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Pharmacotherapeutic group: β1-blocker selective.
ATC code: C07AB12
Nebivolol is a cardioselective β1-adrenergic blocker, has antihypertensive, antianginal and antiarrhythmic action. Reduces high blood pressure (BP) at rest, with physical exertion and stress. Competitively and selectively blocks postsynaptic β1-adrenoreceptors, making them inaccessible to catecholamines, modulates the release of 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 blocker.
- L-nebivolol has a mild vasodilating effect by modulating the release of vasodilating factor (NO) from the vascular endothelium.
The antihypertensive effect is also due to a decrease in the activity of the renin-angiotensin-aldosterone system (RAAS) (it does not directly correlate with changes in plasma renin activity).
The antihypertensive effect develops after 2–5 days of regular use of the drug. A 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 noted after 1–2 months.
By reducing myocardial oxygen demand (decreasing heart rate (HR), reducing 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 cardiac automatism (including in the pathological focus) and the slowing down of atrioventricular conduction.
After ingestion is rapidly absorbed from the gastrointestinal tract. Eating does not affect absorption, so nebivolol can be taken regardless of meal times. Bioavailability is about 12% in patients with “fast” metabolism (the effect of “initial passage”) and can be almost complete in patients with “slow” metabolism.
In blood plasma, both enantiomers are predominantly bound to albumin.
Plasma protein binding for D-nebivolol is 98.1%, for
L-nebivolol - 97.9%.
Nebivolol is metabolized by alicyclic and aromatic hydroxylation and partial N-dealkylation. The resulting hydroxy and amino derivatives are conjugated with glucuronic acid and displayed as
O- and N-glucuronides. The metabolic rate of nebivolol by aromatic hydroxylation is genetically determined by oxidative polymorphism and depends on the CYP2D6 isoenzyme. The metabolic rate does not affect the effectiveness of nebivolol.
Excreted by the kidneys (38%) and through the intestines (48%). The half-life (T1 / 2) in patients with “fast” metabolism: hydroxymetabolites - 24 hours, enantiomers of nebivolol - 10 hours; in patients with “slow” metabolism: hydroxymetabolites -
48 h, nebivolol enantiomers - 30–50 h. The excretion of unchanged nebivolol via the kidneys is less than 0.5% of the oral dose of the drug.
Given the differences in metabolic rates, the dose of the drug should always be chosen individually: patients with a “slow” metabolism require a smaller dose.
- arterial hypertension;
- coronary heart disease: prevention of strokes of stress;
- chronic heart failure (as part of combination therapy).
1 tablet contains:
Active ingredient: nebivolol hydrochloride - 5.45 mg (in terms of nebivolol -
Excipients: Betadex - 23.00 mg; pregelatinized corn starch - 38.40 mg; microcrystalline cellulose - 108.55 mg; Crospovidone - 1.90 mg; colloidal silicon dioxide - 0.90 mg; magnesium stearate - 1.80 mg.
Nebivolol is marketed under different brands and generic names, and comes in different dosage forms:
|Brand name||Manufacturer||Country||Dosage form|
|Nebilong||Micro Labs Ltd||India||pills|
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Dosage and Administration
Orally, preferably at the same time of the day, regardless of the meal time, without chewing and drinking plenty of liquid.
Hypertension and Coronary Heart Disease
The average daily dose of nebivolol is 2.5–5 mg 1 time per day. For patients with renal insufficiency and patients older than 65 years, an initial dose of nebivolol 2.5 mg / day is recommended.
If necessary, the daily dose of nebivolol can be increased to 10 mg (in one step). 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 combination therapy with other drugs that reduce blood pressure.
Chronic heart failure
The dose of nebivolol is selected gradually until an individual optimal maintenance dose is reached. It is necessary to begin treatment of chronic heart failure with β-adrenoreceptor blockers in a clinically stable state over the past two weeks.
Treatment begins with a dose of 1.25 mg 1 time per day with a gradual increase (at intervals of at least 2 weeks) to 2.5–5 mg 1 time per day, if necessary up to a maximum dose of 10 mg 1 time per day. The patient must be under the supervision of a physician for 2 hours after taking the first dose of the drug, as well as after each subsequent dose increase. During the selection of the dosing regimen in case of worsening of the course of chronic heart failure or intolerance of the drug, it is recommended to reduce the dose of nebivolol or stop taking it. Reception of nebivolol is not recommended to stop abruptly (if it is not necessary), since this may lead to a temporary exacerbation of the symptoms of heart failure. If it is necessary to stop taking the drug, the cancellation is carried out gradually, halving the dose twice a week.
