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active ingredient: Nebivolol, hydrochlorothiazide;

1 tablet contains: Nebivolol (in the form of Nebivolol hydrochloride) - 5 mg; hydrochlorothiazide-12.5 mg;

excipients: lactose, monohydrate; corn starch; citric acid, monohydrate; hypromellose (E 15); polysorbate 80; microcrystalline cellulose (PH 102); colloidal silicon dioxide anhydrous; magnesium stearate;

coating mix: Opadry® White 03A580004 (contains hypromellose (E 464), titanium dioxide (E 171), polyethylene glycol (macrogol) stearate; microcrystalline cellulose [E 460(I)]).

Dosage form. Film-coated tablets.

Basic physical and chemical properties: Film — coated tablets, white or almost white in color, round in shape, with a biconvex surface, with the "515" logo on one side and a risk on the other.

Pharmacotherapeutic group. Selective beta-adrenergic blockers with thiazide diuretics.

ATX code C07B B12.

Pharmacological properties.


Nebiar ® Plus 5/12.5 is a combination of Nebivolol, a selective beta-receptor antagonist, and hydrochlorothiazide, a thiazide diuretic. The combination of these ingredients has an additive antihypertensive effect and lowers blood pressure to a greater extent than individual components.

Nebivolol is a racemate that consists of two enantiomers: SRRR-Nebivolol (D‑Nebivolol) and RSSS-Nebivolol (L-Nebivolol). It combines two pharmacological properties:

-due to the D-enantiomer, Nebivolol is a competitive and selective blocker of β1-adrenergic receptors;

– due to its L-enantiomer, it has mild vasodilatory properties due to its metabolic interaction with L-arginine/ nitric oxide (no).

With a single and repeated use of Nebivolol, the heart rate decreases at rest and during exercise, both in patients with normal blood pressure and in patients with arterial hypertension. The antihypertensive effect persists with long-term treatment.

At therapeutic doses, alpha-adrenergic antagonism is not observed. During short-term and long-term treatment with Nebivolol, systemic vascular resistance decreases in patients with arterial hypertension. Despite the decrease in heart rate, the decrease in cardiac output at rest and during exercise is limited due to an increase in stroke volume. The clinical significance of this hemodynamic difference compared to other beta-adrenergic Blockers is still poorly understood.

In patients with arterial hypertension, Nebivolol increases the vascular response to acetylcholine mediated by nitric oxide; in patients with endothelial dysfunction, this response is reduced.

In vitro and in vivo animal experiments have shown that Nebivolol does not have sympathomimetic activity.

In vitro and in vivo animal experiments have shown that Nebivolol has no membrane-stabilizing activity at pharmacological doses.

In healthy volunteers, Nebivolol does not significantly affect the ability to tolerate maximum physical activity or endurance.

Available preclinical and clinical data for hypertensive patients do not indicate a negative effect of Nebivolol on erectile function.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing the excretion of sodium and chloride in approximately equal amounts. The diuretic effect of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and aldosterone secretion, followed by an increase in potassium and bicarbonate losses in the urine and a decrease in serum potassium levels. When using hydrochlorothiazide, diuresis occurs in about 2 hours, and the peak effect is reached approximately 4 hours after taking the drug, while the effect lasts for 6-12 hours.


Co-administration of Nebivolol and hydrochlorothiazide does not affect the bioavailability of each of the active substances. The combined tablet is bioequivalent for the combined use of individual components.


Suction. After oral administration, both Nebivolol enantiomers are rapidly absorbed. The presence of food in the gastrointestinal tract does not affect the absorption of Nebivolol when administered orally.

The bioavailability of orally administered Nebivolol averages 12% in patients with fast metabolism and is almost complete in patients with slow metabolism. At steady state and at the same dose level, the peak plasma concentration of unchanged Nebivolol is approximately 23 times higher in patients with slow metabolism than in patients with fast metabolism. Based on the difference in the rate of metabolism, the dosage of the drug should be prescribed depending on the individual needs of the patient; patients with slow metabolism need lower doses.

The plasma concentration, which is from 1 to 30 mg of Nebivolol, is proportional to the dose. Human age does not affect the pharmacokinetics of Nebivolol.

Distribution. In plasma, both Nebivolol enantiomers bind mainly to albumin. Protein binding is 98.1% for SRRR-Nebivolol and 97.9% for RSSS-Nebivolol.

