Instructions Nebiar plus film-coated tablets 5 mg + 12.5 mg blister No. 30
Composition
active ingredients: 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 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)]).
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, white or almost white in color, round in shape, with a biconvex surface, with the logo "515" on one side and a score on the other.
Pharmacotherapeutic group
Selective beta-adrenergic blockers with thiazide diuretics. ATC code C07B B12.
Pharmacological properties
Pharmacodynamics.
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 reduces blood pressure to a greater extent than the individual components.
Nebivolol is a racemate consisting of two enantiomers: SRRR-nebivolol (D-nebivolol) and RSSS-nebivolol (L-nebivolol). It combines two pharmacological properties:
is a competitive and selective blocker of β1-adrenoreceptors: this effect is possessed by the SRRR enantiomer (D-enantiomer);
has mild vasodilating properties due to interaction with L-arginine/nitric oxide.
With single and repeated administration of nebivolol, heart rate and blood pressure are reduced at rest and during exercise in both normotensive and hypertensive patients. The antihypertensive effect is maintained during long-term treatment.
At therapeutic doses, nebivolol lacks α-adrenergic antagonism.
During short-term and long-term treatment with nebivolol in patients with arterial hypertension, systemic vascular resistance decreases. Despite the decrease in heart rate, the decrease in cardiac output at rest and during exercise may be limited by an increase in stroke volume. The clinical significance of this hemodynamic difference compared with that with other β1-adrenergic blockers is not yet fully 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 possess intrinsic sympathomimetic activity.
In vitro and in vivo animal experiments have shown that at pharmacological doses nebivolol has no membrane-stabilizing activity.
In healthy volunteers, nebivolol has no significant effect on the ability to tolerate maximum physical exertion or on endurance.
Hydrochlorothiazide is a thiazide diuretic. Thiazides act on the renal tubular mechanisms of electrolyte reabsorption, directly increasing the excretion of sodium and chloride in approximately equal amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, and increases aldosterone secretion, with subsequent increases in urinary potassium and bicarbonate losses and decreases in serum potassium. With hydrochlorothiazide, diuresis occurs within approximately 2 hours, and the peak effect is reached approximately 4 hours after administration, while the effect lasts for approximately 6–12 hours.
Non-melanoma skin cancer (NMSC). Available epidemiological data have shown an association between cumulative dose of hydrochlorothiazide 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 subjects, respectively. High-dose hydrochlorothiazide (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 relationship between cumulative dose and response was observed for both BCC and SCC. Another study showed a possible association between lip cancer (LC) and hydrochlorothiazide exposure: 633 patients with lip cancer were compared with 63,067 controls using a risk-adjusted sampling strategy. A cumulative dose-response relationship was demonstrated: the adjusted OR was 2.1 (95% CI: 1.7–2.6), increasing to an OR of 3.9 (3.0–4.9) at high doses (25,000 mg) and an OR of 7.7 (5.7–10.5) at the highest cumulative dose (100,000 mg) (see also section 4.4).
Pharmacokinetics.
The combined use of nebivolol and hydrochlorothiazide does not affect the bioavailability of each of the active substances. The combination tablet is bioequivalent to the combined use of the individual components.
Nebivolol
After oral administration, both enantiomers of nebivolol are rapidly absorbed. The absorption of nebivolol is not affected by food, so nebivolol can be taken regardless of meals.
The bioavailability of oral nebivolol is on average 12% in extensive metabolisers and almost complete in poor metabolisers. At steady state and at the same dose level, the peak plasma concentration of unchanged nebivolol is approximately 23 times higher in poor metabolisers than in extensive metabolisers. When the unchanged drug and active metabolites are taken into account, the difference in peak plasma concentrations is 1.3-1.4 times. Due to the difference in metabolic rates, the dosage of nebivolol should always be adjusted to the individual needs of the patient, in which case poor metabolisers may require lower doses.
The plasma concentration, which ranges from 1 to 30 mg of nebivolol, is proportional to the dose. The patient's age does not affect the pharmacokinetics of nebivolol.
