Universal reference book for medicines
Name of the preparation: NEBILONG H (NEBILONG H)

Active substance: hydrochlorothiazide, nebivolol

Type: Antihypertensive drug

Manufacturer: MICRO LABS (India)
Composition, form of production and packaging
Tablets are
white or almost white, round, flat, with a facet and a risk on one side.

1 tab.

nebivolol 5 mg

hydrochlorothiazide 12.5 mg

Auxiliary substances: lactose monohydrate - 60.44 mg, microcrystalline cellulose - 43.868 mg, betadox (betacyclodextrin) - 30 mg, croscarmellose sodium - 24 mg, sodium docomate - 2 mg, povidone - 5 mg, silicon dioxide colloidal anhydrous - 2 mg, talc - 2 mg, magnesium stearate - 2 mg.

10 pieces.
- Al / Al blisters (1) - cardboard packs.
10 pieces.
- blisters Al / Al (3) - packs cardboard.
10 pieces.
- blisters Al / Al (5) - packs cardboard.
10 pieces.
- blisters Al / Al (10) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2014.

PHARMACHOLOGIC EFFECT

Nebilong H is a combination of nebivolol and hydrochlorothiazide.

Nebivolol

Nebivolol is a lipophilic, cardioselective, beta 1- adrenoblocker with vasodilating properties.
It has antihypertensive, anti-anginal and antiarrhythmic effects. Reduces elevated blood pressure at rest, with physical stress and stress. Competitively and selectively blocks synaptic and postsynaptic beta- 1- adrenoblockers, making them inaccessible to catecholamines, modulating the release of the endothelial vasodilating factor of nitric oxide (NO).
Nebivolol is a racemate consisting of two enantiomers: SRRR-nebivolol (D-nebivolol) and RSSS-nebivolol (L-nebivolol), which combines two pharmacological actions:

- D-nebivolol is a competitive and highly selective beta 1 -adrenoceptor blocker (affinity for beta 1 -adrenoceptors is 293 times higher than for beta 2-adrenoreceptors).

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

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 RAAS (directly correlates with a change in renin activity in blood plasma).

The use of nebivolol improves the indices of systemic and intracardiac hemodynamics.
Nebivolol reduces heart rate and blood pressure at rest and under physical exertion, reduces the end-diastolic pressure of the left ventricle, reduces OPSS, improves diastolic function of the heart (reduces filling pressure), increases the ejection fraction. Reducing the need for myocardium in oxygen (decreasing heart rate, reducing pre-and post-loading), reduces the number and severity of angina attacks and improves the tolerance of exercise.
Antiarrhythmic action is due to the suppression of the automatism of the heart (including in the pathological focus) and the slowing of AV conduction.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic.
Reduces the reabsorption of sodium ions in the cortical segment of the Henle loop, without affecting its area passing through the medulla of the kidney. It blocks carbonic anhydrase in the proximal part of the convoluted renal tubules, enhances the excretion of potassium ions, hydrocarbonates and phosphates by the kidneys. Virtually does not affect the acid-base state. It enhances the excretion of magnesium ions by the kidneys, delays calcium ions in the body and inhibits the excretion of urates.
The diuretic effect develops after 1-2 hours, reaches a maximum after 4 hours, lasts up to 10-12 hours. The diuretic effect decreases with a decrease in the glomerular filtration rate and stops at a value of less than 30 ml / min.
(reduces the volume of urine and increases its concentration).
PHARMACOKINETICS

Nebivolol

After ingestion, nebivolol is rapidly absorbed from the digestive tract.
Eating does not affect suction, so nebivolol can be taken regardless of food intake.Bioavailability averages 12% in patients with "fast" metabolism and is almost complete in patients with "slow" metabolism. The effectiveness of nebivolol does not depend on the metabolic rate.
Clearance in the blood plasma in most patients (with a "fast" metabolism) is achieved within 24 hours, and for hydroxy metabolites - in a few days.
Concentrations in blood plasma of 1-30 mcg / l are proportional to the dose.
The association with blood plasma proteins (predominantly with albumin) for D-nebivolol is 98.1%, and for L-nebivolol, 97.9%.

