Nebivolol-SZ, tablets 5 mg 56 pcs

Pharmacotherapeutic drug group:

beta 1 – adrenoblocker selective

ATC code: [C07AB12]

Pharmacological properties

Pharmacodynamics

The cardioselective β1-adrenoblocker. Nebivolol has hypotensive, antianginal and antiarrhythmic effects. Reduces elevated blood pressure (BP) at rest, during physical exertion and stress. Competitively and selectively blocks postsynaptic β1-adrenoreceptors, making them unavailable for catecholamines, models the release of endothelial vasodilatory factor nitric oxide (NO).

Nebivololol is a racemate of two enantiomers: SRRR-nebivolol (D-nebivolol) and RSSS-nebivolol (L-nebivolol), combining two pharmacological actions:

– D-nebivololol is a competitive and highly selective blocker of β1-adrenoreceptors;

– L-nebivololol has a mild vasodilator effect by modulating the release of vasodilatory factor (NO) from the vascular endothelium.

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

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

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

Pharmacokinetics

Intake. Both enantiomers are rapidly absorbed after oral administration. Food intake has no effect on absorption, therefore nebivololol can be taken regardless of meals. Bioavailability of ingested nebivolol is on average 12% in patients with “fast” metabolism (effect of “primary passage”) and is almost complete in patients with “slow” metabolism.

Distribution. In plasma both enantiomers are predominantly bound to albumin. Binding to plasma proteins is 98.1% for D-nebivololol and 97.9% for L-nebivolol.

Elimation. Nebivolol is metabolized by alicyclic and aromatic hydroxylation and partial N-dealkylation. The formed hydroxy- and amino derivatives conjugate with glucuronic acid and are excreted as O- and N-glucuronides, by the kidneys (38%) and through the intestine (48%). T1/2 in patients with “fast” metabolism: hydroskimetabolites – 24 h, enantiomers of nebivolol – 10 h; in patients with “slow” metabolism: hydroskimetabolites – 48 h, enantiomers of nebivolol – 30 – 50 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;

– coronary heart disease: prevention of angina attacks;

– chronic heart failure (as part of combination therapy).

Pharmacological effect

Pharmacotherapeutic group of the drug:

beta 1 – selective adrenergic blocker

ATX code: [С07АВ12]

Pharmacological properties

Pharmacodynamics

Cardioselective β1-blocker. Nebivolol has hypotensive, antianginal and antiarrhythmic effects. Reduces high blood pressure (BP) at rest, during physical exertion and stress. Competitively and selectively blocks postsynaptic β1-adrenergic receptors, making them inaccessible to catecholamines, and models the release of the endothelial vasodilating factor nitric oxide (NO).

Nebivolol is a racemate of two enantiomers: SRRR-nebivolol (D-nebivolol) and RSSS-nebivolol (L-nebivolol), combining two pharmacological actions:

– D-nebivolol is a competitive and highly selective β1-adrenergic receptor blocker;

– L-nebivolol has a mild vasodilatory effect by modulating the release of vasodilating factor (NO) from the vascular endothelium.

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

A stable hypotensive 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 1-2 months.

By reducing myocardial oxygen demand (decrease in heart rate (HR), decrease in preload and afterload), nebivolol reduces the number and severity of angina attacks and increases exercise tolerance. The antiarrhythmic effect is due to the suppression of pathological automatism of the heart (including in the pathological focus) and the slowing of atrioventricular conduction.

Pharmacokinetics

Suction. After oral administration, both enantiomers are rapidly absorbed. Food intake does not affect absorption, so nebivolol can be taken regardless of meals. The bioavailability of oral nebivolol averages 12% in patients with “fast” metabolizers (first-pass effect) and is almost complete in patients with “slow” metabolizers.

Distribution. In blood plasma, both enantiomers are predominantly associated with albumin. Plasma protein binding is 98.1% for D-nebivolol and 97.9% for L-nebivolol.

Excretion. Nebivolol is metabolized by alicyclic and aromatic hydroskylation and partial N-dealkylation. The resulting hydroxy- and amino derivatives are conjugated with glucuronic acid and are excreted in the form of O- and N-glucuronides, by the kidneys (38%), and through the intestines (48%). T1/2 in patients with “fast” metabolism: hydroskimetabolites – 24 hours, enantiomers of nebivolol – 10 hours; in patients with “slow” metabolism: hydroskimetabolites – 48 hours, enantiomers of nebivolol – 30 – 50 hours. Excretion of unchanged nebivolol through the kidneys is less than 0.5% of the dose of the drug taken orally.

