The antihypertensive effect develops in 2-5 days of treatment, stable effect observed after 1 month.This effect is maintained during long-term treatment.The antihypertensive buy testosterone cypionate effect is also due to a decrease in the activity of the renin-angiotensin-aldosterone system (RAAS) (not directly correlate with changes in the activity of renin in blood plasma).The use of Nebivolol improves system and intracardiac hemodynamics.Nebivolol slows heart rate at rest and during exercise, reduces end-diastolic left ventricular pressure, reduces the total peripheral vascular resistance (SVR), improves diastolic cardiac function (reduced filling pressure), increased ejection fraction and reduces myocardial mass and myocardial mass index.By reducing myocardial oxygen demand (slowing of heart rate, reducing preload), reduces the number and severity of attacks of angina and improve exercise tolerance. Antiarrhythmic effect is due to the suppression of automaticity of the heart (including pathological hearth) and atrio-ventricular slowing (AV) conduction.

Pharmacokinetics
After oral administration of nebivolol is rapidly absorbed from the gastrointestinal tract. Food intake has no effect on the absorption, so nebivolol can be taken regardless of meals.
Nebivolol is extensively metabolised, partly with the formation of active gidroksimetabolitov. Metabolism occurs through alicyclic and aromatic hydroxylation, N-dealkylation and glyukuronirovaniya further formed gidroksimetabolitov glucuronides. Nebivolol metabolic rate by aromatic hydroxylation genetically determined oxidative polymorphism, depending on the activity of the isozyme CYP2D6.
The bioavailability of nebivolol ranges from 12% for patients with high activity isozyme CYP2D6 up to 96% in patients with low activity of CYP2D6.
In healthy patients with extensive metabolism of nebivolol unmodified average the maximum concentration of drug in plasma (C _max ) was 1.48 ng / ml and was reached 1 hour after a single dose of nebivolol orally at a dose of 5 mg. The area under curve (AUC) was 7.76 ng * h / mL. Patients with essential hypertension parameters C _max for D- and L-nebivolol and its hydroxylated metabolites was 7.3 and 13.1 ng / ml were achieved after 2.5 and 2.6 hours, respectively, after a single oral dose of nebivolol 5 mg. AUC24 corresponding figures were 65 and 109 ng * h / mL.
Equilibrium concentration (Css) of nebivolol plasma in most patients (with high activity isozyme CYP2D6) is achieved within 24 hours, for after several days. C _max plasma 1-30 g / l dose proportional. Both isomers of Nebivolol highly bound to plasma proteins (mainly albumin). Plasma protein binding at 98.1% for D-nebivolol and 97.9% for L-nebivolol. Plasma concentrations are proportional to the dose ranging from 1 mg to 30 mg of nebivolol.
One week after the administration of 38% (the amount of the unchanged active substance is less than 0.5%) of the dose excreted by the kidneys and 48% in the intestine.
In patients with a high activity period isozyme CYP2D6 half-life (T1 / 2) of nebivolol plasma averages 10 hours, in patients with low activity of CYP2D6 3-5 times higher. Patients with high activity isozyme CYP2D6 T1 / 2 gidroksimetabolitov buy testosterone cypionate plasma averages 24 hours, in patients with low activity of CYP2D6 2 times higher. It was found that lower concentrations of unchanged nebivolol in patients with high activity isozyme CYP2D6 compensated more intense formation of active hydroxylated metabolites, indicating that the minor differences in the clinical effects of nebivolol in these categories of patients.
Pharmacokinetics nebivolol does not depend on the age and sex of patients.

Indications

• Essential hypertension.
• Chronic heart failure (in combination therapy) in patients older than 65 years.

Contraindications
Hypersensitivity to nebivolol and other ingredients; severe liver function; congestive heart failure; cardiogenic shock; Chronic heart failure (CHF) in the stage of decompensation; sick sinus syndrome, including sinoatrial block (without pacemaker); atrioventricular block II and III degree (without pacemaker); a history of bronchospasm and bronchial asthma; pheochromocytoma (without the simultaneous use of alpha-blockers); metabolic acidosis; bradycardia (heart rate less than 60 beats / min before the start of therapy); severe hypotension (systolic blood pressure less than 90 mm Hg); Serious disturbances of peripheral circulation (intermittent claudication, Raynauda’s syndrome); myasthenia gravis; depression; simultaneous use with floctafenine and sultopride; lactase deficiency, lactose intolerance, glucose-galactose malabsorption; age 18 years.

Precautions
Severe renal impairment (creatinine clearance (CC) of less than 20 ml / min), chronic obstructive pulmonary disease, atrioventricular block I degree, Prinzmetal angina; old age over 65 years, diabetes mellitus, psoriasis, hyperthyroidism, conducting desensitizing therapy, liver function abnormalities.

