Nebivolol-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEBIVOLOL - DARNITSA (NEBIVOLOL - DARNITSA)

Composition:

Active substance: nebivolol;

One tablet contains nebivolol hydrochloride equivalent to 5 mg of nebivolol;

Excipients: hypromellose, polysorbate 80; lactose monohydrate; microcrystalline cellulose; maize starch; sodium croscarmellose; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or almost white, biconvex tablets with two perpendicular score lines for dividing.

Pharmacotherapeutic group.

Selective β-adrenoreceptor blockers.

ATC code C07AB12.

Pharmacological properties.

Pharmacodynamics.

Nebivolol is a racemate consisting 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 β1-adrenoceptor blocker;
• due to the L-enantiomer, it has mild vasodilating properties resulting from metabolic interaction with L-arginine/nitric oxide (NO).

After single and repeated administration, nebivolol reduces heart rate and arterial blood pressure at rest and during exercise, both in individuals with normal blood pressure and in those with arterial hypertension. The antihypertensive effect is maintained during long-term treatment. At therapeutic doses, α-adrenergic antagonism is not observed. During short-term or 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 is limited due to an increase in stroke volume. The clinical significance of this hemodynamic difference, compared to other β-adrenoceptor blockers, has not yet been fully elucidated. In patients with arterial hypertension, nebivolol enhances the vascular response to acetylcholine mediated by nitric oxide; in patients with endothelial dysfunction, this response is reduced.

In a placebo-controlled study involving 2128 patients aged ≥70 years (mean age 75.2 years) with stable chronic heart failure with or without reduced left ventricular ejection fraction, the addition of nebivolol to standard therapy significantly prolonged the time to death or hospitalization related to cardiovascular disease. The effect of nebivolol did not depend on age, sex, or left ventricular ejection fraction in the study participants. In patients receiving nebivolol, a reduced incidence of sudden cardiac death was observed.

According to available preclinical and clinical data, nebivolol has no negative effect on erectile function in patients with hypertension.

Pharmacokinetics.

After oral administration, both enantiomers of nebivolol are rapidly absorbed. Food does not affect the absorption of nebivolol; therefore, it can be taken independently of food intake. Nebivolol is metabolized in the liver, including the formation of active hydroxymetabolites. The metabolism of nebivolol via hydroxylation is subject to genetic oxidative polymorphism dependent on CYP2D6. At steady-state and with the same dose, the maximum plasma concentration of unchanged nebivolol in poor metabolizers is approximately 23 times higher than in extensive metabolizers. In extensive metabolizers, the elimination half-life of the hydroxymetabolites of both enantiomers averages 24 hours, while in poor metabolizers these values are approximately twice as long.

The bioavailability of orally administered nebivolol is on average 12% in extensive metabolizers and nearly complete in poor metabolizers. Plasma concentrations following doses of 1 to 30 mg are proportional to the dose. Age does not affect the pharmacokinetics of nebivolol. Within one week after administration, 38% of the dose is excreted in urine and 48% in feces. Less than 0.5% of the administered dose is excreted unchanged in urine.

Clinical Characteristics

Indications

Essential arterial hypertension.

Chronic heart failure of mild to moderate severity, as an adjunct to standard treatment in patients aged 70 years and older.

Treatment of symptomatic chronic ischemic heart disease.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients;
• hepatic insufficiency or impaired liver function;
• acute heart failure, cardiogenic shock, or episodes of decompensated heart failure requiring intravenous administration of agents with positive inotropic effect.

Additionally, as with other β-blockers, the drug is contraindicated in the following conditions:

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

Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Concomitant use not recommended:

• with Class I antiarrhythmic agents (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone), as they may enhance the effect on AV conduction and increase the negative inotropic effect;
• with calcium antagonists of the verapamil/diltiazem type – negative effects on AV conduction and myocardial contractility. Intravenous administration of verapamil to patients receiving β-blockers may lead to severe arterial hypotension and AV block;
• with centrally-acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) – may lead to worsening of heart failure due to reduction in heart rate, stroke volume, and vasodilation; abrupt withdrawal, particularly before discontinuation of β-blockers, may increase the likelihood of blood pressure rise (withdrawal syndrome).

