Bisoprolol - astrafarm

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BISOPROLOL-ASTRAFARM (BISOPROLOL-ASTRAFARM)

Composition:

Active substance: bisoprolol;

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

Excipients: lactose monohydrate; sodium croscarmellose; microcrystalline cellulose; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, flat cylindrical tablets with bevelled edges and a score line on one side.

Pharmacotherapeutic group.

Selective β-adrenoreceptor blockers. ATC code C07AB07.

Pharmacological Properties

Pharmacodynamics

Bisoprolol is a highly selective β1-adrenoblocker. 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. Therefore, bisoprolol does not affect airway resistance or β2-mediated metabolic effects. The selectivity of bisoprolol for β1-adrenergic receptors extends beyond the therapeutic dose range.

Bisoprolol has no pronounced negative inotropic effect.

The maximum effect of bisoprolol occurs within 3–4 hours after administration. The elimination half-life from plasma is 10–12 hours, resulting in 24-hour efficacy after a single dose. The 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, increased peripheral resistance decreases. The antihypertensive effect of β-blockers is also mediated by reduction of plasma renin activity.

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

Pharmacokinetics

After oral administration, more than 90% of bisoprolol is absorbed from the gastrointestinal tract. Absorption is not affected by food intake. First-pass metabolism in the liver is minimal, contributing to high bioavailability—approximately 90%. Plasma protein binding is approximately 30%. The volume of distribution is 3.5 L/kg.

Bisoprolol is eliminated from the body via two pathways: approximately 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/hour. Due to its long elimination half-life (10–12 hours), the drug maintains therapeutic effect for 24 hours with once-daily administration.

Because the kidneys and liver contribute approximately equally to the elimination of this drug, dosage adjustment is not required in patients with renal or hepatic impairment. Bisoprolol kinetics are linear and independent of age.

Clinical characteristics.

Indications.

Arterial hypertension.

Ischemic heart disease (angina pectoris).

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

Contraindications.

• Hypersensitivity to bisoprolol or to any of the excipients;
• 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 syndrome;
• sinoatrial block;
• symptomatic bradycardia;
• symptomatic arterial hypotension;
• severe bronchial asthma or severe chronic obstructive pulmonary disease;
• advanced peripheral circulatory disorders or Raynaud's disease;
• metabolic acidosis;
• untreated pheochromocytoma.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended.

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 enhancement of 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 (e.g., clonidine, methyldopa, moxonidine, rilmenidine). Possible worsening of heart failure due to reduction in central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly following 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 enhancement of negative inotropic effect.

All indications

Calcium antagonists of the dihydropyridine group (e.g., nifedipine, 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 atrioventricular conduction.

Locally acting β-blockers (e.g., those contained in ophthalmic solutions 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-receptor blockade may mask symptoms of hypoglycemia.

Anesthetic agents. Increased risk of myocardial depression and arterial hypotension (see section "Special precautions").

Cardiac glycosides. Reduction in 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). Combination with bisoprolol 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 or 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.

Rifampicin. Slight reduction in the elimination half-life of bisoprolol, possibly due to induction of hepatic enzymes metabolizing drugs. Dose adjustment is usually not required.

Ergotamine derivatives. Exacerbation of peripheral circulatory disturbances.

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 and pathological states: type 1 diabetes mellitus, severe renal dysfunction, 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, obstructive airway diseases);
• Diabetes mellitus with marked 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.

The formulation contains lactose. Patients with known intolerance to certain sugars should consult their physician before taking this medicinal product.

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 β-blocker therapy during the perioperative period is recommended. The anesthesiologist should consider potential interactions with other drugs, which may lead to bradyarrhythmias, 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 withdrawn 48 hours before general anesthesia.

Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem group, class I antiarrhythmic agents, or centrally acting antihypertensive drugs 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 compelling reasons for therapy. If necessary, bisoprolol should be used with caution. In patients with obstructive airway diseases, treatment with bisoprolol 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 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 treatment.

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

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

Symptoms of thyrotoxicosis may be masked during bisoprolol treatment.

Use of bisoprolol may result in a positive doping test outcome.

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 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 may be used during pregnancy only if 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, the use of Bisoprolol-Astrafarm is not recommended during breastfeeding.

Ability to influence reaction rate when driving or operating machinery.

It is known that in patients with ischemic heart disease, bisoprolol does not affect the ability to drive or operate machinery.

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, when changing the dose of the drug, or when used concomitantly with alcohol.

