Testosterone cypionate injection, cardioselective beta1-adrenergic blocker of the third generation with vasodilating properties. It has antihypertensive, antianginal and antiarrhythmic action. Reduces high blood pressure (BP) at rest, exertion and stress. The hypotensive effect develops in 2-5 days of treatment, stable effect observed after 1 month. 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). The use of Nebivolol improves system and intracardiac hemodynamics. Nebivolol slows the heart rate (HR) and blood pressure at rest and during exercise, reduces end-diastolic left ventricular pressure, reduces the total peripheral vascular resistance, improves diastolic cardiac function (reduced filling pressure) increases the ejection fraction. By reducing myocardial oxygen demand ( slowing heart rate, reducing preload and afterload) reduces the number and severity of attacks of angina and improve exercise tolerance. Antiarrhythmic effect is due to inhibition of cardiac automatism (including in the pathological focus) and slowing of atrioventricular (AV) conduction.

Pharmacokinetics

After oral administration of nebivolol rapidly absorbed from the gastrointestinal tract. Food intake has no effect on the absorption, so nebivolol can be taken regardless of meals. Bioavailability is an average of 12% in patients with metabolism and is almost complete in patients with metabolism. Efficacy nebivolol metabolism is independent of speed. Plasma Clearance in most testosterone cypionate injection patients (with metabolism) is achieved within 24 hours and after several days. Blood plasma concentration of 1-30 mg / l dose proportional. Communication to plasma proteins (mainly albumin) for D-nebivolol is 98.1% and L-nebivolol -. 97.9% Nebivolol actively metabolized partly active form of nebivolol metabolism rate by aromatic hydroxylation oxidative polymorphism genetically determined and depends on isozyme CYP2D6. After the introduction 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. patients with fast  half-life value (T 1/2) enantiomers of nebivolol plasma averages 10 hours. in patients with slow metabolism of these values are increased by 3-5 times. in patients with fast metabolism values T1 / 2 both enantiomers from plasma averages 24 hours, in patients with metabolism, these values were approximately 2 fold increase. On nebivolol does not affect the pharmacokinetics of the age and sex of patients.

CONTRAINDICATIONS

• Hypersensitivity to Nebivolol or one of the components of the drug;
• expressed human liver;
• congestive heart failure;
• cardiogenic shock;
• Chronic heart failure decompensation (requires inotropic therapy);
• sick sinus syndrome, including sinoatrial block;
• atrioventricular block II and III degree (without pacemaker);
• bronchospasm and asthma;
• pheochromocytoma (without the simultaneous use of alpha-blockers);
• depression;
• metabolic acidosis;
• bradycardia (heart rate less than 50 beats / min..);
• severe hypotension;
• expressed severe peripheral circulatory disorders (intermittent claudication, Raynaudas syndrome);
• age of 18 years;
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption (product contains lactose).
• simultaneous reception floctafenine, sultopride (see Interactions with other drugs.);

With care use in patients with severe renal insufficiency (creatinine clearance (CC) of less than 20 ml / min), hepatic dysfunction, diabetes, hyperthyroidism, conducting desensitizing therapy, psoriasis, atrioventricular block I degree, Prinzmetal angina, chronic obstructive pulmonary disease ( COPD), in elderly patients (over 65 years).

Application of 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. Animal studies have shown that nebivolol is excreted in breast milk. No data on the allocation of nebivolol in human milk. Therefore, the drug Nevotenz not recommended for women during lactation. If Nevotenz application during lactation is necessary, breast-feeding should be discontinued.

DOSAGE AND ADMINISTRATION
Nevotenz taken orally at the same time of the day regardless of the meal, not chewing and drinking plenty of fluids.

Arterial hypertension and coronary heart disease

Average daily dose for the treatment of hypertension and coronary heart disease 5 mg (1 tablet) 1 once a day. Optimal effect becomes pronounced within 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. In patients with renal insufficiency and in patients over the age of 65 years starting dose is 2.5 mg / day (1/2 tablets of 5 mg). If necessary, increase the dose to 5 mg. When severe impaired renal function (creatinine clearance less than 20 ml / min) and in patients with severe liver disease, the maximum daily dose is 10 mg. Increasing the dose in these patients should be performed with extreme caution.

Chronic Heart Failure

Treatment chronic heart failure should begin with a gradual increase in dose until the optimal individual maintenance dose. The patient must be under medical 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 Nevotenz 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 congestive heart failure or intolerance to the testosterone cypionate injection drug is recommended to reduce the dose of the drug Nevotenz or, if necessary, immediately stop taking it (in the case of pronounced hypotension, worsening flow of CHF with acute pulmonary edema in case of cardiogenic shock, symptomatic bradycardia or AV block).

Side effect

On the part of the central nervous system: headache, dizziness, fatigue, paresthesia, depression, decreased ability to concentrate, drowsiness, insomnia, dream, hallucinations, loss of consciousness. From the digestive system: nausea, constipation, flatulence , diarrhea, dryness of the oral mucosa. Since the cardiovascular system: bradycardia, heart failure, AV block, orthostatic hypotension, peripheral circulatory disorders (feeling of in the extremities, cyanosis), shortness of breath, heart rhythm disorders, Raynauda’s syndrome, peripheral edema, false angina, worsening of heart failure flow (this side effect primarily occurs during titration of the drug) , marked reduction in blood pressure. Allergic reactions with the skin: itching, rash erythematous character, angioedema, flushing of the skin, alopecia. From the respiratory system: bronchospasm (including the absence of obstructive lung disease in history), bronchospasm in patients with asthma or airway obstruction in the history of rhinitis. Other: photodermatosis, rash, exacerbation of psoriasis flow, visual disturbances (dry eyes) , violation of potency.

