Nebyar® plus

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEBIAR® PLUS (NEBIAR PLUS)

Composition:

Active substances: nebivolol, hydrochlorothiazide;

One tablet contains nebivolol (as nebivolol hydrochloride) — 5 mg; hydrochlorothiazide — 12.5 mg;

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white or almost white, round-shaped, biconvex, with the logo "515" on one side and a score line on the other.

Pharmacotherapeutic group. Selective beta-adrenoreceptor blockers with thiazide diuretics. ATC code C07B B12.

Pharmacological Properties

Pharmacodynamics

The medicinal product 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 provides an additive antihypertensive effect and reduces arterial blood pressure to a greater extent than either component alone.

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

• it is a competitive and selective β1-adrenoceptor blocker: this effect is attributed to the SRRR-enantiomer (D-enantiomer);
• it has mild vasodilating properties due to interaction with L-arginine/nitric oxide.

After single and repeated administration, nebivolol reduces heart rate and arterial blood pressure at rest and during exercise, both in patients with normal blood pressure and in those with arterial hypertension. The antihypertensive effect is maintained during long-term treatment.

At therapeutic doses, nebivolol lacks α-adrenergic antagonistic activity.

During short- and long-term treatment with nebivolol in patients with arterial hypertension, systemic vascular resistance is reduced. Despite the reduction in heart rate, the decrease in cardiac output at rest and during exercise may be limited due to an increase in stroke volume. The clinical significance of this hemodynamic difference compared to other β1-adrenoceptor blockers has not yet been fully elucidated.

In patients with arterial hypertension, nebivolol enhances nitric oxide-mediated vascular response to acetylcholine, which is reduced in patients with endothelial dysfunction.

In vitro and in vivo animal studies have shown that nebivolol does not possess intrinsic sympathomimetic activity.

In vitro and in vivo animal studies have shown that at pharmacological doses, nebivolol lacks membrane-stabilizing activity.

In healthy volunteers, nebivolol does not significantly affect the ability to tolerate maximal physical exertion or endurance.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect 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 enhances aldosterone secretion, leading to increased urinary loss of potassium and bicarbonate and a decrease in serum potassium levels. After administration, diuresis begins approximately 2 hours later, peak effect occurs about 4 hours after intake, and the duration of action lasts approximately 6–12 hours.

Non-melanoma skin cancer (NMSC). Epidemiological data have shown an association between cumulative hydrochlorothiazide dose and the development of NMSC. One study included 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), compared with 1,430,833 and 172,462 control group participants, respectively. High-dose hydrochlorothiazide use (cumulative ≥ 50,000 mg) was associated with an adjusted odds ratio (OR) of 1.29 (95% confidence interval (CI): 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study indicated a possible association between lip cancer (SCC) and hydrochlorothiazide: 633 patients with lip cancer were compared with 63,067 participants in the control group using a risk-set sampling strategy. A dose-response relationship was demonstrated: the adjusted OR was 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high cumulative doses (~25,000 mg) and OR 7.7 (5.7–10.5) at the highest cumulative dose (~100,000 mg) (see also section "Special precautions for use").

Pharmacokinetics

Concomitant administration of nebivolol and hydrochlorothiazide does not affect the bioavailability of either active ingredient. The combined tablet is bioequivalent to the co-administration of the individual components.

Nebivolol

Absorption

After oral administration, both enantiomers of nebivolol are rapidly absorbed. Food does not affect the absorption of nebivolol; therefore, nebivolol can be taken independently of meals.

The bioavailability of orally administered nebivolol averages 12% in patients with rapid metabolism and is nearly complete in patients with slow metabolism. At steady state and equivalent doses, the peak plasma concentration of unchanged nebivolol is approximately 23 times higher in slow metabolizers compared to fast metabolizers. However, when considering unchanged drug and active metabolites, the difference in peak plasma concentrations is only 1.3–1.4 times. Due to differences in metabolic rate, nebivolol dosing must always be individualized, with slow metabolizers potentially requiring lower doses.

Plasma concentrations ranging from 1 to 30 mg of nebivolol are dose-proportional. Patient age does not influence the pharmacokinetics of nebivolol.

Distribution

In plasma, both nebivolol enantiomers are predominantly bound to albumin. Plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol.

