Bisoprol®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BISOPROL® (BISOPROL)

Composition:

Active substance: bisoprolol;

One tablet contains 2.5 mg of bisoprolol fumarate, calculated as 100 % substance;

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, biconvex tablets, with or without a score line. Marbling on the tablet surface is permissible.

Pharmacotherapeutic group. Selective β-adrenoreceptor blockers.

ATC code C07AB07.

Pharmacological Properties.

Pharmacodynamics.

Bisoprolol is a highly selective β1-adrenoblocker. When administered in 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 (HR), cardiac output, and arterial pressure, and improves myocardial oxygen supply by reducing end-diastolic pressure and prolonging diastole. The drug has very low affinity for β2-receptors of bronchial and vascular smooth muscle, as well as for β2-receptors of the endocrine system. Bisoprolol rarely affects bronchial and peripheral arterial smooth muscle or glucose metabolism.

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/h. Due to its long elimination half-life (10–12 hours), the drug maintains its therapeutic effect for 24 hours when administered once daily.

Linearity. Bisoprolol pharmacokinetics are linear, and its parameters do not depend on 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 functional class III chronic heart failure, plasma bisoprolol levels are higher and elimination half-life is prolonged compared to healthy volunteers. The steady-state plasma concentration is 64 ± 21 ng/mL at a daily dose of 10 mg, with an elimination half-life 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;
• advanced stages of peripheral circulatory disorders or Raynaud's disease;
• untreated pheochromocytoma;
• metabolic acidosis;
• hypersensitivity to bisoprolol or to any of the excipients.

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 enhanced 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, especially following discontinuation of β-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 negative inotropic effects on myocardial function in patients with heart failure cannot be excluded.
• Class III antiarrhythmic agents (e.g., amiodarone): possible potentiation of effects on atriovent游戏副本

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 chronic heart failure in patients with the following conditions: type 1 diabetes mellitus, severe renal impairment, severe hepatic impairment, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant valvular heart disease, or myocardial infarction within the past 3 months.

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

• Bronchospasm (in bronchial asthma or 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-adrenoreceptor blockers. In patients undergoing general anesthesia, β-blockers reduce the incidence of arrhythmias and myocardial ischemia during induction, intubation, and the postoperative period. Continuing beta-blocker therapy during the perioperative period is recommended. The anesthesiologist should consider potential interactions with other drugs that may lead to bradyarrhythmias, reflex tachycardia, and reduced compensatory reflex mechanisms in response to 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 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, bisoprolol 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 assessment of benefit versus risk.

In patients with pheochromocytoma, bisoprolol should be administered only 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 pregnancy and/or fetal/newborn development. Generally, β-adrenoblockers reduce placental blood flow, which may lead to intrauterine growth retardation, intrauterine death, spontaneous abortion, or premature 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 expected within the first 3 days of life.

Lactation period. There are no data on the excretion of bisoprolol into 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 a car in patients with ischemic heart disease.

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

Method of Administration and Dosage

The drug Bisoprol® should be taken whole, in the morning with breakfast, washed down 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 beginning of bisoprolol treatment, the patient should not show signs of exacerbation. Transient worsening of heart failure, arterial hypotension, or bradycardia may occur during the titration period and after its completion.

Dosage Titration Period

Treatment of chronic heart failure with bisoprolol should be initiated according to the following titration schedule and may be adjusted depending 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.

Modification of Treatment

If the maximum recommended dose is poorly tolerated, gradual dose reduction may be necessary. If worsening of heart failure, arterial hypotension, or bradycardia occurs during or after the titration period, dosage adjustment is recommended, which may require temporary reduction of bisoprolol dose or interruption of treatment. After stabilization of the patient's condition, 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 tapered gradually by slowly reducing the dose.

Patients with Hepatic or Renal Impairment

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

Elderly Patients do not require dose adjustment.

Children

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

Overdose

Symptoms

Cases of atrioventricular block of grade III, bradycardia, and dizziness have been reported following overdose (e.g., daily dose of 15 mg 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 bisoprolol overdose have been reported to date (maximum dose – 2000 mg), with manifestations including bradycardia or arterial hypotension. All patients recovered. There is considerable 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").

In case of overdose, immediate medical attention is required.

Treatment

In case 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:

For 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.

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

For atrioventricular block of grade II or III: close monitoring and infusion of isoprenaline or transvenous insertion of a cardiac pacemaker.

For worsening of chronic heart failure: intravenous diuretics, inotropic agents, and vasodilators.

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

For 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).

Cardiovascular system.

Very common: bradycardia.

Common: worsening of heart failure, sensation of cold or numbness in extremities, arterial hypotension.

Uncommon: atrioventricular conduction disturbances, bradycardia*, worsening of heart failure*, orthostatic hypotension, arterial hypotension*.

Nervous system.

Common: dizziness*, headache*.

Rare: syncope.

Eye disorders.

Rare: decreased lacrimation (should be considered in contact lens wearers).

Very rare: conjunctivitis.

Ear disorders.

Rare: hearing impairment.

Respiratory system.

Uncommon: bronchospasm in patients with bronchial 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. Treatment with ß-blockers may worsen the condition of patients with psoriasis, 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*.

Uncommon: asthenia*.

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

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

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

Keep out of reach of children.

Packaging. 10 tablets in a blister. 2, 3 or 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.