Nebilan Lannacher (Tablets) Instructions for Use

Marketing Authorization Holder

Lannacher Heilmittel, GmbH (Austria)

ATC Code

C07AB12 (Nebivolol)

Active Substance

Nebivolol (Rec.INN registered by WHO)

Dosage Form

Nebilan Lannacher

Tablets 5 mg: 14 or 28 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, biconvex, with a cross-shaped score line.

Excipients : lactose monohydrate 143.475 mg, corn starch 34.50 mg, croscarmellose sodium 13.8 mg, hypromellose (6 cps) 3.45 mg, microcrystalline cellulose 26.45 mg, colloidal silicon dioxide 0.575 mg, magnesium stearate 2.30 mg.

10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Third-generation beta₁-adrenoblocker with vasodilating properties

Pharmacotherapeutic Group

Selective beta1-adrenergic blocker

Pharmacological Action

Cardioselective third-generation beta₁-adrenergic blocker with vasodilating properties; exerts antihypertensive, antianginal, and antiarrhythmic action.

It selectively and competitively blocks synaptic and postsynaptic beta₁-adrenergic receptors, making them inaccessible to catecholamines, and modulates the release of the endothelial vasodilating factor (NO).

Nebivolol reduces heart rate and blood pressure at rest and during exercise, and improves the diastolic function of the heart (reduces the left ventricular end-diastolic filling pressure).

Nebivolol is a racemate consisting of a mixture of two enantiomers – D- and L-nebivolol, which have different pharmacodynamic properties.

D-Nebivolol is a competitive and highly selective beta₁-adrenergic receptor blocker. L-Nebivolol exerts a mild vasodilating action by modulating the release of the relaxing factor (NO) from the vascular endothelium.

It reduces elevated blood pressure at rest, during exercise, and under stress.

The decrease in blood pressure is due to a reduction in cardiac output, a decrease in circulating blood volume (CBV) and total peripheral vascular resistance, and a decrease in the activity of the renin-angiotensin-aldosterone system.

The antihypertensive effect occurs after 2-5 days, and a stable effect is noted after 1-2 months.

The antihypertensive effect persists during long-term treatment.

By reducing the myocardial oxygen demand (decrease in heart rate, reduction in pre- and afterload), it reduces the number and severity of angina attacks and increases exercise tolerance.

The antiarrhythmic action is due to the suppression of pathological cardiac automatism (including in the pathological focus) and slowing of atrioventricular (AV) conduction.

Pharmacokinetics

Absorption

After oral administration, Nebivolol is rapidly absorbed from the gastrointestinal tract. Food intake does not affect the absorption of the drug, so Nebivolol can be taken regardless of meals.

Oral bioavailability is about 12% in individuals with “rapid” metabolism and is almost complete in individuals with “slow” metabolism.

The efficacy of nebivolol does not depend on the rate of metabolism.

Distribution

Plasma protein binding for D-nebivolol is 98.1%, for L-nebivolol is 97.9%.

Metabolism

Nebivolol is metabolized by acyclic or aromatic hydroxylation, N-dealkylation, and glucuronidation; in addition, glucuronides of hydroxymetabolites are formed.

The metabolism of nebivolol via the aromatic hydroxylation pathway is influenced by the genetic polymorphism of the CYP2D6 enzyme system.

In patients with “rapid” metabolism, the T_1/2 values of nebivolol enantiomers average 10 hours; in patients with “slow” metabolism, these values increase by 3-5 times.

The T_1/2 of hydroxymetabolites is 24 hours in individuals with “rapid” metabolism, and approximately 2 times longer in individuals with “slow” metabolism.

The equilibrium plasma concentration of nebivolol in most patients with “rapid” metabolism is reached within 24 hours; for the hydroxymetabolite, this period increases to several days.

Excretion

The drug is excreted by the intestine (48%) and by the kidneys (38%). The excretion of unchanged nebivolol by the kidneys does not exceed 0.5% of the administered dose.

Indications

• Arterial hypertension (monotherapy or in combination with other antihypertensive agents);
• Ischemic heart disease: prevention of attacks of stable exertional angina;
• Chronic heart failure (as part of combination therapy).

ICD codes

Dosage Regimen

Nebilan Lannacher should be taken orally, regardless of meals, with a sufficient amount of liquid, preferably at the same time of day.

For arterial hypertension and ischemic heart disease, 2.5-5 mg (1/2 of a 5 mg tablet – 1 tablet of 5 mg) once a day. If necessary, the daily dose can be increased to 10 mg (2 tablets of 5 mg at one time).

The maximum daily dose is 10 mg. In patients with renal insufficiency (creatinine clearance more than 20 ml/min), as well as in patients over 65 years of age, the initial dose is 2.5 mg/day (1/2 of a 5 mg tablet). If necessary, the dose is increased to 5 mg. In severe renal impairment (creatinine clearance less than 20 ml/min), the maximum daily dose is 10 mg. Dose increase in such patients should be carried out with particular caution.