Biological Transformation

Nebivolol undergoes extensive metabolism, partly into active hydroxymetabolites. Metabolism occurs via aliphatic and aromatic hydroxylation, N-dealkylation, and glucuronidation; glucuronides of hydroxymetabolites are also formed. The metabolism of nebivolol via aromatic hydroxylation is dependent on the genetic oxidative polymorphism of CYP2D6.

Elimination

In patients with rapid metabolism, the elimination half-life of nebivolol enantiomers is approximately 10 hours. In slow metabolizers, it is 3–5 times longer. In fast metabolizers, plasma levels of the RSSS-enantiomer are slightly higher than those of the SRRR-enantiomer. This difference is increased in slow metabolizers. In fast metabolizers, the half-life of hydroxymetabolites of both enantiomers averages 24 hours, while in slow metabolizers it is prolonged by almost twice.

Steady-state plasma levels of nebivolol are reached within 24 hours in most patients (fast metabolizers), while levels of hydroxymetabolites are achieved after several days.

Within one week after administration, 38% of the dose is excreted in urine and 48% in feces. Less than 0.5% of the dose is excreted unchanged in urine.

Hydrochlorothiazide

Absorption

Hydrochlorothiazide is well absorbed (65–75%) after oral administration. Plasma concentrations are linearly related to the administered dose. Absorption of hydrochlorothiazide depends on intestinal transit time: it increases when transit is slow, for example, when taken 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 concentration was reached within 1–5 hours after administration.

Distribution

Hydrochlorothiazide is 68% bound to plasma proteins, with a volume of distribution of 0.83–1.14 L/kg. Hydrochlorothiazide crosses the placenta but does not cross the blood-brain barrier.

Biological Transformation

Hydrochlorothiazide undergoes minimal metabolism. Almost all of the drug is excreted unchanged in urine.

Elimination

Hydrochlorothiazide is primarily excreted by the kidneys. Within 3–6 hours after oral administration, more than 95% of hydrochlorothiazide is found unchanged in urine. In patients with renal impairment, plasma concentrations of hydrochlorothiazide are increased and elimination half-life is prolonged.

Preclinical Safety Data

Preclinical safety data on the combination of nebivolol and hydrochlorothiazide revealed no special hazard for humans, based on conventional studies of pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenic potential of the individual components.

Clinical Characteristics

Indications

Treatment of essential hypertension.

The fixed-dose combination medicinal product Nibiar® Plus 5/12.5 is indicated for patients whose blood pressure is adequately controlled with the concomitant use of 5 mg nebivolol and 12.5 mg hydrochlorothiazide.

Contraindications

• Hypersensitivity to the active substances or to any of the excipients of the medicinal product;
• hypersensitivity to other substances – sulfonamide derivatives (since hydrochlorothiazide is a sulfonamide derivative);
• hepatic insufficiency or hepatic dysfunction;
• anuria, severe renal impairment (creatinine clearance less than 30 mL/min);
• acute heart failure, cardiogenic shock, or episodes of decompensated heart failure requiring intravenous administration of agents with positive inotropic effect;
• refractory hypokalemia, hypercalcemia, hyponatremia, and symptomatic hyperuricemia.

In addition, as with other β-blockers, the medicinal product Nibiar® Plus is contraindicated in:

• sinus node dysfunction, including sinoatrial block;
• second- and third-degree atrioventricular block (without implanted pacemaker);
• bronchospasm and history of bronchial asthma;
• untreated pheochromocytoma;
• metabolic acidosis;
• bradycardia (heart rate less than 60 beats/min before treatment initiation);
• arterial hypotension (systolic blood pressure less than 90 mm Hg);
• severe peripheral circulatory disorders.

Interaction with other medicinal products and other types of interactions

Pharmacodynamic interactions

Nebivolol

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

Combinations not recommended

Class I antiarrhythmic agents (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone). May enhance the effect on atrioventricular conduction time and increase the negative inotropic effect (see section "Special precautions for use").

Calcium channel blockers of the verapamil/diltiazem type. Negative effects on contractility and atrioventricular conduction. Intravenous administration of verapamil to patients receiving β-blockers may lead to severe hypotension and atrioventricular block (see section "Special precautions for use").

Centrally-acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine). Concomitant use of centrally-acting antihypertensive agents may worsen heart failure due to reduced central sympathetic tone (decreased heart rate and cardiac output, vasodilation) (see section "Special precautions for use"). Abrupt withdrawal, particularly prior to discontinuation of beta-blockers, increases the risk of "rebound" hypertension.