Given differences in metabolic rates, the dose of the drug should always be selected individually: patients with a “slow” metabolism require a lower dose.

Special instructions

Beta-blockers should be withdrawn gradually over
10 days (up to 2 weeks in patients with coronary heart disease).

Monitoring blood pressure and heart rate at the beginning of taking the drug should be daily.

In elderly patients, monitoring of renal function is necessary (1 time per
4-5 months). For exertional angina, the dose of the drug should ensure that the heart rate at rest is within the range of 55-60 beats/min, and during exercise – no more than 110 beats/min.

β-blockers can cause bradycardia: the dose should be reduced if the heart rate is less than 50-55 beats/min. (see section “Contraindications”).

When deciding on the use of Nebivolol in patients with psoriasis, one should carefully weigh the expected benefits of using the drug and the possible risk of exacerbation of psoriasis.

Patients who use contact lenses should take into account that the use of beta-blockers may reduce the production of tear fluid.

When performing surgical interventions, the anesthesiologist should be warned that the patient is taking β-blockers.

Nebivolol does not affect plasma glucose concentrations in patients with diabetes mellitus. However, caution should be exercised when treating these patients because Nebivolol may mask certain symptoms of hypoglycemia (eg, tachycardia) caused by the use of oral hypoglycemic agents and insulin. Monitoring the concentration of glucose in the blood plasma should be carried out once every 4-5 months. (in patients with diabetes mellitus).

With hyperthyroidism, β-blockers can mask tachycardia.

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

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

In smokers, the effectiveness of β-blockers is lower compared to non-smoking patients.

Impact on the ability to drive vehicles and operate machinery

During treatment with Nebivolol (if side effects occur), caution should be exercised when driving vehicles and when engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Nebivolol

Composition

1 tablet contains:

active substance:

nebivolol hydrochloride in terms of nebivolol – 5.0 mg;

excipients:

lactose monohydrate (milk sugar) – 89.87 mg,

pregelatinized starch (starch 1500) – 22.5 mg,

cross-carmellose sodium (primellose) – 9.0 mg,

povidone (medium molecular weight polyvinylpyrrolidone) – 4.5 mg,

microcrystalline cellulose – 17.25 mg,

colloidal silicon dioxide (Aerosil) – 0.38 mg,

calcium stearate – 1.5 mg.

Contraindications

– Hypersensitivity to the active substance or one of the components of the drug;

– acute heart failure;

– chronic heart failure in the stage of decompensation (requiring intravenous administration of drugs with inotropic effects);

– severe arterial hypotension (systolic blood pressure less than 90 mm Hg);

– sick sinus syndrome, including sinoauricular block;

– atrioventricular block II and III degrees (without artificial pacemaker);

– severe bradycardia (heart rate less than 50 beats/min.);

– cardiogenic shock;

– pheochromocytoma (without simultaneous use of alpha-blockers);

– metabolic acidosis;

– severe liver dysfunction;

– severe forms of bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD);

– severe obliterating diseases of peripheral vessels (“intermittent” claudication, Raynaud’s syndrome);

– myasthenia;

– depression;

– lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;

– age under 18 years (efficacy and safety in this age group have not been studied);

– simultaneous use with floctafenine, sultopride (see section “Interaction with other drugs”).

With caution

– renal failure;

– diabetes mellitus;

– hyperfunction of the thyroid gland;

– aggravated allergic anamnesis; carrying out desensitizing therapy, psoriasis;

– BA and COPD;

– atrioventricular block of the first degree;

– Prinzmetal’s angina;

– age over 65 years.

Side Effects

Frequency of side effects: very common (more than 10%), common (more than 1% and less than 10%), uncommon (more than 0.1% and less than 1%), rare (more than 0.01% and less than 0.1%), very rare (less than 0.01%), including individual reports.

Nervous system disorders:

Often: headache, dizziness, fatigue, weakness, paresthesia;

Uncommon: depression, nightmares, confusion, decreased ability to concentrate, drowsiness, insomnia;

Very rare: fainting, hallucinations.

Gastrointestinal disorders:

Common: dry mouth, nausea, constipation, diarrhea;

Uncommon: dyspepsia, flatulence, vomiting.

