Nebivolol-Teva - instructions for use, dose, side effects, contraindications

1 tablet contains: active substance nebivolol (nebivolol hydrochloride) 5.00 (5.45) mg; Excipients: lactose monohydrate 142.21 mg, corn starch 46.00 mg, croscarmellose sodium 13.8 mg, microcrystalline cellulose 16.10 mg, hypromellose-E15 4.6 mg, silicon dioxide colloid 0.69 mg, magnesium stearate 1.15 mg .

Description:Round biconvex tablets white or almost white with a cross-shaped risk on one side.

Pharmacotherapeutic group:beta1-blocker selective

ATX: & nbsp

C.07.A.B.12 Nebivolol

Pharmacodynamics:

Cardioselective beta-blocker with vasodilating properties. Nebivolol is a racemate consisting of two enantiomers: SRRRNebivolol (Dnebivolol) and RSSSNebivolol (LNebivolol), combining two pharmacological actions:

- D- Nebivolol is a competitive and highly selective beta-adrenoreceptor blocker (affinity for beta-adrenoreceptors is 293 times higher than for beta-adrenoreceptors);

- LNebivolol has a vasodilating effect due to the modulation of the release of the relaxing factor from the vascular endothelium.

Reduces elevated blood pressure (BP) at rest, with physical stress and stress. Competitively and selectively blocks synaptic and postsynaptic beta-1 adrenergic receptors, making them inaccessible to catecholamines, modulates release of the endothelial vasodilating factor of nitric oxide. Antihypertensive effect develops on the 2nd-5th day of treatment, stable effect is observed after 1 month. This effect persists with long-term treatment. Antihypertensive 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 blood plasma). The use of nebivolol improves the indices of systemic and intracardiac hemodynamics. Nebivolol reduces the heart rate at rest and under physical exertion, reduces the end-diastolic pressure of the left ventricle, reduces the overall peripheral vascular resistance (OPSS), improves diastolic function of the heart (reduces the filling pressure), increases the ejection fraction, reduces the myocardial mass and myocardial mass index. Reducing the need for myocardium in oxygen (decreasing heart rate, reducing preload and postnaphus),reduces the number and severity of angina attacks and improves the tolerance of exercise. Antiarrhythmic effect is due to the suppression of the automatism of the heart (including in the pathological focus) and the slowing of the atrio-ventricular (AV) conductivity.

Pharmacokinetics:

After oral administration nebivolol quickly absorbed from the gastrointestinal tract. Eating does not affect suction, so nebivolol can be taken regardless of food intake.

Nebivolol is actively metabolized, in part with the formation of active hydroxymetabolites. Metabolism occurs through epicyclic and aromatic hydroxylation, N-dealkylation and glucuronation, in addition, glucuronides of hydroxy metabolites are formed. The metabolic rate of nebivolol by aromatic hydroxylation is genetically determined by oxidative polymorphism and depends on the activity of the isoenzyme CYP2D6.

The bioavailability of nebivolol ranges from 12% in patients with high isoenzyme activity CYP2D6 up to 96% in patients with low activity CYP2D6.

In healthy patients with extensive metabolism nebivolol, the unchanged average maximum concentration of the drug in the blood plasma (C_max) was 1.48 ng / ml and was achieved 1 hour after a single admission of nebivolol inside at a dose of 5 mg. Area under the curve "concentration-time" (AUC) was 7.76 ng / hr / ml. In patients with essential hypertension, the C_max for D- and LNebivolol and their hydroxylated metabolites were 7.3 and 13.1 ng / ml and were achieved through 2.5 and 2.6 hours, respectively, after a single oral administration of nebivolol at a dose of 5 mg. Relevant indicators AUC24 were 65 and 109 ng * h / ml.

The equilibrium concentration (Css) Nebivolol in the blood plasma in most patients (with a high isoenzyme activity CYP2D6) is achieved within 24 hours, a Css for hydroxymetabolites - in a few days. FROM_max in plasma 1-30 mkg / l are proportional to the dose. Both nebivolol isomers bind to a high degree with the blood plasma proteins (mainly with albumins). Binding to plasma proteins by 98.1% for D- nebivolol and 97.9% for L- Nebivolol. Plasma concentrations are proportional to the dose in the range from 1 mg to 30 mg of nebivolol.

