Nebivator (Tablets) Instructions for Use

Marketing Authorization Holder

Torrent Pharmaceuticals, Ltd. (India)

ATC Code

C07AB12 (Nebivolol)

Active Substance

Nebivolol (Rec.INN registered by WHO)

Dosage Form

Nebivator

Tablets 5 mg: 100 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blister packs (10) – cardboard packs.

Clinical-Pharmacological Group

Third-generation beta₁-adrenoblocker with vasodilating properties

Pharmacotherapeutic Group

Beta-adrenergic blockers; selective beta-adrenergic blockers

Pharmacological Action

Cardioselective beta₁-adrenergic blocker of the third generation with vasodilating properties. The active substance is a racemate consisting of two enantiomers: D-nebivolol and L-nebivolol. D-Nebivolol is a competitive and highly selective blocker of β₁-adrenergic receptors;L-Nebivolol exerts a mild vasodilating effect by modulating the release of a vasodilating factor (NO) from the vascular endothelium.

Nebivolol reduces heart rate and blood pressure at rest and during exercise, reduces left ventricular end-diastolic pressure, decreases total peripheral vascular resistance, improves diastolic heart function (reduces filling pressure), increases ejection fraction; causes an antianginal effect in patients with coronary artery disease.

The antihypertensive effect is also due to a decrease in the activity of the renin-angiotensin system (does not directly correlate with changes in plasma renin activity).

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

Sustained antihypertensive effect develops after 1-2 weeks of regular use of the drug, and in some cases – after 4 weeks, stable action is noted after 1-2 months.

Pharmacokinetics

After oral administration, Nebivolol is rapidly absorbed from the gastrointestinal tract. Food intake does not affect absorption. Bioavailability averages 12% in individuals with rapid metabolism (first-pass effect through the liver) and is almost complete in individuals with slow metabolism.

In blood plasma, both enantiomers are predominantly bound to albumin. Plasma protein binding of D-nebivolol is 98.1%, L-nebivolol is 97.9%.

It is metabolized by acyclic and aromatic hydroxylation and partial N-dealkylation. The resulting hydroxy and amino derivatives conjugate with glucuronic acid and are excreted as O- and N-glucuronides.

It is excreted by the kidneys (38%) and through the intestines (48%).

In individuals with rapid metabolism, the T_1/2 of hydroxymetabolites is 24 hours, enantiomers of nebivolol – 10 hours; in individuals with slow metabolism: hydroxymetabolites – 48 hours, enantiomers of nebivolol – 30-50 hours.

The excretion of unchanged nebivolol in urine is less than 0.5%.

Indications

Arterial hypertension.

Stable chronic heart failure of mild to moderate severity (as part of combination therapy) in patients over 70 years of age.

ICD codes

Dosage Regimen

Administer orally. Swallow the tablet whole with water, with or without food.

For arterial hypertension, initiate therapy at 5 mg once daily.

For elderly patients or those with a predisposition to bradycardia, consider a starting dose of 2.5 mg once daily.

The maximum daily dose is 10 mg.

Titrate the dose upwards, if necessary, at intervals of 1-2 weeks.

For stable chronic heart failure (mild to moderate severity, as adjunct therapy in patients over 70), initiate treatment only after stabilization of the condition.

Begin heart failure therapy at 1.25 mg once daily.

Increase the dose to 2.5 mg, then to 5 mg, and finally to the maximum tolerated dose of 10 mg once daily.

Double the dose at 1-2 week intervals, based on patient tolerance.

Monitor patients for signs of worsening heart failure, bradycardia, or hypotension during the titration phase.

In patients with renal impairment (creatinine clearance >20 mL/min), use with caution; no specific dosage adjustment is required.

In patients with mild to moderate hepatic impairment, use with caution; initiate therapy at a low dose.

Do not abruptly discontinue therapy. Gradually reduce the dose over 1-2 weeks under medical supervision.

Adverse Reactions

Immune system disorders: very rarely – angioedema, hypersensitivity reactions.

Psychiatric disorders: infrequently – depression, “nightmare” dreams, psychosis; very rarely – hallucinations, confusion.

Nervous system disorders: very frequently – dizziness; frequently – headache, dizziness, weakness, paresthesia; very rarely – syncope.

Eye disorders: infrequently – visual impairment; rarely – dry eyes.

Cardiac and vascular disorders: very frequently – bradycardia; frequently – worsening of chronic heart failure, first-degree AV block, orthostatic hypotension; infrequently – peripheral edema, bradycardia, heart failure, AV block, marked decrease in blood pressure, progression of concomitant “intermittent” claudication; very rarely – Raynaud’s syndrome.