Biotransformation. Nebivolol is metabolized to a large extent, partly to active hydroxymetabolites. Nebivolol is metabolized by alicyclic and aromatic hydroxylation, N-dealkylation, and glucuronidation; in addition, hydroxymetabolite glucuronides are formed. The metabolism of Nebivolol by aromatic hydroxylation depends on the genetic oxidative polymorphism CYP2D6.

Output. In patients with rapid metabolism, the Half-Life of Nebivolol enantiomers is approximately 10 hours. In patients with a slow metabolism, it is 3-5 times longer. In patients with rapid metabolism, plasma levels of the RSSS enantiomer are slightly higher than for the SRRR enantiomer. In patients with a slow metabolism, this difference increases. In patients with fast metabolism, the Half — Life of hydroxymetabolites of both enantiomers is on average 24 hours, and in patients with slow metabolism, it is almost doubled.

Equilibrium plasma levels of Nebivolol in patients with rapid metabolism are reached in 24 hours, hydroxymetabolites — in a few days.

A week after administration, 38% of the dose is excreted in the urine, 48 % — in the feces. Urinary excretion of unchanged Nebivolol is less than 0.5% of the dose.



Hydrochlorothiazide is well absorbed after oral administration (65 to 75 %). Plasma concentrations depend linearly on the administered dose. Absorption of hydrochlorothiazide depends on the time of passage through the intestine: it increases when the time of intestinal transit is slow, for example, when used with food. When plasma levels were monitored for at least 24 hours, the plasma half-life ranged from 5.6 to 14.8 hours, and peak plasma concentrations were reached within 1-5 hours after taking the drug.


Hydrochlorothiazide binds to protein in plasma by 68 %, and its actual volume of distribution is 0.83–1.14 l/kg. Hydrochlorothiazide passes through the placenta, but not through the blood-brain barrier.


The metabolism of hydrochlorothiazide is very low. Almost all hydrochlorothiazide is excreted unchanged in the urine.


Hydrochlorothiazide is mainly excreted by the kidneys. 3-6 hours after oral administration, more than 95% of hydrochlorothiazide is detected unchanged in the urine. In patients with renal insufficiency, the concentration of hydrochlorothiazide is increased, and the elimination half-life is prolonged.

Clinical characteristics.


Treatment of essential hypertension.


- Hypersensitivity to active substances or other components of the drug;

- hypersensitivity to other substances-sulfonamide derivatives (since hydrochlorothiazide is a derivative of sulfonamide);

- liver failure or impaired liver function;

- anuria, severe renal failure (creatinine clearance less than 30 mL/min);

- acute heart failure, cardiogenic shock or episodes of decompensation of heart failure that require intravenous administration of active substances with a positive inotropic effect;

- sinus node weakness syndrome, including sinoatrial block;

– second-and third-degree atrioventricular block (without an implanted pacemaker);

- bradycardia (before starting treatment, the heart rate is less than 60 beats/min);

- arterial hypotension (systolic blood pressure less than 90 mm Hg). art.);

- severe peripheral circulatory disorders;

- a history of bronchospasm and bronchial asthma;

- untreated pheochromocytoma;

- metabolic acidosis;

- resistant hypokalemia, hypercalcemia, hyponatremia and symptomatic hyperuricemia.

Interactions with other drugs and other types of interactions.

Pharmacodynamic interactions


The following interactions generally apply to beta-adrenergic receptor antagonists.

Combinations that are not recommended

Class I antiarrhythmic drugs (guinidine, hydroguinidine, sibenzoline, flecainidine, disopyramide, lidocaine, mexiletine, propafenone). The effect on the time of atrioventricular conduction may increase and the negative inotropic effect may increase.

Calcium channel blockers such as verapamil/diltiazem. Negative effect on contractility and atrioventricular conduction. Intravenous administration of verapamil to patients treated with beta-blockers may lead to severe hypotension and atrioventricular block.

Antihypertensive agents of Central action (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine). Concomitant use of centrally acting antihypertensive agents may worsen heart failure due to a decrease in central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Sudden withdrawal, especially before stopping the use of beta-blockers, increases the risk of "rebound" hypertension.

Combinations that should be used with caution

Class III antiarrhythmic drugs (amiodarone). The effect on the time of atrioventricular conduction may be potentiated.

Anesthetics are volatile halogens. Concomitant use of beta-blockers and anesthetics may reduce reflex tachycardia and increase the risk of hypotension. Sudden discontinuation of beta-blocker treatment should be avoided. The anesthesiologist should be informed if the patient is receiving Nebiar® Plus.