One week after the introduction of 38% (the amount of unchanged active substance is less than 0.5%), the dose is excreted by the kidneys and 48% by the intestine.

In patients with high isoenzyme activity CYP2D6 the half-life (T1 / 2) of nebivolol from plasma is an average of 10 hours, in patients with low activity CYP2D6 - 3-5 times higher. In patients with high isoenzyme activity CYP2D6 T1 / 2 hydroxy metabolites from the plasma are on average 24 hours, in patients with low activity CYP2D6 - 2 times higher. As it turned out, lower concentrations of unchanged nebivolol in patients with high isoenzyme activity CYP2D6 are compensated by more intensive formation of active hydroxylated metabolites, which indicates a slight difference in the clinical effects of nebivolol in these categories of patients.

The pharmacokinetics of nebivolol does not depend on the age and sex of the patients.

Indications:

- Essential hypertension.

- Chronic heart failure (as part of combination therapy) in patients older than 65 years.

Contraindications:

Hypersensitivity to nebivolol and other components of the drug; severe violations of liver function; acute heart failure; cardiogenic shock; chronic heart failure (CHF) in the stage of decompensation; syndrome of weakness of the sinus node,including sinoatrial blockade (without a pacemaker); atrioventricular blockade of II and III degree (without artificial pacemaker); bronchospasm in the anamnesis and bronchial asthma; pheochromocytoma (without simultaneous use of alpha-blockers); metabolic acidosis; bradycardia (heart rate less than 60 beats / min before therapy); severe arterial hypotension (systolic blood pressure less than 90 mm Hg); severe violations of peripheral circulation ("intermittent limb syndrome, Raynaud's syndrome), myasthenia gravis, depression, simultaneous use with floktaphenin and sultopride, lactase deficiency, lactose intolerance, glucose-galactose malabsorption, age 18 years.

Carefully:Severe renal dysfunction (creatinine clearance less than 20 ml / min), chronic obstructive pulmonary disease, atrioventricular block of degree I, angina of Prinzmetal; elderly age over 65, diabetes, psoriasis, hyperthyroidism, desensitizing therapy, liver function disorders.

Pregnancy and lactation:

In pregnancy, the drug is prescribed only on strict indications, when the benefit to the mother exceeds the risk for the fetus (in connection with the possible development of a newborn bradycardia, arterial hypotension, hypoglycemia and respiratory paralysis).Treatment should be interrupted for 48-72 hours before delivery. In cases where this is not possible, it is necessary to ensure strict observation of the newborn within 48-72 hours after delivery. There is no data on the isolation of nebivolol in breast milk. Therefore, Nebivolol-Teva is not recommended for women during lactation. If Nebivolol-Teva is needed during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside, washing down with the necessary amount of water (100 ml), at the same time of the day, regardless of food intake.

Essential hypertension. The initial dose of 5 mg once a day. The optimal effect develops after 1-2 weeks of treatment, and in some cases - after 4 weeks. If necessary, you can increase the dose to 10 mg per day.

Chronic heart failure. Treatment of CHF should begin with a gradual increase in the dose until an individual optimal maintenance dose is reached. Selection of the dose at the beginning of treatment should be carried out according to the scheme, maintaining two-week intervals and, based on the tolerability of this dose by the patient:(1/4 tablets - 1/2 tablets) of Nebivolol-Teva once a day, can be increased first to 2.5-5 mg (1/2 tablet - 1 tablet) of the drug Nebivolol-Teva, and then - up to 10 mg (2 tablets) once a day. The patient should be under the supervision of a doctor within 2 hours after taking the first dose of the drug, and also after each subsequent increase in the dose. Each dose increase should be carried out not later than 2 weeks.

The maximum recommended dose for CHF therapy is 10 mg Nebivolol-Teva once a day. During titration, regular monitoring of blood pressure, heart rate and symptoms of CHF is recommended. During the titration phase, in case of worsening of CHF flow or intolerance of the drug, it is recommended to reduce the dose of Nebivolol-Teva or, if necessary, to stop it immediately (in case of pronounced arterial hypotension, worsening of CHF with acute pulmonary edema, in case of cardiogenic shock, symptomatic bradycardia or AV blockade).

In patients with renal insufficiency the initial dose of 2.5 mg once a day. If necessary, you can increase the dose to 5 mg per day. With QC less than 20 ml / min and in patients with severe impairment of liver function the maximum daily dose is 10 mg.