Respiratory, thoracic and mediastinal disorders: frequently – dyspnea; infrequently – bronchospasm (including in patients without a history of obstructive pulmonary disease).

Gastrointestinal disorders: frequently – nausea, constipation, diarrhea; infrequently – dyspepsia, flatulence, vomiting.

Skin and subcutaneous tissue disorders: infrequently – erythematous skin rash, itching; very rarely – exacerbation of psoriasis, urticaria; frequency unknown – alopecia.

Other: frequently – increased fatigue; infrequently – photodermatosis, hyperhidrosis; erectile dysfunction; very rarely – coldness/cyanosis of the extremities.

Contraindications

Hypersensitivity to nebivolol; acute heart failure; chronic heart failure in the stage of decompensation (requiring intravenous administration of drugs with positive inotropic action); severe arterial hypotension (systolic blood pressure less than 90 mm Hg); sick sinus syndrome, including sinoatrial block; second and third-degree AV block (without an artificial pacemaker); bradycardia (heart rate less than 60 beats/min); cardiogenic shock; pheochromocytoma (without simultaneous use of alpha-adrenergic blockers); metabolic acidosis; severe liver dysfunction; severe renal impairment (creatinine clearance less than 20 ml/min); bronchospasm and bronchial asthma in history; severe obliterating peripheral vascular diseases (intermittent claudication, Raynaud’s syndrome); myasthenia; depression; simultaneous use with floctafenine, sultopride; breastfeeding period; children and adolescents under 18 years of age.

With caution renal impairment (creatinine clearance more than 20 ml/min); diabetes mellitus; hyperfunction of the thyroid gland; burdened allergic history; psoriasis; COPD; first-degree AV block; Prinzmetal’s angina; use in elderly patients (over 65 years of age); desensitizing therapy; liver dysfunction; peripheral circulation disorders of mild or moderate severity.

Use in Pregnancy and Lactation

Use during pregnancy is possible only for vital indications, when the expected benefit to the mother outweighs the potential risk to the fetus (due to the possibility of fetal growth retardation, intrauterine fetal death, premature birth, as well as the development of bradycardia, arterial hypotension, hypoglycemia, and respiratory paralysis in the newborn).

If it is necessary to use during lactation, the issue of stopping breastfeeding should be decided.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction. Should be used with caution in patients with liver dysfunction.

Use in Renal Impairment

Contraindicated in severe renal impairment (creatinine clearance less than 20 ml/min). Should be used with caution in patients with renal impairment.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in patients over 65 years of age. Monitoring of laboratory parameters of renal function in elderly patients should be performed once every 4-5 months.

Special Precautions

Abrupt discontinuation of beta-adrenergic blockers is unacceptable (with abrupt cessation of treatment, a “withdrawal” syndrome may develop), treatment should be discontinued gradually if possible.

Monitoring of patients taking beta-adrenergic blockers includes observation of heart rate and blood pressure (at the beginning of administration – daily, then once every 3-4 months).

In elderly patients, monitoring of renal function is necessary (once every 4-5 months).

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

Beta-adrenergic blockers can cause bradycardia: the dose should be reduced if the heart rate is less than 50-55 beats/min.

Beta-adrenergic blockers should be used with caution in the following groups of patients: with peripheral circulation disorders; with first-degree AV block, since beta-adrenergic blockers negatively affect the conduction time; with Prinzmetal’s angina due to unhindered α-receptor-mediated vasoconstriction of the coronary artery: beta-adrenergic antagonists may increase the number and duration of angina attacks.

Beta-adrenergic blockers should be used with caution in patients with COPD, as bronchospasm may increase.

Beta-adrenergic blockers should not be used in patients with untreated chronic heart failure until the condition has stabilized.

Treatment of chronic heart failure with nebivolol is carried out against the background of stable cardiovascular parameters no earlier than 6 weeks after the end of the decompensation period. Nebivolol can be used for the therapy of chronic heart failure simultaneously with thiazide diuretics, digoxin, ACE inhibitors or angiotensin II receptor antagonists.

In smoking patients, the effectiveness of beta-adrenergic blockers is lower than in non-smokers.

Nebivolol does not affect blood glucose concentration in patients with diabetes mellitus, however, under the influence of nebivolol, signs of hypoglycemia (tachycardia, palpitations) caused by the use of hypoglycemic agents may be masked. In patients with diabetes mellitus, blood glucose concentration should be monitored once every 4-5 months.

Beta-adrenergic blockers should be used with caution in patients with hyperfunction of the thyroid gland because clinical signs of hyperthyroidism, such as tachycardia, may be masked under their influence. Abrupt withdrawal of nebivolol may cause exacerbation of disease symptoms and the development of a thyrotoxic crisis.

