Bisoprolol-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BISOPROLOL-ZDOROVYE (BISOPROLOL-ZDOROVYE)

Composition:

Active substance: bisoprolol;

Each tablet contains 5 mg or 10 mg of bisoprolol fumarate;

Excipients: anhydrous calcium hydrogen phosphate; microcrystalline cellulose; corn starch; crospovidone; anhydrous colloidal silicon dioxide; magnesium stearate; dry mixture "Opadry white" containing titanium dioxide (E 171), hypromellose, triacetin; Yellow FCF, Orange Yellow S (E 110), tartrazine (E 102).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated, round, biconvex tablets, light yellow to yellow in color (5 mg tablets), light orange to orange with a pinkish tint (10 mg tablets).

Pharmacotherapeutic group. Selective beta-adrenoreceptor blockers. ATC code C07AB07.

Pharmacological properties.

Pharmacodynamics. Bisoprolol is a highly selective β1-adrenoceptor blocker. It has no intrinsic sympathomimetic activity and no clinically significant membrane-stabilizing properties. The drug has very low affinity for β2-receptors of bronchial and vascular smooth muscle, as well as for β2-receptors involved in metabolic regulation. Thus, bisoprolol does not affect airway resistance or β2-mediated metabolic effects. The β1-adrenoceptor selectivity of bisoprolol extends beyond the therapeutic dose range.

Bisoprolol has no pronounced negative inotropic effect.

The maximum effect of bisoprolol occurs 3–4 hours after oral administration. The plasma elimination half-life (T½) is 10–12 hours, resulting in 24-hour efficacy after a single dose. Maximum antihypertensive effect is achieved within 2 weeks of treatment.

In intensive therapy of patients with ischemic heart disease without chronic heart failure, bisoprolol reduces cardiac output and myocardial oxygen demand by decreasing heart rate and stroke volume. With long-term therapy, elevated peripheral resistance decreases. The antihypertensive effect of β-blockers is also mediated by reduced plasma renin activity.

Bisoprolol suppresses the response to sympathetic-adrenergic activity by blocking cardiac β1-receptors. This leads to a reduction in heart rate and myocardial contractility, thereby decreasing myocardial oxygen demand. This mechanism provides the desired therapeutic effect in patients with angina pectoris and ischemic heart disease.

Pharmacokinetics.

Absorption. After oral administration, more than 90% of bisoprolol is absorbed from the gastrointestinal tract. Absorption is not affected by food intake. The first-pass effect is ≤ 10%. Bioavailability is approximately 90%.

Distribution. Volume of distribution is 3.5 L/kg. Plasma protein binding is approximately 30%.

Metabolism and elimination. Bisoprolol is eliminated from the body via two pathways: 50% is metabolized in the liver into inactive metabolites and excreted by the kidneys, and 50% is excreted unchanged by the kidneys. Total bisoprolol clearance is 15 L/h. Due to its long half-life (10–12 hours), the drug maintains therapeutic effect for 24 hours with once-daily administration.

Linearity. Bisoprolol pharmacokinetics are linear and independent of age.

Special patient groups. Since bisoprolol is eliminated equally by the kidneys and liver, dosage adjustment is not required in patients with hepatic or renal impairment. Pharmacokinetics in patients with stable chronic heart failure and hepatic or renal dysfunction have not been studied. In patients with NYHA class III chronic heart failure, plasma bisoprolol levels are higher and T½ is longer compared to healthy volunteers. The steady-state plasma concentration is 64±21 ng/mL at a daily dose of 10 mg, with a T½ of 17±5 hours.

Clinical characteristics.

Indications.

• Arterial hypertension;
• Ischemic heart disease (angina pectoris);
• Chronic heart failure with systolic dysfunction of the left ventricle, in combination with ACE inhibitors, diuretics, and if necessary, cardiac glycosides.

Contraindications.

