Biprolol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BIPROLOL (BIPROLOL)

Composition:

Active substance: bisoprolol fumarate;

1 tablet contains 5 mg or 10 mg of bisoprolol fumarate (calculated as 100% anhydrous substance);

Excipients: microcrystalline cellulose, crospovidone, iron oxide yellow (E 172), iron oxide red (E 172) (in the composition of the 10 mg tablet), lactose monohydrate, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets: round-shaped, light yellow tablets with speckles, biconvex surface, with a score line;

10 mg tablets: round-shaped, beige to beige with an orange tint, with speckles, biconvex surface, with a score line.

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

Pharmacological Properties

Pharmacodynamics

Bisoprolol is a selective β1-adrenoceptor blocker. When administered at therapeutic doses, it does not exhibit intrinsic sympathomimetic activity and has no clinically significant membrane-stabilizing properties. It exerts an antianginal effect by reducing myocardial oxygen demand through decreasing heart rate (HR) and cardiac output, as well as lowering arterial blood pressure. It also enhances myocardial oxygen supply by reducing end-diastolic pressure and prolonging diastole.

It produces a hypotensive effect by reducing cardiac output, inhibiting renal renin secretion, and affecting baroreceptors in the aortic arch and carotid sinus. With prolonged use, bisoprolol primarily reduces elevated peripheral vascular resistance. In chronic heart failure, it suppresses the activated sympathetic-adrenal and renin-angiotensin-aldosterone systems. It has very low affinity for β2-receptors in bronchial and vascular smooth muscle, as well as in the endocrine system. The drug rarely affects bronchial and peripheral arterial smooth muscle tone or glucose metabolism. After single administration, the effect lasts up to 24 hours.

Pharmacokinetics

Absorption. After oral administration, the drug is well absorbed from the gastrointestinal tract. Bioavailability is approximately 90% and is not affected by food intake. Maximum plasma concentration (Cmax) is reached within 1–3 hours after administration. Plasma protein binding is approximately 30%.

Metabolism and Elimination. The first-pass effect in the liver is minimal (less than 10%). Approximately 50% of the dose undergoes hepatic biotransformation into inactive metabolites. About 98% of the drug is excreted by the kidneys, with 50% eliminated unchanged and the remainder as metabolites; approximately 2% of the dose is excreted via the intestines. The elimination half-life is 10–12 hours.

Bisoprolol pharmacokinetics are linear, and its parameters are independent of age.

Dose adjustment is not required in patients with mild to moderate hepatic or renal impairment.

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.

• Hypersensitivity to bisoprolol or to any of the excipients;
• Acute heart failure or decompensated heart failure requiring intravenous inotropic therapy;
• Cardiogenic shock;
• Second- or third-degree AV block (except in patients with a permanent pacemaker);
• Sick sinus syndrome;
• Marked sinoatrial block;
• Symptomatic bradycardia (heart rate less than 50 beats/min before initiation of treatment);
• Symptomatic arterial hypotension (systolic blood pressure below 90 mm Hg);
• Severe forms of peripheral circulatory disorders or Raynaud's disease;
• Severe form of bronchial asthma;
• Metabolic acidosis;
• Untreated phaeochromocytoma.

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations.

Floctafene: β-blockers may interfere with compensatory cardiovascular responses to hypotension or shock that may be induced by floctafene.

Sultopride: increased risk of ventricular arrhythmia.

Not recommended combinations.

In the treatment of heart failure.

Class I antiarrhythmic agents (e.g., disopyramide, quinidine, lidocaine, phenytoin, flecainide, propafenone): increased negative effect on AV conduction and myocardial inotropic function.

For all indications.

Calcium antagonists of the verapamil type and, to a lesser extent, the diltiazem type: increased negative effect on myocardial inotropic function and AV conduction. Intravenous administration of verapamil to patients receiving β-blockers may lead to marked arterial hypotension and AV block.

Centrally acting antihypertensive agents (e.g., clonidine, guanfacine, methyldopa, moxonidine, rilmenidine): possible worsening of heart failure symptoms due to reduced central sympathetic tone (marked decrease in heart rate, cardiac output, vasodilation). Rapid withdrawal of combined therapy increases the risk of "rebound hypertension." To reduce the risk of this complication, the β-adrenoblocker should be discontinued several days before stopping treatment with the above-mentioned group of agents. If a drug from this group needs to be replaced by a β-adrenoblocker, the latter should not be initiated earlier than several days after discontinuation of the former.

Combinations requiring caution.

In the treatment of arterial hypertension or ischemic heart disease (angina pectoris).

Class I antiarrhythmic agents (e.g., disopyramide, quinidine, lidocaine, phenytoin, flecainide, propafenone): increased negative effect on AV conduction and myocardial inotropic function.

