Instructions for use Honorio tablets 5 mg blister No. 30
Composition
active ingredient: nebivolol;
1 tablet contains nebivolol 5 mg in the form of nebivolol hydrochloride;
Excipients: croscarmellose sodium, lactose monohydrate, corn starch, microcrystalline cellulose, hypromellose, colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: white or almost white tablets, four-leaf clover shaped on one side, convex on the other side, with two perpendicularly intersecting lines on both sides.
Pharmacotherapeutic group
Selective β-adrenergic blockers. ATC code C07A B12.
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 antagonist of β-receptors: this effect is explained by the SRRR enantiomer (d-enantiomer);
- It has mild vasodilating properties due to its 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 normotensive and hypertensive subjects. 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 decrease in heart rate, the decrease in cardiac output at rest and during exercise is limited due to the increase in stroke volume. The clinical significance of this hemodynamic difference compared with other β-adrenergic blockers is not yet fully understood.
In patients with hypertension, nebivolol increases the vascular response to acetylcholine (ACh) mediated by nitric oxide; in patients with endothelial dysfunction, this response is reduced.
In a placebo-controlled mortality/morbidity 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 (LVEF) (mean LVEF 36 ± 12.3% with the following distribution: LVEF less than 35% in 56% of patients, LVEF 35–45% in 25% of patients, LVEF greater than 45% in 19% of patients), lasting an average of 20 months, nebivolol as the main drug in standard therapy significantly prolonged the time to death or hospitalization due to cardiovascular pathology (primary efficacy endpoint) with a relative risk reduction of 14% (absolute reduction of 4.2%). This risk reduction developed after 6 months of treatment and was maintained throughout the treatment period (median duration 18 months). The effect of nebivolol was independent of age, gender or left ventricular ejection fraction of the study participants. The benefit in preventing all-cause mortality compared with placebo did not reach statistical significance (absolute reduction 2.3%).
Patients treated with nebivolol had a reduced incidence of fatal events (4.1% versus 6.6%, a relative reduction of 38%).
In vitro and in vivo animal experiments have shown that nebivolol does not have its own sympathomimetic activity.
In vitro and in vivo animal experiments have shown 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 hypertension.
Pharmacokinetics.
After oral administration, both enantiomers of nebivolol are rapidly absorbed. The absorption of nebivolol is not affected by food, so it can be taken with or without food.
In extensive metabolizers, the half-life of the enantiomers of nebivolol is on average 10 hours. In poor 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. In extensive metabolizers, this difference is greater.
In individuals with rapid metabolizers, the half-life values of the hydroxymetabolites of both enantiomers average 24 hours, and in individuals with slow metabolizers, these values are approximately 2 times greater.
Steady-state plasma levels are reached within 24 hours in most patients with rapid metabolism, and within several days for hydroxymetabolites.
Plasma concentrations, which range from 1 to 30 mg of nebivolol, are dose-proportional. Age does not affect the pharmacokinetics of nebivolol.
In plasma, both enantiomers are predominantly bound to albumin. Plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol.
One week after administration, 38% of the dose is excreted in the urine and 48% in the 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 for humans.
Indication
Essential arterial hypertension. Chronic heart failure of mild and moderate severity - as an addition to standard treatment methods for elderly patients (≥ 70 years). Chronic ischemic heart disease, treatment of symptomatic, chronic ischemic heart disease.
Contraindication
Hypersensitivity to the active substance or to any of the excipients. Hepatic failure or impaired liver function. Acute heart failure, cardiogenic shock or episodes of decompensated heart failure requiring intravenous administration of active substances with a positive inotropic effect. Sick sinus syndrome, including sinoatrial block, atrioventricular block II-III degree (without an artificial pacemaker). Bronchospasm and bronchial asthma in history. Untreated pheochromocytoma. Metabolic acidosis. Bradycardia (before the start of treatment, the heart rate was less than 60 beats per minute). Arterial hypotension (systolic blood pressure less than 90 mm Hg), severe peripheral circulatory disorders.