Insulin and oral antidiabetic medications. Although Nebivolol does not affect glucose levels, concomitant use may mask certain symptoms of hypoglycemia (rapid heartbeat, tachycardia).

Interactions to consider

Digitalis glycosides. Concomitant use may increase the time of atrioventricular conduction. No interactions have been found in clinical trials of Nebivolol. Nebivolol does not affect the kinetics of digoxin.

Dihydropyridine-type calcium antagonists (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine). Concomitant use increases the risk of hypotension; the risk of further deterioration of ventricular pumping function in patients with heart failure cannot be excluded.

Antipsychotics, antidepressants (tricyclic agents, barbiturates, and phenothiazines). Concomitant use may increase the hypotensive effect of beta-blockers (additive effect).

Nonsteroidal anti-inflammatory drugs (NSAIDs). They do not affect the antihypertensive effect of Nebivolol.

Sympathomimetic agents. Concomitant use may counteract the effect of beta-blockers. Beta-adrenergic agents can lead to non-resistant alpha-adrenergic activity of sympathomimetic agents with both alpha-and beta-adrenergic effects (risk of hypertension, severe bradycardia, and Cardiac Block).


Simultaneous use is not recommended

Lithium. Thiazides reduce the renal clearance of lithium, so when used concomitantly with hydrochlorothiazide, the risk of lithium toxicity increases. Therefore, the use of Nebiar® Plus in combination with lithium is not recommended. If the use of such a combination is considered necessary, careful monitoring of serum lithium levels is recommended.

Medications that affect potassium levels. The effect of reducing potassium content inherent in hydrochlorothiazide may be enhanced by the combined use of other medications that are associated with potassium loss and hypokalemia (for example, other potassium diuretics, laxatives, corticosteroids, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G sodium or salicylic acid derivatives). Therefore, such a compatible application is not recommended.

Concomitant use requires caution

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs (e.g. acetylsalicylic acid (>3 g/day), COX-2 inhibitors, and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics.

Calcium salts. Thiazide diuretics may increase serum calcium levels due to reduced excretion. If calcium supplements need to be prescribed, serum calcium levels should be monitored and adjusted accordingly.

Digitalis glycosides. Hypokalemia or hypomagnesemia caused by thiazides may contribute to digitalis-induced cardiac arrhythmia.

Medications that are affected by changes in serum potassium levels. Monitoring of serum potassium and ECG is recommended when Nebiar® Plus 5/12. 5 is used with medications that are affected by changes in serum potassium (e.g. digitalis glycosides and antiarrhythmic drugs), and with medications that cause torsades de pointes (ventricular tachycardia) (including some antiarrhythmic drugs), since hypokalemia is a risk factor for torsades de pointes (ventricular tachycardia):

- class IA antiarrhythmic drugs (e.g. guinidine, hydroguinidine, disopyramide);

- Class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetilide, ibutilide);

- some antipsychotic agents (e.g. thioridazine, chlorpromazine, levomepromazine, trifluorperazine, ciamemazine, sulpiride, sultoprid, amisulpride, thiapride, pimoid, haloperidol, droperidol);

- others, for example: bepridil, cisapride, difemanil, erythromycin intravenously, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine intravenously.

Non-depolarizing skeletal muscle relaxants (e.g. tubocurarin). Hydrochlorothiazide may enhance the effect of non-depolarizing skeletal muscle relaxants.

Antidiabetic medications (oral medications and insulin). Treatment with thiazide may affect glucose tolerance. You may need to adjust the dosage of the antidiabetic drug.

Metformin. Metformin should be used with caution due to the risk of lactic acidosis due to possible kidney damage associated with the use of hydrochlorothiazide.

Beta blockers and diazoxide. Thiazides may enhance the hyperglycemic effect of beta-blockers other than Nebivolol and diazoxide.

Pressor amines (for example, norepinephrine). The effect of pressor amines may decrease.

Medications used to treat gout (probenecid, sulfinpyrazone, allopurinol). It may be necessary to adjust the doses of medications that reduce uric acid levels, since hydrochlorothiazide can increase the level of uric acid in the blood serum. You may need to increase the dose of probenecid or sulfinpyrazone. Concomitant use of thiazide may increase hypersensitivity reactions to allopurinol.

Amantadine. Thiazides increase the risk of side effects caused by amantadine.

Salicylates. In the case of high doses of salicylates, hydrochlorothiazide may increase their toxic effect on the central nervous system.