For all indications.

Calcium antagonists of the dihydropyridine type (e.g., nifedipine, felodipine, amlodipine): increased risk of arterial hypotension. A further deterioration of ventricular pump function, or acceleration or worsening of heart failure, cannot be excluded in patients with latent heart failure.

Class III antiarrhythmic agents (e.g., amiodarone): possible potentiation of effects on AV conduction and negative inotropic effect (suppression of compensatory sympathetic responses).

Other β-blockers, including topical agents (e.g., those contained in eye drops for glaucoma treatment): enhanced systemic effects of bisoprolol.

Parasympathomimetic agents, including cholinesterase inhibitors (tacrine): possible prolongation of AV conduction time and increased risk of bradycardia.

Insulin and oral antidiabetic agents: enhanced hypoglycemic effect of these agents. β-Adrenoceptor blockade may mask symptoms of hypoglycemia. This interaction is more likely with non-selective β-blockers.

General anesthetics: increased risk of myocardial depression and development of hypotensive reactions (see section "Special precautions").

Cardiac glycosides: reduction in heart rate, prolonged AV conduction.

Non-steroidal anti-inflammatory drugs (NSAIDs): reduced antihypertensive effect of bisoprolol.

β-Sympathomimetic agents (isoprenaline, dobutamine, orciprenaline): combination with bisoprolol may reduce the effects of both agents.

Sympathomimetic agents activating α- and β-adrenoceptors (e.g., adrenaline, noradrenaline): combination with bisoprolol unmasks α-adrenoceptor-mediated vasoconstrictor effects, leading to increased blood pressure and worsening of intermittent claudication symptoms. This interaction is more likely with non-selective β-blockers. Higher doses of adrenaline may be required when treating allergic reactions.

Tricyclic antidepressants, barbiturates, phenothiazines, other antihypertensive agents or agents with antihypertensive properties: increased risk of arterial hypotension.

Moxisylyte: possible development of severe postural hypotension.

Baclofen, amifostine: enhanced antihypertensive activity of bisoprolol.

Combinations to be considered.

Mefloquine: increased risk of bradycardia.

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

Ergotamine derivatives (including ergotamine-containing migraine medications): exacerbation of peripheral circulatory disorders.

Rifampicin: possible slight reduction in the elimination half-life of bisoprolol due to induction of hepatic enzymes. Dose adjustment is usually not required.

Corticosteroids: reduced antihypertensive effect due to water and sodium retention.

Bisoprolol does not affect prothrombin time in patients receiving stable doses of warfarin.

The effect of the drug may be enhanced when used concomitantly with alcohol.

Special precautions for use.

Treatment with Bisoprolol is generally long-term and requires regular medical supervision.

Treatment of stable chronic heart failure with bisoprolol should be initiated with a titration phase. The drug should be prescribed only when the patient's clinical condition is stable and adequate medical monitoring is possible. In case of intolerance or worsening heart failure symptoms (severe arterial hypotension, acute pulmonary edema) during dose escalation, it is recommended first to reduce the dose or discontinue the drug.

Treatment must not be stopped abruptly, especially in patients with ischemic heart disease. Abrupt discontinuation may lead to a "withdrawal syndrome" characterized by disease exacerbation; therefore, treatment should be tapered gradually under medical supervision, taking into account individual patient responses. Initiation and discontinuation of bisoprolol therapy require regular monitoring.

Currently, there is insufficient therapeutic experience with bisoprolol in the treatment of heart failure in patients with the following conditions or pathological states:

• Insulin-dependent diabetes mellitus (type I);
• Severe renal impairment;
• Severe hepatic impairment;
• Restrictive cardiomyopathy;
• Congenital heart defects;
• Hemodynamically significant acquired valvular heart disease;
• Myocardial infarction within the last 3 months.

For all indications.

The drug should be used with caution in patients:

• With diabetes mellitus and significant fluctuations in blood glucose levels. Bisoprolol may mask symptoms of hypoglycemia (e.g., tachycardia, palpitations, increased sweating);
• With bronchospasm (in bronchial asthma, obstructive airway diseases (including in medical history)). Pulmonary function testing is recommended before initiating treatment. In patients with bronchial asthma or other chronic obstructive lung diseases, concomitant bronchodilator therapy is indicated. In some cases, during treatment, increased airway tone may necessitate higher doses of β2-sympathomimetics.