Cardiovascular system disorders:

Uncommon: bradycardia, worsening of CHF, acute heart failure, slowing of atrioventricular conduction, atrioventricular block, marked decrease in blood pressure, orthostatic hypotension, cardiac arrhythmias, cardialgia, exacerbation of intermittent claudication, peripheral edema, Raynaud’s syndrome.

Disorders of the skin and subcutaneous tissues:

Uncommon: erythematous skin rash, itching;

Very rare: worsening of psoriasis, photodermatosis, increased sweating;

In some cases: angioedema.

Visual disorders:

Uncommon: visual impairment.

Respiratory system disorders:

Often: shortness of breath;

Uncommon: bronchospasm, rhinitis.

Reproductive system disorders:

Uncommon: erectile dysfunction.

Other disorders: alopecia.

Interaction

Pharmacodynamic interaction

With the simultaneous use of β-blockers with blockers of “slow” calcium channels (SCBC) (verapamil and diltiazem), the negative effect on myocardial contractility and AV conduction increases. IV administration of verapamil is contraindicated while using nebivolol.

When nebivolol is used concomitantly with antihypertensive drugs, nitroglycerin or BMCC, severe arterial hypotension may develop (special caution is required when combined with prazosin).

The simultaneous use of baclofen and amifostine with antihypertensive drugs can cause a significant drop in blood pressure, so dose adjustment of antihypertensive drugs is required.

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

With the simultaneous use of nebivolol with class I antiarrhythmic drugs and amiodarone, the negative inotropic effect may be enhanced and the time of excitation through the atria may be prolonged.

With simultaneous use of nebivolol with cardiac glycosides, there was no increase in the effect on slowing AV conduction.

The simultaneous use of nebivolol and drugs for general anesthesia may suppress reflex tachycardia and increase the risk of developing arterial hypotension.

There is no clinically significant interaction between nebivolol and non-steroidal anti-inflammatory drugs (NSAIDs).

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

Concomitant use of nebivolol and floctafenine is contraindicated
since there is a threat of a pronounced decrease in blood pressure or shock.

The simultaneous use of nebivolol and sultopride is contraindicated, as the risk of developing ventricular arrhythmia, especially of the “pirouette” type, increases.

When nebivolol is used simultaneously with insulin and oral hypoglycemic agents, the symptoms of hypoglycemia (tachycardia) may be masked.

When used concomitantly, sympathomimetic agents inhibit the activity of nebivolol.

Pharmacokinetic interaction

With simultaneous use of nebivolol with drugs that inhibit serotonin reuptake, or other drugs that are biotransformed with the participation of the CYP2D6 isoenzyme, the concentration of nebivolol in the blood plasma increases, the metabolism of nebivolol slows down, which can lead to the risk of bradycardia.

When used concomitantly with digoxin, nebivolol does not affect the pharmacokinetic parameters of digoxin.

With simultaneous use of nebivolol with cimetidine, the concentration of nebivolol in the blood plasma increases.

The simultaneous use of nebivolol and ranitidine does not affect the pharmacokinetic parameters of nebivolol.

With simultaneous use of nebivolol with nicardipine, the concentrations of active substances in the blood plasma increase slightly, but this does not have clinical significance.

Concomitant use of nebivolol and ethanol, furosemide or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol.

No clinically significant interaction between nebivolol and warfarin has been established.

Overdose

Symptoms: marked decrease in blood pressure, nausea, vomiting, cyanosis, sinus bradycardia, atrioventricular (AV) block, bronchospasm, loss of consciousness, cardiogenic shock, coma, cardiac arrest, hypoglycemia, convulsions.

Treatment: gastric lavage, taking activated carbon. In case of a pronounced decrease in blood pressure, it is necessary to place the patient in a horizontal position with elevated legs, and, if necessary, administer intravenous fluids and vasopressors. For bradycardia, 0.5–2 mg of atropine should be administered intravenously; if there is no positive effect, a transvenous or intracardiac pacemaker may be installed.

In case of AV block (II-III stage), intravenous administration of β-adrenergic stimulants is recommended; if they are ineffective, the issue of installing an artificial pacemaker should be considered. In case of heart failure, treatment begins with the administration of cardiac glycosides and diuretics; if there is no effect, it is advisable to administer dopamine, dobutamine or vasodilators. For bronchospasm, β2-adrenergic receptor stimulants are used intravenously. For ventricular extrasystole – lidocaine (class IA antiarrhythmic drugs cannot be administered). For hypoglycemia – intravenous dextrose (glucose) solution, for convulsions – diazepam.

Manufacturer

North Star NAO, Russia