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Nebivolol is a cardioselective beta 1 adrenoblokatorom III generation with vasodilating properties. It has antihypertensive, antianginal and antiarrhythmic action.Nebivolol slows the heart rate (HR) and lowers blood pressure at rest and during exercise, reduces end-diastolic left ventricular pressure, reduces the total peripheral vascular resistance, improves diastolic cardiac function (reducing end-diastolic left ventricular filling pressure) increases the ejection testosterone cypionate for sale fraction. Selectively and competitively blocks synaptic and post-synaptic beta 1 -adrenergic receptors, making them inaccessible to catecholamines release modulates endothelial vasodilator factors – nitric oxide (NO).
Nebivolol is a racemate consisting of two enantiomers: SRRR-nebivolol (D-nebivolol) and the RSSS -nebivolola (L-nebivolol), which combines two pharmacological activities:
– the D-nebivolol is a competitive and highly selective blocker of beta 1 -adrenoceptor;
– of L-nebivolol has a mild vasodilator effect by modulating the release of relaxing factor (NO) from the vascular endothelium.
The hypotensive effect develops in 2 – 5 days of treatment, stable effect observed after 1 – 2 months. This effect is maintained during long-term therapy.
The antihypertensive effect is also due to a decrease in the activity of the renin-angiotensin-aldosterone system (not directly correlate with changes in the activity of renin in blood plasma).
By reducing myocardial oxygen demand (slowing of heart rate, reducing preload and afterload) 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 in the pathological focus) and atrioventricular conduction slowing. Pharmacokinetics After oral administration of nebivolol is rapidly absorbed from the gastrointestinal tract (GIT). Eating does not affect the suction, so nebivolol can be administered independently from the meal. Bioavailability is an average of 12% in patients with “fast” metabolism (the effect of “first pass”), and is almost complete in patients with “slow” metabolism.

Contraindications

• Hypersensitivity to Nebivolol or any of the components of the drug;
• severe hepatic insufficiency;
• acute heart failure, cardiogenic shock, congestive heart failure in the stage of decompensation (requires inotropic therapy);
• sick sinus syndrome, including sinoatrial block;
• atrioventricular block II and III degree (without pacemaker);
• bronchial asthma or bronchospasm history;
• pheochromocytoma (without the simultaneous use of alpha-blockers);
• depression;
• metabolic acidosis;
• bradycardia (heart rate less than 50 beats / min );
• severe hypotension (systolic blood pressure less than 90 mmHg);
• the age of 18 years (effectiveness and safety have not been established);
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption (product contains lactose);
• simultaneous reception floctafenine, sultopride (see “Interaction with other medicinal products” section.);
• severe peripheral circulatory disorders;
• breastfeeding.

Carefully

Severe renal impairment (creatinine clearance (CC) of less than 20 ml / min), diabetes, hyperthyroidism, conducting desensitizing therapy, psoriasis, allergic history, atrioventricular block I degree, Prinzmetal angina, chronic obstructive pulmonary disease (COPD), peripheral circulatory disorders mild to moderate, the use in elderly patients (over 65 years).

Application of pregnancy and during breastfeeding

When pregnancy  is prescribed only under strict indications, where the benefits to the mother outweighs the risk to the fetus (in connection with the possibility of fetal growth retardation, fetal death, premature birth, as well as the development of the newborn bradycardia, hypotension, hypoglycemia and respiratory paralysis ). If the use of beta-blockers during pregnancy necessary, to apply more preferably selective beta 1 adrenoblokatory. Treatment testosterone cypionate for sale should be interrupted for 48 – 72 hours before delivery. In cases where this is not possible, it is necessary to control the utero-placental blood flow and fetal growth, as well as to ensure strict monitoring of the newborn for the first 3 days after delivery.
Animal studies have shown that nebivolol is excreted in breast milk. Data whether nebivolol with human breast milk are absent allocated. However, most beta-blockers, particularly lipophilic compounds (e.g., nebivolol and its metabolites) in one degree or another infiltrating breast milk. If use of the drug Nebivolol Sandoz ® during lactation is necessary, breast-feeding should be discontinued.