Distribution
In plasma, both enantiomers of nebivolol bind predominantly to albumin. Plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol.
Biotransformation
Nebivolol is extensively metabolized, partly to active hydroxy metabolites. Nebivolol is metabolized by alicyclic and aromatic hydroxylation, N-dealkylation and glucuronidation; in addition, glucuronides of hydroxy metabolites are formed. The metabolism of nebivolol by aromatic hydroxylation depends on the genetic oxidative polymorphism of CYP2D6.
Breeding
In patients with extensive metabolism, the half-life of the enantiomers of nebivolol is approximately 10 hours. In patients with poor metabolism, it is 3-5 times longer. In patients with extensive metabolism, plasma levels of the RSSS enantiomer are slightly higher than for the SRRR enantiomer. In patients with poor metabolism, this difference increases. In patients with extensive metabolism, the half-life of the hydroxy metabolites of both enantiomers is on average 24 hours, while in patients with poor metabolism it is almost twice as long.
Steady-state plasma levels are reached in most patients (rapid metabolizers) within 24 hours for nebivolol and within a few days for the hydroxymetabolites.
One week after administration, 38% of the dose is excreted in the urine and 48% in the feces. Urinary excretion of unchanged nebivolol is less than 0.5% of the dose.
Hydrochlorothiazide
Absorption
Hydrochlorothiazide is well absorbed (65 to 75%) after oral administration. Plasma concentrations are linearly related to the dose administered. The absorption of hydrochlorothiazide is dependent on intestinal transit time: it increases when intestinal transit time is slow, e.g. when administered with food. When plasma levels were monitored for at least 24 hours, the plasma elimination half-life ranged from 5.6 to 14.8 hours, with peak plasma concentrations occurring 1 to 5 hours after dosing.
Distribution
Hydrochlorothiazide is 68% bound to plasma proteins and has an apparent volume of distribution of 0.83–1.14 L/kg. Hydrochlorothiazide crosses the placenta but not the blood-brain barrier.
Biotransformation
The metabolism of hydrochlorothiazide is very low. Almost all hydrochlorothiazide is excreted unchanged in the urine.
Breeding
Hydrochlorothiazide is excreted primarily by the kidneys. More than 95% of hydrochlorothiazide is recovered in the urine as unchanged drug 3–6 hours after oral administration. In patients with renal disease, plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged.
Indication
Treatment of essential hypertension.
Contraindication
Hypersensitivity to the active substances or to other components of the medicinal product;
hypersensitivity to other substances - sulfonamide derivatives (since hydrochlorothiazide is a sulfonamide derivative);
liver failure or liver dysfunction;
anuria, severe renal failure (creatinine clearance less than 30 ml/min);
acute heart failure, cardiogenic shock or episodes of decompensated heart failure requiring intravenous administration of active substances with a positive inotropic effect;
resistant hypokalemia, hypercalcemia, hyponatremia, and symptomatic hyperuricemia.
In addition, like other β-blockers, the drug Nebiar® Plus is contraindicated in:
sick sinus syndrome, including sinoatrial block;
second and third degree atrioventricular block (without an implanted pacemaker);
bronchospasm and bronchial asthma in history;
untreated pheochromocytoma;
metabolic acidosis;
bradycardia (before the start of treatment, the heart rate is less than 60 beats/min);
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 interactions listed below apply to beta-adrenergic receptor antagonists in general.
Class I antiarrhythmic drugs (guanidine, hydroguanidine, sibenzoline, flecainidine, disopyramide, lidocaine, mexiletine, propafenone). The effect on atrioventricular conduction time and the negative inotropic effect may be increased.
Calcium channel blockers such as verapamil/diltiazem. Negative effects on contractility and atrioventricular conduction. Intravenous administration of verapamil to patients treated with β-blockers may result in severe hypotension and atrioventricular block.