Caution is required when using the medicinal product concomitantly with:

• Class III antiarrhythmic agents (amiodarone) – may enhance the effect on AV conduction;
• halogenated volatile anesthetics – may suppress reflex tachycardia and increase the risk of arterial hypotension. According to general recommendations, abrupt discontinuation of β-blocker therapy should be avoided. If the patient is taking nebivolol, this should be communicated to the anesthesiologist;
• insulin and oral antidiabetic agents – although nebivolol does not affect blood glucose levels, it may mask symptoms of hypoglycemia such as tachycardia and palpitations;
• baclofen (antispastic agent), amifostine (adjunctive antineoplastic agent) – concomitant use with antihypertensive agents may lead to significant reduction in blood pressure; therefore, the dose of antihypertensive agents should be adjusted.

Concomitant use requires consideration:

• cardiac glycosides (digitalis group) – AV conduction may be slowed; however, clinical studies have not reported significant interactions; nebivolol does not affect digoxin kinetics;
• calcium antagonists of the dihydropyridine type (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine) – increased risk of arterial hypotension, and in patients with heart failure, ventricular pump function may deteriorate;
• antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, phenothiazine derivatives) – antihypertensive effect may be enhanced (additive effect);
• nonsteroidal anti-inflammatory drugs – do not affect the antihypertensive effect of nebivolol;
• sympathomimetics may counteract the antihypertensive effect of β-blockers; agents with β-adrenergic activity may lead to unopposed α-adrenergic activity of sympathomimetics possessing both α- and β-adrenergic effects (risk of arterial hypertension, severe bradycardia, and heart block).

Interactions due to the pharmacokinetics of the medicinal product:

• since the CYP2D6 isoenzyme is involved in nebivolol metabolism, concomitant use of medicinal products that inhibit this enzyme (paroxetine, fluoxetine, thioridazine, quinidine) increases plasma levels of nebivolol and thus increases the risk of excessive bradycardia and other adverse reactions;
• cimetidine increases plasma levels of nebivolol without altering clinical efficacy;
• ranitidine does not affect the pharmacokinetics of nebivolol;
• provided nebivolol is taken with food and antacids are taken between meals, these medicinal products may be co-administered;
• concomitant administration of nebivolol and nicardipine slightly increases plasma concentrations of both agents without affecting clinical efficacy;
• concomitant alcohol intake and use of furosemide or hydrochlorothiazide do not affect the pharmacokinetics of nebivolol;
• nebivolol does not affect the pharmacodynamics or pharmacokinetics of warfarin.

Special precautions for use.

The following warnings and precautions are common to beta-adrenoreceptor blockers.

Anesthesia.

Maintaining beta-adrenoreceptor blockade reduces the risk of cardiac arrhythmias during induction of anesthesia and intubation. Beta-blockers should be discontinued at least 24 hours before surgery. Caution is required when using certain anesthetics that may cause myocardial depression, such as cyclopropane, ether, or trichloroethylene. Vagal reactions can be prevented by intravenous administration of atropine.

Cardiovascular system.

Beta-adrenoreceptor blockers should generally not be prescribed to patients with untreated chronic heart failure until their condition becomes stable. Discontinuation of beta-blocker therapy in patients with ischemic heart disease should be gradual, over a period of 1–2 weeks. If necessary, to prevent exacerbation of angina, concomitant initiation of alternative antianginal treatment is recommended. Beta-blockers may cause bradycardia. If the resting heart rate decreases to 50–55 beats per minute and/or symptoms indicative of bradycardia develop, the dose should be reduced.

Beta-adrenoreceptor blockers should be used with caution in the treatment of:

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

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

c) patients with Prinzmetal’s (variant) angina, due to unopposed α-adrenoreceptor-mediated coronary artery vasoconstriction: beta-blockers may increase the frequency and duration of angina attacks.

Combination of nebivolol with calcium antagonists of the verapamil and diltiazem type, antiarrhythmic agents of Class I, and centrally acting antihypertensive agents is generally not recommended (for detailed information, see section "Interaction with other medicinal products and other forms of interaction").

Metabolism and endocrine system.

Nebivolol does not affect blood glucose levels in patients with diabetes mellitus. Nevertheless, caution is required when using it in such patients, as nebivolol may mask certain signs of hypoglycemia, such as tachycardia and palpitations. Beta-adrenoreceptor blockers may also mask symptoms of tachycardia in hyperthyroidism. Upon abrupt discontinuation of therapy, these symptoms may become exacerbated.

Respiratory system.

Beta-adrenoreceptor blockers should be used with caution in patients with obstructive respiratory diseases, as bronchoconstriction may be intensified.

Other.

Regular monitoring of the patient is required at the beginning of treatment with nebivolol for chronic heart failure. Treatment should not be discontinued abruptly unless absolutely necessary.