Chronic heart failure treatment of chronic heart failure (CHF) should begin with a gradual increase in the dose until an individual optimal maintenance dose is reached.

Dose selection at the beginning of treatment should be carried out according to the following scheme, maintaining weekly intervals and based on the patient’s tolerance of this dose: a dose of 1.25 mg of Nebilan Lannacher (1/4 of a 5 mg tablet) once a day can be increased first to 2.5-5 mg of Nebilan Lannacher (1/2 tablet of 5 mg – 1 tablet), and then to 10 mg (2 tablets of 5 mg) once a day.

The patient should be under medical supervision for 2 hours after taking the first dose of the drug, and after each subsequent dose increase.

Each dose increase should be made no less than every 2 weeks.

The maximum recommended dose for CHF therapy is 10 mg of the drug once a day.

During titration, regular monitoring of blood pressure, heart rate, and symptoms of CHF severity is recommended.

During the titration phase, in case of worsening of chronic heart failure or drug intolerance, it is recommended to reduce the dose or, if necessary, immediately stop its administration (in case of pronounced arterial hypotension, worsening of CHF with acute pulmonary edema, in case of cardiogenic shock, symptomatic bradycardia, or AV block).

Adverse Reactions

Nervous system disorders headache, dizziness, increased fatigue, paresthesia; depression, drowsiness, “nightmares”, hallucinations, confusion, psychosis, convulsions, insomnia, amnesia.

Digestive system disorders nausea, constipation, diarrhea, dry oral mucosa, flatulence.

Cardiovascular system disorders bradycardia, orthostatic hypotension, dyspnea, edema, AV block, worsening of chronic heart failure, exacerbation of “intermittent” claudication; cardiac arrhythmias, Raynaud’s syndrome, cardialgia, pronounced decrease in blood pressure.

Visual disorders visual impairment (dry eyes).

Allergic reactions skin itching, erythematous rash, angioedema, skin hyperemia, alopecia.

Respiratory system disorders bronchospasm (including in the absence of a history of obstructive pulmonary diseases), bronchospasm in patients with a history of bronchial asthma or airway obstruction, rhinitis.

Other photodermatosis, hyperhidrosis, exacerbation of psoriasis, erectile dysfunction.

Contraindications

• Severe liver dysfunction;
• Acute heart failure, cardiogenic shock, chronic heart failure in the stage of decompensation (requiring inotropic therapy);
• AV block II-III degree;
• Sick sinus syndrome, sinoatrial block;
• Severe bradycardia (heart rate less than 50/min);
• Severe arterial hypotension;
• Severe peripheral circulatory disorders (intermittent claudication, Raynaud’s syndrome);
• Severe form of bronchial asthma and bronchospasm in history;
• Pheochromocytoma (without simultaneous use of alpha-adrenergic blockers);
• Metabolic acidosis;
• Myasthenia gravis, muscle weakness;
• Depression;
• Lactose intolerance, lactase deficiency or glucose-galactose malabsorption;
• Concomitant use with floctafenine, sultopride;
• Age under 18 years;
• Lactation period;
• Hypersensitivity to nebivolol or other components of the drug.

With caution the drug should be used in severe renal failure (creatinine clearance (CC) less than 20 ml/min), liver function disorders, diabetes mellitus, hyperthyroidism, desensitizing therapy, psoriasis, first-degree atrioventricular block, Prinzmetal’s angina, chronic obstructive pulmonary disease (COPD), in elderly patients (over 65 years of age).

Use in Pregnancy and Lactation

During pregnancy, the drug is prescribed when the benefit to the mother outweighs the risk to the fetus (due to the possible development of bradycardia, arterial hypotension, hypoglycemia, and respiratory paralysis in the newborn).

Treatment should be discontinued 48-72 hours before delivery.

Animal studies have shown that Nebivolol is excreted in breast milk.

If the use of the drug during lactation is necessary, breastfeeding should be discontinued.

Use in Hepatic Impairment

The drug is contraindicated in severe liver dysfunction.

Use with caution in liver function disorders.

Use in Renal Impairment

Use the drug with caution in severe renal failure (creatinine clearance (CC) less than 20 ml/min).

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Use with caution in elderly (over 65 years of age) individuals. In elderly patients, it is recommended to monitor renal function (once every 4-5 months).

Special Precautions

In exertional angina, the dose of the drug should provide a resting heart rate within 55-60 beats/min, and during exercise – no more than 110 beats/min.

Monitoring of heart rate and blood pressure is necessary, at the beginning of administration – daily; for the concentration of blood glucose levels in patients with diabetes (once every 4-5 months).

In elderly patients, it is recommended to monitor renal function (once every 4-5 months).

Beta-adrenergic blockers should be used with caution in patients with chronic obstructive pulmonary disease, as bronchospasm may increase.