Dosing and Administration

The drugis taken orally in one and the same time of the day regardless of the meal, not chewing and drinking plenty of fluids.
The tablet can be divided into four equal parts on a cruciform risk. Arterial hypertension and coronary heart disease Average daily dose for the treatment of arterial hypertension, coronary heart disease and 2.5 – 5 mg (2.1 mg tablet 5 – 1 5 mg tablet) 1 time per day. Clinically significant effect appears after 1 – 2 weeks of treatment, and in some cases – in 4 weeks. Possible use of the drug in monotherapy or in combination therapy. If necessary, the daily dose can be increased to 10 mg (2 tablets of 5 mg per dose). The maximum daily dose – 10 mg. Patients with kidney disease: initial dose of 2.5 mg / day (2.1 to 5 mg tablets). If necessary, the daily dose can be raised to 5 mg. Elderly patients: patients over 65 years of the initial dose is 2.5 mg / day (1.2 to 5 mg tablets). If necessary, the daily dose can be raised to 5 mg. However, taking into account the limited experience of the drug in elderly patients, it is necessary to be careful and conduct a thorough examination of patients over the age of 65 years. Chronic heart failure, chronic heart failure treatment should begin with gradual dose titration to achieve individual optimal maintenance dose. Dose selection in the beginning treatment should be implemented in stages.Each increase in the dose should be administered at least 2 weeks, depending on the individual sensitivity of the organism: a dose of 1.25 mg nebivolol Sandoz ® (1/4 5 mg tablets) once a day one may first be increased to 2 5 – 5 mg nebivolol Sandoz ® (1/2 tablet 5 mg – 5 mg 1 tablet) and then – 10 mg (2 tablets of 5 mg), 1 time per day. The patient should be under medical supervision for 2 hours after the first dose of the drug, as well as after each subsequent dose increases. The maximum recommended dose for the treatment of chronic heart failure is 10 mg  1 time per day. During titration we recommend regular monitoring of blood pressure, heart rate and heart failure symptom. During the titration in the case of worsening of heart failure or intolerance to the drug is recommended to reduce the dose of the drug testosterone cypionate for sale or, if necessary, immediately stop taking it (in the case of pronounced hypotension at worsening heart failure with acute pulmonary edema in case of cardiogenic shock, symptomatic bradycardia or atrioventricular block). Treatment with Nebivolol Sandoz ® is not recommended to stop abruptly (if it is not necessary), because this can lead to transient worsening of heart failure. If necessary, the dose should be reduced gradually (half-weekly). For patients receiving medical treatment of cardiovascular diseases, including diuretics, digoxin angiotensin-converting enzyme inhibitors and / or angiotensin II receptors, prior to treatment with  should dose to stabilize these drugs during the last two weeks. Patients with renal failure: the mild and moderate renal impairment (creatinine clearance ˃ 20 ml / min) the need for correcting the dose absent, so it is necessary to select a dose individually, gradually increasing to the maximum tolerated. There is no experience with the drug in patients with severe renal dysfunction (creatinine clearance ˂ 20 ml / min), so it is welcome in these patients is not recommended. Elderly patients: the need for a dosage adjustment is not available, so you need to individually select the dose is gradually increased to the maximum tolerated.

Overdose

Symptoms: marked reduction of blood pressure, bradycardia, atrioventricular block, cardiogenic shock, acute heart failure, cardiac arrest, bronchospasm, loss of consciousness, coma, nausea, vomiting, cyanosis, hypoglycaemia.
In case of overdose or the occurrence of hypersensitivity reactions should be carefully monitored for the patient in intensive care. It is necessary to monitor the concentration of glucose in the blood.Treatment: gastric lavage, activated charcoal. In the case of pronounced reduction in blood pressure is necessary to give the patient the position of “lying” with raised legs, if necessary – in / in a liquid and vasopressors. You may need mechanical ventilation. If bradycardia is introduced into / in the 0.5 – 2 mg atropine, with no positive effect can be staged or transvenous intracardiac electrical stimulator. When atrioventricular block (II -. III v) recommend the use of beta-agonists. Effect of beta-blockers can be neutralized by slow intravenous isoprenaline, starting with a dose of 5 g / min or dobutamine, starting with a dose of 2.5 g / min, to achieve the desired effect. In severe cases, can be combined with isoprenaline dopamine. If these doses do not give the desired effect, it is necessary to consider the intravenous administration of 50-100 mg / kg glucagon. If necessary, the injection should be repeated after 1 hour, followed by intravenous injection of 70 micrograms / kg / h of glucagon. With the ineffectiveness of the use of beta-agonists should consider setting an artificial 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 bronchospasm injected beta 2 -adrenomimetiki. When ventricular arrhythmia – lidocaine (antiarrhythmic agents should not be administered IA class). In convulsions -. Intravenous diazepam When hypoglycemia is recommended intravenous dextrose (glucose).

 

