Nebivolol, tablets 5 mg 14 pcs

Pharmacotherapeutic group:

The selective β1-adrenoblocker.

The ATX code: C07AB12

Pharmacological properties

Pharmacodynamics

Nebivolol is a cardioselective β1-adrenoblocker and has antihypertensive, antianginal and antiarrhythmic effects. It reduces high blood pressure (BP) at rest, under physical stress and stress.

Competitively and selectively blocks postsynaptic β1-adrenoreceptors, making them inaccessible to catecholamines, modulates the release of endothelial vasodilatory factor nitric oxide (NO).

Nebivololol is a racemate of two enantiomers: SRRR-nebivolol

(D-nebivololol) and RSSS-nebivolol (L-nebivolol), combining two pharmacological actions:

• D-nebivololol is a competitive and highly selective blocker
  of β1-adrenoreceptors;
• L-nebivolol has a mild vasodilatory effect by modulating the release of vasodilatory factor (NO) from the vascular endothelium.

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

Hypotensive effect develops after ‑25 days of regular use of the drug. Sustained antihypertensive effect develops after 1-2 weeks of regular use of the drug, and in some cases – after 4 weeks, a stable effect is observed after ‑12 months.

With decreasing myocardial oxygen demand (heart rate (HR), decreasing ante- and post-load), nebivololol reduces the number and severity of angina attacks and increases exercise tolerance. Antiarrhythmic action is caused by the suppression of cardiac automatism (including in the pathological focus) and slowing of atrioventricular conduction.

Pharmacokinetics

Babsorption

After oral administration, it is rapidly absorbed from the gastrointestinal tract. Food intake has no effect on absorption, so nebivololol can be taken regardless of the time of meal. Bioavailability is approximately 12% in patients with “fast” metabolism (“primary passage” effect) and may be almost complete in patients with “slow” metabolism.

Distribution

In plasma both enantiomers are predominantly bound to albumin.

The binding to plasma proteins for D-nebivololol is 98.1%, for L-nebivolol is 97.9%.

Metabolism

Nebivololol is metabolized by alicyclic 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. The rate of metabolism of nebivolol by aromatic hydroxylation is genetically determined by oxidative polymorphism and depends on the CYP2D6 isoenzyme. The metabolic rate does not affect the efficacy of nebivolol.

Elimation

Extracted by the kidneys (38%) and through the intestine (48%). Half-life (T1/2) in patients with “fast” metabolism: hydroxymetabolites – 24 h, enantiomers of nebivololol – 10 h; in patients with “slow” metabolism: hydroxymetabolites – 48 h, enantiomers of nebivololol – 3050 ‑h. Excretion of unchanged nebivololol through the kidneys is less than 0.5% of the dose of the drug taken orally.

With regard to differences in metabolic rate, the dose of the drug should always be adjusted individually: patients with “slow” metabolism require a lower dose.

Indications

• arterial hypertension
• ischemic heart disease: prevention of attacks of angina pectoris
• chronic heart failure (as part of combination therapy).
  

Active ingredient

Nebivolol

Composition

1 tablet contains:

Active substance:

nebivololol hydrochloride – 5.45 mg (in terms of nebivololol –

5.00 mg).

Auxiliary substances:

Betadex – 23.00 mg;

Pregelatinized corn starch – 38.40 mg;

Microcrystalline cellulose – 108.55 mg;

crospovidone – 1.90 mg;

colloidal silica – 0.90 mg;

magnesium stearate – 1.80 mg.

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How to take, the dosage

Overly, preferably at the same time of day, regardless of the time of meals, without chewing and with plenty of liquid.

Arterial hypertension and coronary heart disease

The average daily dose of nebivololol is 2.55 mg once daily. For patients with renal impairment and patients over 65 years of age, a starting dose of 2.5 mg nebivololol is recommended daily.

If necessary, the daily dose of nebivololol can be increased to 10 mg (in one dose). The optimal therapeutic effect becomes pronounced after 1-2 weeks of taking the drug, and in some cases – after 4 weeks. Nebivolol can be used in combined therapy with other drugs reducing blood pressure.

Chronic heart failure

The dose of nebivololol is adjusted gradually until an individual optimal maintenance dose is achieved. Treatment of chronic heart failure with β-adrenoreceptor blockers should be initiated when clinically stable over the last two weeks.

The treatment starts with a dose of 1.25 mg once daily with gradual increase (at intervals of at least 2 weeks) to 2.55 mg once daily, if necessary to a maximum dose of 10 mg once daily. The patient should be under medical supervision for 2 hours after the first dose of the drug, as well as after each subsequent dose increase. During the dosing regimen selection, in case of deterioration of chronic heart failure or intolerance of the drug, it is recommended to reduce the dose of nebivolol or stop taking it. Nebivolol should not be stopped abruptly (unless necessary), as this may lead to a temporary exacerbation of the symptoms of heart failure. If discontinuation is necessary, withdrawal should be done gradually by halving the dose weekly.