Combinations to be used with caution

Class III antiarrhythmic agents (amiodarone). May potentiate the effect on atrioventricular conduction time.

Volatile halogenated anesthetics. Concomitant use of beta-blockers and anesthetics may attenuate reflex tachycardia and increase the risk of arterial hypotension (see section "Special precautions for use"). Abrupt discontinuation of beta-blocker therapy should be avoided. The anesthesiologist should be informed if the patient is receiving Nibiar® Plus.

Insulin and oral antidiabetic agents. Although nebivolol does not affect glucose levels, concomitant use may mask certain symptoms of hypoglycemia (e.g., palpitations, tachycardia). Concomitant use of beta-blockers with sulfonylurea derivatives may increase the risk of severe hypoglycemia (see section "Special precautions for use").

Baclofen (antispastic agent), amifostine (adjunct in anticancer therapy). Concomitant use with antihypertensive agents may significantly reduce blood pressure; therefore, the dose of the antihypertensive agent should be appropriately adjusted.

Combinations to be considered

Digitalis glycosides. Concomitant use may increase atrioventricular conduction time. No interaction was observed in clinical trials of nebivolol. Nebivolol does not affect digoxin kinetics.

Calcium antagonists of the dihydropyridine type (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine). Concomitant use increases the risk of arterial hypotension; a further deterioration in ventricular pump function in patients with heart failure cannot be excluded.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs). Do not affect the antihypertensive action of nebivolol.

Sympathomimetic agents. Concomitant use may counteract the effects of beta-blockers. Beta-adrenergic agents may lead to unopposed alpha-adrenergic activity of sympathomimetic agents with both alpha- and beta-adrenergic effects (risk of arterial hypertension, severe bradycardia, and heart block).

Hydrochlorothiazide

Potential interactions related to hydrochlorothiazide.

Concomitant use not recommended

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

Medicinal products affecting potassium levels. The potassium-lowering effect of hydrochlorothiazide may be enhanced when used concomitantly with other medicinal products associated with potassium loss and hypokalemia (e.g., other potassium-wasting diuretics, laxatives, corticosteroids, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, sodium penicillin G, or salicylate derivatives). Therefore, such concomitant use is not recommended.

Concomitant use requires caution

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs (e.g., acetylsalicylic acid (> 3 g/day), COX-2 inhibitors, and nonselective 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 are required, serum calcium levels should be monitored and adjusted accordingly.

Digitalis glycosides. Hypokalemia or hypomagnesemia induced by thiazides may predispose to digitalis-induced cardiac arrhythmias.

Medicinal products affected by changes in serum potassium levels. Monitoring of serum potassium and ECG is recommended when Nibiar® Plus 5/12.5 is used concomitantly with medicinal products affected by changes in serum potassium levels (e.g., digitalis glycosides and antiarrhythmic agents), and with medicinal products that may cause torsades de pointes (ventricular tachycardia) (including certain antiarrhythmic agents), since hypokalemia is a risk factor for torsades de pointes:

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• certain antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• others, e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vinca alkaloids.

Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine). Hydrochlorothiazide may potentiate the effect of non-depolarizing skeletal muscle relaxants.

Antidiabetic medicinal products (oral agents and insulin). Thiazide treatment may affect glucose tolerance. Dose adjustment of antidiabetic agents may be required (see section "Special precautions for use").

Metformin. Metformin should be used with caution due to the risk of lactic acidosis associated with possible renal impairment caused by hydrochlorothiazide.

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

Pressor amines (e.g., noradrenaline). The effect of pressor amines may be reduced.

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone, allopurinol). Dose adjustment of uric acid-lowering agents may be necessary, as hydrochlorothiazide may increase serum uric acid levels. Higher doses of probenecid or sulfinpyrazone may be required. Concomitant use of thiazides may enhance hypersensitivity reactions to allopurinol.

Amantadine. Thiazides increase the risk of adverse reactions caused by amantadine.

Salicylates. In case of high-dose salicylate use, hydrochlorothiazide may enhance their toxic effects on the central nervous system.

Cyclosporine. Concomitant treatment with cyclosporine increases the risk of hyperuricemia and gout-like complications.