• Acute heart failure or decompensated heart failure requiring inotropic therapy;
• Cardiogenic shock;
• Second- or third-degree atrioventricular block (except in patients with a pacemaker);
• Sinus node dysfunction;
• Sinoatrial block;
• Symptomatic bradycardia;
• Symptomatic arterial hypotension;
• Severe bronchial asthma;
• Advanced stages of peripheral circulatory disorders or Raynaud's disease;
• Untreated pheochromocytoma;
• Metabolic acidosis;
• Hypersensitivity to bisoprolol or other components of the drug.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended for use.

Treatment of chronic heart failure.

Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): possible potentiation of effects on atrioventricular conduction and enhanced negative inotropic effect.

All indications.

Calcium antagonists (verapamil group, and to a lesser extent, diltiazem): negative effect on myocardial contractility and atrioventricular conduction. Intravenous administration of verapamil in patients receiving β-blockers may lead to severe arterial hypotension and atrioventricular block.

Centrally-acting antihypertensive agents (clonidine, methyldopa, moxonidine, rilmenidine): possible worsening of heart failure due to reduction in central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Sudden withdrawal of these agents, especially if preceded by discontinuation of β-blockers, may increase the risk of rebound hypertension.

Combinations to be used with caution.

Treatment of arterial hypertension or ischemic heart disease (angina pectoris).

Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): possible potentiation of effects on atrioventricular conduction and enhanced negative inotropic effect.

All indications.

Dihydropyridine-type calcium antagonists (e.g., nifedipine, felodipine, amlodipine): possible increased risk of arterial hypotension. An increased negative effect on myocardial inotropic function in patients with heart failure cannot be excluded.

Class III antiarrhythmic agents (e.g., amiodarone): possible potentiation of effects on atrioventricular conduction.

Locally-acting β-blockers (e.g., those contained in eye drops for glaucoma treatment): possible enhancement of systemic effects of bisoprolol.

Parasympathomimetics: possible prolongation of atrioventricular conduction time and increased risk of bradycardia.

Insulin and oral hypoglycemic agents: enhanced hypoglycemic effect. β-Adrenoceptor blockade may mask symptoms of hypoglycemia.

Anesthetic agents: increased risk of myocardial depression and arterial hypotension (see section "Special precautions for use").

Cardiac glycosides: reduced heart rate, prolonged atrioventricular conduction time.

Nonsteroidal anti-inflammatory drugs (NSAIDs): possible attenuation of the antihypertensive effect of bisoprolol.

β-Sympathomimetics (e.g., orciprenaline, isoprenaline, dobutamine): concomitant use may reduce the therapeutic effect of both agents. Higher doses of adrenaline may be required to treat allergic reactions.

Sympathomimetics activating both α- and β-adrenoceptors (e.g., adrenaline, noradrenaline): possible manifestation of α-adrenoceptor-mediated vasoconstrictive effects, leading to increased blood pressure and worsening of intermittent claudication. Such interaction is more likely with non-selective β-blockers.

Concomitant use with antihypertensive agents and drugs with hypotensive effects (e.g., tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of arterial hypotension.

Possible combinations.

Mefloquine: possible increased risk of bradycardia.

MAO inhibitors (except MAO-B inhibitors): enhanced hypotensive effect of β-blockers, but risk of hypertensive crisis exists.

Special precautions for use.

Treatment of stable chronic heart failure with bisoprolol should be initiated with a titration phase.

In patients with ischemic heart disease, treatment should not be stopped abruptly unless absolutely necessary, as this may lead to transient worsening of the condition. Initiation and discontinuation of bisoprolol therapy require regular monitoring.

Currently, there is insufficient therapeutic experience in treating heart failure in patients with the following conditions and pathological states: type 1 diabetes (insulin-dependent), severe renal impairment, severe hepatic impairment, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant acquired valvular heart diseases, myocardial infarction within the last 3 months.