Patients with a renal failure (KK less than 20 ml / min.)
The initial dose is 2.5 mg / day. If necessary, the daily dose can be increased to 5 mg. In patients with impaired renal function (QC less than 20 ml / min), the dose should be increased with extreme caution.
For patients older than 65 years, the initial dose is 2.5 mg / day. If necessary, the daily dose can be increased to 5 mg. However, taking into account the limited experience of using the drug in elderly patients, it is necessary to be careful and conduct a thorough examination of patients over the age of 65 years. Elderly patients do not need to adjust the dose, so it is necessary to individually select the dose, gradually increasing it to the maximum tolerated dose.
The frequency of side effects listed below was determined according to the classification of the World Health Organization - very often (more than 10%), often (more than 1% and less than 10%), infrequently (more than 0.1% and less than 1%), rarely (more than 0 , 01% and less than 0.1%), very rarely (less than 0.01%), the frequency is unknown (according to the available data it is impossible to estimate the frequency of development).
On the part of the immune system: the frequency is unknown - angioedema, hypersensitivity.
On the part of the psyche: infrequently - “nightmarish” dreams, depression; very rarely - hallucinations, psychosis, confusion.
From the nervous system: often - headache, dizziness, weakness, paresthesia; very rarely - fainting.
On the part of the organ of vision: the frequency is unknown - impaired vision, dry eyes.
From the gastrointestinal tract: often - nausea, constipation, diarrhea; infrequently - dyspepsia, flatulence, vomiting.
Since the cardiovascular system: very often - bradycardia (in patients with CHF); often - aggravation of CHF, atrioventricular block I degree, orthostatic hypotension; infrequently - bradycardia, heart failure, slowing atrioventricular conductivity / atrioventricular block, pronounced decrease in blood pressure, progression of concomitant "intermittent" claudication; very rarely - Raynaud's syndrome.
On the part of the skin and subcutaneous tissues: often - edema; infrequently - skin eruption of erythematous character, skin itch; very rarely - aggravation of the course of psoriasis; frequency is unknown - alopecia.
On the part of the respiratory system: often - shortness of breath; infrequently - bronchospasm (including in the absence of obstructive pulmonary disease in history).
Reproductive system: infrequently - erectile dysfunction.
General disorders: very often - dizziness (in patients with CHF); often - increased fatigue, edema, intolerance of the drug; infrequently - photodermatosis, hyperhidrosis (in patients with CHF); very rarely - cooling / cyanosis of the extremities.
Renal failure (creatinine clearance (KK) less than 20 ml / min), abnormal liver function, diabetes mellitus, hyperthyroidism, atrioventricular block I stage, desensitization therapy, psoriasis, allergic diseases in history, chronic obstructive pulmonary disease, impaired peripheral circulation , Prinzmetal angina, over 65 years old.
With simultaneous use of “slow” calcium channels (BMCC) with blockers (verapamil, diltiazem), the negative effect on myocardial contractility and atrioventricular conductivity is enhanced. Intravenous administration of verapamil is not recommended against the background of the use of nebivolol.
With simultaneous use of nebivolol with antihypertensive drugs, nitroglycerin, severe hypotension may develop (special caution is necessary when used simultaneously with prazosin).
With simultaneous use of nebivolol with antihypertensive drugs of central action (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine), heart failure can worsen due to a decrease in sympathetic tone (decrease in heart rate and cardiac output, symptoms of vasodilation). In the case of abrupt cancellation of these drugs, especially before the cancellation of nebivolol, the development of ricochet hypertension (syndrome of "cancellation") is possible.
Concomitant use of nebivolol and BMCA of the dihydropyridine series (amlodipine, felodipine, licidipine, nifedipine, nicardipine, nimodipine, Nitrendipine) may increase the risk of arterial hypotension. An increased risk of further deterioration of the pumping function of the ventricles in patients with heart failure cannot be ruled out.