Contrast agents containing iodine. In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high iodine doses. Rehydration of the patient is required prior to administration.

Potential interactions due to both nebivolol and hydrochlorothiazide

Concomitant use to be considered

Other antihypertensive agents. Concomitant use with other antihypertensive agents may result in additive or potentiated hypotensive effects.

Antipsychotics, tricyclic antidepressants, barbiturates, narcotic drugs, and alcohol. Concomitant use of Nibiar® Plus 5/12.5 with these medicinal products may enhance the hypotensive effect and/or lead to postural hypotension.

Pharmacokinetic interactions

Nebivolol

Since the CYP2D6 isoenzyme is involved in nebivolol metabolism, concomitant use with substances that inhibit this enzyme, such as paroxetine, fluoxetine, thioridazine, and quinidine, may lead to increased plasma levels of nebivolol, with an increased risk of excessive bradycardia and adverse reactions.

Concomitant use of cimetidine increases plasma levels of nebivolol without changing the clinical effect. Concomitant use of ranitidine does not affect nebivolol pharmacokinetics. Nibiar® Plus 5/12.5 and antacids can be administered if the medicinal product is taken with food and the antacid is taken between meals.

Combination of nebivolol with nicardipine slightly increases plasma levels of both agents without changing the clinical effect. Concomitant use of alcohol, furosemide, or hydrochlorothiazide does not affect nebivolol pharmacokinetics. Nebivolol does not affect the pharmacokinetics or pharmacodynamics of warfarin.

Hydrochlorothiazide

Absorption of hydrochlorothiazide is impaired in the presence of anion-exchange resins (e.g., cholestyramine and colestipol resins).

Cytotoxic agents. When hydrochlorothiazide is used concomitantly with cytotoxic agents (e.g., cyclophosphamide, fluorouracil, methotrexate), increased bone marrow toxicity (e.g., granulocytopenia) should be anticipated.

Special precautions for use

All warnings regarding each component individually, as listed below, also apply to the fixed-dose combination medicinal product Nebiar® Plus. See also section "Adverse reactions".

Nebivolol

The following warnings generally apply to beta-adrenergic blockers.

Anesthesia. Maintaining beta-blockade reduces the risk of arrhythmias during induction of anesthesia and intubation. If beta-blockade is to be discontinued prior to surgery, beta-adrenergic blockers should be withdrawn at least 24 hours beforehand.

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

Vagal reactions can be prevented by intravenous administration of atropine.

Cardiovascular disorders. In general, beta-adrenergic blockers should not be administered to patients with untreated congestive heart failure unless their condition has been stabilized.

In patients with ischemic heart disease, beta-blocker therapy should be discontinued gradually over 1–2 weeks. If necessary, concomitant replacement therapy should be initiated to prevent exacerbation of angina.

Beta-adrenergic receptor antagonists may cause bradycardia. If the pulse rate falls below 50–55 beats/min at rest and/or the patient experiences symptoms indicative of bradycardia, the dose should be reduced.

Beta-adrenergic receptor antagonists should be used with caution:

• In patients with peripheral circulatory disorders (Raynaud's disease or intermittent claudication), as these disorders may worsen;
• In patients with first-degree atrioventricular (AV) block due to the negative effect of beta-blockers on AV conduction time;
• In patients with Prinzmetal's angina due to coronary artery spasm resulting from alpha-receptor stimulation in the context of beta-receptor blockade: beta-adrenergic blockers may increase the frequency and duration of angina attacks.

In general, combination of nebivolol with calcium channel blockers of the verapamil and diltiazem type, Class I antiarrhythmic agents, and centrally acting antihypertensive agents is not recommended. For detailed information, see section "Interaction with other medicinal products and other forms of interaction".

Metabolic/endocrine disorders. Nebivolol does not affect glucose levels in patients with diabetes mellitus. However, caution is advised in diabetic patients, as nebivolol may mask certain symptoms of hypoglycemia (e.g., tachycardia, palpitations). Beta-blockers may additionally increase the risk of severe hypoglycemia when used concomitantly with sulfonylurea derivatives. Patients with diabetes mellitus should be advised to closely monitor their blood glucose levels (see section "Interaction with other medicinal products and other forms of interaction").

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

Other. Patients with a history of psoriasis should use beta-adrenergic receptor antagonists only after careful assessment of necessity.