The drug should be used with caution in patients with the following conditions:

• Bronchospasm (in bronchial asthma, obstructive airway diseases);
• Diabetes mellitus with significant fluctuations in blood glucose levels; in such cases, symptoms of hypoglycemia (tachycardia, palpitations, sweating) may be masked;
• Strict diet;
• Desensitization therapy. Like other β-blockers, bisoprolol may enhance sensitivity to allergens and increase the severity of anaphylactic reactions. In such cases, treatment with adrenaline may not always produce a positive therapeutic effect;
• First-degree atrioventricular block;
• Prinzmetal's angina;
• Peripheral arterial occlusive diseases (symptoms may worsen at the beginning of therapy);
• General anesthesia.

In patients scheduled for general anesthesia, the use of β-blockers reduces the incidence of arrhythmias and myocardial ischemia during induction, intubation, and the postoperative period. It is recommended to continue β-blocker therapy during the perioperative period. The anesthesiologist must be informed about the use of β-adrenoreceptor blockers, as the physician must consider potential interactions with other drugs that could lead to bradyarrhythmia, reflex tachycardia, and reduced capacity of reflex mechanisms to compensate for blood loss. If bisoprolol must be discontinued prior to surgery, the dose should be gradually reduced and the drug discontinued 48 hours before general anesthesia.

Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem group, antiarrhythmic drugs of class I, or centrally acting antihypertensive agents is not recommended (see section "Interaction with other medicinal products and other types of interactions").

Although cardioselective β-blockers (β1) have less effect on lung function compared to non-selective β-blockers, their use, like all β-blockers, should be avoided in obstructive airway diseases unless there are compelling reasons for therapy. If use is necessary, the drug should be administered with caution. In patients with obstructive airway diseases, bisoprolol therapy should be initiated at the lowest possible dose, and patients should be monitored for the emergence of new symptoms (such as dyspnea, exercise intolerance, cough).

In bronchial asthma or other chronic obstructive lung diseases that may cause symptoms, concomitant therapy with bronchodilators is indicated. In some cases, patients with bronchial asthma may require higher doses of β2-sympathomimetics due to increased airway resistance during treatment.

β-blockers (e.g., bisoprolol) should be prescribed to patients with psoriasis (including in medical history) only after careful benefit-risk assessment.

In patients with pheochromocytoma, the drug should be prescribed only after initiation of α-adrenoblocker therapy. Symptoms of thyrotoxicosis may be masked during treatment. Use of the drug may result in a positive doping test outcome.

The drug contains dyes: Yellow West FCF, Orange Yellow S (E 110), Tartrazine (E 102), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy. Bisoprolol has pharmacological properties that may have harmful effects on pregnancy and/or fetal/neonatal development. Generally, β-adrenoblockers reduce placental blood flow, which may lead to intrauterine growth retardation, intrauterine fetal death, spontaneous abortion, or preterm labor. Adverse effects in the fetus and newborn (e.g., hypoglycemia, bradycardia) may occur. If β-blocker therapy is necessary, a β1-selective adrenoblocker is preferred.

The drug should be used during pregnancy only when the expected benefit to the mother outweighs the potential risk to the fetus. Uteroplacental blood flow and fetal growth should be monitored. If harmful effects on pregnancy or the fetus occur, alternative treatment should be considered.

After delivery, the newborn should be under close observation. Hypoglycemia and bradycardia should be anticipated during the first 3 days of life.

Lactation period. There are no data on the excretion of bisoprolol in human breast milk; therefore, the drug is not recommended during breastfeeding.

Ability to affect reaction rate when driving or operating machinery. In clinical studies involving patients with ischemic heart disease, the drug did not affect the ability to drive a car. However, in individual cases, the drug may impair the ability to drive or operate complex machinery. Particular attention should be paid at the beginning of treatment, when changing the dose, or when used concomitantly with alcohol.

Method of Administration and Dosage

The drug should be taken without chewing, in the morning on an empty stomach, during or after breakfast, with a small amount of liquid.