Interaction with other medicinal products and other types of interactions
Simultaneous use with group I antiarrhythmic drugs (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone) is not recommended - the effect on AV conduction and the negative inotropic effect may be enhanced; with calcium antagonists of the verapamil/diltiazem type - a negative effect on atrioventricular (AV) conduction and myocardial contractility. Intravenous administration of verapamil to patients taking β-blockers may lead to significant arterial hypotension and AV blockade; with centrally acting antihypertensive drugs (clonidine, guanfacine, moxonidine, methyldopa, rilmenidine) - may lead to increased heart failure due to a decrease in heart rate, stroke volume and vasodilation. With sudden withdrawal, particularly before the end of β-blocker use, the likelihood of an increase in blood pressure (withdrawal syndrome) may increase.
Simultaneously with β-blockers, antiarrhythmic drugs of group II (amiodarone) should be taken with caution - the effect on AV conduction may be enhanced, and halogen-containing volatile anesthetics - reflex tachycardia may be suppressed and the risk of hypotension may increase. If the patient uses nebivolol, the anesthesiologist should be informed about this.
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 - simultaneous use with antihypertensives is likely to increase the drop in blood pressure, so the dose of antihypertensive drugs should be adjusted appropriately.
Interactions due to pharmacokinetics of the drug. Since the CYP2D6 isoenzyme is involved in the metabolism of nebivolol, the joint use of drugs that inhibit this enzyme (paroxetine, fluoxetine, thioridazine, quinidine) increases the level of nebivolol in plasma and, thus, increases the risk of significant bradycardia and other adverse reactions. Cimetidine increases the level of nebivolol in plasma, but without changing the clinical efficacy. Ranitidine does not affect the pharmacokinetics of nebivolol. Provided that nebivolol is taken with meals, and the antacid is taken between meals, both drugs can be prescribed for simultaneous use. With the combined use of nebivolol and nicardipine, the plasma concentrations of both substances increased slightly without changing the clinical efficacy. The simultaneous use of alcohol, furosemide or hydrochlorothiazide does not affect the pharmacokinetics of nebivolol. Nebivolol does not affect the pharmacokinetics of warfarin.
Application features
The following warnings and precautions are common to β-adrenergic blockers.
Maintenance of β-blockade reduces the risk of cardiac arrhythmias during intubation and induction of anesthesia. β-blockers should be discontinued at least 24 hours before surgery. Caution is required when using certain anesthetics that cause myocardial depression, such as cyclopropane, ether, or trichloroethylene. Vagal reactions in the patient can be prevented by intravenous atropine.
As a rule, patients with untreated chronic heart failure should not be given β-adrenergic blockers until their condition is stable.
Discontinuation of β-blocker therapy in patients with coronary artery disease should be gradual, i.e. over 1–2 weeks. If necessary, it is recommended to simultaneously initiate treatment with a replacement drug to prevent exacerbation of the disease.
Beta-blockers can cause bradycardia. If the resting heart rate decreases to 50–55 beats per minute and/or the patient develops symptoms suggestive of bradycardia, a dose reduction is recommended.
β-Adrenergic blockers should be used with caution in the treatment of: a) patients with peripheral circulatory disorders (Raynaud's syndrome, intermittent claudication), as exacerbation of these diseases may develop; b) patients with first-degree atrioventricular block due to the negative effect of β-adrenergic blockers on conduction; c) patients with Prinzmetal's angina due to unobstructed, α-adrenergic mediated vasoconstriction of the coronary arteries (β-adrenergic blockers may increase the frequency and duration of angina attacks).
Nebivolol does not affect blood glucose levels in patients with diabetes mellitus. However, caution should be exercised when using it in this category of patients, as nebivolol may mask some signs of hypoglycemia, such as tachycardia and palpitations.
Beta-blockers may mask the symptoms of tachycardia in hyperthyroidism. These symptoms may worsen if therapy is abruptly discontinued.
