to affect 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 Nebitens at a dose of 5 mg 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

Essential Arterial Hypertension

Adults:

The dose is 1 tablet (5 mg of nebivolol) once daily. It is advisable to take it at the same time each day. The antihypertensive effect becomes evident within 1–2 weeks of treatment, but optimal efficacy may sometimes be observed only after 4 weeks.

Combination with other antihypertensive agents.

β-blockers can be used both for monotherapy and in combination with other antihypertensive medicinal products. To date, an additional antihypertensive effect has been observed only when Nebitenz 5 mg was 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. 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 Nebitenz in such patients is contraindicated.

Elderly patients.

For patients aged over 65 years, the recommended initial dose is 2.5 mg once daily. If necessary, the dose may be increased to 5 mg. However, due to insufficient experience with use in patients over 75 years of age, administration requires caution and careful monitoring of these patients.

Chronic Heart Failure.

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

Initial dose titration should follow the scheme below, maintaining intervals of 1 to 2 weeks and monitoring patient tolerance:

• 1.25 mg nebivolol once daily may be increased 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 of 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 effects may prevent all patients from reaching the maximum recommended dose. If necessary, a previously achieved dose may be reduced stepwise or readjusted.

If worsening of heart failure symptoms or intolerance to the medicinal product occurs during the dose titration phase, the dose of nebivolol should be reduced initially, or, if necessary, the medicinal product should be discontinued immediately (in cases 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 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 over a period of 1 week.

Patients with renal impairment.

Since dose titration to the maximum 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 level ≥ 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 Nebitenz in these patients is contraindicated.

Elderly patients.

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

Method of Administration

Oral administration.

Tablets may be taken with food.

Children.

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

Overdose.

Overdose of β-adrenoblockers may result in bradycardia, arterial hypotension, bronchospasm, and acute heart failure. Treatment of overdose includes gastric lavage, administration of activated charcoal and laxatives. Mechanical ventilation may also be required. Monitoring of blood glucose levels is recommended. If necessary, intensive therapy in a hospital setting should be initiated:

• For bradycardia and increased vagal tone – administration of atropine or methylatropine;
• For hypotension and shock – intravenous administration of plasma expanders and catecholamines.

Beta-blocking effects can be counteracted 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; the injection may be repeated within one hour if needed, and, if necessary, intravenous glucagon infusion may be initiated at a rate of 70 µg/kg/hour. In extreme cases of therapy-resistant bradycardia, a temporary pacemaker may be indicated.

Adverse reactions.

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

Essential arterial hypertension.

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. The most commonly reported adverse reactions in patients treated with nebivolol were bradycardia and dizziness. The following adverse reactions, which were at least potentially related to the drug and considered relevant and significant in the treatment of chronic heart failure, have been reported:

• Worsening of heart failure;
• Orthostatic hypotension;
• Drug intolerance;
• First-degree AV block;
• Edema of the lower limbs.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. No special storage conditions required.

Keep out of the reach and sight of children.

Packaging. 10 tablets in a blister, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Actavis Ltd.

Manufacturer's address and place of business.

BLB015-016, Zejtun Industrial Estate, ZTN3000, Malta.