Nebicard

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEBICARD

Composition:

Active substance: nebivolol;

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

Excipients: lactose monohydrate, maize starch, sodium croscarmellose, hydroxypropylmethylcellulose, microcrystalline cellulose, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex tablets, white or almost white, with a cross-shaped break line on one side and smooth on the other.

Pharmacotherapeutic group.

Selective β-adrenoceptor 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 at rest and during exercise in both individuals with normal blood pressure and 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 and long-term treatment with nebivolol in patients with arterial hypertension, systemic vascular resistance decreases. 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 nitric oxide-mediated vascular response to acetylcholine; this response is reduced in patients with endothelial dysfunction. The use of nebivolol as an addition to standard therapy in chronic heart failure, with or without reduced left ventricular ejection fraction, significantly prolonged the time to death or hospitalization due to cardiovascular disease. The effect of nebivolol does not depend on age, gender, or left ventricular ejection fraction. In patients receiving nebivolol, a reduction in the incidence of sudden death has been observed.

In vitro and in vivo experiments in animals have shown that nebivolol does not possess sympathomimetic activity.

In vitro and in vivo experiments in animals have shown that at pharmacological doses, nebivolol has no membrane-stabilizing activity.

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

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

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 at the same dose, the maximum plasma concentration of unchanged nebivolol in slow metabolizers is approximately 23 times higher than in extensive metabolizers. When considering the sum of unchanged drug and its active metabolites, the difference in maximum plasma concentration ranges from 1.3 to 1.4 times. The dose of the medicinal product should be adjusted according to individual patient needs: slow metabolizers may require lower doses.

In slow metabolizers, this value is 3–5 times higher. In extensive metabolizers, the concentration of the RSSS-enantiomer is slightly higher than that of the SRRR-enantiomer. This difference is greater in slow metabolizers.

In extensive metabolizers, the elimination half-life of the hydroxymetabolites of both enantiomers averages 24 hours, while in slow metabolizers these values are approximately twice as long.

The bioavailability of orally administered nebivolol averages 12% in extensive metabolizers and is nearly complete in slow metabolizers. Based on differences in metabolic rate, the dosing of Nebicard should be determined according to individual patient needs: individuals with slow metabolism require lower doses. In extensive metabolizers, the elimination half-life of nebivolol enantiomers from plasma averages 10 hours, while in slow metabolizers these values are 3–5 times higher. Plasma concentrations ranging from 1 to 30 mg of nebivolol are dose-proportional. In plasma, both enantiomers are predominantly bound to albumin. Plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol. Age does not influence 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.

Safety preclinical data

Preclinical data based on conventional genotoxicity and carcinogenicity studies revealed no risk to humans.

Clinical characteristics.

Indications.

Essential arterial hypertension. Chronic heart failure of mild or 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 other components of the medicinal product;
• hepatic insufficiency or impaired liver function;
• acute heart failure, cardiogenic shock, or episodes of heart failure decompensation requiring intravenous administration of active substances with positive inotropic effect;
• sinus node weakness syndrome, including sinoatrial block, second- or third-degree atrioventricular (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 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

Below are general data on interactions with β-adrenoreceptor antagonists.

Concomitant use not recommended:

• with Class I antiarrhythmic agents (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone) – may enhance effects on AV conduction and increase negative inotropic effect; (see section "Special precautions");
• 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 marked arterial hypotension and AV block (see section "Special precautions");
• with centrally-acting antihypertensive agents (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) – may lead to worsening of heart failure due to reduced heart rate, stroke volume, and vasodilation (see section "Special precautions"). Sudden withdrawal, particularly before discontinuation of β-blockers, increases the likelihood of rising arterial pressure (withdrawal syndrome).

Caution is required during concomitant use:

• with Class III antiarrhythmic agents (amiodarone) – may enhance effects on AV conduction;
• with halogenated volatile anesthetics – possible suppression of reflex tachycardia and increased risk of arterial hypotension (see section "Special precautions"). Abrupt discontinuation of β-blocker therapy should be avoided. If the patient is taking Nebicard, the anesthesiologist should be informed;
• with insulin and oral antidiabetic agents – although Nebicard does not affect blood glucose levels, it may mask symptoms of hypoglycemia such as tachycardia and palpitations. Concomitant use of β-blockers with sulfonylurea derivatives may increase the risk of severe hypoglycemia (see section "Special precautions");
• with baclofen (antispastic agent) and amifostine (adjunct antineoplastic agent) – concomitant use with antihypertensive agents may lead to significant reduction in arterial pressure; therefore, the dose of antihypertensive agents should be adjusted accordingly.