In elderly patients the initial dose of 2.5 mg once a day. If necessary, you can increase the dose to 5 mg per day.

Side effects:

The frequency of adverse reactions listed below was determined according to the following (classification of the World Health Organization): very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely - less than 0.01%, including individual reports.

From the cardiovascular system (SSS): infrequent bradycardia, worsening of CHF flow, slowing of atrioventricular conduction, atrioventricular blockade, marked decrease in blood pressure, orthostatic hypotension, cardiac rhythm disturbances, cardialgia, progression of concomitant intermittent claudication, peripheral edema.

From the nervous system: often - increased fatigue, headache, dizziness, paresthesia; infrequently - "nightmarish dreams", decreased ability to concentrate, drowsiness, insomnia, depression; very rarely - hallucinations, fainting.

From the sense organs: infrequently, weakening of vision.

From the respiratory system: often shortness of breath; infrequently - bronchospasm, rhinitis.

From the digestive system: often - dryness of the oral mucosa, constipation, nausea, diarrhea; infrequently - vomiting, flatulence.

From the skin: very rarely - exacerbation of psoriasis, photodermatosis, hyperhidrosis.

Allergic reactions: infrequently - itchy skin, erythematous rash; rarely

- angioedema.

On the part of the reproductive system: infrequently - impotence.

Overdose:

There are no data on cases of an overdose of nebivolol.

Symptoms: bradycardia, marked decrease in blood pressure, pronounced bradycardia, AV-blockade, cardiogenic shock, cardiac arrest, loss of consciousness, coma, nausea, vomiting, cyanosis, bronchospasm, acute heart failure.

Treatment: the patient is hospitalized and placed in the intensive care unit. Immediately it is necessary to determine the concentration of glucose in the blood. Gastric lavage, activated charcoal, maintenance of cardiovascular function, monitoring of cardiac and lung function, circulating blood volume monitoring and diuresis.

If necessary, a complex of resuscitation measures is carried out.

The effect of beta adrenoblockers can be neutralized by slow intravenous (iv) isoprenaline administration at an initial dose of about 5 μg / min or dobutamine at an initial dose of about 2.5 μg / min. With severe bradycardia, enter / in 0.5-2 mg of atropine, in the absence of a positive effect, a transvenous pacemaker is possible. With heart failure treatment begins with the introduction of cardiac glycosides and diuretics, in the absence of effect, it is advisable to administer dopamine, dobutamine or vasodilators. When bronhospazme apply in / in stimulants of β2-adrenoreceptors. With ventricular estrasystole - lidocaine (you can not inject antiarrhythmic drugs IA class).

Interaction:

Contraindicated simultaneous use of nebivolol and floktaphenina. There is a threat of a marked decrease in blood pressure or shock.

Contraindicated simultaneous use of nebivolol and sultopride. The risk of developing a ventricular artifact is increased, especially as a pirouette.

Reduction of contractile function of the heart and slowing of atrioventricular conduction occurs when combined with blockers of "slow" calcium channels.In / in the introduction of verapamil / diltiazem on the background of beta-blockers leads to a decrease in blood pressure, atrioventricular blockade and cardiac arrest.

Hypotensive drugs (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) can lead to a decrease in cardiac activity due to a decrease in sympathetic activity (a decrease in heart rate, a reduction in cardiac output, symptoms of vasodilation).

Amiodarone in combination with nebivolol can promote an increase in the degree of atrioventricular blockade.

Simultaneous use of nebivolol and preparations for general anesthesia can cause suppression of reflex tachycardia and increase the risk of developing arterial hypotension; in relation to slow calcium channel blockers (BCCI), while using beta-blockers with BCCC (verapamil and diltiazem) the effect on myocardial contractility and AV conductivity. Contraindicated in / in the administration of verapamil on the background of nebivolol.

When combined with antihypertensive drugs, nitroglycerin or BCCC, severe arterial hypotension may develop (special caution is necessary when combined with prazosin).

With simultaneous use with non-steroidal anti-inflammatory drugs, clinically significant interaction is not established. Acetylsalicylic acid as an antiplatelet agent can be used concomitantly with nebivolol.

With simultaneous application nebivolol did not affect the pharmacokinetic parameters of digoxin.

