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 (in combination therapy).

Active ingredient

Composition

1 tablet contains:

the active ingredient:

nebivololol hydrochloride in terms of nebivololol – 5.0 mg;

excipients:

Lactose monohydrate (milk sugar) – 89.87 mg,

Pregelatinized starch (starch 1500) – 22.5 mg,

sodium cross-carmellose (primellose) – 9.0 mg,

povidone (polyvinylpyrrolidone medium molecular weight) – 4.5 mg,

microcrystalline cellulose – 17.25 mg,

/p>

colloidal silicon dioxide (aerosil) – 0.38 mg,

calcium stearate – 1.5 mg.

How to take, the dosage

Nebivolol tablets are taken orally, once a day, preferably at the same time, regardless of meals, with plenty of fluid.

The average daily dose for treatment of arterial hypertension and coronary heart disease is 2.5 mg to 5 mg of Nebivolol (1/2 tablet 5 mg to 1 tablet 5 mg).

Nebivololol can be used in monotherapy or in combination with other blood pressure lowering agents.

In patients with renal impairment and in patients over 65 years of age, the recommended starting dose is 1/2 tablet
(1/2 tablet 5 mg) of Nebivololol per day. If necessary, the daily dose can be increased to a maximum of 10 mg (2 tablets of 5 mg at a time).

The treatment of chronic heart failure should begin with a slow increase in dose until an individual optimal maintenance dose is reached. The dose selection at the beginning of treatment should be as follows: at one to two week intervals and guided by the patient’s tolerance of this dose: an initial dose of 1.25 mg (1/4 tablet of 5 mg with a cross-shaped rib) once daily, can be increased first to 2.5 to 5 mg of Nebivolol (1/2 tablet 5 mg to 1 tablet 5 mg), and then to 10 mg (2 tablets 5 mg) once daily.

The maximum daily dose is 10 mg (2 tablets 5 mg) once daily.

At the start of therapy and at each dose increase, the patient should be monitored for at least
2 hours to make sure that the clinical condition remains stable (especially: BP, HR, conduction disturbances, and symptoms of worsening of the course of chronic heart failure).

The use of nebivololol is not recommended in patients with severe renal and/or hepatic impairment due to lack of experience of use.

Interaction

Pharmacodynamic interaction

Concomitant use of β-adrenoblockers with “slow” calcium channel blockers (CMBs) (verapamil and diltiazem) increases the negative effect on myocardial contractility and AV conduction. IV administration of verapamil with nebivolol is contraindicated.

The concomitant use of nebivololol with hypotensive agents, nitroglycerin or BMCCs may cause severe arterial hypotension (particular caution is required when combined with prazosin).

The concomitant use of baclofen and amifostine with hypotensive drugs may cause a significant drop in blood pressure; therefore, correction of the dose of hypotensive drugs is required.

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 heart rate and cardiac output, vasodilation symptoms). In case of abrupt withdrawal of these drugs, especially prior to withdrawal of nebivolol, the development of “ricochet” arterial hypertension is possible.

The concomitant use of nebivololol with class I antiarrhythmic drugs and with amiodarone may increase the negative inotropic effect and prolongation of the excitation time through the atria.

In concomitant use of nebivololol with cardiac glycosides no increased effect on delayed AV conduction was found.

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

The use of nebivololol and nonsteroidal anti-inflammatory drugs (NSAIDs) is not clinically significant.

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

The concomitant use of nebivolol and floktafenin is contraindicated,
since there is a risk of marked BP decrease or shock.

The concomitant use of nebivolol and sultopride is contraindicated because of the increased risk of ventricular arrhythmias, especially pirouette.

In concomitant use of nebivololol with insulin and hypoglycemic agents for oral administration, symptoms of hypoglycemia (tachycardia) may be masked.

In concomitant use, sympathomimetic agents inhibit the activity of nebivololol.

Pharmacokinetic interaction

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

When used concomitantly with digoxin, nebivololol has no effect on the pharmacokinetic parameters of digoxin.

In concomitant use of nebivololol with cimetidine, plasma concentrations of nebivololol are increased.

The concomitant use of nebivololol and ranitidine has no effect on the pharmacokinetic 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 between nebivololol and warfarin has been established.

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 start of therapy should be daily.

In elderly patients, renal function should be monitored (once every
4-5 months). For angina pectoris, the drug dose should provide a resting HR of 55-60 bpm, and not more than 110 bpm on exertion.

The β-adreno-blockers may cause bradycardia: the dose should be reduced if the HR is less than 50-55 bpm (see Antibiotics). (see Contraindications).

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

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 operating machinery

When treating with Nebivololol (in case of side effects), caution should be exercised when driving vehicles and engaging in potentially dangerous activities requiring increased concentration and quick psychomotor reactions.

Contraindications

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

– acute heart failure;

– Chronic decompensated heart failure (requiring intravenous administration of drugs with inotropic action);

– severe arterial hypotension (systolic BP less than 90 mm Hg).

– syndrome of weak sinus node, including sinoauricular blockade;

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

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

– cardiogenic shock;

– pheochromocytoma (without concomitant use of alpha-adrenoblockers);

– metabolic acidosis;

Side effects

Percentage of side effects: 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%), including individual reports.

Nervous system disorders:

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

Infrequently: Depression, “nightmare” dreams, confusion, decreased ability to concentrate, drowsiness, insomnia;

Very rare: fainting, hallucinations.

Gastrointestinal disorders:

Often: dry mucous membrane of the mouth, nausea, constipation, diarrhea;

Infrequently: dyspepsia, flatulence, vomiting.

Cardiovascular system disorders:

Infrequent: bradycardia, worsening the course of CHF, acute heart failure, slowed atrioventricular conduction, atrioventricular block, marked BP decrease, orthostatic hypotension, heart rhythm disorders, cardialgia, worsening of “intermittent” claudication, peripheral edema, Raynaud’s syndrome.

Skin and subcutaneous tissue disorders:

Infrequent: erythematous skin rash, itching;

Very rare: aggravation of the course of psoriasis, photodermatosis, increased sweating;

In rare cases: angioedema.

Visual disorders:

Infrequent: visual disturbances.

Respiratory system disorders:

Often: shortness of breath;

Infrequent: bronchospasm, rhinitis.

Reproductive system disorders:

Infrequent: erectile dysfunction.

Other disorders: allopecia.

Overdose

Symptoms: marked BP decrease, nausea, vomiting, cyanosis, sinus bradycardia, atrioventricular (AV) blockade, 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, if there is no positive effect, a transvenous or intracardiac electrostimulator may be placed.

In case of AV blockade (stage II-III), it is recommended that β-adrenergic stimulators be administered intravenously; 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, intravenous β2-adrenoreceptor stimulators are used. In ventricular extrasystole – lidocaine (class IA antiarrhythmic agents should not be administered). In hypoglycemia – intravenous dextrose (glucose) solution, in convulsions – diazepam.

Similarities