Bivoneb

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BIVONEB (BIVONEB)

Composition:

Active substance: nebivolol;

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

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

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex tablets, white to almost white, with a cross-shaped notch on one side and the letter "H" on the other.

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), thus combining two pharmacological properties:

• it is a competitive and selective beta-receptor antagonist: this effect is attributed 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 arterial blood pressure at rest and during exercise in both individuals with normal blood pressure and those with arterial hypertension. The antihypertensive effect is maintained during long-term treatment.

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

During short-term or 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 beta-adrenoceptor blockers has not yet been fully elucidated.

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

In a placebo-controlled morbidity-mortality study involving 2128 patients aged ≥ 70 years (mean age 75.2 years) with stable chronic heart failure with or without reduced left ventricular ejection fraction (LVEF) (mean LVEF 36 ± 12.3 %, with the following distribution: LVEF < 35 % in 56 % of patients, LVEF 35–45 % in 25 % of patients, LVEF > 45 % in 19 % of patients), which lasted on average 20 months, nebivolol as a primary medication added to standard therapy 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 emerged after 6 months of treatment and persisted throughout the treatment period (mean duration – 18 months). The effect of nebivolol was independent of age, gender, or left ventricular ejection fraction in the study participants. The benefit regarding prevention of all-cause mortality compared to placebo did not reach statistical significance (absolute reduction – 2.3 %).

In patients treated with nebivolol, a reduction in the incidence of sudden death was observed (4.1 % compared to 6.6 %, relative reduction by 38 %).

Experiments in vitro and in vivo in animals showed that nebivolol has no intrinsic sympathomimetic activity.

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

In healthy volunteers, nebivolol does not significantly affect maximal exercise tolerance or endurance.

According to available preclinical and clinical data, nebivolol has no negative impact on erectile function in patients with hypertensive disease.

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 genetically determined 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 drug dose should always be adjusted according to individual patient needs. Therefore, individuals with slow metabolism may require lower doses.

In patients with rapid metabolism, the elimination half-life of nebivolol enantiomers averages 10 hours. In patients 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 elimination half-life values of hydroxymetabolites of both enantiomers average 24 hours, while in individuals with slow metabolism, these values are approximately twice as high.

Steady-state plasma levels of nebivolol are achieved within 24 hours in most patients with rapid metabolism, while steady-state levels of hydroxymetabolites are reached over several days.

Plasma concentrations of nebivolol ranging from 1 to 30 mg are dose-proportional. Age does not affect 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 accounts for less than 0.5 % of the dose.

Clinical characteristics.

Indications.

Arterial hypertension

Treatment of essential arterial hypertension.

Chronic heart failure (CHF)

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

Contraindications.

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

Additionally, as with other beta-blockers, the drug is contraindicated in the following conditions:

• sinus node dysfunction, including sinoatrial block;
• second- or third-degree atrioventricular block (AV block) (without a permanent pacemaker);
• bronchospasm or history of bronchial asthma;
• untreated pheochromocytoma;
• metabolic acidosis;
• bradycardia (heart rate less than 60 beats per minute prior to 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 interactions.

Pharmacodynamic interactions:

The information below provides general data on interactions with beta-adrenoreceptor antagonists.

Concomitant use not recommended:

• with Class I antiarrhythmic agents (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone) – may enhance effects on AV conduction and increase the negative inotropic effect (see section "Special precautions");
• with calcium antagonists of the verapamil/diltiazem type – negative effects on AV conduction and myocardial contractility; intravenous administration of verapamil to patients receiving beta-blockers may lead to severe arterial hypotension and AV block (see section "Special precautions");
• with centrally-acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) – concomitant use of centrally-acting antihypertensive drugs may exacerbate heart failure due to reduced central sympathetic tone (decreased heart rate and stroke volume, vasodilation) (see section "Special precautions"). Upon abrupt discontinuation, particularly before stopping beta-blocker therapy, the risk of increased blood pressure may rise (withdrawal syndrome).

Caution is advised when combining with:

• Class III antiarrhythmic agents (amiodarone) – may enhance effects on AV conduction;
• halogenated volatile anesthetics – concomitant use of beta-blockers and anesthetics may suppress reflex tachycardia and increase the risk of arterial hypotension (see section "Special precautions"). As a general rule, avoid abrupt withdrawal of beta-blocker therapy. If a patient is taking nebivolol, the anesthesiologist must 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 (adjunctive anticancer agent) – simultaneous use with antihypertensive agents may lead to significant reduction in blood pressure; therefore, the dose of antihypertensive agents should be adjusted accordingly.

Consider when used concomitantly:

• cardiac glycosides of the digitalis group – concomitant use may increase AV conduction time; however, clinical studies have not shown signs of this interaction; nebivolol does not affect digoxin kinetics;
• dihydropyridine-type calcium antagonists (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine) – concomitant use may increase the risk of arterial hypotension and may worsen ventricular pump function in patients with heart failure;
• antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, 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 effect of beta-blockers. Beta-adrenergic agents may lead to unopposed alpha-adrenergic activity of sympathomimetics possessing both alpha- and beta-adrenergic effects (risk of arterial hypertension, severe bradycardia, and heart block).

Pharmacokinetic interactions:

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 pronounced bradycardia and other adverse reactions.