Nebivolol is actively metabolized, in part with the formation of active hydroxymetabolites.
Metabolized by acyclic and aromatic hydroxylation is genetically determined by oxidative polymorphism and depends on the isoenzyme CYP2D6.
After the administration 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 "fast" metabolism, the half-life (T 1/2 ) of the enantiomers of nebivolol from plasma is an average of 10 hours. In patients with "slow" metabolism, these values ​​increase 3-5 times.

In patients with "fast" metabolism, the T 1/2 values ​​of the hydroxy metabolites of both enantiomers from plasma are averaged 24 hours, in patients with "slow" metabolism these values ​​are approximately 2-fold increased.

The pharmacokinetics of nebivolol is not affected by age and sex of patients.

Hydrochlorothiazide

When ingested, absorbed quickly, but incomplete.
The time to reach the maximum concentration in the blood plasma is about 4 hours. The bioavailability of hydrochlorothiazide is 60-80%. The connection with plasma proteins is 40%.
It penetrates the placental barrier, and is excreted into breast milk.
It is not metabolized. It is excreted by the kidneys basically unchanged through glomerular filtration and active tubular secretion. The half-life is about 8 hours.
INDICATIONS

- Arterial hypertension (patients who are shown combined therapy).

DOSING MODE

Inside, it is desirable to take at the same time, 1 time per day, regardless of the time of ingestion, without chewing and drinking with a sufficient amount of liquid.
At the beginning of therapy should take 1 tablet a day.
If the therapeutic effect is not enough, after 2 weeks the dose can be increased to 2 tablets.

The maximum daily dose is 2 tablets per day.

Patients with severe impairment of kidney function (QC less than 30 ml / min), the use of the drug is not recommended (see Contraindications).

SIDE EFFECT

Nebivolol

The frequency of side effects is presented in the following gradation: 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%), including individual messages.

From the nervous system: often: headache, dizziness, fatigue, weakness, parasthesia;
infrequently: depression, vivid dreams, confusion, insomnia; very rarely: syncope, hallucinations, amnesia.
From the gastrointestinal tract: often: nausea, constipation, diarrhea;
infrequently: flatulence, indigestion, vomiting.
Cardio-vascular system: infrequent: bradycardia, heart failure, AV blockade, orthostatic hypotension, peripheral circulatory disorders (cold sensation in the extremities, cyanosis), shortness of breath, heart rhythm disturbances, Raynaud's syndrome, peripheral edema, kardialgia, aggravation the course of chronic heart failure, marked decrease in blood pressure.

On the part of the skin: infrequently: skin rash erythematous nature, skin itching, hyperemia of the skin;
very rarely: aggravation of psoriasis, alopecia; in some cases: angioedema.
On the part of the respiratory system: infrequently: bronchospasm (including in the absence of obstructive pulmonary disease in the anamnesis), bronchospasm in patients with bronchial asthma or airway obstruction in an anamnesis.

Other: photodermatosis, hyperhidrosis, visual impairment (dry eyes), sexual dysfunction.

Hydrochlorothiazide

Violation of water-electrolyte balance:

hypokalemia, hyponatremia, hypercalcemia and hypochloraemic alkalosis: dryness of the oral mucosa, thirst, irregular heart rhythm, lability of mood or psyche, convulsions and muscle pain, nausea, vomiting, unusual fatigue or weakness.
Hypochloremic alkalosis can cause hepatic encephalopathy or hepatic coma;
- hyponatremia: confusion, convulsions, slowing down the process of thinking, increased fatigue, increased excitability, convulsions, lethargy.

Metabolic phenomena: hyperglycemia, glucosuria, hyperuricemia with exacerbation of gout.

Treatment with thiazides can reduce glucose tolerance and latent diabetes mellitus can manifest.
When using high doses, lipid concentrations in the serum can increase.
From the digestive tract: cholecystitis or pancreatitis, cholestatic jaundice, diarrhea, sialadenitis, constipation, anorexia.

From the cardiovascular system: arrhythmias, orthostatic hypotension, vasculitis.

From the nervous system: dizziness, temporarily blurred vision, headache, paresthesia.

From the hematopoiesis: very rarely: leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia.

Allergic reactions: urticaria, purpura, necrotizing vasculitis, Stevens-Johnson syndrome, respiratory distress syndrome (including pneumonitis and noncardiogenic pulmonary edema), photosensitivity, anaphylactic reactions up to shock.

Other: decreased potency, impaired renal function, interstitial nephritis.