The effectiveness of beta-adrenergic blockers in smokers is lower than in non-smoking patients.

During surgical interventions, the anesthesiologist should be informed about the patient taking nebivolol.

The drug may enhance the manifestations of peripheral arterial circulation disorders.

In diabetes mellitus, the drug may mask hypoglycemia.

In hyperthyroidism, the drug may neutralize tachycardia.

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

Patients using contact lenses should take into account that during treatment with beta-adrenergic blockers, a decrease in the production of tear fluid is possible.

The use of the drug in athletes may lead to positive doping test results.

Discontinuation of beta-adrenergic blockers should be carried out gradually, over 10 days (up to 2 weeks in patients with ischemic heart disease).

Effect on the ability to drive vehicles and mechanisms

No negative effect on the ability to drive vehicles or other complex mechanisms while taking Nebilan Lannacher has been observed; however, caution should be exercised when driving vehicles and operating machinery.

Overdose

Symptoms pronounced decrease in blood pressure, nausea, vomiting, cyanosis, severe bradycardia, atrioventricular block (AV block), acute heart failure, bronchospasm, loss of consciousness, coma, cardiogenic shock, cardiac arrest.

Treatment gastric lavage, activated charcoal; in case of a pronounced decrease in blood pressure, place the patient in a horizontal position with legs elevated, if necessary, intravenous administration of fluids and vasopressors, if necessary – glucagon; for bradycardia – intravenous administration of 0.5-2 mg of atropine, if there is no positive effect, transvenous or intracardiac pacing may be performed; for AV block II-III degree, the administration of beta-adrenergic stimulants is recommended; if they are ineffective, the installation of an artificial pacemaker should be considered; for heart failure, treatment begins with the administration of cardiac glycosides and diuretics; if there is no effect, the administration of dopamine, dobutamine, or vasodilators is advisable; for bronchospasm — intravenous administration of beta-2-adrenergic agonists. For ventricular extrasystoles – lidocaine (class Ia drugs are not used). For convulsions — intravenous diazepam.

Drug Interactions

Floctafenine: in case of shock or arterial hypotension caused by floctafenine, beta-adrenergic blockers weaken the compensatory mechanisms of the cardiovascular system.

Sultopride: increased risk of ventricular arrhythmia, especially of the “torsade de pointes” type.

With simultaneous use of beta-adrenergic blockers with slow calcium channel blockers (CCBs) (verapamil, diltiazem), the negative effect on myocardial contractility and AV conduction is enhanced. Intravenous administration of verapamil against the background of nebivolol is contraindicated. When combined with antihypertensive agents, nitroglycerin, or CCBs, pronounced arterial hypotension may develop (particular caution is necessary when combined with prazosin).

With simultaneous use with class I antiarrhythmic drugs and with amiodarone, an increase in the negative inotropic effect and prolongation of atrial excitation conduction time is possible.

With simultaneous use of nebivolol with cardiac glycosides, no effect on slowing AV conduction was detected. Simultaneous use of nebivolol and drugs for general anesthesia can cause suppression of reflex tachycardia and increase the risk of arterial hypotension.

No clinically significant interaction between nebivolol and non-steroidal anti-inflammatory drugs (NSAIDs) has been established. Acetylsalicylic acid as an antiplatelet agent can be used simultaneously with nebivolol.

Simultaneous use of tricyclic antidepressants, barbiturates, and phenothiazine derivatives may enhance the hypotensive effect of nebivolol.

Baclofen, amifostine: their simultaneous use with antihypertensive drugs can cause a significant drop in blood pressure, so dose adjustment of antihypertensive drugs is required.

Mefloquine: theoretically, co-administration of mefloquine with nebivolol may lead to QT interval prolongation.

Insulin and other hypoglycemic drugs: although Nebivolol does not affect glucose levels, its use simultaneously with insulin and other hypoglycemic drugs may mask the symptoms of hypoglycemia (palpitations and tachycardia).

With simultaneous use with eye drops containing beta-adrenergic blockers, the effect of nebivolol may be enhanced.

Pharmacokinetic interaction

With simultaneous use with drugs that inhibit serotonin reuptake, or with other agents biotransformed with the participation of the CYP2D6 isoenzyme, the metabolism of nebivolol slows down. With simultaneous use, Nebivolol does not affect the pharmacokinetic parameters of digoxin.

With simultaneous use with cimetidine, the plasma concentration of nebivolol increases (data on the effect on the pharmacological effects of the drug are lacking). Simultaneous use of ranitidine does not affect the pharmacological parameters of nebivolol.

With simultaneous use of nebivolol with nicardipine, the plasma concentrations of the active substances increase somewhat, but this has no clinical significance.

Simultaneous intake of ethanol, furosemide, or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol.

No clinically significant interaction between nebivolol and warfarin has been established. With simultaneous use, sympathomimetic agents suppress the activity of nebivolol.

Storage Conditions

Does not require special storage conditions. Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.