Cyclosporine. Co-treatment with cyclosporine increases the risk of hyperuricemia and gout-type complications.

Application features.


The following caveats apply in general to beta blockers.

Anesthesia. Prolongation of beta-blockade reduces the risk of arrhythmia during introductory anesthesia and intubation. If beta-blockade is discontinued in preparation for surgery, the beta-blocker should be discontinued at least 24 hours in advance.

Caution should be exercised when using certain anesthetics that cause myocardial depression.

The patient can be protected from vagal reactions by intravenous administration of atropine.

Cardiovascular disorders. In general, beta blockers should not be used in patients with untreated congestive heart failure unless their condition has been stabilized.

In patients with cardiac ischemia, treatment with beta-blockers should be discontinued gradually, i.e. within 1-2 weeks. If necessary, you should start replacement therapy at the same time to prevent exacerbation of angina pectoris.

Beta-adrenergic receptor antagonists can cause bradycardia — if the pulse rate falls below 50-55 beats/min at rest and/or the patient has symptoms indicating bradycardia, doses should be reduced.

Beta-adrenergic receptor antagonists should be used with caution:

- patients with peripheral circulatory disorders (Raynaud's disease or intermittent claudication syndrome), as these disorders may worsen;

- patients with first-degree atrioventricular (AV) block — due to the negative effect of beta-blockers on the time of AV conduction;

- patients with Prinzmetal angina — due to spasm of the coronary arteries, which is due to the activation of alpha-receptors against the background of beta-receptor blockade: beta-blockers can increase the number and duration of angina attacks.

In general, the combination of Nebivolol with calcium channel blockers such as verapamil and diltiazem with Class I antiarrhythmic drugs and with Central-acting antihypertensive agents is not recommended.

Metabolic / endocrine disorders. Nebivolol does not affect glucose levels in diabetics. However, caution should be exercised during treatment, as Nebivolol may mask the symptoms of hypoglycemia (tachycardia, rapid heartbeat).

Beta-adrenergic blockers may mask the symptoms of tachycardia in hyperthyroidism. Sudden discontinuation of the drug may increase symptoms.

Respiratory disorders. Beta-adrenergic receptor antagonists should be used with caution in patients with chronic obstructive pulmonary disorders, as airway obstruction may worsen.

Others. Patients with a history of psoriasis should use beta-adrenergic receptor antagonists only after careful evaluation of the feasibility.

Beta-adrenergic receptor antagonists may increase sensitivity to allergens and the severity of anaphylactic reactions.


Renal disorders. The maximum effect of thiazide diuretics can be expected only in the absence of impaired renal function. In patients with renal dysfunction, thiazides may increase azotemia. Patients with impaired renal function may develop cumulative effects of the active substance. If there is an obvious progression of renal dysfunction, which will manifest itself in an increase in non-protein nitrogen, a thorough reassessment of diuretic withdrawal therapy is necessary.

Metabolic and endocrine effects. Thiazide therapy may impair glucose tolerance. You may need to adjust the dose of insulin or oral hypoglycemic medications. Latent diabetes mellitus may occur during thiazide therapy.

Thiazide diuretic therapy is associated with increased cholesterol and triglyceride levels. Thiazide therapy may increase hyperuricemia and/or gout in some patients.

Electrolyte imbalance. In any patient receiving diuretic therapy, the level of electrolytes in the blood serum should be determined with appropriate frequency.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs of fluid or electrolyte imbalance include dry mouth, thirst, weakness, lethargy, dizziness, agitation, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disorders such as nausea or vomiting.

The risk of hypokalemia is highest in patients with cirrhosis of the liver, in patients with rapid diuresis, in the case of inadequate oral electrolyte intake, and in patients receiving concomitant corticosteroid or ACTH therapy. A particularly high risk of hypokalemia exists in patients with QT prolongation syndrome, congenital or iatrogenic. Hypokalemia increases the cardiotoxicity of digitalis glycosides and the risk of cardiac arrhythmia. For patients at risk of hypokalemia, more frequent monitoring of plasma potassium levels is indicated, starting one week after the start of therapy.

In hot weather, patients who are prone to edema may experience mild hyponatremia. Chlorine deficiency is usually mild and does not require treatment.

Thiazides may reduce urinary calcium excretion and may cause a periodic slight increase in serum calcium levels in the absence of established calcium metabolism disorders. Significant hypercalcemia may be a manifestation of latent hyperparathyroidism. Thiazides should be discontinued before parathyroid function analysis.