CONTRAINDICATIONS

- Hypersensitivity to nebivolol or one of the components of the drug, as well as to other beta-blockers, increased sensitivity to hydrochlorothiazide and other sulfonamide derivatives;

severe hepatic impairment;

- acute heart failure;

- cardiogenic shock;

- Chronic heart failure in the stage of decompensation (requiring inotropic therapy);

- syndrome of weakness of the sinus node, including sinoatrial block;

- AV blockade II and III degree (without artificial pacemaker);

- severe forms of bronchial asthma and COPD;

- pheochromocytoma (without simultaneous use of alpha-blockers);

- Depression;

metabolic acidosis;

- bradycardia (heart rate less than 60 beats per minute);

- severe arterial hypotension (systolic blood pressure less than 90 mm Hg)

- severe violations of peripheral circulation ("intermittent" lameness, Raynaud's syndrome);

- age under 18 years (effectiveness and safety not established);

- lactose intolerance, lactase deficiency or glucose-galactose malosorption (the preparation contains lactose);

- simultaneous administration with floktaphenin, sulphoprid (see the section Drug Interactions);

- hypovolemia;

- Hardly controlled diabetes mellitus;

acute renal failure;

- Addison's disease;

- anuria, chronic renal failure (CC less than 30 ml / min);

- refractory hypokalemia, hyponatremia, hypercalcemia.

Carefully:

Nebivolol: renal insufficiency, liver dysfunction, diabetes mellitus, hyperthyroidism, episodes of bronchospasm in the anamnesis, allergic diseases in the anamnesis (it is possible to increase sensitivity to allergens, weight allergic reactions and decrease the therapeutic response to adrenaline), psoriasis, AV blockade of I degree, angina Prinzmetal, COPD, in elderly patients (over 65 years), peripheral atherosclerosis, pheochromocytoma (against the background of alpha-blocker therapy).

Hydrochlorothiazide: AV blockade of I degree, IHD, hepatic insufficiency, renal failure (QC more than 30 ml / min), thyrotoxicosis, pheochromocytoma (against the background of treatment with alpha-blockers), water-electrolyte disorders (hyponatremia, hypokalemia, hypercalcemia), depression including in the anamnesis), myasthenia gravis, gout, psoriasis, elderly age, simultaneous reception of cardiac glycosides.

PREGNANCY AND LACTATION

Nebivolol

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 childbirth. 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, the drug is not recommended for women during lactation. If the use of the drug nebivolol during lactation is necessary, then breastfeeding should be discontinued.
Hydrochlorothiazide

Hydrochlorothiazide penetrates the placental barrier.
Contraindicated use of the drug in the first trimester of pregnancy. In the second and third trimesters of pregnancy, the drug can be prescribed only in case of acute necessity, when the benefit to the mother exceeds the potential risk to the fetus and / or the child. There is a danger of fetal or neonatal jaundice, thrombocytopenia and other consequences.
Hydrochlorothiazide penetrates into breast milk, so if the use of the drug is absolutely necessary, then breast-feeding should be discontinued.

SPECIAL INSTRUCTIONS

The abolition of beta-blockers should be carried out gradually, within 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.

Older patients need control of kidney function (1 time in 4-5 months).

With angina pectoris, the selected dose of the drug should provide a heart rate at rest within 55-60 beats / min, with a load of 110 beats per minute.

Patients using contact lenses should take into account that the use of beta-blockers may reduce the production of tear fluid.

Nebivolol does not affect the concentration of glucose in the blood plasma in patients with diabetes mellitus.
However, caution should be exercised in the treatment of these patients, since nebivolol may mask certain symptoms of hypoglycemia (eg, tachycardia) caused by the use of hypoglycemic agents.
Controlling the concentration of glucose in the blood plasma should be done 1 time in 4-5 months (in patients with diabetes mellitus).

Beta-adrenoblockers should be used with caution in patients with COPD, as bronchospasm may increase.

With hyperfunction of the thyroid gland, the drug levels tachycardia.

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

On the background of therapy with beta-blockers, the exacerbation of psoriasis is possible.
Patients with this disease Nebilong H should be administered with caution.
In the period of therapy with Nebilong H, it is necessary to monitor the acid-base state and the content of electrolytes (potassium, sodium, calcium).