With simultaneous use with antiarrhythmic agents of the first class and with amiodarone, an increase in the negative inotropic effect and an extension of the time of excitation to the atria are possible.

When used simultaneously with drugs that inhibit serotonin reuptake, or other means, biotransforming with the participation of isoenzyme CYP2D6, the metabolism of nebivolol slows down.

With simultaneous use with cimetidine, the concentration of nebivolol in the blood plasma increases (there is no evidence of an effect on the pharmacological effects of the drug). The simultaneous use of ranitidine did not affect the pharmacokinetic parameters of nebivolol.

With the simultaneous use of nebivolol with nicardipine, concentrations of active substances in the blood plasma increased slightly, but this has no clinical significance.

Simultaneous administration of ethanol, furosemide or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol. Clinically significant interactions of nebivolol and warfarin have not been established.

Special instructions:

The abolition of beta-blockers should be carried out gradually, within 10 days. Treatment of CHF with Nebivolol-Teva is carried out against a background of stable indicators hemodynamics, not earlier than 6 weeks after the end of the decompensation period. Nebivolol-Teva can be safely used for the treatment of CHF along with thiazide diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.

At the beginning of treatment, blood pressure and heart rate should be monitored daily.

The effectiveness of beta-blockers in smokers is lower than that of non-smokers.

Nebivolol does not affect the concentration of glucose in patients with diabetes mellitus. However, care should be taken when treating these patients, since Nebivolol-Teva may mask certain symptoms of hypoglycemia (eg, tachycardia) caused by hypoglycemic drugs.

If nebivolol is necessary in patients with psoriasis, the expected benefit of therapy and the possible risk of exacerbation of psoriasis should be carefully evaluated. Beta-adrenoblockers should be used with caution in the increased function of the thyroid gland due to the fact that under the influence of beta-adrenoblockers clinical signs of hyperthyroidism, such as tachycardia, can be masked. Abrupt withdrawal can cause exacerbation symptoms and development thyrotoxic crisis.

Nebivolol can enhance the symptoms of peripheral circulatory disorders. Patients wearing contact lenses should take into account that the use of beta-blockers may reduce tear fluid production.

When planning surgical interventions, the doctor / anesthesiologist should be warned that the patient is taking beta-blockers. Beta-blockers should be canceled at least 24 hours before the preparation for anesthesia.

It is possible to increase the severity of the reaction of hypersensitivity and the lack of effect from the usual doses of epinephrine (adrenaline) against the background of a weighed allergic anamnesis.

Beta-adrenoblockers should be used with caution in patients with chronic obstructive pulmonary disease, as bronchospasm may worsen. Before the start of treatment, it is recommended to perform an external respiration function in patients with a history of bronchopulmonary anamnesis.

When Nebivolol-Teva is used in patients with pheochromocytoma, there is a risk of developing paradoxical arterial hypertension (unless an effective blockade of alpha-adrenergic receptors has been previously achieved).

With the simultaneous use of clonidine, its administration can be stopped only a few days after the discontinuation of Nebivolol-Teva.

It is recommended to stop Nebivolol-Teva with the development of depression. The control of the concentration of glucose in the blood plasma should be performed 1 time in 4-5 months (in patients with diabetes mellitus).

Control of laboratory indicators of kidney function should be performed once every 4-5 months (in elderly patients).

Effect on the ability to drive transp. cf. and fur:There was no adverse effect on the ability to drive vehicles or other complex mechanisms against nebivolol taking, however,due to a possible excessive reduction in blood pressure, development of dizziness and other adverse reactions, caution should be exercised when performing actions requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets 5 mg.

7 tablets in a blister of PVC / PVDC / aluminum foil;

2 or 4 blisters together with instructions for use in cardboard pack.

10 tablets in a blister of PVC / PVDC / aluminum foil;

3 blisters together with instructions for use in a cardboard bundle.

Packaging:tablets 5 mg (blister) 7 x 2/4 (a pack of cardboard); tablets 5 mg (blister) 10 х 3 (a pack of cardboard)

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not apply at the end of the period on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001208

Date of registration:15.11.2011

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Works Private, Ltd. Co. Hungary

Representation: & nbspTeva Teva Israel

Information update date: & nbsp01.08.2015

Illustrated instructions

Instructions

Nebivolol Teva (Nebivolol-Teva)