Patients with renal impairment (CK less than 20 ml/min)

The starting dose is 2.5 mg/day. If necessary, the daily dose can be increased to 5 mg. In patients with impaired renal function (CKR less than 20 ml/min) the dose should be increased with special caution.

Patients of advanced age

For patients over 65 years of age, the starting dose is 2.5 mg/day. If necessary, the daily dose may be increased to 5 mg. However, taking into account the limited experience of using the drug in elderly patients, caution should be exercised and patients over 65 years of age should be carefully evaluated. There is no need for dose adjustment in elderly patients, so the dose should be adjusted individually, gradually increasing it to the maximum tolerated dose.

Interaction

Pharmacodynamic interaction

Concomitant use with “slow” calcium channel blockers (CMBs) (verapamil, diltiazem) increases the negative effects on myocardial contractility and atrioventricular conduction. Intravenous administration of verapamil is not recommended with nebivolol.

The concomitant use of nebivololol with hypotensive drugs, nitroglycerin may cause severe arterial hypotension (special caution is required when concomitant use with prazosin).

The concomitant use of nebivololol with hypotensive drugs of central action (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) may worsen the course of heart failure by reducing the sympathetic tone (reduced HR and cardiac output, vasodilation symptoms). In the case of abrupt withdrawal of these drugs, especially before withdrawal of nebivolol, the development of “ricochet” arterial hypertension (withdrawal syndrome) is possible.

The concomitant use of nebivololol and dihydropyridine type PBMCs (amlodipine, felodipine, lycidipine, nifedipine, nicardipine, nimodipine, nitrandipine) may increase the risk of arterial hypotension. An increased risk of further deterioration of ventricular pump function in patients with heart failure cannot be excluded.

Concomitant use with class I antiarrhythmic drugs (quinidine, flecainide, disopyramide, Michelitin) and with amiodarone may increase the negative inotropic effect and prolongation of atrial excitation time.

In concomitant use with cardiac glycosides no increased effect on delayed atrioventricular conduction was found.

The concomitant use of nebivololol and drugs for general anesthesia may cause suppression of reflex tachycardia and increase the risk of arterial hypotension.

There are no clinically significant interactions with nonsteroidal anti-inflammatory drugs.

Acetylsalicylic acid as an antiplatelet agent can be used concomitantly with nebivololol.

The concomitant use of nebivololol with tricyclic antidepressants, barbiturates and phenothiazine derivatives may increase the antihypertensive effect of nebivolol.

The concomitant use of nebivololol with insulin and hypoglycemic agents for oral administration may mask some symptoms of hypoglycemia (palpitations, tachycardia).

Concomitant administration with floktafenin is contraindicated: nebivololol may interfere with the compensatory cardiovascular reactions associated with hypotension or shock, which may be caused by floktafenin.

The concomitant use of nebivololol with baclofen, amifostine leads to increased arterial hypotension.

Concomitant use with sultopride leads to an increased risk of pirouette ventricular arrhythmias.

Concomitant use of sympathomimetic agents inhibits the activity of nebivololol.

Pharmacokinetic interaction.

Concomitant use of nebivololol with drugs that inhibit serotonin reuptake or with other drugs biotransformed with participation of CYP2D6 isoenzyme, increases plasma concentrations of nebivololol, nebivolol metabolism slows, which may lead to risk of bradycardia.

In concomitant use with digoxin, nebivololol has no effect on the pharmacokinetic parameters of digoxin.

Concomitant use with cimetidine increases plasma concentrations of nebivololol (data on the effect on the pharmacological effects of the drug are not available).

The concomitant use of nebivololol and ranitidine has no effect on the pharmacological parameters of nebivololol.

Concomitant use of nebivololol with nicardipine slightly increases plasma concentrations of the active substances, but this has no clinical significance.

The concomitant use of nebivololol and ethanol, furosemide or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol.

No clinically significant interaction of nebivololol and warfarin has been established.

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Special Instructions

The withdrawal of β-adreno-blockers should be done gradually, over 10 days (up to 2 weeks in patients with coronary heart disease).

The monitoring of BP and HR at the beginning of the drug should be daily.

In elderly patients, renal function control is necessary (once every 4-5 months). In angina pectoris, the drug dose should provide a resting HR of 55-60 beats/min, and not more than 110 beats/min during exercise.

The β-adrenoblockers can cause bradycardia: the dose should be reduced if the HR is less than 50-55 beats/min (see Contraindications).

When considering the use of Nebivololol in patients with psoriasis, the anticipated benefit of the drug must be carefully weighed against the possible risk of exacerbation of psoriasis.

Patients who wear contact lenses should be aware that the use of β-adrenoblockers may decrease tear fluid production.

In surgical procedures, the anesthesiologist should be advised that the patient is taking β-adrenoblockers.

Nebivololol has no effect on plasma glucose concentrations in patients with diabetes mellitus. However, caution should be exercised when treating these patients since Nebivolol may mask certain symptoms of hypoglycemia (e.g., tachycardia) caused by the use of hypoglycemic agents for oral administration and insulin. Monitoring of plasma glucose concentrations should be performed once every 4-5 months (in diabetic patients).