Thiazides have been shown to increase urinary magnesium excretion, which can lead to hypomagnesemia.

Lupus erythematosus. Systemic lupus erythematosus has been reported to worsen or activate when thiazides are used.

Anti-doping test. The hydrochlorothiazide contained in this medication may cause a positive anti-doping test result.

Other. Patients with or without a history of allergies or asthma may experience hypersensitivity reactions.

Photosensitivity reactions have occasionally been reported with thiazide diuretics. If photosensitivity reactions occur during treatment, it is recommended to stop therapy. If it is considered necessary to resume treatment, it is recommended to protect the corresponding surfaces from solar or artificial UV radiation.

Acute angle-closure glaucoma. Hydrochlorothiazide, which is a sulfonamide, has been associated with a idiosyncrasy reaction leading to acute transient myopia and acute angle-closure glaucoma. Symptoms include an acute decrease in visual acuity or the appearance of pain in the eyes. They usually occur within a time interval of several hours to one week after the start of treatment. Untreated acute angle-closure glaucoma can lead to permanent vision loss.

The first step is to discontinue hydrochlorothiazide as soon as possible. If intraocular pressure is not controlled, immediate therapeutic or surgical treatment may be necessary. A risk factor for angle-closure glaucoma is also a history of allergy to sulfonamides or penicillins.

Protein-bound iodine. Thiazides can reduce protein-bound iodine levels without signs of thyroid disorders.

Non-melanoma skin cancer.

The results of pharmacoepidemiological studies showed a concomitant dose-dependent relationship between the use of hydrochlorothiazide and the occurrence of basal cell carcinoma and squamous cell carcinoma. The photosensitizing effect of hydrochlorothiazide may cause the development of such pathologies. Patients taking hydrochlorothiazide alone or in combination with other medications should be informed about the risk of non-melanoma skin cancer and advised to regularly check their skin for new lesions, as well as changes in existing ones, and report any suspicious skin lesions.

Dosage and administration.

Nebiar ® Plus 5/12.5 is intended for patients whose blood pressure is adequately controlled by the combined use of 5 mg Nebivolol and 12.5 mg hydrochlorothiazide.

You should take 1 tablet (5 mg/ 12.5 mg) per day, preferably at the same time. The drug can be taken with a meal.

Patients with renal insufficiency. Nebiar ® Plus 5/12.5 should not be used in patients with severe renal insufficiency.

Patients with hepatic insufficiency. The experience of using the drug in such patients is limited, so use for such patients is contraindicated.

Elderly patients. Due to insufficient experience in using the drug in patients over 75 years of age, its use requires caution and careful monitoring.

Children. Studies on the use of the drug in children and adolescents have not been conducted, so the drug is not recommended for this age group.



There are no data on Nebivolol overdose. Symptoms of beta-blocker overdose include bradycardia, hypotension, bronchospasm, and acute heart failure.

An overdose of hydrochlorothiazide is associated with electrolyte depletion (hypokalemia, Hypochloremia, hyponatremia) and dehydration due to excessive diuresis. The most common symptoms of hydrochlorothiazide overdose are nausea and drowsiness. Hypokalemia can lead to muscle spasms and/or cardiac arrhythmia associated with concomitant use of digitalis glycosides or appropriate antiarrhythmic drugs.


In case of overdose or hypersensitivity, the patient needs intensive care and careful monitoring. It is necessary to monitor the glucose level. Serum electrolytes and creatinine should be monitored. Absorption of drug residues that still remain in the gastrointestinal tract can be prevented by gastric lavage and the use of activated charcoal and a laxative. CPR may be required. Bradycardia or massive vagal reactions should be treated with atropine or methylatropine.

Hypotension and shock should be treated with plasma/plasma substitutes and, if necessary, catecholamines. It is necessary to correct the violation of the electrolyte balance. The effects of beta-blockers can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting at a dose of 5 mcg/min, or dobutamine, starting at a dose of 2.5 MCG/min, until the desired effect is achieved. In severe cases that are difficult to treat, isoprenaline should be combined with dopamine. If this does not give the desired effect, the feasibility of intravenous administration of 50-100 mcg/kg of glucagon should be considered. If necessary, the injection should be repeated within an hour, and then (if necessary) an intravenous infusion of 70 mcg/kg/h of glucagon should be performed. In extremely severe cases of treatment-resistant bradycardia, an artificial pacemaker can be installed.

Tags: Hydrochlorothiazide, nebivolol