Centrally acting antihypertensives (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine). Concomitant use of centrally acting antihypertensives may worsen heart failure due to decreased central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Abrupt withdrawal, especially before discontinuation of beta-blockers, increases the risk of rebound hypertension.
Combinations to be used with caution
Class III antiarrhythmic drugs (amiodarone). The effect on atrioventricular conduction time may be potentiated.
Anesthetics - volatile halogens. The simultaneous use of beta-blockers and anesthetics may weaken reflex tachycardia and increase the risk of arterial hypotension. Abrupt withdrawal of beta-blocker treatment should be avoided. The anesthesiologist should be informed if the patient is receiving Nebiar® Plus.
Insulin and oral antidiabetic agents: Although nebivolol does not affect glucose levels, concomitant use may mask certain symptoms of hypoglycemia (palpitations, tachycardia).
Baclofen (antispastic agent), amifostine (adjunctive agent in the treatment of anticancer drugs). Concomitant use with antihypertensive agents may significantly reduce blood pressure, so the dose of the antihypertensive agent should be adjusted accordingly.
Interactions to consider
Digitalis glycosides. Concomitant use may increase atrioventricular conduction time. No interaction has been observed in clinical trials with nebivolol. Nebivolol does not affect the kinetics of digoxin.
Dihydropyridine calcium antagonists (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine). Concomitant use increases the risk of arterial hypotension; the risk of further deterioration of ventricular pumping function in patients with heart failure cannot be excluded.
Antipsychotics, antidepressants (tricyclics, barbiturates and phenothiazines). Concomitant use may increase the hypotensive effect of beta-blockers (additive effect).
Nonsteroidal anti-inflammatory drugs (NSAIDs): Do not affect the antihypertensive effect of nebivolol.
Sympathomimetic agents: Concomitant use may antagonize the effect 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 hypertension, severe bradycardia and heart block).
Hydrochlorothiazide
Potential interactions related to hydrochlorothiazide.
Concomitant use is not recommended.
Lithium. Thiazides reduce the renal clearance of lithium, so the risk of lithium toxicity increases when used simultaneously with hydrochlorothiazide. Therefore, the use of Nebicard 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.
Medicinal products affecting potassium levels: The potassium-lowering effect of hydrochlorothiazide may be potentiated by concomitant use of other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G sodium or salicylic acid 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 non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics.
Calcium salts: Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements are prescribed, serum calcium levels should be monitored and adjusted accordingly.
Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may contribute to digitalis-induced cardiac arrhythmias.
Medicinal products affected by changes in serum potassium. Monitoring of serum potassium and ECG is recommended when Nebicard Plus 5/12.5 is used with medicinal products affected by changes in serum potassium (e.g. digitalis glycosides and antiarrhythmics) and with medicinal products inducing torsades de pointes (ventricular tachycardia) (including some antiarrhythmics), as hypokalaemia is a risk factor for the development of torsades de pointes:
Class Ia antiarrhythmic drugs (e.g. guanidine, hydroguanidine, disopyramide);
certain antipsychotic agents (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimoid, haloperidol, droperidol);
others, such as bepridil, cisapride, diphemanil, erythromycin intravenously, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine intravenously.
Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine). Hydrochlorothiazide may potentiate the effect of non-depolarizing skeletal muscle relaxants.
Antidiabetic drugs (oral agents and insulin). Thiazide therapy may affect glucose tolerance. Dosage adjustment of the antidiabetic drug may be necessary.
Metformin: Metformin should be used with caution due to the risk of lactic acidosis due to possible renal 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 (e.g., noradrenaline): The effect of pressor amines may be reduced.
Medicines used to treat gout (probenecid, sulfinpyrazone, allopurinol). Dose adjustment of uric acid-lowering medicines may be necessary, as hydrochlorothiazide may increase serum uric acid levels. The dose of probenecid or sulfinpyrazone may need to be increased. Concomitant use of thiazides may increase hypersensitivity reactions to allopurinol.
Amantadine: Thiazides increase the risk of adverse reactions caused by amantadine.