Interaction with other drugs

Pharmacodynamic interactions
Concomitant use of nebivolol and floctafenine. There is a risk of arterial hypotension or shock.
Concomitant use of nebivolol and sultopride due to the increased risk of ventricular tachycardia. An incorrect combination of an application with class I antiarrhythmics (quinidine, gidrohinidin, tsibenzolin, flecainide , disopyramide, lidocaine, mexiletine, propafenone) may increase the negative inotropic effects and an elongation of time through the atrioventricular node. with the simultaneous use of beta-blockers blockers “slow” calcium channels (BCCI) (verapamil and diltiazem) amplified negative effect on myocardial contractility and atrioventricular conduction. Intravenous verapamil is contraindicated in patients receiving nebivolol. At simultaneous application with antihypertensive medications central action (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) possible worsening of heart failure by reducing sympathetic tone (decreased heart rate and cardiac output, vasodilation symptoms). In the case of abrupt withdrawal of these drugs, especially to the abolition of nebivolol, may develop “rebound” hypertension. Combinations that should be used with caution While the use of antiarrhythmic drugs class III (amiodarone) may intensify the effect of the duration of the through the atrioventricular node.Concomitant use nebivolol and medical funds for general anesthesia can cause suppression of the reflex tachycardia and increase the risk of hypotension. Concomitant use of insulin and hypoglycemic drugsfor Ingestion may mask some symptoms of hypoglycaemia (palpitations, tachycardia). Concomitant use of baclofen and amifostine with antihypertensive drugs can cause a significant drop in blood pressure, thus requiring dose adjustment of antihypertensive drugs. Combinations to be taken into account simultaneous use of nebivolol with cardiac glycosides can cause slowing of atrioventricular conduction.Nebivolol does not affect the pharmacokinetic parameters of digoxin. The simultaneous use of nebivolol and BCCI dihydropyridine (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine) may increase the risk of hypotension. We can not exclude an increased risk of further reducing myocardial contractility in heart failure patients. In combination with antihypertensive drugs, nitroglycerin may develop severe hypotension (special caution is needed in combination with prazosin). The simultaneous use of tricyclic antidepressants, barbiturates and derivatives of phenothiazines may potentiate the hypotensive effect nebivolol. Clinically significant interaction nebivolol and non-steroidal anti-inflammatory drugs (NSAIDs) has been established. Aspirin as an antiplatelet agent may be used in conjunction with nebivolol. with simultaneous use of sympathomimetic agents inhibit nebivolol activity. The pharmacokinetic interaction while the use of drugs that inhibit the reuptake of serotonin or other means biotransformed involving isoenzyme CYP2D6 (e.g., paroxetine, fluoxetine, thioridazine, quinidine), nebivolol metabolism slows, increasing its concentration in blood plasma, which can lead to increased risk of severe bradycardia and adverse events. while the use of cimetidine may increase nebivolol plasma concentration of unchanged clinical effect. simultaneous use of ranitidine did not affect the pharmacokinetic parameters of nebivolol. in an testosterone cypionate for sale application of nebivolol with nicardipine concentration of both substances in plasma slightly increased without changing the clinical effect. simultaneous administration of ethanol, furosemide or hydrochlorothiazide It does not affect the pharmacokinetics of nebivolol. Do not set a clinically significant interaction between nebivolol and warfarin.

 

special instructions

Beta-blockers should not be used in patients with untreated congestive heart failure as long as the state is not stable.
It is unacceptable abrupt discontinuation of beta-blockers. Abolition of beta-blockers should be carried out gradually, within 10 days (up to 2 weeks in patients with CAD).
The efficacy of beta-blockers in smokers is lower than non-smokers.
Control of blood pressure and heart rate at the start of dosing should be every day, then . 1 time in 3-4 months
in elderly patients, renal function monitoring is required (1 every 4-5 months).
angina dose voltage should provide resting heart rate in the range of 55-60 beats / min, a load – no more than 110 beats / min.
Beta-blockers can cause bradycardia: the dose should be reduced if the heart rate less than 50-55 beats / min (see section “Contraindications”.).
Beta-blockers should be used with caution in these groups of patients:
– with disturbances of peripheral circulation (syndrome or Raynaud’s disease, “intermittent” claudication), because it is possible worsening of these symptoms;
– with atrioventricular block I degree, as beta-blockers adversely affect the duration of the pulse;
– with angina Prinzmetal due to the smooth-mediated alpha-receptors vasoconstriction of coronary artery:. beta-adrenergic antagonists may increase the number and duration of angina attacks
Patients who use contact lenses should bear in mind that during treatment with beta-blockers may reduce the production of tear fluid.
During the surgery should alert the anesthetist that the patient It takes Nebivolol Sandoz ® . Continuation of beta blockade reduces the risk of arrhythmias during general anesthesia and intubation. When preparing for surgery involves interruption of beta-blockade should stop taking beta-adrenergic antagonists, at least 24 hours prior to surgery.
It should be used with caution anesthetics that cause myocardial depression. Vagal response in the patient can be prevented by intravenous administration of atropine.
Nebivolol Sandoz ® does not affect the glucose concentration in the blood plasma of patients with diabetes.
However, caution should be exercised in the treatment of these patients because nebivolol may mask certain symptoms of hypoglycemia (such as palpitations , tachycardia) caused by the use of hypoglycemic agents. In patients with diabetes control blood plasma glucose concentration should be 1 diabetes every 4-5 months.
Beta-blockers may also mask the symptoms of tachycardia with hyperthyroidism.
Beta-blockers should be used with caution in patients with chronic obstructive pulmonary disease, as it may worsen bronchospasm.
Beta-blockers may increase the sensitivity to allergens and the severity of anaphylactic reactions.
If necessary, use of the drug Nebivolol Sandoz ® in patients with psoriasis should carefully evaluate the potential benefits of therapy and the possible risk of exacerbation of psoriasis. probol