Arterial hypertension; ischemic heart disease (angina pectoris).

Treatment should be initiated gradually with low doses, followed by dose escalation. The recommended dose is 5 mg (1 tablet of 5 mg) once daily. For mild hypertension (diastolic pressure up to 105 mm Hg), a dose of 2.5 mg is suitable.

If necessary, the daily dose may be increased to 10 mg (1 tablet of 10 mg) once daily. Further dose increases are justified only in exceptional cases. The maximum recommended dose is 20 mg once daily.

Dose adjustments should be determined individually by the physician based on pulse rate and therapeutic benefit.

Chronic heart failure with left ventricular systolic dysfunction, in combination with ACE inhibitors, diuretics, and, if necessary, cardiac glycosides.

Standard therapy for chronic heart failure includes ACE inhibitors (or angiotensin receptor blockers in case of ACE inhibitor intolerance), β-blockers, diuretics, and, if necessary, cardiac glycosides.

The drug is indicated for treatment of patients with chronic heart failure without signs of acute decompensation.

Treatment must be initiated and supervised by a physician experienced in managing chronic heart failure.

Treatment of stable chronic heart failure with this drug should be initiated according to the titration schedule below and adjusted based on individual patient response.

• 1.25 mg* bisoprolol fumarate once daily for 1 week; if well tolerated, increase to
• 2.5 mg* bisoprolol fumarate once daily for the next 1 week; if well tolerated, increase to
• 3.75 mg* bisoprolol fumarate once daily for the next 1 week; if well tolerated, increase to
• 5 mg bisoprolol fumarate once daily for the next 4 weeks; if well tolerated, increase to
• 7.5 mg bisoprolol fumarate once daily for the next 4 weeks; if well tolerated, increase to
• 10 mg bisoprolol fumarate once daily as maintenance therapy.

* At the beginning of therapy for chronic heart failure, it is recommended to use Bisoprolol-Zdorovia, film-coated tablets, 2.5 mg.

The maximum recommended dose of bisoprolol fumarate is 10 mg once daily.

During the titration phase, close monitoring of vital signs (arterial pressure, heart rate) and symptoms of worsening heart failure is required. Symptoms may develop from the first day of treatment.

Modification of treatment. If the maximum recommended dose is poorly tolerated, gradual dose reduction may be considered. If progressive worsening of heart failure, arterial hypotension, or bradycardia occurs during or after the titration phase, dose adjustment is recommended, which may require temporary reduction of bisoprolol dose or, possibly, interruption of treatment. After stabilization of the patient's condition, re-initiation of bisoprolol therapy should always be considered.

The drug should not be discontinued abruptly, especially in patients with ischemic heart disease, as this may lead to worsening of the patient's condition. If discontinuation is necessary, therapy should be tapered gradually by reducing the dose (e.g., halving the dose weekly).

Treatment of stable chronic heart failure is usually long-term.

The duration of treatment is prolonged and depends on the nature and severity of the disease.

Patients with hepatic and/or renal impairment.

Arterial hypertension; ischemic heart disease. Dose adjustment is generally not required in patients with mild to moderate hepatic or renal impairment. In patients with severe renal impairment (creatinine clearance <20 mL/min) or severe hepatic impairment, the dose should not exceed 10 mg daily. Limited data are available on the use of bisoprolol in dialysis patients. No dosage adjustment is necessary.

Chronic heart failure. There are no pharmacokinetic data on bisoprolol in patients with chronic heart failure and concomitant hepatic or renal impairment; therefore, dose escalation should be performed cautiously.

Elderly patients do not require dose adjustment.

Children. Clinical data on the efficacy and safety of the drug in pediatric patients are lacking; therefore, the drug should not be used in this patient population.