Beta-adrenoreceptor blockers should be prescribed to patients with a history of psoriasis only after careful risk-benefit assessment. Beta-blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.

Excipients.

The medicinal product contains lactose monohydrate and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

For information on dosage and administration, see section "Dosage and administration".

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., is essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

Nebivolol exerts pharmacological effects that may adversely affect pregnancy and/or the fetus/newborn. In general, beta-blockers reduce placental blood flow, which has been associated with intrauterine growth retardation, fetal death, abortion, and premature delivery. Adverse effects (e.g., hypoglycemia and bradycardia) may occur in the fetus and newborn. If beta-blocker therapy is necessary, β1-selective beta-adrenoreceptor blockers are preferred.

Nebivolol should not be used during pregnancy unless clearly necessary. If treatment with nebivolol is considered essential, uteroplacental blood flow and fetal growth should be closely monitored. If adverse effects on pregnancy or the fetus are observed, alternative therapy should be considered. Newborns should be carefully observed. Hypoglycemia and bradycardia may be expected within the first 3 days of life.

Breastfeeding period.

Animal studies have shown that nebivolol passes into animal milk. It is unknown whether this substance passes into human breast milk. Most beta-blockers, particularly lipophilic compounds such as nebivolol and its active metabolites, pass into breast milk to varying degrees. Therefore, breastfeeding is not recommended during treatment with nebivolol.

Ability to influence reaction speed when driving or operating machinery.

No specific studies have been conducted. Pharmacokinetic studies have shown that nebivolol does not affect psychomotor function. However, it should be considered that dizziness and fatigue may occasionally occur.

Method of Administration and Dosage

Dosing Regimen

Administer orally. Swallow the tablets with sufficient liquid (e.g., one glass of water). Can be taken independently of food intake.

Essential Arterial Hypertension

Adult patients should take 1 tablet (5 mg of nebivolol) once daily, preferably at the same time each day. The medication may be taken with or without food. The antihypertensive effect becomes evident within 1–2 weeks of treatment, although optimal response may sometimes only be observed after 4 weeks.

Combination with other antihypertensive agents

Nebivolol can be used as monotherapy or in combination with other antihypertensive agents. To date, an additional antihypertensive effect has been observed only when combined with 12.5–25 mg hydrochlorothiazide.

Patients with renal impairment

The recommended initial dose is 2.5 mg once daily. If necessary, the daily dose may be increased to 5 mg.

Patients with hepatic impairment

Experience with the use of this medicinal product in such patients is limited; therefore, nebivolol is contraindicated.

Elderly patients (aged 65 years and older)

For this patient group, the recommended initial dose is 2.5 mg once daily, which may be increased to 5 mg if necessary. Due to limited experience with use in patients aged 75 years and older, administration requires caution and careful monitoring of these patients.

Chronic Heart Failure

Treatment of chronic heart failure should begin with gradual dose titration to reach the individual optimal maintenance dose. This medicinal product should be prescribed to patients with chronic heart failure who have not experienced episodes of acute decompensation within the preceding 6 weeks. It is recommended that the prescribing physician has experience in managing heart failure. Patients already receiving other cardiovascular medications (diuretics, digoxin, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists) should have been on stable doses of these medications for at least the previous 2 weeks before initiating nebivolol therapy.

Initial dosing should follow the schedule below, with intervals of 1 to 2 weeks between dose increases, based on patient tolerability: start with 1.25 mg nebivolol once daily, which may be increased to 2.5 mg once daily, then to 5 mg once daily, and subsequently to 10 mg once daily. The maximum recommended dose is 10 mg once daily.

At the beginning of treatment and with each dose increase, the patient should remain under the supervision of an experienced physician for at least 2 hours to ensure clinical stability (particularly regarding blood pressure, heart rate, myocardial conduction disturbances, and worsening of heart failure symptoms). The occurrence of adverse reactions indicates that the patient should not be treated with the highest recommended doses. If necessary, a previously achieved dose may be gradually reduced or readjusted.

If symptoms of heart failure worsen or the drug is not tolerated during the titration phase, the dose of nebivolol should be reduced initially, or, if necessary, the drug should be discontinued immediately (in cases of severe arterial hypotension, worsening heart failure symptoms with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia, or AV block).

Chronic heart failure treatment with nebivolol is usually long-term.

Nebivolol therapy should not be discontinued abruptly, as this may lead to a temporary worsening of heart failure. If discontinuation is necessary, the dose should be gradually reduced by halving it every week over a 1-week interval.

