Honorio

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ONORIO (ONORIO)

Composition:

Active substance: nebivolol;

1 tablet contains 5 mg of nebivolol in the form of nebivolol hydrochloride;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets, cloverleaf-shaped on one side, convex on the other side, with two perpendicular intersecting grooves on both sides.

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 actions:

• It is a competitive and selective β-receptor antagonist: this effect is attributed to the SRRR enantiomer (d-enantiomer);
• It has mild vasodilating properties due to interaction with L-arginine/nitric oxide.

Single and repeated doses of nebivolol reduce heart rate and blood pressure 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.

In therapeutic doses, α-adrenergic antagonism is not observed.

During short- and long-term treatment with nebivolol in patients with arterial hypertension, systemic vascular resistance decreases. Despite 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 (ACh), mediated by nitric oxide; in patients with endothelial dysfunction, this response is reduced.

In a placebo-controlled morbidity/mortality trial involving 2128 patients aged ≥ 70 years (mean age 75.2 years) with stable chronic heart failure with or without reduced left ventricular ejection fraction (LVEF) (mean LVEF 36 ± 12.3%, distributed as follows: LVEF < 35% in 56% of patients, LVEF 35–45% in 25%, LVEF > 45% in 19%), lasting on average 20 months, nebivolol as an add-on therapy to standard treatment significantly prolonged the time to death or hospitalization due to cardiovascular disease (primary efficacy endpoint), reducing the relative risk by 14% (absolute reduction – 4.2%). This risk reduction emerged after 6 months of treatment and persisted throughout the treatment period (mean duration – 18 months). The effect of nebivolol was independent of age, gender, or left ventricular ejection fraction in study participants. Benefit regarding prevention of all-cause mortality compared to placebo did not reach statistical significance (absolute reduction – 2.3%).

In patients treated with nebivolol, a reduction in mortality rates was observed (4.1% vs. 6.6%, relative reduction by 38%).

In vitro and in vivo animal experiments showed that nebivolol has no intrinsic sympathomimetic activity.

In vitro and in vivo animal experiments showed that nebivolol, at pharmacological doses, has no membrane-stabilizing effect.

In healthy volunteers, nebivolol has no significant effect on maximal exercise tolerance or endurance.

Available preclinical and clinical data have not shown that nebivolol negatively affects erectile function in patients with hypertensive disease.

Pharmacokinetics.

After oral administration, both enantiomers of nebivolol are rapidly absorbed. Food does not affect the absorption of nebivolol; therefore, it can be taken with or without food.

Nebivolol is completely metabolized, partly forming active hydroxymetabolites. The metabolism of nebivolol occurs via aliphatic or aromatic hydroxylation, N-dealkylation, and glucuronidation; in addition, glucuronides of hydroxymetabolites are formed. The metabolism of nebivolol via hydroxylation is subject to a genetically determined oxidative polymorphism dependent on CYP2D6. The oral bioavailability of nebivolol is 12% in individuals with rapid metabolism and is nearly complete in those with slow metabolism. At steady state and with the same dose, the maximum plasma concentration of unchanged nebivolol in individuals with slow metabolism is approximately 23 times higher than in those with rapid metabolism. When considering the sum of unchanged drug and its active metabolites, the difference in maximum plasma concentration is 1.3 to 1.4 times. Due to differences in metabolic rates, the dose of the medicinal product ONORIO should always be adjusted according to individual patient needs; therefore, individuals with slow metabolism may require lower doses.

In individuals with rapid metabolism, the mean elimination half-life of nebivolol enantiomers is approximately 10 hours. In individuals with slow metabolism, this value is 3–5 times higher. In individuals with rapid metabolism, the concentration of the RSSS-enantiomer is slightly higher than that of the SRRR-enantiomer. This difference is greater in individuals with rapid metabolism.

In individuals with rapid metabolism, the mean elimination half-life of hydroxymetabolites of both enantiomers is approximately 24 hours, while in individuals with slow metabolism, these values are about twice as high.

Steady-state plasma levels are achieved within 24 hours in most patients with rapid metabolism, and within several days for hydroxymetabolites.

Plasma concentrations of 1 to 30 mg of nebivolol are dose-proportional. Age does not influence the pharmacokinetics of nebivolol.

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

Approximately one week after administration, 38% of the dose is excreted in urine and 48% in feces. Renal excretion of unchanged nebivolol is less than 0.5% of the dose.

Preclinical safety data.

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

Clinical characteristics.

Indications.

Essential arterial hypertension. Mild to moderate chronic heart failure ― as an adjunct to standard therapy in elderly patients (≥ 70 years of age). Chronic ischemic heart disease, 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. Sinus node dysfunction, including sinoatrial block, second- or third-degree atrioventricular (AV) block (without a pacemaker). Bronchospasm or history of bronchial asthma. Untreated phaeochromocytoma. Metabolic acidosis. Bradycardia (heart rate less than 60 beats per minute prior to initiation of treatment). Arterial hypotension (systolic blood pressure less than 90 mm Hg), severe disorders of peripheral circulation.

Interaction with other medicinal products and other forms of interactions.