With simultaneous use with class I antiarrhythmic drugs (quinidine, flekainid, disopyramide, micelitin) and with amiodarone, it is possible to increase the negative inotropic effect and lengthen the time of arousal in the atria.
With simultaneous use with cardiac glycosides, no increase in the effect on the slowing of atrioventricular conductivity was revealed.
The simultaneous use of nebivolol and drugs for general anesthesia can cause the suppression of reflex tachycardia and increase the risk of arterial hypotension.
No clinically significant interaction with non-steroidal anti-inflammatory drugs has been established.
Acetylsalicylic acid as an antiplatelet agent can be used simultaneously with nebivolol.
The simultaneous use of nebivolol with tricyclic antidepressants, barbiturates and phenothiazine derivatives may enhance the antihypertensive effect of nebivolol.
The simultaneous use of nebivolol with insulin and hypoglycemic agents for oral administration may mask some of the symptoms of hypoglycemia (rapid heartbeat, tachycardia).
Simultaneous reception with floktafenin is contraindicated: nebivolol is able to prevent the compensatory reactions of the cardiovascular system associated with arterial hypotension or shock, which can be caused by floctafenin.
Simultaneous reception of nebivolol with baclofen, amifostine leads to increased arterial hypotension.
At simultaneous use with a sultoprid the increased risk of developing of ventricular arrhythmia like "pirouette" is noted.
When applied simultaneously, sympathomimetic agents suppress the activity of nebivolol.
With simultaneous use of nebivolol with drugs that inhibit serotonin reuptake, or with other biotransforming agents involving the CYP2D6 isoenzyme, plasma concentration of nebivolol increases, nebivolol metabolism slows down, which may lead to the risk of bradycardia.
When used simultaneously with digoxin, nebivolol does not affect the pharmacokinetic parameters of digoxin.
With simultaneous use with cimetidine concentration of nebivolol in the blood plasma increases (data on the effect on the pharmacological effects of the drug are not available).
The simultaneous use of nebivolol and ranitidine does not affect the pharmacological parameters of nebivolol.
With the simultaneous use of nebivolol with nicardipine, the concentration of active substances in the blood plasma increases slightly, but this has no clinical significance.
Simultaneous use of nebivolol and ethanol, furosemide, or hydrochlorothiazide does not affect nebivolol pharmacokinetics.
No clinically significant interaction of nebivolol and warfarin has been established.
Pregnancy and Lactation
Nebivolol can have a harmful effect on the course of pregnancy, on the fetus and the newborn. Reduction of placental perfusion under the action of
β-blockers can cause fetal developmental delay, fetal death, miscarriage, and premature birth. Newborns may experience bradycardia, lower blood pressure, hypoglycemia, and respiratory paralysis. Use during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus. Nebivolol should be discontinued 48-72 hours before delivery. In cases where this is not possible, it is necessary to ensure strict monitoring of newborns within 48-72 hours after delivery.
Animal studies have shown that nebivolol is excreted in milk from lactating animals. If necessary, the use of the drug during lactation breastfeeding should be stopped.
Cancellation of β-blockers should be carried out gradually over 10 days (up to 2 weeks in patients with ischemic heart disease).
Control of blood pressure and heart rate at the beginning of the drug should be daily.
In elderly patients, monitoring of renal function is necessary (1 time in 4-5 months). In case of angina, the dose of the drug should provide a heart rate at rest within
55-60 beats / min, with a load - 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 the drug Nebivolol in patients with psoriasis, one should carefully relate the perceived benefits of using the drug and the possible risk of exacerbation of the course of psoriasis.
Patients using contact lenses should take into account that, with the use of β-blockers, there may be a decrease in 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 concentration in patients with diabetes mellitus. However, caution should be exercised in treating these patients, since Nebivolol may mask certain symptoms of hypoglycemia (for example, tachycardia) caused by the use of hypoglycemic oral and insulin drugs. Control of plasma glucose concentration should be carried out 1 time in 4-5 months. (in diabetic patients).
With hyperfunction of the thyroid gland, β-blockers may mask tachycardia.
β-blockers should be used with caution in patients with chronic obstructive pulmonary disease, as bronchospasm may increase.
β-blockers can increase the sensitivity to allergens and the severity of anaphylactic reactions.