Overdose. Symptoms. Cases of atrioventricular block of degree III, bradycardia, and dizziness have been reported following overdose (e.g., administration of 15 mg daily instead of 7.5 mg). The most common signs of β-blocker overdose are bradycardia, arterial hypotension, acute heart failure, hypoglycemia, and bronchospasm. Several cases of overdose have been reported in patients with arterial hypertension and/or ischemic heart disease (maximum dose – 2000 mg of bisoprolol), with manifestations including bradycardia and/or arterial hypotension. All patients recovered. There is wide individual variability in sensitivity to a single high dose of bisoprolol; patients with heart failure may be more sensitive to the drug. Therefore, treatment should be initiated with gradual dose escalation (see section "Method of Administration and Dosage").

Treatment. In case of overdose, drug administration should be discontinued and supportive and symptomatic therapy should be initiated. Limited data suggest that bisoprolol is poorly dialyzable. In suspected overdose, based on expected pharmacological effects and recommendations for other β-blockers, the following general measures should be considered:

In bradycardia: intravenous administration of atropine. If no response, isoprenaline or another agent with positive chronotropic effect should be administered cautiously. In exceptional cases, transvenous insertion of a temporary pacemaker may be required.

In arterial hypotension: intravenous fluid administration and vasoconstrictors. Intravenous glucagon may be beneficial.

In atrioventricular block of degree II or III: careful monitoring, infusion of isoprenaline, or transvenous cardiac pacing.

In acute exacerbation of chronic heart failure: intravenous administration of diuretics, inotropic agents, and vasodilators.

In bronchospasm: bronchodilators (e.g., isoprenaline), β2-adrenergic agonists, and/or aminophylline.

In hypoglycemia: intravenous glucose administration.

Adverse reactions.

Undesirable effects are classified by frequency of occurrence into the following categories: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10,000 and < 1/1000), very rare (< 1/10,000), not known (frequency cannot be determined from available data).

Cardiac disorders: very common – bradycardia (in patients with chronic heart failure); common – signs of worsening heart failure (in patients with chronic heart failure); uncommon – atrioventricular conduction disorders, bradycardia (in patients with arterial hypertension or ischemic heart disease), signs of worsening heart failure (in patients with arterial hypertension or ischemic heart disease).

Nervous system disorders: common – dizziness*, headache*; rare – syncope.

Eye disorders: rare – reduced tear production (should be considered in contact lens wearers); very rare – conjunctivitis.

Ear and labyrinth disorders: rare – hearing impairment.

Respiratory system disorders: uncommon – bronchospasm in patients with bronchial asthma or obstructive respiratory diseases in medical history; rare – allergic rhinitis.

Gastrointestinal disorders: common – nausea, vomiting, diarrhea, constipation.

Skin and subcutaneous tissue disorders: rare – hypersensitivity reactions including pruritus, erythema, rash; very rare – alopecia. During treatment with β-blockers, worsening of psoriasis, manifesting as psoriatic rash, may occur.

Musculoskeletal and connective tissue disorders: uncommon – muscle weakness, cramps.

Hepatic disorders: rare – hepatitis.

Vascular disorders: common – cold sensation or numbness in extremities, arterial hypotension (in patients with chronic heart failure); uncommon – orthostatic hypotension (in patients with chronic heart failure), arterial hypotension (in patients with arterial hypertension or ischemic heart disease).

Reproductive system disorders: rare – erectile dysfunction.

Psychiatric disorders: uncommon – depression, sleep disturbances; rare – nightmares, hallucinations.

Laboratory findings: rare – increased blood triglyceride levels, increased plasma liver enzyme activity (AST, ALT).

General disorders: common – asthenia (in patients with chronic heart failure), fatigue*; uncommon – asthenia (in patients with arterial hypertension or ischemic heart disease).

* Applies only to patients with arterial hypertension or ischemic heart disease. These symptoms usually occur at the beginning of therapy, are mild, and resolve within the first 1–2 weeks.

Shelf life. 2 years.

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

Keep out of reach of children.

Packaging. Tablets, 10×3 in blisters in a box.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Manufacturer's address and place of business.

22 Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.