The use of nebivolol in patients with pheochromocytoma is possible only with the simultaneous use of alpha-adrenergic blockers.

Beta-adrenergic blockers may increase sensitivity to allergens and the severity of anaphylactic reactions. Nebivolol may be the cause of a severe reaction to a number of allergens when prescribed to patients with a history of a severe anaphylactic reaction to these allergens. Such patients may not respond to the usual doses of epinephrine (adrenaline) used to treat anaphylactic shock.

When deciding on the prescription of the drug to patients with psoriasis, the expected benefit from the use of nebivolol and the possible risk of exacerbation of psoriasis should be carefully weighed.

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.

If surgical intervention is required during therapy with nebivolol, the anesthesiologist surgeon must be informed about the nature of the therapy being carried out. Continuation of beta-adrenergic blockade reduces the risk of arrhythmia during anesthesia induction and intubation. If preparation for surgery implies interruption of beta-adrenergic blockade, beta-adrenergic antagonists should be discontinued at least 24 hours before surgery.

Anesthetics that cause myocardial depression should be used with caution.

Vagal reactions in a patient can be prevented by intravenous administration of atropine.

Effect on the ability to drive vehicles and mechanisms

Nebivolol does not affect the speed of psychomotor reactions. During the administration of nebivolol, dizziness and a feeling of fatigue are sometimes possible, so patients taking Nebivolol should refrain from engaging in potentially hazardous activities.

Drug Interactions

Simultaneous use with floctafenine is contraindicated. Nebivolol can prevent compensatory reactions of the cardiovascular system associated with arterial hypotension or shock, which can be caused by floctafenine.

Simultaneous use of nebivolol and sultopride is contraindicated, since their simultaneous use is associated with an increased risk of ventricular arrhythmia, especially polymorphic ventricular tachycardia of the “torsades de pointes” type.

With simultaneous use with class I antiarrhythmic agents (quinidine, hydroquinidine, flecainide, cibenzoline, disopyramide, lidocaine, mexiletine, propafenone), an increase in the negative inotropic effect and prolongation of the excitation conduction time through the AV node is possible.

With simultaneous use of beta-adrenergic blockers with slow calcium channel blockers (verapamil and diltiazem), the negative effect on myocardial contractility and AV conduction is enhanced. Intravenous administration of verapamil against the background of nebivolol intake is contraindicated.

With simultaneous use with centrally acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine), worsening of heart failure is possible due to a decrease in sympathetic tone (decrease in heart rate and cardiac output, symptoms of vasodilation). In case of abrupt withdrawal of these drugs, especially before the withdrawal of nebivolol, the development of “rebound” arterial hypertension (“withdrawal” syndrome) is possible.

With simultaneous use with class III antiarrhythmic agents (amiodarone), the effect on the conduction time through the AV node may be enhanced.

With simultaneous use of nebivolol with insulin and oral hypoglycemic agents, symptoms of hypoglycemia (palpitations, tachycardia) may be masked.

Simultaneous use of nebivolol and drugs for general anesthesia can cause suppression of reflex tachycardia and increase the risk of arterial hypotension.

Simultaneous intake of nebivolol with baclofen, amifostine, with antihypertensive drugs can cause a significant drop in blood pressure, so correction of the doses of antihypertensive drugs is required.

With simultaneous use of nebivolol with cardiac glycosides, slowing of AV conduction is possible. Nebivolol does not affect the pharmacokinetic parameters of digoxin.

Simultaneous use of nebivolol and dihydropyridine slow calcium channel blockers (amlodipine, felodipine, lercanidipine, nifedipine, nicardipine, nimodipine, nitrendipine) may increase the risk of arterial hypotension. An increase in the risk of further decrease in myocardial contractility in patients with heart failure cannot be excluded.

With simultaneous use of nebivolol with antihypertensive agents, nitroglycerin, pronounced arterial hypotension may develop (special caution is necessary when combined with prazosin).

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

No clinically significant interaction between nebivolol and NSAIDs has been established. Acetylsalicylic acid as an antiplatelet agent can be used simultaneously with nebivolol. With simultaneous use, sympathomimetic agents may suppress the activity of beta-adrenergic blockers.

When using nebivolol in combination with drugs that inhibit serotonin reuptake or other drugs metabolized with the participation of the CYP2D6 isoenzyme (for example, paroxetine, fluoxetine, thioridazine, quinidine), the metabolism of nebivolol slows down, the concentration of nebivolol in the blood plasma increases, which may lead to the risk of bradycardia and other side effects.

Rifampicin enhances the metabolism of nebivolol.

With simultaneous use of nebivolol with nicardipine, the concentrations of active substances in the blood plasma slightly increase without changing the clinical effect.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.