In patients with obstructive airway diseases, β-adrenergic blockers should be used with caution as airway constriction may be increased.
Patients with a history of psoriasis should be prescribed β-blockers only after careful consideration.
Beta-adrenergic blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.
This medicine contains lactose and 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 have adverse effects on pregnancy and/or the fetus/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. It should only be used if clearly needed. If treatment with nebivolol is considered necessary, uteroplacental circulation and foetal growth should be monitored. If harmful effects on pregnancy or foetus are observed, alternative treatment should be considered. The newborn/infant should be closely monitored. Symptoms of hypoglycaemia and bradycardia can generally be expected within the first three days after birth.
Breastfeeding period.
Animal studies have shown that nebivolol passes into breast milk. It is not known whether this substance passes into human breast milk. Most β-blockers, namely lipophilic compounds (such as nebivolol and its active metabolites), pass into breast milk, although to varying degrees. Therefore, breastfeeding is not recommended during the use of nebivolol.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies have been conducted on the effect on the reaction rate when driving vehicles or working with other mechanisms. Pharmacological studies have shown that nebivolol does not affect psychomotor function. It should be borne in mind that dizziness and fatigue may sometimes occur.
Method of administration and doses
Essential hypertension. For adult patients, the dose is 5 mg (1 tablet) of nebivolol per day. The drug can be taken with meals, preferably at the same time. The hypotensive effect appears after 1–2 weeks of treatment, but sometimes the optimal effect is observed only after 4 weeks. ONORIO can be used both for monotherapy and in combination with other antihypertensive agents. So far, an additional hypotensive effect has been observed only when it is combined with 12.5–25 mg of hydrochlorothiazide.
Patients with renal insufficiency: the recommended initial dose is 2.5 mg per day. If necessary, the daily dose can be increased to 5 mg.
Patients with hepatic insufficiency: experience with the drug in such patients is limited, therefore the use of nebivolol is contraindicated.
Elderly patients: for patients over 65 years of age, the recommended initial dose is 2.5 mg per day. If necessary, the daily dose can be increased to 5 mg. Experience with the drug in patients over 75 years of age is limited, so caution and close monitoring are required when prescribing the drug to such patients.
Chronic heart failure. Treatment of chronic heart failure begins with slow dose titration until the individual optimal maintenance dose is achieved. Such patients are prescribed the drug if there is chronic heart failure without episodes of its acute decompensation within the last 6 weeks. The doctor should have experience in the treatment of heart failure. Patients who are using other cardiovascular drugs (diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) should have an already selected dose of these drugs for the last 2 weeks before starting treatment with nebivolol. Initial dose titration should be carried out according to the following scheme, maintaining intervals of 1 to 2 weeks and focusing on the patient's tolerability of the dose: 1.25 mg of nebivolol per day can be increased to 5 mg per day, and subsequently to 10 mg once a day (a 5 mg tablet of ONORIO can be divided into 4 equal parts). The maximum recommended dose is 10 mg per day. At the beginning of treatment and with each dose increase, the patient should be under the supervision of an experienced physician for at least 2 hours to ensure that the clinical condition remains stable (especially blood pressure, heart rate, myocardial conduction disorders, and worsening of heart failure symptoms). If necessary, the dose already reached can be gradually reduced again or returned to it again. If symptoms of heart failure worsen or if the drug is not tolerated during the titration phase, it is recommended to first reduce the dose of nebivolol or, if necessary, immediately discontinue it (in the event of severe hypotension, worsening of heart failure symptoms with acute pulmonary edema, cardiogenic shock, symptomatic bradycardia or atrioventricular block). As a rule, treatment of chronic heart failure with nebivolol is long-term. Treatment with nebivolol should not be stopped abruptly, as this may lead to an increase in heart failure symptoms. If drug withdrawal is necessary, the dose should be reduced gradually, reducing it by half per week.
Chronic ischemic heart disease.