Concomitant use with cimetidine increases plasma levels of nebivolol but does not alter the clinical efficacy of nebivolol. Concomitant use with ranitidine does not affect the pharmacokinetics of nebivolol. If the medicinal product Bivoneb is taken with food, and an antacid is administered between meals, both medicinal products may be prescribed 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 should be discontinued prior to surgery, beta-adrenergic blockers should be withdrawn at least 24 hours beforehand.

Use of certain anesthetics that cause myocardial depression requires caution. Vagal reactions in the patient 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-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 the 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 these conditions may worsen;
• Patients with first-degree AV block due to the negative influence of beta-adrenergic blockers on conduction;
• Patients with Prinzmetal's (vasospastic) angina due to unopposed alpha-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 (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 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 monitor blood glucose levels carefully (see section "Interaction with other medicinal products and other forms of interaction").

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 psoriasis in their medical history 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 when initiating treatment with nebivolol for chronic heart failure. For information on dosage and administration, see section "Dosage and administration".

Treatment should not be abruptly discontinued unless absolutely necessary (see section "Dosage and administration"). For additional information, refer to section "Dosage and administration".

Excipients

The medicinal product Bivoneb contains lactose monohydrate 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 sodium (23 mg) per tablet, i.e., is essentially "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, intrauterine death, abortion, and premature delivery. Adverse reactions (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 should not be used during pregnancy unless there is a clear necessity. If treatment with nebivolol is considered necessary, 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 observed. Hypoglycemia and bradycardia are generally expected within the first three days of life.

Breastfeeding

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. A risk to newborns/infants cannot be excluded. Therefore, breastfeeding during nebivolol treatment is not recommended.

Fertility

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

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 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 recommended 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 observed after 4 weeks.

Combination with Other Antihypertensive Agents

Beta-blockers may be used as monotherapy or in combination with other antihypertensive medicinal products. To date, an additional antihypertensive effect has only been observed when 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 (1/2 tablet) 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 this medicinal product is contraindicated in such patients.

Elderly Patients

For patients aged 65 years and older, the recommended initial dose is 2.5 mg (1/2 tablet) once daily. If necessary, the dose may be increased to 5 mg. However, due to limited experience with use in patients aged 75 years and older, caution and close monitoring are required when administering the medicinal product to these patients.

Chronic Heart Failure (CHF)

Treatment of CHF should begin with slow dose titration to achieve the individual optimal maintenance dose. This medicinal product should be prescribed to patients who have stable CHF without episodes of acute decompensation during the preceding 6 weeks. It is recommended that the prescribing physician has experience in managing CHF. 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 medicinal products for at least the previous 2 weeks before initiating therapy with this product.

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 (1/4 tablet) of nebivolol once daily, increase to 2.5 mg (1/2 tablet) 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 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 of heart failure symptoms). Not all patients can tolerate the highest recommended doses due to adverse reactions. If necessary, a previously achieved dose may be gradually reduced or treatment may be reinitiated at a lower dose.

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

Treatment of stable chronic heart failure with nebivolol is generally 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 reduced by halving it every week over a 1-week interval.

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 this medicinal product is contraindicated in these patients.

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 Bivoneb in children and adolescents (under 18 years of age) have not been studied. Data are unavailable. Therefore, the use of this medicinal product in children and adolescents (under 18 years of age) is not recommended.

Overdose

Data regarding overdose with this medicinal product are lacking.

Symptoms

Symptoms of beta-blocker overdose include bradycardia, arterial hypotension, bronchospasm, and acute heart failure.

Treatment

In case of overdose or development of hypersensitivity reactions, continuous 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 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. Arterial 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 a dose of 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. The injection may be repeated within one hour, and if needed, followed by continuous intravenous infusion of glucagon at 70 µg/kg/hour. 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; they are classified according to system organ classes and frequency of occurrence:

System organ disorders	Common (≥ 1/100 to <1/10)	Uncommon (≥ 1/1000 to <1/100)	Very rare (< 1/10000)	Frequency not known
Immune system disorders				Angioneurotic edema, hypersensitivity
Psychiatric disorders		Night terrors, depression
Nervous system disorders	Headache, dizziness, paraesthesia		Syncope
Eye disorders		Visual disturbance
Cardiac disorders		Bradycardia, heart failure, slowing of AV conduction / AV block
Vascular disorders		Arterial hypotension, worsening of intermittent claudication
Respiratory, thoracic and mediastinal disorders	Dyspnoea	Bronchospasm
Gastrointestinal disorders	Constipation, nausea, diarrhoea	Dyspepsia, flatulence, vomiting
Skin and subcutaneous tissue disorders		Pruritus, erythematous rash	Worsening of psoriasis	Urticaria
Reproductive system and breast disorders		Impotence
General disorders and administration site conditions	Increased fatigue, oedema

In addition, the following adverse reactions have been reported with some beta-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 that were 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, considered potentially related to the drug and clinically significant in the treatment of CHF, 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 nebivol, and in 1% of patients receiving placebo;
• Drug intolerance was observed in 1.6% of patients receiving nebivolol and in 0.8% of patients receiving placebo;
• First-degree AV block occurred in 1.4% of patients receiving nebivolol and in 0.9% of patients receiving placebo;
• Peripheral edema occurred in 1.0% of patients receiving nebivolol and in 0.2% of patients receiving placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC. Keep out of reach of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Hetero Labs Limited / Hetero Labs Limited.

Manufacturer's address and location of operations.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India / Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.