In thyroid hyperfunction, β-adrenoblockers may mask tachycardia.

β-adrenoblockers should be used with caution in patients with chronic obstructive pulmonary disease because bronchospasm may increase.

The β-adrenoblockers may increase allergen sensitivity and the severity of anaphylactic reactions.

The effectiveness of β-adrenoblockers is lower in smokers compared to nonsmokers.

Impact on driving and other machinery

At the time of treatment, caution should be exercised while driving vehicles and engaging in other potentially dangerous activities requiring increased concentration and rapid psychomotor reactions.

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Contraindications

• high sensitivity to any of the drug components;
• acute heart failure;
chronic heart failure in decompensation stage (requiring intravenous injection of drugs with inotropic action)
• expressed arterial hypotension (systolic BP less than 90 mmHg.
• significant arterial hypotension (systolic BP less than 90 mm Hg.)
• syndrome of sinus node weakness including sinoauricular block;
• atrioventricular block of II-III degree (without artificial pacemaker);
• bronchospasm and bronchial asthma in history;
• pheochromocyma (without concomitant use of a-adrenoblockers);
• metabolic acidosis;
• bradycardia (HR less than 50 beats/min);
• cardiogenic shock;
• severe hepatic dysfunction;
• severe peripheral circulatory disorders (intermittent claudication, Raynaud’s syndrome);
• myasthenia;
• depression;
• current use with floktafenine, sultopride (see “Interaction with other medicinal products.
• Above 18 years of age (efficacy and safety not established).

With caution

Renal insufficiency (creatinine clearance (CK) less than 20 ml/min), liver function disorders, diabetes mellitus, thyroid hyperfunction, 1st degree atrioventricular block, desensitization therapy, psoriasis, allergic diseases in anamnesis, chronic obstructive pulmonary disease, peripheral circulatory disorders, Prinzmetal angina, age over 65 years.

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Side effects

The incidence of the side effects listed below was determined according to the World Health Organization classification – very common (more than 10%), common (more than 1% and less than 10%), infrequent (more than 0.1% and less than 1%), rare (more than 0.01% and less than 0.1%), very rare (less than 0.01%), frequency unknown (according to available data the incidence cannot be estimated).

Immune system disorders: frequency unknown – angioedema, hypersensitivity.

Psychiatric disorders: infrequent – “nightmares” dreams, depression; very rare – hallucinations, psychosis, confusion.

Nervous system disorders: often – headache, dizziness, weakness, paresthesia; very rarely – fainting.

An organ of vision: frequency is unknown – visual impairment, dry eyes.

Gastrointestinal tract: common – nausea, constipation, diarrhea; infrequent – dyspepsia, flatulence, vomiting.

Cardiovascular system disorders: very common – bradycardia (in patients with CHF); common – aggravation of the course of CHF, atrioventricular block of degree I, orthostatic hypotension; infrequent – bradycardia, heart failure, slowed atrioventricular conduction/atrioventricular block, marked BP reduction, progression of associated “intermittent” claudication; very rare – Raynaud’s syndrome.

Skin and subcutaneous tissue: frequently – edema; infrequently – erythematous skin rash, itching, very rarely – worsening of psoriasis course; frequency unknown – alopecia.

Respiratory system: often – dyspnea; infrequently – bronchospasm (including in the absence of obstructive lung disease in the history).

Reproductive system: infrequent – erectile dysfunction.

General disorders: very frequently – dizziness (in patients with CHF); frequently – fatigue, edema, intolerance to the drug; infrequently – photodermatosis, hyperhidrosis (in patients with CHF); very rarely – coldness/cyanosis of extremities.

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Overdose

Symptoms:Serious decrease in BP, nausea, vomiting, cyanosis, bradycardia, atrioventricular block, acute heart failure, bronchospasm, loss of consciousness, cardiogenic shock, coma, cardiac arrest, hypoglycemia, seizures.

Treatment:Gastric lavage, administration of activated charcoal. In case of marked BP decrease, the patient should be given a horizontal position with elevated legs, if necessary, IV administration of fluids and vasopressors. In bradycardia, 0.5-2 mg of atropine should be administered by IV, and if there is no positive effect, a transvenous or intracardiac pacemaker may be placed.

In atrioventricular block (stage II-III), it is recommended that β-adrenomimetics should be administered by IV, and if they are ineffective, an artificial pacemaker should be considered. In cardiac insufficiency, treatment begins with administration of cardiac glycosides and diuretics; if there is no effect, it is reasonable to administer dopamine, dobutamine or vasodilators. In bronchospasm, IV β2-adrenomimetics are used. In ventricular extrasystole, lidocaine may be administered (Class IA antiarrhythmic agents are not used). Diazepam is recommended for seizures by intravenous injection. In hypoglycemia is shown with intravenous injection of dextrose (glucose).

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Similarities

Nebilet, Binelol, Nebilong, Nebivolol, Nebivolol-Teva, Nebivator, Nebivololol-SZ