Nebolet

INSTRUCTIONS for medical use of the medicinal product NEBILETâ (NEBILETâ)

Composition:

Active substance: nebivolol;

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

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

Pharmaceutical form. Tablets.

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

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 mediated by 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.

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

During short-term and long-term treatment with nebivolol in patients with arterial hypertension, systemic vascular resistance decreases. Despite the 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 nitric oxide-mediated vascular response to acetylcholine (ACh); in patients with endothelial dysfunction, this response is reduced.

In a placebo-controlled morbidity-mortality study involving 2128 patients aged ≥70 years (mean age 75.2 years) with stable chronic heart failure with reduced or preserved 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 emerged 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 left ventricular ejection fraction in study participants. Benefit regarding prevention of all-cause mortality compared to placebo did not reach statistical significance (absolute reduction – 2.3%).

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

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

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

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

Available preclinical and clinical data have not shown that nebivolol negatively affects erectile function in patients with hypertension.

Pharmacokinetics.

After oral administration, both enantiomers of nebivolol are rapidly absorbed. 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 who are rapid metabolizers and is nearly complete in those who are slow metabolizers. 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 ranges from 1.3 to 1.4 times. Due to differences in metabolic rates, the dose of Nebilet® should always be adjusted according to individual patient needs; therefore, lower doses may be required in slow metabolizers.

In rapid metabolizers, 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 rapid metabolizers.

In rapid metabolizers, 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 of nebivolol in the range of 1 to 30 mg are dose-proportional. 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 accounts for less than 0.5% of the dose.

Preclinical Safety Data.

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

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 listed in the section "Composition";
• 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.

Additionally, like other β-blockers, Nebilet® 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 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 associated 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 be increased (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 severe 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 exacerbate heart failure due to reduced central sympathetic tone (reduced heart rate and stroke volume, vasodilation) (see section "Special precautions for use"). Upon abrupt discontinuation, particularly before stopping β-blocker therapy, the risk of increased blood pressure may rise (withdrawal syndrome).

Use with caution when combined:

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 a patient is taking Nebilet®, the anesthesiologist should be informed.

Insulin and oral antidiabetic agents: although nebivolol does not affect blood glucose levels, concomitant use may mask certain symptoms of hypoglycemia (palpitations, tachycardia). Concurrent 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): concomitant use with antihypertensive agents may lead to a significant decrease in blood pressure; therefore, the dose of antihypertensive agents should be adjusted accordingly.

Consider when used concomitantly:

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, a worsening of 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 effect of nebivolol.

Sympathomimetic agents: concomitant use may counteract the antihypertensive effect of β-blockers. Substances with β-adrenergic activity may enhance α-adrenergic activity of sympathomimetics that have 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 thus increase the risk of pronounced bradycardia and 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 Nebilet® is taken with food and the antacid is administered between meals, both medicinal products may be used 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-adrenoblockers.

Anesthesia.

Maintaining 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-adrenoreceptor blockers should be withdrawn at least 24 hours beforehand.

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

Cardiovascular system.

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

Beta-adrenoblocker 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 angina exacerbation.

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

Beta-adrenoreceptor 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-adrenoreceptor blockers on conduction;

c) patients with Prinzmetal's angina due to unopposed α-adrenoreceptor-mediated coronary artery vasoconstriction: beta-adrenoreceptor 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 types of interactions").

Metabolism and endocrine system.

Nebiletâ does not affect blood glucose levels in diabetic patients. Nevertheless, caution is required when administering it to these patients, as nebivolol may mask certain symptoms of hypoglycemia (tachycardia, palpitations). Beta-blockers may further increase the risk of severe hypoglycemia when used concomitantly with sulfonylurea derivatives. Diabetic patients should be advised to closely monitor their blood glucose levels (see section "Interaction with other medicinal products and other types of interactions").

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

Respiratory system.

Beta-adrenoblockers should be used with caution in patients with chronic obstructive airway diseases, as bronchoconstriction may be intensified.

Other.

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

Beta-adrenoreceptor 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. For information on method of administration and dosage, see section "Dosage and administration".

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

The medicinal product contains lactose. Nebilet® 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., it 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-adrenoblockers 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 beta-blocker therapy is necessary, β1-selective beta-adrenoblockers are preferred.

Nebivolol must not be used during pregnancy unless clearly necessary. If treatment with nebivolol is considered necessary, 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 observed. Hypoglycemia and bradycardia are generally expected within the first three days.

Lactation 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. Risk to newborns/infants cannot be excluded. Therefore, mothers receiving nebivolol should not breastfeed.

Fertility

Nebivolol did not affect fertility in rats, except at doses several times higher than the maximum recommended human dose, where adverse effects on reproductive organs in male and female rats and mice were 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 Nebiletâ 5 mg does not affect psychomotor function. However, the possible occurrence of dizziness and fatigue should be taken into account when driving or operating machinery.

Dosage and Administration

Dosing regimen

Arterial hypertension

Adults:

The dose is 1 tablet (5 mg of nebivolol) once daily. It is recommended to take it at the same time each day. The antihypertensive effect becomes apparent 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 Nebilet® 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 Nebilet® 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 the use of the medicinal product in patients aged over 75 years, its use requires caution and careful monitoring of these patients.

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 chronic heart failure without episodes of acute decompensation during the past 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 medications for at least the past 2 weeks prior to initiating therapy with Nebilet®.

Initial dose titration should follow the scheme below, with intervals of 1 to 2 weeks between dose increases, based on patient tolerability: starting with 1.25 mg of nebivolol once daily, increasing to 2.5 mg 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 arterial pressure, heart rate, myocardial conduction disturbances, and worsening of heart failure symptoms). The occurrence of adverse effects may prevent treatment escalation to the maximum recommended dose in all patients. 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 first be reduced, or, if necessary, the medicinal product should be discontinued immediately (in case of severe hypotension, worsening heart failure symptoms with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia, or atrioventricular block).

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

Nebivolol treatment should not be 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 one 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

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

Elderly patients

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

Administration method

Oral administration.

The tablets may be taken with or without food.

Children

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

Overdose

Data regarding overdose with Nebilet® are not available.

Symptoms

Symptoms of β-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 should be ensured. Blood glucose levels should be monitored. Gastric lavage, activated charcoal, and laxatives may prevent absorption of any remaining medicinal product in the gastrointestinal tract. Mechanical ventilation may also be required. For the 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.

The β-blocking effect 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 case of resistance, isoprenaline may be combined with dopamine. If this is ineffective, glucagon may be administered intravenously 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 a rate of 70 µg/kg/hour. In extreme cases of therapy-resistant bradycardia, temporary cardiac pacing may be required.

Adverse reactions.

Adverse events in arterial hypertension and chronic heart failure are listed separately 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:

System organ class	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		Nightmares, depression
Nervous system disorders	Headache, dizziness, paraesthesia		Syncope
Eye disorders		Visual disturbance
Cardiac disorders		Bradycardia, heart failure, slowing of atrioventricular 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 β-adrenoblockers: hallucinations, psychosis, 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 (31.5%) patients 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, considered at least potentially related to the drug and regarded as clinically 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 was observed 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 was observed 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 authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep the medicinal product out of the reach of children.

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

Prescription status. Prescription only.

Manufacturer. BERLIN-CHEMIE AG / BERLIN-CHEMIE AG.

Manufacturer's address and place of business.

Glienicker Weg 125, 12489 Berlin, Germany / Glienicker Weg 125, 12489 Berlin, Germany.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A. / Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder.

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