With prolonged course treatment, it is necessary to carefully monitor the clinical symptoms of water-electrolyte balance disorders, primarily in patients at high risk: patients with cardiovascular disease and impaired liver function;
in case of severe vomiting or when signs of disturbance of the water-electrolyte balance appear, such as dryness of the mucous membrane of the cavity, thirst, weakness, lethargy, drowsiness, anxiety, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, complaints from the side GIT.
Hypokalemia can be avoided by the use of potassium-containing drugs or foods rich in potassium (fruits, vegetables), especially in the case of increased loss of potassium (increased diuresis, prolonged treatment or simultaneous treatment with cardiac glycosides or corticosteroid drugs.

It is shown that thiazides increase the excretion of magnesium by the kidneys: this can lead to hypomagnesemia.

With reduced renal function, control of creatinine clearance is required.
In such patients, the drug can cause azotemia, and cumulative effects can also develop. If the renal dysfunction is obvious, when oliguria occurs, the possibility of drug cancellation should be weighed. Patients with impaired liver function or with progressive liver diseases should be cautioned with thiazides, since a small disturbance of the water-electrolyte balance, as well as the content of ammonium in the serum, can cause hepatic coma.
In patients with peripheral circulatory disorders, caution should be exercised when prescribing Nebilong N.

Alcohol, barbiturates, narcotic drugs intensify the orthostatic hypotensive effect of thiazide diuretics.

Thiazides can reduce the amount of iodine that binds to blood serum proteins without showing signs of thyroid dysfunction (due to hydrochlorothiazide).

Patients with pheochromocytoma should not be prescribed Nebelong H until treatment with alpha-blockers is prescribed.
In this case, it is necessary to monitor blood pressure. It is recommended to stop Nebilong H with the development of depression caused by taking the beta-blocker (due to the content of nebivolol in it). Particular attention is required in cases of surgical intervention under general anesthesia in patients taking beta-blockers. Such patients should abolish Nebilong H 48 hours prior to surgery, warn the anesthetist that the patient is taking Nebilong N. As a means for general anesthesia, a drug with a minimum negative inotropic effect should be chosen. With a history of anaphylactic reactions, regardless of the cause of their occurrence, especially when conducting desensitizing therapy, treatment with Nebilong H (due to the content of nebivolol) can increase the risk of allergic reactions and promote the development of resistance to epinephrine (adrenaline) treatment in conventional doses.
In patients with hyperuricemia, the risk of developing attacks of gout aggravation is increased.
In this case, the dose of Nebilong H should be selected individually under the control of the concentration of uric acid in the serum. Before the study of the function of parathyroid glands, the treatment with Nebilong H should be stopped, as transient hypercalcemia may occur on the background of its administration.
Impact on the ability to drive vehicles and manage mechanisms

During the period of therapy, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

OVERDOSE

Nebivolol

Symptoms: marked decrease in blood pressure, bradycardia, severe intracardiac conduction disorders, shock, asystole, respiratory arrest, bronchospasm, loss of consciousness, convulsions, coma, nausea, vomiting, cyanosis, hypoglycaemia, hyperkalemia.

Treatment: gastric lavage, reception of activated charcoal.
In the case of a marked decrease in blood pressure, it is necessary to give the patient a horizontal position with raised legs, if necessary in / in the administration of liquid or vasopressors.
With bradycardia, I / in 0.5-2 mg of atropine is administered, in the absence of a positive effect, the transvenous Ildi of the intracardiac artificial pacemaker can be staged.

With AV-blockade (II-III degree) it is recommended iv administration of beta-adrenomimetics, if they are ineffective, consider setting up an artificial pacemaker.
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 enter in / in beta 2 -adrenomimetiki.
With convulsions in / in the introduction of diazepam.

With ventricular extrasystole, lidocaine (do not administer antiarrhythmic drugs in the IA class).

Hydrochlorothiazide

The most noticeable manifestation of an overdose of hydrochlorothiazide is acute tachycardia, marked decrease in blood pressure, shock, weakness, confusion, dizziness and spasms of the calf muscles, paresthesia, impaired consciousness, fatigue, nausea, vomiting, thirst, polyuria, oliguria or anuria (due to hemoconcentration), hypokalemia, hyponatremia, hypochloraemia, alkalosis, increased urea nitrogen in the blood (especially in patients with renal insufficiency).

Treatment: there is no specific antidote.