Overdose Symptoms: marked reduction of blood pressure, bradycardia, AV block, cardiogenic shock, acute heart failure, cardiac arrest, bronchospasm, loss of consciousness, coma, nausea, vomiting, cyanosis.

Treatment: gastric lavage, activated charcoal. In the case of pronounced reduction in blood pressure is necessary to give the patient a horizontal position with legs raised, if necessary, on / in a fluid and vasopressors; as a follow-up, the introduction of 1-10 mg of glucagon. If bradycardia is introduced into / in the 0.5-2 mg atropine, with no positive effect can raise the transvenous pacemaker. When AV block (II-III cent.) is recommended intravenously the introduction of beta-agonists, while their inefficiency 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 beta2-agonists. When ventricular arrhythmia lidocaine (should not be administered antiarrhythmic drugs IA class). In convulsions intravenous diazepam .

INTERACTION WITH OTHER DRUGS

Floctafenine: in the event of shock or hypotension caused by reception floctafenine, beta-blockers attenuate compensatory mechanisms of the cardiovascular system. Sultopride: increased risk of ventricular arrhythmias, especially type. When concomitant use of beta-blockers blockers calcium channels (BCCI) (verapamil and diltiazem) amplifies a negative effect on myocardial contractility and AV conduction. Contraindicated in / with testosterone cypionate injection the introduction of verapamil in patients receiving nebivolol. In combination with antihypertensive drugs, nitroglycerin or BCCI may develop severe hypotension (special caution is required when combined with prazosin). 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 nebivolol application with cardiac glycosides have not revealed the growing influence of the slowing of AV conduction.The simultaneous use of nebivolol and drugs for general anesthesia can cause suppression of the reflex tachycardia and increase the risk of hypotension. Clinically significant interaction nebivolol and nonsteroidal anti-inflammatory drugs (NSAIDs) has been established. Aspirin as an antiplatelet agent may be used in conjunction with nebivolol. The simultaneous use of tricyclic antidepressants, barbiturates and derivatives of phenothiazines may potentiate the hypotensive effect of nebivolol. Pharmacokinetic interactions In an application with drugs that inhibit the reuptake of serotonin, or other means, biotransformed with participation of isoenzyme of CYP2D6, nebivolol metabolism slows down. in an application nebivolol had no effect on the pharmacokinetic parameters of digoxin. in an application with cimetidine concentration of nebivolol in blood plasma increases (on the impact of the data on the pharmacological effects of the drug available). Concurrent administration of ranitidine had no effect on the pharmacokinetic parameters of nebivolol. at concomitant use of nebivolol with nicardipine concentration of active substances in the blood increases slightly plasma, but this has no clinical significance.simultaneous treatment with ethanol, furosemide or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol. Do not set a clinically significant interaction between nebivolol and warfarin. with simultaneous use of sympathomimetic agents inhibit the activity nebivolol.

SPECIAL INSTRUCTIONS
Cancellation of beta-blockers should be carried out gradually, within 10 days (up to 2 weeks in patients with coronary heart disease).
Control of blood pressure and heart rate at the start of drug administration should be daily.
In elderly patients is necessary to monitor renal function (1 times . 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.
Beta-blockers can cause bradycardia: the dose should be reduced if the heart rate less than 50-55 u. / min. (see. Section Contraindications).
In deciding on the appointment of the drug Nevotenz patients with psoriasis should be closely correlate prospective advantage of the drug and the possible risk of exacerbation of psoriasis.
Patients who use contact lenses should bear in mind that during treatment with beta-blockers may reduce production of tear fluid.
during the surgery should alert the anesthetist that the patient is taking Nevotenz.
Nevotenz no effect on plasma concentrations of glucose in patients with diabetes.
However, caution should be exercised when treating these patients because Nevotenz may mask certain symptoms of hypoglycemia (eg, tachycardia) caused by the use of hypoglycemic agents.
Monitoring of glucose concentrations in blood plasma should be performed 1 time in 4-5 months. (in patients with diabetes).
Beta-blockers should be used with caution in patients with COPD, since it may worsen bronchospasm.
When hyperthyroidism drug eliminates tachycardia.
Beta-blockers may increase the sensitivity to allergens and the severity of anaphylactic reactions.
The efficacy of beta-blockers lower in smokers than non-smokers patients.

Effects on ability to drive vehicles and mechanisms

Research studies have shown that nebivolol does not affect the speed of psychomotor reactions. Pilots flying personnel with hypertension I degree (admitted to the flight operations), the drug is prescribed in an initial dose of 2.5 mg. Subsequently (no sooner than 2 weeks), with good tolerability and lack of control of blood pressure may increase the dose to 2.5 mg. The recommended testosterone cypionate injection dose of 5 mg / day. Some patients may experience side effects, most commonly dizziness due to blood pressure reduction. Should you experience such effects, the patient should not drive vehicles or to engage in potentially hazardous activities that require special attention and speed of psychomotor reactions. These effects usually occur immediately after the onset of treatment or when the dose is increased.