Use during pregnancy and breastfeeding period
during pregnancy drug prescribed only under strict indications, where the benefits to the mother outweighs the risk to the fetus (in connection with the possible development of the newborn bradycardia, 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 monitoring of the newborn for 48-72 hours after delivery. No data buy testosterone cypionate on the allocation of nebivolol in human milk. Therefore, the drug Nebivolol not recommended for women during lactation. If use of the drug Nebivolol during lactation is necessary, breast-feeding should be discontinued.

Dosing and Administration
Inside, squeezed the required amount of water (100 ml) at the same time of day, regardless of meals. Essentsial hypertension. The initial dose of 5 mg 1 time per day. Optimal effect develops within 1-2 weeks of treatment, and in some cases 4 weeks. If necessary, the dose may be increased to 10 mg per day. Chronic heart failure. CHF Treatment should start with a gradual increase in the dose until the individual optimal maintenance dose. Dose selection at the beginning of treatment it is necessary to carry out the scheme, maintaining a two-week intervals, based on the tolerability of the patient dose: the dose is 1.25 2.5 mg (1/4 tablet 1/2 tablets) of the drug Nebivolol -Teva 1 times per day can be increased first to 2.5 – 5 mg (2.1 -1 tablet tablet) Nebivolol -Teva drug and then -. 10 mg (2 tablets) 1 times a day The patient must be under a doctors supervision for 2 hours after the first dose and after each successive dose increases. Any increase in dose should be administered at least 2 weeks. The maximum recommended dose for the treatment of chronic heart failure is 10 mg nebivolol -Teva 1 time per day. During titration we recommend regular monitoring of blood pressure, heart rate and heart failure symptom.During the titration phase, in case of worsening of heart failure or current drug intolerance it is recommended to reduce the dose of the drug Nebivolol -Teva or, if necessary, immediately stop taking it (in the case of pronounced hypotension, worsening of heart failure flow with acute pulmonary edema in case of cardiogenic shock, symptomatic AV blockade or bradycardia). in patients with renal insufficiency initial dose of 2.5 mg 1 time per day. If necessary to increase the dose up to 5 mg per day. When CC less than 20 ml / min and in patients with severe liver function disorders a maximum daily dose is 10 mg. In elderly patients, an initial dose of 2.5 mg 1 time per day. If necessary to increase the dose up to 5 mg per day.

Side effects:
The frequency of adverse reactions listed below was determined according to the following (World Health Organization): very often – at least 10%; often – at least 1% but less than 10%; infrequently – at least 0.1% but less than 1%; rare – less than 0.01% but less than 0.1%; very rarely – less than 0.01%, including isolated reports. On the part of the cardiovascular system (CVS): rarely – bradycardia, exacerbation of CHF flow, slow atrioventricular conduction, atrioventricular block, marked reduction in blood pressure, orthostatic hypotension, cardiac arrhythmias, cardialgia , accompanying the progression of intermittent claudication, peripheral edema. nervous system: often – fatigue, headache, dizziness, paresthesia; infrequently, decreased ability to concentrate, drowsiness, insomnia, depression; – very rare, faint. From the sensory organs: rarely impaired vision. The respiratory system: often shortness of breath; rarely bronchospasm, rhinitis. From the digestive system: often dryness of the oral mucosa, constipation, nausea, diarrhea; rarely vomiting, flatulence. For the skin: very rarely worsening of psoriasis, photodermatosis, hyperhidrosis. Allergic reactions: rarely itching, rash erythematous; very rarely angioneurotic edema. Reproductive system: rarely impotence.

Overdose
No data on cases of Nebivolol overdose. Symptoms: bradycardia, marked reduction in blood pressure, bradycardia, AV-block, cardiogenic shock, cardiac arrest, loss of consciousness, coma, nausea, vomiting, cyanosis, bronchospasm, acute heart failure. Treatment: the patient is hospitalized and placed in intensive care. Immediately necessary to determine the blood glucose concentration. Perform gastric lavage, activated charcoal, maintain the function of the cardiovascular system, the monitoring of indicators of heart and lung function, control blood volume and urine output. If necessary, the complex of resuscitation. The effect of beta-blockers can be counteracted by slow intravenous (i / v) isoprenaline administration at an initial dose of about 5 mcg / min of dobutamine, or at an initial dose of about 2.5 g / min. If bradycardia is introduced into / in the 0.5-2 mg atropine, with no positive effect can raise the transvenous pacemaker. In heart failure, treatment is initiated with the introduction of cardiac glycosides and diuretics, with no effect expedient administration of dopamine, dobutamine or vasodilators. When used in bronchospasm / stimulants in β ₂ -atsrenoretseptorov. When ventricular  – lidocaine (antiarrhythmic agents should not be administered IA class).