Salicylates: When high doses of salicylates are used, hydrochlorothiazide may potentiate their toxic effects on the central nervous system.
Cyclosporine: Concomitant treatment with cyclosporine increases the risk of hyperuricemia and gout-like complications.
Iodinated contrast media: In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine preparations. The patient should be rehydrated before use.
Potential interactions due to both nebivolol and hydrochlorothiazide
Other antihypertensive drugs: When used concomitantly with other antihypertensive drugs, additive hypotensive effects or potentiation of their action may occur.
Antipsychotics, tricyclic antidepressants, barbiturates, narcotics and alcohol. The combined use of Nebiar® Plus 5/12.5 with these drugs may enhance the hypotensive effect and/or lead to postural hypotension.
Pharmacokinetic interactions
Nebivolol
Since the CYP2D6 isoenzyme is involved in the metabolism of nebivolol, concomitant use with substances that inhibit this enzyme, in particular 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 the level of nebivolol in the blood plasma without changing the clinical effect. Concomitant use of ranitidine does not affect the pharmacokinetics of nebivolol. If the drug Nebiar® Plus 5/12.5 is taken with food, and the antacid - between meals, both drugs can be prescribed.
The combination of nebivolol with nicardipine slightly increases the plasma levels of both drugs without changing the clinical effect. Concomitant use of alcohol, furosemide or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol. Nebivolol does not affect the pharmacokinetics and pharmacodynamics of warfarin.
Hydrochlorothiazide
The absorption of hydrochlorothiazide is impaired in the presence of anionic ion exchange resins (e.g. cholestyramine and colestipol resins).
Cytotoxic agents: When hydrochlorothiazide is administered concomitantly with cytotoxic agents (e.g. cyclophosphamide, fluorouracil, methotrexate), an increase in bone marrow toxicity (including granulocytopenia) should be expected.
Application features
Nebivolol
The following warnings apply to beta-blockers in general.
Anesthesia: Continued beta-blockade reduces the risk of arrhythmias during induction of anesthesia and intubation. If beta-blockade is discontinued in preparation for surgery, the beta-blocker should be discontinued at least 24 hours beforehand.
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, beta-blocker treatment should be discontinued gradually, i.e. over 1–2 weeks. If necessary, replacement therapy should be initiated at the same time to prevent exacerbation of angina.
Beta-adrenergic receptor antagonists can cause bradycardia; if the heart rate falls below 50–55 beats/min at rest and/or the patient has symptoms suggestive of bradycardia, the dose should be reduced.
patients with peripheral circulatory disorders (Raynaud's disease or intermittent claudication syndrome), as these disorders may be exacerbated;
patients with first-degree atrioventricular (AV) block due to the negative effect of beta-blockers on AV conduction time;
Patients with Prinzmetal's angina due to coronary artery spasm caused by alpha-receptor activation against the background of beta-receptor blockade: beta-blockers may 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 centrally acting antihypertensive agents is not recommended.
Metabolic/endocrine disorders: Nebivolol does not affect glucose levels in diabetics. However, caution is required during treatment as nebivolol may mask symptoms of hypoglycemia (tachycardia, palpitations).
Beta-adrenergic blockers may mask the tachycardia symptoms of hyperthyroidism. Abrupt withdrawal of the drug may exacerbate the symptoms.
Respiratory disorders: Beta-adrenergic receptor antagonists should be administered with caution to patients with chronic obstructive pulmonary disease, as airway obstruction may be exacerbated.
Others: Patients with a history of psoriasis should use beta-adrenergic receptor antagonists only after careful consideration.
Beta-adrenergic receptor antagonists may increase sensitivity to allergens and the severity of anaphylactic reactions.
Hydrochlorothiazide
Renal impairment. The maximum effect of thiazide diuretics can only be expected in the absence of impaired renal function. In patients with renal dysfunction, thiazides may increase azotemia. In patients with impaired renal function, cumulative effects of the active substance may develop. In the case of obvious progression of renal function disorders, manifested by an increase in non-protein nitrogen, a careful reassessment of therapy is necessary with regard to the withdrawal of the diuretic.