In smokers, the effectiveness of β-adrenergic blockers is lower compared with non-smoking patients.
Impact on ability to drive vehicles and other mechanisms
During the period of treatment, care must be taken when driving and occupying other potentially dangerous activities that require high concentration of attention and speed of psychomotor reactions.
Symptoms: marked reduction in blood pressure, nausea, vomiting, cyanosis, bradycardia, atrioventricular block, acute heart failure, bronchospasm, loss of consciousness, cardiogenic shock, coma, cardiac arrest, hypoglycemia, convulsions.
Treatment: gastric lavage, taking activated carbon. In the case of a pronounced decrease in blood pressure, it is necessary to give the patient a horizontal position with raised legs, if necessary, in / in the introduction of fluid and vazopressorov. For bradycardia, 0.5-2 mg of atropine should be administered intravenously. In the absence of a positive effect, a transvenous or intracardiac pacemaker can be delivered. In case of atrioventricular blockade (II-III stages), it is recommended intravenous injection of β-adrenomimetics, if they are ineffective, consideration should be given to setting up an artificial pacemaker. In heart failure, treatment begins with the introduction of cardiac glycosides and diuretics, in the absence of an effect, the administration of dopamine, dobutamine or vasodilators is advisable. When bronchospasm is used in / in β2-adrenomimetics. In ventricular premature beats, lidocaine may be prescribed (class IA antiarrhythmic drugs are not used). When convulsions is recommended in / in the introduction of diazepam. When hypoglycemia is shown in / in the introduction of dextrose (glucose).
- Brand name: Nebivolol
- Active ingredient: Nebivolol
- Dosage form: pills of a round, biconvex form from white to white with a yellowish shade of color, with a cruciform risk on one side.
- Manufacturer: Izvarino Pharma
- Country of Origin: Russia
- ChemInform Abstract: Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Mo-Catalyzed Chromene Formation in Synthesis. Enantioselective Total Synthesis of the Antihypertensive Agent (S,R,R,R)-Nebivolol.
- Sulfoxide-Directed Stereocontrolled Access to 2H-Chromans: Total Synthesis of the (S,R,R,R)-Enantiomer of the Antihypertensive Drug Nebivolol
- Location of the hydroxyl functions in hydroxylated metabolites of nebivolol in different animal species and human subjects as determined by on-line high-performance liquid chromatography-diode-array detection
- X-ray investigations of nebivolol and its isomers
- Effects of varying degrees of renal impairment on the pharmacokinetic disposition of nebivolol
- Effect of chronic administration of fluoxetine on the pharmacokinetics of nebivolol
- Single-dose pharmacokinetics and anticoagulant activity of warfarin is unaffected by nebivolol in healthy volunteers
- Effects of hepatic impairment on the pharmacokinetic disposition of nebivolol: A dual acting nitric oxide modulating/ cardioselective beta-antagonist
- Lack of pharmacokinetic interaction between nebivolol and spironolactone
- No interaction between nebivolol and digoxin in healthy volunteers
- Pharmacokinetic disposition of nebivolol in extensive and poor CYP2D6 metabolizers
- Pharmacokinetics of nebivolol and ramipril are not affected by co-administration
- No pharmacokinetic interaction between nebivolol and furosemide in healthy subjects
- No effect of concomitant administration of nebivolol and losartan in healthy volunteers genotyped for CYP2D6 status
- Simultaneous determination of fixed dose combination of nebivolol and valsartan in human plasma by liquid chromatographic-tandem mass spectrometry and its application to pharmacokinetic study
- Rapid quantification of nebivolol in human plasma by liquid chromatography coupled with electrospray ionization tandem mass spectrometry
- Long-Term Therapy With Nebivolol Does Not Cause Nitrate Tolerance
- Enantioselective Total Synthesis of the Antihypertensive Agent (S,R,R,R)-Nebivolol
- Allergic contact dermatitis to nebivolol
- A pharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2-receptor antagonists cimetidine and ranitidine
- The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension
- Nebivolol decreases systemic oxidative stress in healthy volunteers
- Die räumliche Betrachtung und Beschreibung von Nebivolol: Stereochemie der Beta-Blocker
- Exercise tolerance with nebivolol and atenolol