Induction of vomiting, gastric lavage, reception of activated charcoal.
In the case of a marked decrease in blood pressure or shock, the volume of circulating blood (BCC) and electrolytes (potassium, sodium) should be compensated.
It is necessary to control the water-electrolyte balance (especially the potassium content in the blood serum) and kidney function.

DRUG INTERACTION

Nebivolol

Floktaphenin: in the case of shock or arterial hypotension caused by the use of floktaphenina, beta-adrenoblockers weaken the compensatory mechanisms of the cardiovascular system.

Sultopride: increased risk of ventricular arrhythmia, especially the type of "feasting".
With simultaneous use of beta-blockers with blockers "slow" calcium channel (BCCI) (verapamil and diltiazem) amplifies a negative effect on the myocardial contractility and AV-conduction.
Contraindicated in / in the administration of verapamil on the background of nebivolol. When a single application with antihypertensives, nitroglycerin or BCCI may develop severe hypotension (special caution is required in combination with prazosin).
While the use of antiarrhythmic drugs increases the risk cardiodepressive bradycardia activities and in combination with any antiarrhythmic agent. Since amiodarone also increases the risk of AV-blockade. The risk of ventricular arrhythmia, called sotalol, amiodarone increases, dronedarone, quinidine and procainamide (to avoid joint application).
With the simultaneous use of nebivolol with cardiac glycosides, there was no evidence of an increase in the effect on AV conduction slowing.

Concomitant 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 NSAIDs not established. Acetylsalicylic acid as an antiplatelet agent may be used with odnovremennos nebivolol.
SCS and estrogens, progestins weaken the antihypertensive effect of beta-blockers.
Simultaneous application tritsiklichenskih antidepressants, barbiturates, and phenothiazine derivatives, ethanol, anxiolytics, hypnotics may enhance the antihypertensive effect of nebivolol.
The allergens used for immunotherapy, or allergen extracts for skin tests increase the risk of severe systemic allergic reactions or anaphylaxis in patients receiving nebivolol.
Iodine-containing radiopaque agents for intravenous administration increase the risk of anaphylactic reactions.

Pharmacokinetic interaction

While the use of drugs that inhibit the reuptake of serotonin, or by other means involving biotransformed isoenzymes CYP2D6, nebivolol metabolism slows down, which can lead to the risk of bradycardia.
With simultaneous use nebivolol had no effect on the pharmacokinetic parameters of digoxin.

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).
Concurrent administration of ranitidine had no effect on pharmacological parameters of nebivolol.
When applied simultaneously with nebivolol nikardininom concentration of active substances in the blood plasma increased somewhat, but it has no clinical significance.
Simultaneous reception of ethanol, furosemide or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol.
Clinically significant interactions of nebivolol and warfarin have not been established.

With simultaneous application of sympathomimetic agents inhibit the activity nebivalola.
When nebivolol joint application with insulin and hypoglycemic agents for oral administration may be masked symptoms of hypoglycemia (tachycardia, tremor).
Hydrochlorothiazide
should avoid the simultaneous application of:
- lithium salts (lithium renal clearance is reduced, toxicity is increased).
Be wary of the following preparations:
- antihypertensive drugs (potentiated their action may be necessary to dose adjustment);
- cardiac glycosides (hypokalemia and hypomagnesemia, coupled with the effect of thiazide diuretics may enhance the toxicity of cardiac glycosides);
- amiodarone (its use in conjunction with thiazide diuretics can lead to increased risk of arrhythmias associated with hypokalemia);
- hypoglycemic agents for oral administration (decreases their efficiency, may develop hyperglycemia);
- corticosteroid agents, calcitonin (increase the degree of potassium excretion);
- NSAIDs (may reduce diuretic effect and antihypertensive effects of thiazides);
- nedepolyariziruyuschimi relaxants (their effect can be enhanced);
- amantadine (amantadine hydrochlorothiazide clearance may decrease, which leads to an increase in amantadine concentrations in plasma and possible toxicity);
- colestyramine, which reduces the absorption of hydrochlorothiazide;
- ethanol, barbiturates and narcotics, which increase the risk of orthostatic hypotension.
TERMS OF RELEASE FROM PHARMACY

On prescription.

TERMS AND CONDITIONS OF STORAGE

In the dark place at a temperature of no higher than 25 ° C.
Keep out of the reach of children. Shelf life - 3 years.
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