Dosage and Administration

Tablets of Bisoprolol-AstraPharm should be swallowed whole, without chewing, in the morning on an empty stomach, during or after breakfast, with a small amount of liquid.

Hypertension; ischemic heart disease (angina pectoris).

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

If necessary, the daily dose may be increased to 10 mg (1 tablet of Bisoprolol-AstraPharm 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 a physician, depending on pulse rate and therapeutic response.

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.

Bisoprolol-AstraPharm is indicated for the 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 Bisoprolol-AstraPharm should be initiated according to the titration schedule below 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.

* At the initiation of chronic heart failure therapy, a starting dose of 2.5 mg of bisoprolol is recommended;
** Use appropriate dosage forms.

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

During the titration phase, vital signs (blood pressure, heart rate) and symptoms of worsening heart failure must be closely monitored. Symptoms may develop from the first day of treatment.

Modifications of therapy.

If the maximum recommended dose is poorly tolerated, a 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 dose reduction of bisoprolol or, possibly, interruption of treatment. After patient stabilization, re-initiation of bisoprolol therapy should always be considered.

Treatment with the drug should not be discontinued abruptly, especially in patients with ischemic heart disease, as this may lead to clinical deterioration. 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 bisoprolol therapy is prolonged and depends on the nature and severity of the disease.

Patients with hepatic and/or renal impairment.

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 of Bisoprolol-AstraPharm once daily. Limited data are available on the use of bisoprolol in patients on dialysis. No dosage adjustment is necessary.

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

Elderly patients do not require dose adjustment.

Children.

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

Overdose.

Symptoms.

Cases of overdose (e.g., administration of a daily dose of 15 mg instead of 7.5 mg) have been associated with 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 (maximum dose reported: 2000 mg) have been documented. Bradycardia and/or arterial hypotension were observed. All patients recovered. There is considerable variability in individual 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 "Dosage and Administration").

Treatment.

In case of overdose, seek immediate medical attention.

Discontinue bisoprolol and initiate supportive and symptomatic therapy. 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 atropine. If no response, administer isoprenaline or another agent with positive chronotropic effect cautiously. In exceptional cases, transvenous pacemaker insertion may be required.
• In arterial hypotension: intravenous fluid administration and vasoconstrictors. Intravenous glucagon may be beneficial.
• In second- or third-degree atrioventricular block: close monitoring, infusion of isoprenaline, or transvenous pacemaker insertion.
• In acute exacerbation of chronic heart failure: intravenous diuretics, inotropic agents, and vasodilators.
• In bronchospasm: bronchodilators (e.g., isoprenaline), β2-adrenergic agonists, and/or aminophylline.
• In hypoglycemia: intravenous glucose.

Adverse Reactions.

Cardiovascular system: bradycardia (in patients with chronic heart failure), signs of worsening heart failure (in patients with chronic heart failure), atrioventricular conduction disturbances, bradycardia (in patients with arterial hypertension or ischemic heart disease), signs of worsening heart failure (in patients with arterial hypertension or ischemic heart disease), sensation of cold or numbness in extremities, arterial hypotension (in patients with arterial hypertension or ischemic heart disease), orthostatic hypotension (in patients with chronic heart failure).

Nervous system: dizziness*, headache*, syncope/loss of consciousness.

Eye disorders: reduced tear production (should be considered in contact lens wearers), conjunctivitis.

Ear disorders: hearing impairment.

Respiratory system: bronchospasm in patients with bronchial asthma or a history of obstructive airway diseases, allergic rhinitis.

Gastrointestinal tract: nausea, vomiting, diarrhea, constipation.

Skin: hypersensitivity reactions including itching, redness, rash; alopecia. During treatment with β-blockers, worsening of psoriasis may occur, manifesting as psoriatic rash.

Musculoskeletal system: muscle weakness, cramps.

Hepatobiliary system: hepatitis.

Reproductive system: erectile dysfunction.

Psychiatric disorders: depression, sleep disturbances, nightmares, hallucinations.

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

General disorders: asthenia (in patients with chronic heart failure), fatigue*; asthenia uncommonly (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 disappear within the first 1–2 weeks.

In case of adverse events or unwanted reactions, inform your doctor immediately.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister; 2, 3, 6, or 9 blisters per box.

Prescription status.

Prescription only.

Manufacturer.

LLC "ASTRAFARM".

Manufacturer's address and location of business activity.

6 Kyivska St., Vyshneve, Kyiv-Sviatoshyn District, Kyiv Oblast, 08132, Ukraine.