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

Hydrochlorothiazide

Renal disorders. The maximum effect of thiazide diuretics can only be expected in the absence of renal impairment. In patients with renal dysfunction, thiazides may exacerbate azotemia. Cumulative effects of the active substance may occur in patients with impaired renal function. If there is clear progression of renal dysfunction, as indicated by increasing non-protein nitrogen levels, therapy should be carefully re-evaluated and discontinuation of the diuretic considered.

Metabolic and endocrine effects. Thiazide therapy may impair glucose tolerance. Adjustment of insulin or oral hypoglycemic agent dosage may be required (see section "Interaction with other medicinal products and other forms of interaction"). Latent diabetes mellitus may become apparent during thiazide therapy.

Thiazide diuretic therapy has been associated with increased cholesterol and triglyceride levels. Thiazide therapy may exacerbate hyperuricemia and/or precipitate gout in some patients.

Electrolyte imbalance. Serum electrolyte levels should be monitored periodically in any patient receiving diuretic therapy.

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

The risk of hypokalemia is highest in patients with hepatic cirrhosis, those with rapid diuresis, those with inadequate oral electrolyte intake, and those receiving concomitant therapy with corticosteroids or ACTH (see section "Interaction with other medicinal products and other forms of interaction"). The risk of hypokalemia is particularly high in patients with QT prolongation syndrome, whether congenital or iatrogenic. Hypokalemia increases the cardiotoxicity of digitalis glycosides and the risk of cardiac arrhythmias. More frequent monitoring of plasma potassium levels is recommended for patients at risk of hypokalemia, starting one week after initiation of therapy.

Mild hyponatremia may occur in hot weather in patients prone to edema. Chloride deficiency is usually mild and does not require treatment.

Thiazides may reduce calcium excretion in urine and may cause occasional mild increases in serum calcium levels in the absence of established calcium metabolism disorders. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before assessing parathyroid function.

Thiazides have been shown to increase magnesium excretion in urine, potentially leading to hypomagnesemia.

Acute respiratory toxicity

Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening pulmonary function, and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who have previously experienced ARDS after taking hydrochlorothiazide.

Lupus erythematosus. Exacerbation or activation of systemic lupus erythematosus has been reported with thiazide use.

Antidoping test. Hydrochlorothiazide contained in this medicinal product may cause a positive antidoping test result.

Other. Hypersensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

Photosensitivity reactions have been rarely reported with thiazide diuretics. If photosensitivity reactions occur, therapy should be discontinued. If re-initiation of treatment is deemed necessary, protection of exposed skin from sunlight or artificial UV radiation is recommended.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and typically occur within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss.

The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, emergency medical or surgical treatment may be required. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Iodine, protein-bound. Thiazides may reduce protein-bound iodine levels without evidence of thyroid dysfunction.

Non-melanoma skin cancer

Pharmacoepidemiological studies have shown a dose-dependent association between hydrochlorothiazide use and the occurrence of basal cell carcinoma and squamous cell carcinoma. The photosensitizing effect of hydrochlorothiazide may contribute to the development of these conditions. Patients taking hydrochlorothiazide alone or in combination with other medicinal products should be informed about the risk of non-melanoma skin cancer and advised to regularly check their skin for new lesions or changes in existing ones and to report any suspicious skin changes.

Suspicious skin lesions should undergo histological examination via biopsy.

Patients should be advised to limit exposure to sunlight and UV radiation and to use appropriate protection when exposed to sunlight or UV radiation to minimize the risk of skin cancer.

The appropriateness of hydrochlorothiazide use should also be carefully reconsidered in patients with a history of skin cancer (see section "Adverse reactions").

Combination of nebivolol/hydrochlorothiazide

In addition to the warnings related to individual components, the following statement applies directly to the Nebiar® Plus 5/12.5 formulation.

Excipients

Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption syndrome. This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient data on the use of Nebiar® Plus 5/12.5 in pregnant women. Animal studies with the two individual components are insufficient to determine the effect of the combination of nebivolol and hydrochlorothiazide on reproductive function (see preclinical safety data).

Nebivolol

There are insufficient data on the use of nebivolol in pregnant women to identify potential adverse effects. However, nebivolol has pharmacological effects that may pose a risk to pregnancy and/or the fetus/newborn.

