Bisoprolol-zdorovya

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

Composition:

Active substance: bisoprolol;

One tablet contains 2.5 mg of bisoprolol fumarate;

Excipients: calcium hydrogen phosphate anhydrous; microcrystalline cellulose; maize starch; crospovidone; colloidal anhydrous silicon dioxide; magnesium stearate; dry mixture "Opadry white" containing titanium dioxide (E 171), hypromellose, triacetin.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated, round, biconvex tablets, white or almost white in color.

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

Pharmacological Properties

Pharmacodynamics

Bisoprolol is a highly selective β1-adrenoblocker. When administered at therapeutic doses, it has no intrinsic sympathomimetic activity and no clinically significant membrane-stabilizing properties. It exerts antianginal and antihypertensive effects. It reduces myocardial oxygen demand by decreasing heart rate, cardiac output, and arterial blood pressure, while enhancing myocardial oxygen supply by reducing end-diastolic pressure and prolonging diastole. The drug has very low affinity for β2-receptors in bronchial and vascular smooth muscle, as well as for β2-receptors of the endocrine system. Therefore, it affects bronchial and peripheral arterial smooth muscle and glucose metabolism only in rare cases.

Pharmacokinetics

Absorption. 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 clearance of bisoprolol is 15 L/hour. Due to its long elimination half-life (T½) of 10–12 hours, the drug maintains its 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 liver and kidneys, dosage adjustment is not required in patients with impaired liver or kidney function. Pharmacokinetics in patients with stable chronic heart failure or with hepatic or renal impairment have not been fully studied. In patients with NYHA Class III chronic heart failure, plasma bisoprolol levels are higher and T½ is prolonged 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. Treatment of chronic heart failure with left ventricular systolic dysfunction in combination with ACE inhibitors, diuretics, and, if necessary, cardiac glycosides.

Contraindications.

• Acute heart failure or decompensated heart failure requiring intravenous inotropic therapy;
• cardiogenic shock;
• second- or third-degree atrioventricular block;
• sick sinus syndrome;
• sinoatrial block;
• symptomatic bradycardia;
• symptomatic arterial hypotension;
• severe form of bronchial asthma;
• severe form of peripheral arterial obstructive diseases or Raynaud's disease;
• untreated phaeochromocytoma;
• metabolic acidosis;
• hypersensitivity to bisoprolol or to any of the excipients of the drug.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended for use.

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 marked hypotension and atrioventricular block.

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

Antihypertensive agents with central mechanism of action (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, particularly following discontinuation of β-adrenoceptor blockers, may increase the risk of rebound hypertension.

Combinations that should be used with caution.

Dihydropyridine calcium antagonists (e.g., felodipine, amlodipine): possible increased risk of arterial hypotension. A potential increase in the 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: reduced reflex tachycardia and increased risk of arterial hypotension.

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

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

β-sympathomimetics (e.g., isoprenaline, dobutamine): possible reduction in the therapeutic effect of both agents.

Sympathomimetics activating both α- and β-adrenoceptors (e.g., adrenaline, noradrenaline): possible manifestation of α-adrenoceptor-mediated vasoconstrictive effect, 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): increased antihypertensive 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 abruptly discontinued 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 chronic heart failure in patients with the following conditions and pathological states: type 1 diabetes, severe renal impairment, severe hepatic impairment, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant valvular heart disease, 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; symptoms of hypoglycemia 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.

It is essential to inform the anesthesiologist about the use of β-blockers. 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 should consider the potential interaction with other drugs, which may 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, with class I antiarrhythmic drugs, or with centrally acting antihypertensive agents is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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 strong indications for therapy. If necessary, the drug should be used 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 (e.g., dyspnea, exercise intolerance, cough).

In patients with bronchial asthma or other chronic obstructive lung diseases, 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 bisoprolol treatment.

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

In patients with pheochromocytoma, bisoprolol should only be prescribed after initiation of α-adrenoblocker therapy.

Symptoms of thyrotoxicosis may be masked during bisoprolol treatment.

Use during pregnancy or breastfeeding.