Concomitant use is not recommended with antiarrhythmic agents of Class I (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone) — may enhance effects on AV conduction and increase negative inotropic effect; with calcium antagonists of the verapamil/diltiazem type — negative effects on atrioventricular (AV) conduction and myocardial contractility. Intravenous administration of verapamil in patients receiving β-blockers may lead to marked arterial hypotension and AV block; with centrally-acting antihypertensives (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) — may lead to worsening of heart failure due to reduced heart rate, stroke volume, and vasodilation. The abrupt withdrawal of these agents, particularly before discontinuation of β-blockers, may increase the likelihood of elevated blood pressure (withdrawal syndrome).

Caution is advised when using β-blockers concomitantly with antiarrhythmic agents of Class II (amiodarone) — may enhance effects on AV conduction; and halogenated volatile anesthetics — may suppress reflex tachycardia and increase the risk of hypotension. If a patient is taking nebivolol, this should be communicated to the anesthesiologist.

Insulins and oral antidiabetic agents — although nebivolol does not affect blood glucose levels, it may mask symptoms of hypoglycemia such as tachycardia and palpitations.

Baclofen, amifostine — concomitant use with antihypertensives may likely enhance the blood pressure-lowering effect; therefore, the dose of antihypertensive agents should be appropriately adjusted.

When used concomitantly, the following should be considered: cardiac glycosides (digitalis group) slow AV conduction, although clinical studies have not shown evidence of this interaction. Nebivolol does not affect digoxin kinetics; calcium antagonists of the dihydropyridine type (amlodipine, felodipine, lacidipine, nifedipine, nimodipine, nitrendipine) may increase the risk of arterial hypotension and, in patients with heart failure, may worsen ventricular pump function; antipsychotics, antidepressants (tricyclic antidepressants, barbiturates, phenothiazine derivatives) may enhance the antihypertensive effect (additive effect principle); nonsteroidal anti-inflammatory drugs do not affect the antihypertensive action of nebivolol; 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 developing arterial hypertension, severe bradycardia, and heart block).

Interactions due to the pharmacokinetics of the drug. Since the CYP2D6 isoenzyme is involved in the metabolism of nebivolol, concomitant use of drugs that inhibit this enzyme (paroxetine, fluoxetine, thioridazine, quinidine) increases plasma levels of nebivolol, thereby increasing the risk of significant 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 administered between meals, both agents may be co-administered. When nebivolol and nicardipine are used concomitantly, plasma concentrations of both substances increase slightly without affecting clinical efficacy. Concomitant use of alcohol, furosemide, or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol. Nebivolol does not affect the pharmacokinetics of warfarin.

Special precautions for use.

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

Maintaining beta-receptor blockade reduces the risk of cardiac rhythm disturbances during intubation and induction of anesthesia. Beta-adrenergic 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 in patients can be prevented by intravenous administration of atropine.

Beta-adrenergic blockers should generally not be prescribed to patients with untreated chronic heart failure until their condition becomes stable.

Beta-adrenergic blocker therapy in patients with ischemic heart disease should be discontinued gradually over a period of 1–2 weeks. If necessary, to prevent disease exacerbation, concomitant initiation of treatment with an alternative agent is recommended.

Beta-adrenergic blockers may cause bradycardia. If the resting heart rate decreases to 50–55 beats per minute and/or symptoms suggestive of bradycardia develop, dose reduction is recommended.

Beta-adrenergic blockers should be used with caution in treating:
a) patients with peripheral circulatory disorders (Raynaud's syndrome, intermittent claudication), as these conditions may worsen;
b) patients with first-degree atrioventricular block due to the negative effect of beta-adrenergic blockers on conduction;
c) patients with Prinzmetal's angina due to unopposed alpha-adrenergic receptor-mediated vasoconstriction of coronary arteries (beta-blockers may increase the frequency and duration of angina attacks).

Nebivolol does not affect blood glucose levels in patients with diabetes mellitus. Nevertheless, caution is required when using nebivolol in these patients, as it may mask certain signs of hypoglycemia, such as tachycardia and palpitations.

Beta-adrenergic blockers may mask symptoms of tachycardia associated with hyperthyroidism. Upon abrupt discontinuation of therapy, these symptoms may intensify.

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

Beta-adrenergic blockers should be prescribed to patients with psoriasis in their medical history only after careful consideration of the individual risk-benefit ratio.

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

This medication contains lactose and therefore should not be administered to patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

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

Nebivolol should not be used during pregnancy. Use is possible only if there is unequivocal necessity. If treatment with nebivolol is considered necessary, uteroplacental circulation and fetal growth should be closely monitored. If harmful effects on pregnancy or the fetus are observed, alternative therapy should be considered. Close monitoring of the newborn/infant is required. Hypoglycemia and bradycardia are generally expected within the first three days after birth.

Breastfeeding period

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 to varying degrees. Therefore, breastfeeding during nebivolol treatment is not recommended.

Ability to influence reaction speed when driving or operating machinery.

No studies have been conducted on the effect of nebivolol on reaction speed when driving or operating machinery. Pharmacological 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.