Concomitant use should be considered:

• digitalis glycosides – AV conduction may be slowed, although clinical studies have not confirmed this interaction. 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 worsen;
• antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, phenothiazine derivatives) – antihypertensive effect may be enhanced (additive effect principle);
• nonsteroidal anti-inflammatory drugs – do not affect the antihypertensive action of Nebicard;
• sympathomimetics – may counteract the antihypertensive effect of β-blockers. Active substances 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 drug:

• since the isoenzyme CYP2D6 is involved in nebivolol metabolism, concomitant use of drugs that inhibit this enzyme (paroxetine, fluoxetine, thioridazine, quinidine) increases plasma levels of nebivolol and thereby 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;
• if Nebicard is taken with food and antacids are taken between meals, these drugs may be prescribed concomitantly;
• concomitant use of nebivolol and nicardipine slightly increases plasma concentrations of both substances without altering clinical efficacy;
• concomitant use of alcohol, furosemide, or hydrochlorothiazide does 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-adrenoreceptor blockers should be discontinued at least 24 hours prior to surgery. Caution is required when using certain anesthetics that may depress myocardial function, 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, treatment with an alternative agent should be initiated simultaneously to prevent disease exacerbation. Beta-blockers may cause bradycardia. If resting heart rate decreases to 50–55 beats per minute and/or symptoms of bradycardia develop, the dose should be reduced.

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

• Patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as these conditions may worsen;
• Patients with first-degree atrioventricular block due to the negative effect of beta-blockers on conduction;
• Patients with Prinzmetal's (variant) angina due to unopposed α-adrenoreceptor-mediated vasoconstriction of coronary arteries: 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 (see section "Interaction with other medicinal products and other forms of interaction" for details).

Metabolism and endocrine system.

Nebicard 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 symptoms of hypoglycemia, such as tachycardia and palpitations. Beta-blockers may additionally increase the risk of severe hypoglycemia when used concomitantly with sulfonylurea derivatives. Patients with diabetes should be advised to carefully monitor their blood glucose levels (see section "Interaction with other medicinal products and other forms of interaction"). Beta-blockers may mask symptoms of tachycardia associated with hyperthyroidism. These symptoms may intensify following abrupt discontinuation of therapy.

Respiratory system.

Beta-adrenoreceptor blockers should be used with caution in patients with obstructive airway diseases, as they may increase airway constriction.

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

Other.

Beta-adrenoreceptor blockers should be prescribed to patients with a history of psoriasis only after careful consideration.

Beta-adrenoreceptor blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.

Monitoring of the patient's condition is required at the beginning of treatment with nebivolol for chronic heart failure (see section "Dosage and administration").

Therapy should not be abruptly discontinued unless absolutely necessary (see section "Dosage and administration").

The medicinal product contains lactose monohydrate and therefore should not be used in patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Nebivolol has pharmacological effects that may adversely affect pregnancy and/or the fetus/newborn. In general, beta-adrenoreceptor blockers reduce placental blood flow, which has been associated with intrauterine growth retardation, intrauterine death, abortion, and premature delivery. Adverse effects (e.g., hypoglycemia and bradycardia) may occur in the fetus and newborn. If treatment with beta-blockers is necessary, beta1-selective beta-adrenoreceptor blockers are preferred, and monitoring of uteroplacental blood flow and fetal growth should be performed. If adverse effects are confirmed, alternative treatment should be considered. The newborn should be closely monitored. Hypoglycemia and bradycardia are generally expected within the first three days of life.

Lactation.

Animal studies have shown that nebivolol passes into breast 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 (although to varying degrees). Breastfeeding is not recommended during treatment with nebivolol.

Ability to influence reaction speed when driving or operating machinery.

No specific studies have been conducted. Pharmacodynamic studies have shown that Nebicard does not affect psychomotor function. However, it should be taken into account that dizziness and fatigue may occasionally occur.

Method of Administration and Dosage.

Essential arterial hypertension.

Adult patients should take 1 tablet (5 mg nebivolol) once daily, preferably at the same time each day. The medication can be taken with food. The antihypertensive effect becomes evident within 1–2 weeks of treatment, although optimal efficacy may only be observed after 4 weeks.