Metabolic and endocrine effects. Thiazide therapy may impair glucose tolerance. Adjustment of insulin or oral hypoglycemic agents may be necessary. Latent diabetes mellitus may become manifest during thiazide therapy.
Thiazide diuretic therapy has been associated with increases in cholesterol and triglyceride levels. Thiazide therapy may exacerbate hyperuricemia and/or gout in some patients.
Electrolyte imbalance: Serum electrolyte levels should be determined at appropriate intervals in any patient receiving diuretic therapy.
Thiazides, including hydrochlorothiazide, may cause fluid or electrolyte imbalance (hypokalemia, hyponatremia, and hypochloraemic alkalosis). Signs of fluid or electrolyte imbalance include dry mouth, thirst, weakness, lethargy, dizziness, agitation, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.
The risk of hypokalemia is highest in patients with cirrhosis of the liver, in patients with rapid diuresis, in cases of inadequate oral electrolyte intake, and in patients receiving concomitant therapy with corticosteroids or ACTH. The risk of hypokalemia is particularly high in patients with long QT syndrome, congenital or iatrogenic. Hypokalemia increases the cardiotoxicity of digitalis glycosides and the risk of cardiac arrhythmias. In patients at risk of hypokalemia, more frequent monitoring of plasma potassium levels is indicated, starting one week after the start of therapy.
Mild hyponatremia may occur in patients prone to edema in hot weather. Chloride deficiency is usually mild and does not require treatment.
Thiazides may reduce urinary calcium excretion and may cause intermittent mild elevations of serum calcium in the absence of established disorders of calcium metabolism. Significant hypercalcemia may be a manifestation of latent hyperparathyroidism. Thiazides should be discontinued before parathyroid function testing is performed.
Thiazides have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia.
Acute respiratory toxicity
Very rare cases of severe acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported following the administration of hydrochlorothiazide. Pulmonary oedema usually develops within minutes to hours of taking hydrochlorothiazide. Early symptoms include dyspnoea, fever, worsening pulmonary function and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be given to patients who have previously experienced ARDS after taking hydrochlorothiazide.
Lupus erythematosus: Thiazides have been reported to exacerbate or activate systemic lupus erythematosus.
Anti-doping test: The hydrochlorothiazide contained in this medicinal product may cause a positive result in an anti-doping test.
Photosensitivity reactions have been reported rarely with thiazide diuretics. If photosensitivity reactions occur during treatment, it is recommended to discontinue therapy. If treatment is deemed necessary, it is recommended to protect the affected areas from sunlight or artificial UV radiation.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours to weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss.
The mainstay of treatment is to discontinue the drug as soon as possible. If intraocular pressure remains uncontrolled, urgent medical or surgical treatment may be necessary. Risk factors for the development of acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.
Protein-bound iodine: 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 the use of hydrochlorothiazide and the occurrence of basal cell carcinoma and squamous cell carcinoma. The photosensitizing effect of hydrochlorothiazide may be the cause of the development of such pathologies. Patients taking hydrochlorothiazide alone or in combination with other drugs should be informed of the risk of non-melanoma skin cancer and advised to regularly examine their skin for new lesions, as well as changes in existing ones, and to report any suspicious skin lesions.
Suspicious skin lesions are subject to histological examination by biopsy.
Patients should be advised to limit exposure to sunlight and UV rays and to use appropriate protection when exposed to sunlight and UV rays to minimize the risk of skin cancer.
The use of hydrochlorothiazide should also be carefully reconsidered in patients with a history of skin cancer (see section 4.8).
Excipients. The drug Nebiar® Plus contains lactose monohydrate. This drug should not be taken by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding
Pregnancy
There are no adequate data from the use of Nebivolol Plus 5/12.5 in pregnant women. Animal studies with the two individual components are insufficient to establish the effect of the combination of nebivolol and hydrochlorothiazide on reproductive function.