Interaction with other medicinal products
Concomitant use of nebivolol and floctafenine. There is a threat of significant decrease in blood pressure or shock.
Concomitant use of nebivolol and sultopride. Increased risk of ventricular Artime, especially type.
The decrease of contractile function of the heart and slowing of atrioventricular conduction occurs in combination with blockers calcium channels. In / in the introduction of verapamil / diltiazem on the background of beta-blockers leads to a decrease in blood pressure, blockade and heart failure.
Antihypertensive drugs (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) can buy testosterone cypionate lead to a decrease in cardiac performance by reducing sympathetic activity (slowing of heart rate , decreased cardiac output, vasodilation symptoms). Amiodarone combined with nebivolol may contribute to an increase in the degree atrioventricular block.
The simultaneous use of nebivolol and drugs for general anesthesia can cause suppression of the reflex tachycardia and increase the risk of hypotension; in relation to calcium channel blockers slow (BCCI) reinforce the negative effect on myocardial contractility and AV conduction, while the use of beta-blockers with BCCI (verapamil and diltiazem). Contraindicated in / with the introduction of verapamil in patients receiving nebivolol.
In combination with antihypertensive drugs, nitroglycerin or BCCI may develop severe hypotension (special caution is needed in combination with prazosin).
While the use of nonsteroidal anti-inflammatory drugs clinically significant interaction has been established. Aspirin as an agent may be used in conjunction with nebivolol.
At simultaneous application of nebivolol had no effect on the pharmacokinetic parameters of digoxin.
While the use of antiarrhythmic drugs of class I and with amiodarone may increase the negative inotropic effects and an elongation time of the excitation by the atria.
In an use of drugs that inhibit the reuptake of serotonin, or other means, biotransformed with participation of CYP2D6 isoenzyme, nebivolol metabolism slows down.
in an application with cimetidine concentration in blood plasma nebivolol increases (data on the effect on the pharmacological effects of the drug are not available). Concurrent administration of ranitidine had no effect on the pharmacokinetic parameters of nebivolol.
At simultaneous application of nebivolol with nicardipine concentration of active substances in the blood plasma increases slightly, but this has no clinical significance.
Simultaneous treatment with ethanol, furosemide or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol. No clinically significant interaction found nebivolol and warfarin.

Important information
Cancellation of beta-blockers should be carried out gradually, within 10 days. CHF Treatment with nebivolol -Teva carried out against the background of a stable hemodynamic parameters, not earlier than 6 weeks after the end of the period of decompensation. The drug Nebivolol -Teva can safely be used for CHF treatment with thiazide diuretics, digoxin, ACE inhibitors or angiotensin II receptor antagonists.
In the beginning of treatment should be monitored daily blood pressure and heart rate. The effectiveness of beta-blockers in smokers is lower than non-smokers. Nebivolol has no effect on the concentration of glucose in patients with diabetes. However, caution should be exercised when treating these patients, because the drug Nebivolol -Teva may mask certain symptoms of hypoglycemia (eg, tachycardia) caused by the intake of hypoglycemic drugs.
If necessary, the use of nebivolol in patients with psoriasis should carefully evaluate the potential benefits of therapy and the possible risk exacerbation of psoriasis. Beta-blockers should be used with caution at elevated thyroid function due to the fact that under the effect of beta-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of the drug may cause an aggravation of symptoms and development of thyrotoxic crisis.
Nebivolol may exacerbate the symptoms of peripheral circulatory disorders. Patients wearing contact lenses should bear in mind that during treatment with beta-blockers may reduce the production of tear fluid.
When planning a surgery should alert the physician / anesthesiologist that the patient is taking beta-blockers. Beta-blockers should be canceled at least 24 hours before the start of preparation for anesthesia.
Perhaps the increased severity of hypersensitivity reactions and the lack of effect of conventional doses of epinephrine (adrenaline) with aggravated allergic history.
Beta-blockers should be used with caution in patients with chronic obstructive pulmonary disease, as it may worsen bronchospasm. Before treatment is recommended to study the external breathing function in patients with a history of bronchopulmonary history.
Using the drug Nebivolol -Teva in patients with pheochromocytoma have a risk of paradoxical hypertension (if not previously reached effective blockade of the alpha-adrenergic receptors).
With the simultaneous use of clonidine its reception may be terminated only a few days after discontinuation of the drug Nebivolol -Teva.
It is recommended to discontinue therapy with nebivolol -Teva in the development of depression. Controlling the glucose concentration in the blood plasma should be 1 every 4-5 months (in patients with diabetes).
Monitoring of laboratory parameters of renal function should be performed 1 time in 4-5 months (in elderly patients).

Effects on ability to drive vehicles and work with the technique
of any negative impact on the ability to drive vehicles or other complex mechanisms in patients receiving nebivolol was not observed, however, due to the possible excessive reduction in blood pressure, development of dizziness and other adverse reactions, care should be taken when performing actions that require high concentration and speed of psychomotor reactions.