In general, beta-blockers reduce placental blood flow, which has been associated with intrauterine growth retardation, fetal death, miscarriage, and premature delivery. Adverse effects (e.g., hypoglycemia, bradycardia) may occur in the fetus and newborn. If beta-blocker therapy is necessary, beta1-selective beta-adrenergic blockers are preferred.

Nebivolol should not be used during pregnancy unless clearly necessary.

If treatment with nebivolol is considered necessary, uteroplacental blood flow and fetal growth should be monitored. Alternative treatment should be considered if there are adverse effects on pregnancy or the fetus. Close monitoring of the newborn is required. Hypoglycemia and bradycardia should generally be expected within the first 3 days of life.

Hydrochlorothiazide

Clinical experience with hydrochlorothiazide in pregnancy is limited, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on its pharmacological mechanism of action, its use during the second and third trimesters may impair fetoplacental perfusion and cause effects in the fetus and neonate such as jaundice, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational edema, gestational hypertension, or late toxemia of pregnancy due to the risk of reduced plasma volume and placental hypoperfusion without beneficial effects on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where alternative treatments are not possible.

Breastfeeding period

It is unknown whether nebivolol is excreted in human breast milk. Animal studies have shown that nebivolol is excreted in breast milk. Most beta-blockers, particularly lipophilic compounds such as nebivolol, pass into breast milk, although to varying degrees.

Hydrochlorothiazide is excreted in human breast milk in small amounts. High doses of thiazides causing intense diuresis may suppress milk production.

Nebiar® Plus 5/12.5 is not recommended during breastfeeding.

If Nebiar® Plus 5/12.5 is used during breastfeeding, the dose should be kept as low as possible.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect on the ability to drive or operate machinery have not been conducted. However, when driving or operating machinery, it should be considered that antihypertensive therapy may occasionally cause dizziness and fatigue.

Dosage and Administration

Dosage regimen

Adults. Nebiar® Plus 5/12.5 is indicated for patients whose blood pressure is adequately controlled with the combination of 5 mg nebivolol and 12.5 mg hydrochlorothiazide.

The dosage is one tablet (5 mg/12.5 mg) once daily, preferably at the same time each day.

Patients with renal impairment. Nebiar® Plus 5/12.5 is contraindicated in patients with severe renal impairment (see also sections "Contraindications" and "Special precautions").

Patients with hepatic impairment. Experience with the use of the drug in patients with hepatic impairment or impaired liver function is limited; therefore, the use of Nebiar® Plus 5/12.5 is contraindicated in such patients.

Elderly patients. Due to limited experience with the use of the drug in patients aged 75 years and older, caution and careful monitoring are required.

Administration method

Administer orally.

The tablets may be taken with or without food.

Children

The efficacy and safety of Nebiar® Plus 5/12.5 in children and adolescents (under 18 years of age) have not been studied. Data are unavailable. Therefore, use in children and adolescents is not recommended.

Overdose

Symptoms

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

Hydrochlorothiazide overdose may lead to electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. The most common symptoms of hydrochlorothiazide overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or cardiac arrhythmias, especially when digoxin or other antiarrhythmic agents are used concomitantly.

Treatment

In case of overdose or increased sensitivity, the patient requires intensive therapy and close monitoring. Glucose levels should be monitored. Serum electrolytes and creatinine should be monitored. Residual drug in the gastrointestinal tract may be removed by gastric lavage, activated charcoal, and a laxative. Mechanical ventilation may be necessary. Bradycardia or severe vagal reactions should be treated with atropine or methylatropine.

Arterial hypotension and shock should be treated with blood plasma/plasma substitutes and, if necessary, catecholamines. Electrolyte imbalances should be corrected. The effects of beta-blockers may be counteracted by slow intravenous infusion of isoprenaline hydrochloride, starting at a dose of 5 mcg/min, or dobutamine, starting at a dose of 2.5 mcg/min, titrated to the desired effect. In severe, refractory cases, isoprenaline should be combined with dopamine. If this remains ineffective, intravenous administration of 50–100 mcg/kg glucagon should be considered. If necessary, the glucagon injection may be repeated within one hour, followed by (if needed) a continuous intravenous infusion of 70 mcg/kg/hour. In extremely severe cases of treatment-resistant bradycardia, a temporary pacemaker may be implanted.

Adverse reactions

Adverse reactions are listed separately for each active substance.