Nebivolol
The pharmacological effects of nebivolol may adversely affect the course of pregnancy, the fetus and the infant.
In general, β-blockers reduce placental blood flow, which has been associated with growth retardation, intrauterine death, miscarriage, and premature birth. Adverse effects (e.g., hypoglycemia and bradycardia) may occur in the fetus and newborn. If treatment with β-blockers is necessary, β1-selective β-blockers are preferable.
Nebivolol should not be used during pregnancy unless clearly necessary.
If nebivolol treatment is deemed necessary, uteroplacental blood flow and fetal growth should be monitored. In case of threatening effects on the course of pregnancy or the fetus, alternative treatment should be used. The newborn should be closely monitored. Symptoms of hypoglycemia and bradycardia should generally be expected during the first 3 days.
Hydrochlorothiazide
Experience with hydrochlorothiazide in pregnant women is limited, especially in the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on its mechanism of pharmacological action, its use in the second and third trimesters may impair feto-placental perfusion and cause effects in the fetus and infant such as jaundice, electrolyte imbalance and thrombocytopenia.
Hydrochlorothiazide should not be used in gestational edema, gestational hypertension, or late toxemia of pregnancy due to the risk of decreased plasma volume and placental hypoperfusion without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women, except in rare situations when other treatments cannot be used.
Breastfeeding period
It is not known whether nebivolol is excreted in human milk. Animal studies have shown that nebivolol is excreted in breast milk. Most beta-blockers, especially lipophilic compounds such as nebivolol, are excreted in breast milk, although to varying degrees.
Hydrochlorothiazide is excreted in human milk in small amounts. Large doses of thiazides, which cause intense diuresis, may suppress milk production.
It is not recommended to use the drug Nebiar® Plus 5/12.5 during breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies on the effects on the ability to drive and use machines have been conducted. However, when driving or using machines, it should be taken into account that dizziness and fatigue may occasionally occur during antihypertensive therapy.
Method of administration and doses
Dosage regimen
Adults. Nebivolol Plus 5/12.5 is indicated for patients whose blood pressure is adequately controlled with the combined use of 5 mg nebivolol and 12.5 mg hydrochlorothiazide.
The dosage is one tablet (5 mg/12.5 mg) per day, preferably at the same time of day.
Patients with renal insufficiency. The drug Nebiar® Plus 5/12.5 is contraindicated in patients with severe renal insufficiency (see also sections “Contraindications” and “Special instructions for use”).
Patients with hepatic insufficiency. Experience with the use of the drug in patients with hepatic insufficiency or impaired liver function is limited, therefore the use of the drug Nebiar® Plus 5/12.5 is contraindicated in such patients.
Elderly patients. Due to limited experience with the drug in patients over 75 years of age, its use requires caution and careful monitoring.
Method of application
Administer orally.
The tablets can be taken with meals.
Children
Studies on the use of the drug in children and adolescents have not been conducted, therefore the drug is not recommended for this age group.
Overdose
Symptoms
There are no data on nebivolol overdose. Symptoms of beta-blocker overdose include bradycardia, hypotension, bronchospasm and acute heart failure.
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 may lead to muscle spasms and/or cardiac arrhythmias associated with concomitant use of digitalis glycosides or related antiarrhythmic drugs.
Treatment
In case of overdose or hypersensitivity, the patient requires intensive care and close observation. Glucose levels should be monitored. Serum electrolytes and creatinine should be monitored. Absorption of drug residues still in the gastrointestinal tract can be prevented by gastric lavage and the use of activated charcoal and a laxative. Artificial respiration may be necessary. Bradycardia or massive vagal reactions should be treated with atropine or methyltropine.
Hypotension and shock should be treated with plasma/plasma substitutes and, if necessary, catecholamines. Electrolyte imbalances should be corrected. The effects of beta-blockers can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting at 5 mcg/min, or dobutamine, starting at 2.5 mcg/min, until the desired effect is achieved. In severe, refractory cases