Combination with other antihypertensive agents. Nebicard can be used both as monotherapy and in combination with other antihypertensive drugs. 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 drug 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 insufficient experience with patients aged 75 years and older, use of the drug requires caution and careful monitoring.

Chronic heart failure.

Treatment of chronic heart failure (CHF) should begin with gradual dose titration until the individual optimal maintenance dose is reached. This medication should be prescribed only to patients with stable chronic heart failure who have not experienced episodes of acute decompensation within the past 6 weeks. The prescribing physician must have 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 drugs for at least the past 2 weeks before initiating treatment with Nebicard. Initial dose titration should follow the schedule below, with intervals of 1 to 2 weeks between dose increases, based on patient tolerance: increase from 1.25 mg nebivolol once daily 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 after 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, conduction disturbances, and worsening of heart failure symptoms). The occurrence of adverse reactions may indicate that the patient cannot tolerate the highest recommended doses. If needed, the achieved dose may be gradually reduced or readjusted. In case of worsening heart failure symptoms or drug intolerance 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 hypotension, worsening heart failure symptoms with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia, or AV block). Nebivolol therapy should not be stopped abruptly, as this may exacerbate heart failure symptoms. If discontinuation is necessary, the dose should be gradually tapered by reducing it twice weekly. Chronic heart failure treatment with nebivolol is generally long-term.

Chronic ischemic heart disease.

Treatment of chronic ischemic heart disease (CIHD) 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 tolerance: from 1.25 mg 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. The information below regarding special patient groups applies to patients with both CIHD and CHF.

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

Patients with hepatic impairment. Nebivolol is contraindicated in patients with hepatic impairment due to limited clinical experience.

Elderly patients.

Since dose titration to the maximum tolerated dose is individualized, dose adjustment is not required.

Method of administration.

Oral use.

The tablets may be taken with food.

Children.

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

Overdose.

There are no reported cases of nebivolol overdose.

In overdose with β-adrenergic blockers, the following symptoms may occur: bradycardia, arterial hypotension, bronchospasm, and acute heart failure.

In case of overdose or development of hypersensitivity reactions, continuous patient monitoring and treatment in an intensive care unit are required. Treatment of overdose includes gastric lavage, administration of activated charcoal, and laxatives. Mechanical ventilation may also be necessary. Blood glucose levels should be monitored. If required, intensive inpatient therapy should be initiated: for bradycardia and increased vagal tone — administration of atropine or methylatropine; for hypotension and shock — intravenous infusion of plasma/plasma substitutes and catecholamines. Beta-blocking effects can be counteracted by slow intravenous infusion of isoprenaline hydrochloride, starting at 5 μg/min, or dobutamine, starting at 2.5 μg/min, titrated to desired effect. In resistant cases, isoprenaline may be combined with dopamine. If the above measures are ineffective, glucagon should be administered at a dose of 50–100 μg/kg; repeat injections may be given within one hour if needed, and intravenous glucagon infusion may be initiated at 70 μg/kg/hour if necessary. In extreme cases, mechanical ventilation and implantation of an artificial pacemaker may be required.

Side effects.

Adverse reactions in arterial hypertension and chronic heart failure are listed separately due to differences in the underlying pathological processes of these conditions.

Arterial hypertension.

The adverse reactions, which in most cases were of mild to moderate severity, are listed in the 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, psychosis, confusion, cold extremities/cyanosis, Raynaud's syndrome, dry eyes, and ocular-mucocutaneous 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 (31.5%) patients taking placebo reported adverse reactions possibly related to the drug. The most commonly reported adverse reactions, occurring in approximately 11% of patients treated with nebivolol, were bradycardia and dizziness. The incidence of these reactions in patients receiving placebo was approximately 2% and 7%, respectively.

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

• Worsening of heart failure was observed 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 1.0% of patients receiving placebo;
• Drug intolerance was observed 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 1.0% 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 clinical trial data studying patients with CHF. It is reasonable to assume that the safety and tolerability results obtained with nebivolol in patients with CHF also apply to patients with IHD.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions.

Shelf life. 4 years. Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 2 blisters in a cardboard package.

10 tablets in a blister; 5 blisters connected into one in a cardboard package.

Prescription category. Prescription only.

Manufacturer.

TORRENT PHARMACEUTICALS LTD.

Manufacturer's address and location of business operations.

Indrad Plant, Vill. Indrad, Taluka Kadi, Dist. Mehsana Gujarat 382721, India.