Although cardioselective β1-blockers 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 clinical reasons for their use. If bisoprolol is necessary, it should be used with caution. In patients with obstructive airway diseases, bisoprolol therapy should be initiated at the lowest possible dose. Patients should be carefully monitored for the emergence of new symptoms (e.g., dyspnea, exercise intolerance, cough);

• On a strict diet;
• With first-degree AV block, vasospastic angina (Prinzmetal's angina);
• During desensitization with specific immunotherapy (SIT). The drug may increase sensitivity to allergens and the severity of anaphylactic reactions. When treating anaphylaxis, epinephrine should be used with caution, as its usual positive effect may be diminished. As an alternative to high-dose epinephrine, intensive supportive measures may be used, including fluid administration and β-agonists (intravenous salbutamol or isoprenaline) to relieve bronchospasm, or noradrenaline to treat arterial hypotension;
• With peripheral arterial occlusive diseases (possible symptom exacerbation, increased complaints, especially at the beginning of therapy). The drug is contraindicated in severe forms of these conditions;
• Undergoing general anesthesia. In patients receiving general anesthesia, β-blockers reduce the incidence of arrhythmias and myocardial ischemia during induction, intubation, and the postoperative period. Currently, it is recommended not to discontinue ongoing β-blocker therapy during the perioperative period. The anesthesiologist must be informed about bisoprolol use prior to surgery, as they must consider potential interactions with other drugs that could lead to bradyarrhythmia, blunted reflex tachycardia, and reduced compensatory reflex mechanisms in response to blood loss, or sudden drop in blood pressure. If bisoprolol must be discontinued before surgery, the dose should be tapered gradually, with the last dose administered 48 hours before the start of general anesthesia.

The drug should not be used in patients with pheochromocytoma unless effective α-adrenergic blockade has been previously established.

The drug should be prescribed to patients with myasthenia gravis, psoriasis (including family history), or depression (including history) only after careful benefit-risk assessment.

Use of bisoprolol in hyperthyroidism may mask adrenergic symptoms of the disease.

Concomitant use of bisoprolol with calcium antagonists of the verapamil or diltiazem type, class I antiarrhythmic drugs, or centrally acting antihypertensive agents is generally not recommended (see detailed information in the section "Interaction with other medicinal products and other types of interactions").

The drug gives a negative result in anti-doping tests.

The use of the drug is not recommended in patients with carbohydrate intolerance disorders such as congenital galactosemia, glucose-galactose malabsorption syndrome, or lactase deficiency due to its lactose content.

Use during pregnancy or breastfeeding.

Bisoprolol has pharmacological properties that may cause harmful effects on the course of pregnancy and/or fetal/neonatal development.

During pregnancy, the drug should be used only if the expected benefit to the mother outweighs the potential risk to the fetus. Generally, β-adrenoblockers reduce placental blood flow, which may lead to intrauterine growth retardation, intrauterine death, 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. Placental blood flow, maternal condition, and fetal development 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 medical supervision. Hypoglycemia and bradycardia may be expected during the first 3 days of life.

There are no data on the excretion of bisoprolol in breast milk or on the safety of its effects on breastfed infants. Therefore, the use of the drug is not recommended during breastfeeding.

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

Dosage and Administration

The medication should be taken once daily, without chewing, with a small amount of liquid, regardless of food intake, preferably in the morning.

Arterial hypertension, ischemic heart disease (angina pectoris).

The recommended dose is 5 mg daily (1 tablet of 5 mg).

In patients with grade II arterial hypertension (diastolic blood pressure up to 105 mm Hg), initial treatment should begin with a dose of 2.5 mg daily (1/2 tablet of 5 mg). If necessary, the daily dose may be increased to 10 mg (1 tablet of 10 mg).

Dose adjustments are determined individually by the physician, depending on the patient's condition.

Maximum daily dose – 20 mg of the medication per day.

Bisoprolol should be used with caution in patients with arterial hypertension and ischemic heart disease associated with heart failure.

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 medication should be prescribed for patients with chronic heart failure without signs of exacerbation, according to the following titration schedule, with adjustments based on individual patient response:

• 1.25 mg* of bisoprolol fumarate once daily for 1 week, increasing to
• 2.5 mg of bisoprolol fumarate once daily for the next 1 week, increasing to
• 3.75 mg* of bisoprolol fumarate once daily for the next 1 week, increasing to
• 5 mg of bisoprolol fumarate once daily for the next 4 weeks, increasing to
• 7.5 mg of bisoprolol fumarate once daily for the next 4 weeks, increasing to
• 10 mg of bisoprolol fumarate once daily as maintenance therapy.

*At the beginning of treatment for chronic heart failure, bisoprolol formulations allowing appropriate dose titration are recommended.

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

Close monitoring is required at the beginning of treatment for chronic heart failure. During the titration phase, vital signs (blood pressure, heart rate) and symptoms of worsening heart failure must be closely monitored.

Dose modification.

If worsening 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, temporary discontinuation of treatment. After stabilization of the patient's condition, treatment should be continued.