Essential arterial hypertension. The recommended dose for adult patients is 5 mg (1 tablet) of nebivolol once daily. The drug may be taken with or without food, preferably at the same time each day. The antihypertensive effect becomes evident within 1–2 weeks of treatment, although optimal response may sometimes be observed only after 4 weeks. ONORIO can be used both as monotherapy and in combination with other antihypertensive agents. To date, an additional antihypertensive effect has been observed only when nebivolol is combined with 12.5–25 mg of hydrochlorothiazide.

Patients with renal impairment: The recommended initial dose is 2.5 mg once daily. The daily dose may be increased to 5 mg if necessary.

Patients with hepatic impairment: Experience with the use of this drug in such patients is limited; therefore, nebivolol is contraindicated.

Elderly patients: For patients aged over 65 years, the recommended initial dose is 2.5 mg once daily. The daily dose may be increased to 5 mg if necessary. Experience with the use of this drug in patients over 75 years of age is limited; therefore, caution and close monitoring are required when prescribing to these patients.

Chronic heart failure. Treatment of chronic heart failure should begin with slow dose titration until the individual optimal maintenance dose is reached. This medication should be prescribed to patients who have chronic heart failure without episodes of acute decompensation during the preceding 6 weeks. The prescribing physician must have experience in the management of 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 previous 2 weeks before starting nebivolol. Initial dose titration should follow the schedule below, with intervals of 1 to 2 weeks between dose increases, based on patient tolerability: starting with 1.25 mg of nebivolol once daily, increasing to 5 mg once daily, and subsequently to 10 mg once daily (the ONORIO 5 mg tablet may be divided into 4 equal parts). 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). If necessary, the achieved dose may be reduced stepwise or readjusted. In case of worsening heart failure symptoms or drug intolerance during the titration phase, it is recommended to first reduce the dose of nebivolol or, if necessary, discontinue it immediately (in the event of severe arterial hypotension, worsening heart failure symptoms with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia, or atrioventricular block). Generally, treatment of chronic heart failure with nebivolol is long-term. Nebivolol therapy should not be stopped abruptly, as this may lead to worsening of heart failure symptoms. If discontinuation is necessary, the dose should be tapered gradually, reducing it by half each week.

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 according to tolerability: from 1.25 mg nebivolol once daily 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 nebivolol once daily. Data for special patient groups apply to patients with both CHF and IHD.

Patients with renal impairment: Dose adjustment is not required in mild to moderate renal impairment, as dose titration is performed individually. Experience with the use of this drug in patients with severe renal impairment (serum creatinine ≥ 250 µmol/L) is limited; therefore, nebivolol is not recommended in these patients.

Patients with hepatic impairment: Experience with the use of this drug in such patients is limited; therefore, nebivolol is contraindicated.

Elderly patients: Since dose titration is performed individually, no dose adjustment is required.

Children.

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

Overdose.

Symptoms: bradycardia, arterial hypotension, bronchospasm, acute heart failure.
Treatment: gastric lavage, administration of activated charcoal and laxatives. Blood glucose levels should be monitored. If necessary, intensive therapy should be administered in a hospital setting: for bradycardia and increased vagal tone — administration of atropine; for arterial hypotension and shock — intravenous administration of plasma expanders and catecholamines. Beta-blocking effects may be counteracted by slow intravenous infusion of isoprenaline hydrochloride, starting at 5 µg/min, or dobutamine, starting at 2.5 µg/min, titrated to the desired effect. In refractory cases, isoprenaline may be combined with dopamine. If these measures are ineffective, glucagon should be administered at a dose of 50–100 µg/kg; the injection may be repeated within one hour if needed, and, if necessary, intravenous glucagon infusion may be initiated at 70 µg/kg/hour. In extreme cases, artificial ventilation of the lungs and temporary cardiac pacing may be required.

Adverse reactions.

Adverse reactions in essential arterial hypertension and chronic heart failure are listed separately due to differences in the underlying conditions causing these states.

Essential arterial hypertension.

Isolated cases of urticaria have been reported.

In addition, the following adverse reactions associated with some β-adrenoblockers have been reported: hallucinations, psychosis, confusion, cold extremities/cyanosis, Raynaud's syndrome, dryness of the eye mucosa, and practolol-type toxicity.

Chronic heart failure. The most commonly reported adverse reactions in patients receiving nebivolol were bradycardia and dizziness. The following adverse reactions, potentially at least possibly related to the use of nebivolol, were considered as characteristic and significant in the treatment of chronic heart failure: worsening of heart failure symptoms; orthostatic hypotension; first-degree atrioventricular block; peripheral edema; drug intolerance.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets per blister; 2 (10 × 2), or 3 (10 × 3), or 6 (10 × 6), or 9 (10 × 9) blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturers.

Primary and secondary packaging, quality control, batch release authorization:

SALUTAS Pharma GmbH.

Manufacturer's location and address of operations.

Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.

Primary and secondary packaging, quality control, batch release authorization:

LEK S.A.

Manufacturer's location and address of operations.

Podlipie 16, Strzyżów, 95-010, Poland.

Domaniewska 50C, Warsaw, 02-672, Poland.