Adults
Treatment of chronic coronary heart disease should begin with a gradual increase in dose until the optimal maintenance dose is determined 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 then 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 CKD.
Patients with renal insufficiency: in mild and moderate renal insufficiency, dose adjustment is not required, since dose titration is carried out individually. Experience with the drug in patients with severe renal insufficiency (serum creatinine ≥ 250 μmol/l) is limited, therefore the use of nebivolol in such patients is not recommended.
Patients with hepatic insufficiency: experience with the drug in such patients is limited, therefore nebivolol is contraindicated.
Elderly patients: since dose titration is carried out individually, dose adjustment is not required.
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: bradycardia, hypotension, bronchospasm, acute heart failure. Treatment: gastric lavage, administration of activated charcoal and laxatives. Monitoring of blood glucose levels is recommended. If necessary, intensive therapy is performed in a hospital setting: for bradycardia and increased vagotonia - administration of atropine, for hypotension and shock - intravenous administration of plasma substitutes and catecholamines. The beta-blocking effect can be stopped by slow intravenous administration of isoprenaline hydrochloride, starting with a dose of 5 μg/min, or dobutamine, starting with a dose of 2.5 μg/min until the expected effect is achieved. In refractory cases, isoprenaline can be combined with dopamine. If the above measures do not help, glucagon is prescribed at a rate of 50 - 100 mcg/kg, if necessary, the injection can be repeated within an hour and, if necessary, an intravenous infusion of glucagon at a rate of 70 mcg/kg/h. In extreme cases, artificial ventilation of the lungs and connection of an artificial pacemaker are performed.
Adverse reactions
Adverse reactions in essential hypertension and chronic heart failure are listed separately due to the differences in the underlying diseases of these conditions.
Essential hypertension.
| Organ system | Frequent (≥ 1/100 to < 1/10) | Infrequent (≥ 1/1000 to < 1/100) | Rare (< 1/10,000) |
| From the psyche | | Terrible dreams, depression | |
| From the nervous system | Headache, dizziness, paresthesia | | Syncope |
| From the organ of vision | | Vision impairment | |
| From the heart | | Bradycardia, heart failure, atrioventricular conduction delay/atrioventricular block | |
| From the vascular side | | Arterial hypotension, worsening intermittent claudication | |
| Respiratory system | Dyspnea | Bronchospasm | |
| From the digestive tract | Constipation, nausea, diarrhea | Dyspepsia, flatulence, vomiting | |
| From the skin side | | Pruritus, erythematous skin rash | Angioedema, psoriasis exacerbation |
| From the genitals | | Impotence | |
| General violations | Increased fatigue, edema | | |
Isolated cases of urticaria have been reported.
In addition, the following adverse reactions have been reported with some β-blockers: hallucinations, psychosis, confusion, coldness/cyanosis of the extremities, Raynaud's syndrome, dry eye, and practolol-like toxicity.
Chronic heart failure. The most common adverse reactions reported in patients receiving nebivolol were bradycardia and dizziness. The following adverse reactions, potentially at least partially related to the use of nebivolol, were considered characteristic and relevant in the treatment of chronic heart failure: worsening of heart failure symptoms; orthostatic hypotension; first degree atrioventricular block; lower limb edema, drug intolerance.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister; 2 (10 ´ 2), or 3 (10 ´ 3), or 6 (10 ´ 6), or 9 (10 ´ 9) blisters in a cardboard box.
Vacation category
According to the recipe.
Manufacturers
Primary and secondary packaging, control, batch release authorization:
Salutas Pharma GmbH.
Location of the manufacturer and address of its place of business.
Otto-von-Güricke-Allee 1, 39179, Barleben, Germany.
Primary and secondary packaging, control, batch release authorization:
Lek S.A.
Location of the manufacturer and address of its place of business.
Podlipie Street, 16, Stryków, 95-010, Poland.
Domaniewska St. 50 C, Warsaw, 02-672, Poland.