Nebivolol

Adverse reactions reported after monotherapy with nebivolol were mostly mild to moderate in severity. They are presented in the table below and classified by organ systems and frequency of occurrence.

System organs	Common (≥ 1/100 to <1/10)	Uncommon (≥ 1/1000 to <1/100)	Rare (≥ 1/10000 )	Frequency unknown
Immune system disorders				Angioneurotic edema, hypersensitivity
Psychiatric disorders		Night terrors, depression
Nervous system disorders	Headache, dizziness, paresthesia		Syncope
Eye disorders		Visual disturbances
Cardiac disorders		Bradycardia, heart failure, AV conduction delay/AV block
Vascular disorders		Arterial hypotension, worsening of intermittent claudication
Respiratory system disorders	Dyspnea	Bronchospasm
Gastrointestinal disorders	Constipation, nausea, diarrhea	Dyspepsia, flatulence, vomiting
Skin disorders		Pruritus, erythematous skin rash	Worsening of psoriasis	Urticaria
Genital disorders		Impotence
General disorders	Increased fatigue, edema

In addition, the following adverse reactions have been reported with some β-adrenoblockers: hallucinations, psychosis, confusion, cold extremities/cyanosis, Raynaud's syndrome, dry eyes, and propylthiouracil-like toxicity.

Hydrochlorothiazide

The adverse reactions listed below have been reported during treatment with hydrochlorothiazide as monotherapy.

Blood and lymphatic system disorders: leucopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow suppression.

Immune system disorders: anaphylactic reaction.

Metabolism and nutrition disorders: anorexia, dehydration, gout, diabetes mellitus, metabolic alkalosis, hyperuricaemia, electrolyte imbalance (including hypokalaemia, hyponatraemia, hypomagnesaemia, hypochloraemia, hypercalcaemia), hyperglycaemia, hyperamylasaemia.

Psychiatric disorders: apathy, disorientation, depression, nervousness, restlessness, sleep disturbances.

Nervous system disorders: convulsions, decreased level of consciousness, coma, headache, dizziness, paraesthesia, paresis.

Eye disorders: frequency unknown: choroidal effusion, acute myopia, acute angle-closure glaucoma. Xanthopsia, blurred vision, myopia (exacerbation), decreased lacrimation.

Ear and labyrinth disorders: vertigo.

Cardiac disorders: cardiac arrhythmia, palpitations.

Vascular disorders: orthostatic hypotension, thrombosis, embolism, shock.

Respiratory, thoracic and mediastinal disorders: respiratory distress syndrome, pneumonia, interstitial lung disease, pulmonary oedema; very rare: acute respiratory distress syndrome (ARDS) (see section "Special precautions").

Gastrointestinal disorders: dry mouth, nausea, vomiting, gastric discomfort, diarrhoea, constipation, abdominal pain, paralytic ileus, flatulence, sialadenitis, pancreatitis.

Hepatobiliary disorders: cholestatic jaundice, cholecystitis.

Skin and subcutaneous tissue disorders: pruritus, purpura, urticaria, photosensitivity reaction, rash, cutaneous lupus erythematosus, necrotizing vasculitis, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders, bone disorders: muscle spasms, myalgia.

Renal and urinary disorders: renal impairment, acute renal failure, interstitial nephritis, glycosuria.

Reproductive system and breast disorders: erectile dysfunction.

General disorders: asthenia, pyrexia, fatigue, thirst.

Laboratory findings: changes in electrocardiogram, increased blood cholesterol level, increased blood triglyceride level.

Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency unknown: non-melanoma skin cancer (NMSC) (basal cell carcinoma and squamous cell carcinoma).

Non-melanoma skin cancer: epidemiological studies have shown an association between the occurrence of non-melanoma skin cancer and cumulative dose of hydrochlorothiazide (cumulative dose-effect relationship) (see sections "Special precautions" and "Pharmacodynamics").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years from the date of manufacture in bulk.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets per blister, 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer: JSC "Kyivmedpreparat" (packaging of in bulk product manufactured by Fine Foods and Pharmaceuticals N.T.M. S.P.A., Italy).

Manufacturer's address and place of business

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.

Marketing Authorisation Holder: LLC "ARTERIUM LTD".

Address of Marketing Authorisation Holder: 139 Saksaganskogo Street, Kyiv, 01032, Ukraine.