Chronic Ischemic Heart Disease

Adults

Treatment of chronic ischemic heart disease should begin with gradual dose escalation to determine the optimal maintenance dose for each patient.

The initial dose should be increased every 1–2 weeks, depending on tolerability, from 1.25 mg nebivolol to 2.5 mg nebivolol once daily, then to 5 mg once daily, and subsequently to 10 mg once daily. The maximum recommended dose is 10 mg nebivolol once daily. Data for special patient groups apply to patients with both CHF and IHD.

Patients with renal impairment

Since dose titration to the maximally tolerated dose is individual, dose adjustment is not required in patients with mild to moderate renal impairment. There is no experience with the use of this medicinal product in patients with severe renal impairment (serum creatinine level ≥ 250 µmol/L); therefore, nebivolol is not recommended in such patients.

Patients with hepatic impairment

Limited data are available on the use of nebivolol in patients with hepatic impairment; therefore, the use of this medicinal product is contraindicated in such patients.

Elderly patients

Since dose titration to the maximally tolerated dose is individual, dose adjustment is not required.

Children

Studies on the efficacy and safety of nebivolol in children have not been conducted; therefore, the use of this medicinal product is not recommended in this age group.

Overdose

There are no available data on nebivolol overdose.

Symptoms
Overdose with β-adrenoblockers may result in bradycardia, arterial hypotension, bronchospasm, and acute heart failure.

Treatment of overdose
Gastric lavage, administration of activated charcoal, and laxatives are required. Mechanical ventilation may also be necessary. Blood glucose levels should be monitored. In cases of overdose or increased sensitivity, careful medical supervision is essential, and intensive therapy should be administered in a hospital setting:

• For bradycardia and increased vagal tone: administer atropine or methylatropine.
• For arterial hypotension and shock: administer plasma expanders and catecholamines intravenously.
• To counteract β-blocking effects: slowly administer isoprenaline hydrochloride intravenously, starting at 5 µg/min, or dobutamine starting at 2.5 µg/min, titrated to achieve the desired effect.
• In refractory cases, isoprenaline may be combined with dopamine.
• If the above measures are ineffective, administer glucagon at a dose of 50–100 µg/kg; repeat the injection within one hour if needed, and, if necessary, initiate intravenous glucagon infusion at 70 µg/kg/hour.
• In extreme cases, when bradycardia is unresponsive to treatment, implantation of an artificial pacemaker may be required.

Adverse reactions.

Adverse reactions are listed separately for essential arterial hypertension and chronic heart failure due to differences in the underlying pathophysiological processes associated with these conditions.

Essential arterial hypertension

Adverse reactions were mostly mild to moderate in severity (see table below); they are classified according to system organ classes and frequency of occurrence.

In addition, the following adverse reactions have been reported with some β-adrenoblockers: hallucinations, psychoses, confusion, cold extremities/cyanosis, Raynaud's syndrome, dry eyes, and ocular-muco-cutaneous toxicity of the practolol type.

Chronic heart failure

Information on adverse reactions in patients with heart failure was obtained from placebo-controlled clinical trials, in which 1067 patients received nebivolol and 1061 patients received placebo. In this study, a total of 449 patients (42.1%) taking nebivolol and 334 patients (31.5%) taking placebo reported adverse reactions possibly related to the study drug. The most commonly reported adverse reactions in patients treated with nebivolol were bradycardia and dizziness (occurring in approximately 11% of patients). The corresponding frequency in the placebo group was approximately 2% and 7%, respectively.

The following adverse reactions, considered at least potentially related to nebivolol use and regarded as characteristic and significant in the treatment of chronic heart failure, were reported:

• Worsening of heart failure occurred in 5.8% of patients receiving nebivolol and in 5.2% of patients receiving placebo;
• Orthostatic hypotension occurred in 2.1% of patients receiving nebivolol and in 1% of patients receiving placebo;
• Drug intolerance occurred in 1.6% of patients receiving nebivolol and in 0.8% of patients receiving placebo;
• First-degree AV block occurred in 1.4% of patients receiving nebivolol and in 0.9% of patients receiving placebo;
• Lower limb edema occurred in 1% of patients receiving nebivolol and in 0.2% of patients receiving placebo.

Chronic ischemic heart disease.

Data on adverse reactions in patients with IHD were obtained through a specific analysis of data from the same clinical trial described for CHF. It is reasonable to assume that the safety and tolerability results observed with nebivolol in patients with CHF are also applicable to patients with IHD.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

14 tablets in a blister pack; 2 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of its business activities.

13, Boryspylska Street, Kyiv, 02093, Ukraine.