Patients with hepatic 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 less than 20 mL/min) and/or severe hepatic impairment, the maximum daily dose should not exceed 10 mg of bisoprolol.

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

For elderly patients (unless significant renal or hepatic impairment is present), dose adjustment of bisoprolol is generally not required; however, this patient group may exhibit increased sensitivity even to standard doses.

For all indications.

Treatment with this medication is long-term. The duration depends on the nature and course of the disease. Treatment should not be discontinued abruptly or the recommended dose changed, especially in patients with angina pectoris, without consulting a physician, as this may lead to worsening of the patient's condition. Discontinuation of the medication should be gradual, with a slow dose reduction.

Children.

Clinical data on the efficacy and safety of the medication in pediatric patients are lacking; therefore, the medication 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 associated with third-degree AV block, bradycardia, and dizziness. Several cases of bisoprolol overdose (maximum dose – 2000 mg) have been reported. Symptoms included bradycardia or arterial hypotension.

Symptoms: bradycardia, arterial hypotension, acute heart failure, bronchospasm, respiratory depression, seizures, arrhythmias (including second- and third-degree AV block), dizziness, hypoglycemia. There is considerable variability in individual sensitivity to high single doses of bisoprolol; patients with heart failure may be more sensitive to the drug.

In case of overdose, immediate medical attention is required.

Treatment: discontinue the medication, gastric lavage, administration of activated charcoal. If necessary, supportive and symptomatic therapy. Limited data suggest that bisoprolol is unlikely to be effectively removed by dialysis.

• In case of bradycardia: intravenous administration of atropine. If no response, isoprenaline or another agent with positive chronotropic effect should be administered cautiously. In some cases, transvenous cardiac pacing may be required.
• In case of arterial hypotension: intravenous fluids and vasopressor agents, glucagon.
• In case of second- or third-degree AV block: infusion of isoprenaline or orciprenaline; if necessary, transvenous cardiac pacing.
• In case of acute worsening of chronic heart failure: intravenous diuretics, inotropic agents, vasodilators.
• In case of bronchospasm: bronchodilators (e.g., isoprenaline, orciprenaline), β2-adrenergic agonists and/or theophylline (aminophylline).
• In case of hypoglycemia: intravenous glucose.

The patient should remain under close medical supervision.

Side effects.

Cardiovascular system.

• Bradycardia (dose-dependent effect).
• Onset or worsening of heart failure symptoms, sensation of coldness or numbness in extremities, arterial hypotension (mainly in patients with chronic heart failure), worsening of condition at the beginning of treatment in patients with intermittent claudication or other peripheral circulatory disorders.
• Impaired AV conduction, orthostatic hypotension.
• Chest pain.

Nervous system, psychiatric disorders.

• Dizziness*, headache*.
• Sleep disturbances, depression.
• Hallucinations, nightmares, syncope.

Respiratory system.

• Bronchospasm (especially in patients with bronchial asthma or history of obstructive lung diseases).
• Allergic rhinitis.

Gastrointestinal tract/hepatobiliary system.

• Dry mouth, abdominal pain, nausea, vomiting, diarrhea, constipation.
• Cases of hepatotoxicity − increased plasma activity of liver enzymes (AST, ALT), hepatitis, jaundice.

Skin and subcutaneous tissue.

• Hypersensitivity reactions such as itching, hyperemia (flushing), rash; increased sweating.
• Alopecia, psoriasiform rashes, development or exacerbation of psoriasis symptoms.

Eye organs.

• Decreased tear secretion (should be considered in contact lens wearers).
• Conjunctivitis.

Ear organs.

• Hearing disturbances.

Musculoskeletal system.

• Muscle weakness, tremor/seizures.

Urinary and reproductive organs.

• Impairment of potency.

General disorders.

• Increased fatigue*, asthenia.

Laboratory parameters.

• Increased triglyceride levels, increased activity of liver enzymes (AST, ALT) in blood.

*Applies only to patients with arterial hypertension or ischemic heart disease.

These symptoms usually occur at the beginning of therapy, are generally mild in severity, and resolve within 1–2 weeks.

If adverse effects or unwanted reactions occur, inform your doctor immediately.

Shelf life. 5 years.

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

Storage conditions. In the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister, 3 or 6 blisters per carton; 60 or 90 tablets per container, 1 container per carton.

Prescription category. Prescription only.

Manufacturer. Public Joint-Stock Company "Scientific-Production Center "Borshchagovskiy Chemical and Pharmaceutical Plant".

Limited Liability Company "Agrofarm".

Manufacturer's address and place of business.

17, Miru Street, Kyiv, 03134, Ukraine.

113-A, Tsentralna Street, Irpin, Kyiv Region, 08200, Ukraine.