Pregnancy. Bisoprolol has pharmacological properties that may cause harmful effects on the course of 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 delivery. 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.

Bisoprolol 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 therapy 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 breast milk; therefore, bisoprolol is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery. In clinical studies, the drug did not affect the ability to drive in patients with ischemic heart disease.

In individual cases, the drug may affect the ability to drive or operate complex machinery. Particular attention should be paid at the beginning of treatment, during dose adjustments, or when combined with alcohol.

Method of Administration and Dosage.

The drug should be taken without chewing, in the morning with breakfast, swallowing with a small amount of liquid.

Standard therapy for chronic heart failure includes ACE inhibitors or angiotensin II antagonists, β-blockers, diuretics, and, if necessary, cardiac glycosides.

At the start of bisoprolol treatment, the patient should not show signs of exacerbation. Transient worsening of heart failure, arterial hypotension, or bradycardia may occur during and after the titration period.

Dosage Titration Period. Treatment of chronic heart failure with bisoprolol should begin according to the following titration schedule and may be adjusted based on individual patient response.

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

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

Close monitoring of vital signs (arterial pressure, heart rate) and symptoms of worsening heart failure is required during the titration period. Symptoms may develop from the first day of treatment initiation.

Modifications in Treatment.

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

Treatment of stable chronic heart failure with bisoprolol is long-term.

Treatment should not be discontinued abruptly or dosage changed without consulting a physician, as this may lead to worsening of the patient's condition. If discontinuation is necessary, treatment should be terminated gradually by slowly reducing the dose.

Patients with Hepatic or Renal Impairment.

There are no pharmacokinetic data available for bisoprolol in patients with chronic heart failure combined with hepatic or renal impairment; therefore, dose escalation must be performed with particular caution.

Elderly Patients do not require dose adjustment.

Children. Clinical data on efficacy and safety of the drug in pediatric patients are lacking; therefore, bisoprolol is not recommended for use in pediatric practice.

Overdose. Cases of overdose (e.g., administration of a daily dose of 15 mg instead of 7.5 mg) have been reported, resulting in third-degree atrioventricular block, bradycardia, and dizziness. The most common signs of β-blocker overdose include bradycardia, arterial hypotension, acute heart failure, hypoglycemia, and bronchospasm. Several cases of bisoprolol overdose have been reported to date (maximum dose – 2000 mg), with manifestations including bradycardia or arterial hypotension. All patients recovered. There is wide variability in individual sensitivity to a single high dose of bisoprolol, and 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").

In case of overdose, immediate medical attention is required.

In the event of overdose, bisoprolol treatment should be discontinued and supportive and symptomatic therapy 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 case of bradycardia: intravenous administration of atropine. If no response, cautiously administer isoprenaline or another agent with positive chronotropic effect. In exceptional cases, transvenous insertion of a temporary pacemaker may be required.

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

In case of second- or third-degree atrioventricular block: close monitoring and infusion of isoprenaline or transvenous pacemaker insertion.

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

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

In case of hypoglycemia: intravenous glucose administration.

Side effects.

Adverse reactions are classified by frequency of occurrence as follows: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10000 and < 1/1000), very rare (< 1/10000).

Cardiovascular system: very common – bradycardia; common – worsening of heart failure, sensation of cold or numbness in extremities, arterial hypotension; uncommon – atrioventricular conduction disturbances, orthostatic hypotension.

Nervous system: common – dizziness, headache; rare – fainting.

Eye disorders: rare – decreased tear production (should be considered when wearing contact lenses); very rare – conjunctivitis.

Ear disorders: rare – hearing impairment.

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

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

Skin: rare – hypersensitivity reactions (itching, erythema, rash); very rare – alopecia. During treatment with β-blockers, worsening of psoriasis may occur, manifesting as psoriatic rash.

Musculoskeletal system: uncommon – muscle weakness, cramps.

Liver: rare – hepatitis.

Reproductive system: 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, fatigue.

Shelf life. 2 years.

Storage conditions. Store in 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 category. Prescription only.

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

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, building 22.