Biprol (Tablets) Instructions for Use

ATC Code

C07AB07 (Bisoprolol)

Active Substance

Bisoprolol (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Beta₁-adrenoblocker

Pharmacotherapeutic Group

Selective beta1-adrenergic blocker

Pharmacological Action

Selective beta₁-adrenergic blocker without intrinsic sympathomimetic activity, does not possess membrane-stabilizing properties.

It reduces plasma renin activity, decreases myocardial oxygen demand, and reduces heart rate at rest and during exercise. It has antihypertensive, antiarrhythmic, and antianginal effects. When used in low doses, it blocks cardiac β₁-adrenergic receptors, reduces catecholamine-stimulated formation of cAMP from ATP, decreases the intracellular flow of calcium ions, and has negative chronotropic, dromotropic, bathmotropic, and inotropic effects; it inhibits conduction and excitability and reduces myocardial contractility.

When used in high doses, it exerts beta₂-adrenergic blocking action.

Total peripheral vascular resistance increases at the beginning of drug use (within the first 24 hours) as a result of reciprocal increase in α-adrenergic receptor activity and elimination of β₂-adrenergic receptor stimulation), then returns to the initial level after 1-3 days, and decreases with long-term use of the drug.

The antihypertensive effect is associated with a decrease in cardiac output, sympathetic stimulation of peripheral vessels, a reduction in the activity of the renin-angiotensin-aldosterone system (which is particularly important for patients with initial hypersecretion of renin), restoration of sensitivity in response to decreased blood pressure, and an effect on the central nervous system. In arterial hypertension, the initial effect occurs within 2-5 days, and the stable effect occurs after 1-2 months.

The antianginal effect is due to a reduction in myocardial oxygen demand resulting from decreased heart rate and reduced contractility, prolonged diastole, and improved myocardial perfusion. Due to an increase in end-diastolic pressure in the left ventricle and increased stretching of ventricular muscle fibers, it may increase myocardial oxygen demand, especially in patients with chronic heart failure.

The antiarrhythmic effect is due to the elimination of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased cAMP levels, arterial hypertension), a decrease in the rate of spontaneous excitation of the sinus and ectopic pacemakers, and slowing of AV conduction (primarily in the antegrade and, to a lesser extent, in the retrograde directions through the AV node) and via accessory pathways.

When used in average therapeutic doses, unlike non-selective beta-blockers, it has a less pronounced effect on organs containing β₂-adrenergic receptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchi, and uterus) and on carbohydrate metabolism; it does not cause sodium ion retention in the body; the severity of the atherogenic effect does not differ from that of propranolol. When used in high doses (200 mg and more), it exerts a blocking effect on both subtypes of β-adrenergic receptors, mainly in the bronchi and vascular smooth muscles.

Pharmacokinetics

Absorption and Distribution

When taken orally, it is well absorbed from the gastrointestinal tract (absorption – 80-90%); food intake does not affect absorption. C_max in blood plasma is reached in 1-3 hours. Plasma protein binding is about 30%. It penetrates the blood-brain barrier, placental barrier in small amounts, and is excreted in breast milk.

Metabolism and Excretion

It is metabolized in the liver, T_1/2 is 10-12 hours. It is excreted by the kidneys (50% unchanged); less than 2% is excreted in the bile.

Indications

• Arterial hypertension;
• Coronary artery disease: prevention of angina attacks.

ICD codes

Dosage Regimen

Tablets

Take orally, in the morning, on an empty stomach; do not chew the tablets.

The drug is prescribed at a dose of 5 mg once a day. If necessary, the dose can be increased to 10 mg once a day. The maximum daily dose is 20 mg.

In patients with impaired renal function with creatinine clearance less than 20 ml/min or with severe hepatic impairment, the maximum daily dose is 10 mg.

Adverse Reactions

From the central and peripheral nervous system: increased fatigue, weakness, dizziness, headache, sleep disorders, depression, anxiety, confusion or short-term memory loss, hallucinations, asthenia, myasthenia, paresthesia in the extremities (in patients with intermittent claudication and Raynaud’s syndrome), tremor.

From the organ of vision: visual impairment, decreased tear secretion, dry and painful eyes, conjunctivitis.

From the cardiovascular system: sinus bradycardia, palpitations, impaired myocardial conduction, AV block (up to the development of complete transverse block and cardiac arrest), arrhythmias, decreased myocardial contractility, development (worsening) of chronic heart failure (ankle and foot swelling; shortness of breath), decreased blood pressure, orthostatic hypotension, manifestation of angiospasm (worsening of peripheral circulation disorders, cold lower extremities, Raynaud’s syndrome), chest pain, withdrawal syndrome (increased frequency of angina attacks, increased blood pressure).

From the digestive system: dry oral mucosa, nausea, vomiting, abdominal pain, constipation or diarrhea, changes in liver enzyme activity (increased ALT and AST), bilirubin levels, liver function disorders (dark urine, jaundice of sclera or skin, cholestasis), taste changes.

From the respiratory system: nasal congestion, difficulty breathing when prescribed in high doses (loss of selectivity) and/or in predisposed patients – laryngo- and bronchospasm.

From the endocrine system: hyperglycemia (in patients with type 2 diabetes mellitus), hypoglycemia (in patients receiving insulin), hypothyroid state.

Allergic reactions: skin itching, rash, urticaria.

Dermatological reactions: increased sweating, skin hyperemia, exanthema, psoriasiform skin reactions, exacerbation of psoriasis symptoms.

From the hematopoietic system: thrombocytopenia (unusual bleeding and hemorrhage), agranulocytosis, leukopenia.

From the reproductive system: decreased libido, impotence.

Other: back pain, arthralgia, changes in triglyceride levels, withdrawal syndrome (increased frequency of angina attacks, increased blood pressure).

Effect on the fetus with the use of the drug, intrauterine growth retardation, hypoglycemia, fetal bradycardia are possible.

Contraindications

• Shock (including cardiogenic);
• Collapse;
• Pulmonary edema;
• Acute heart failure;
• Chronic heart failure in the stage of decompensation;
• AV block II and III degree;
• Sinoatrial block;
• Sick sinus syndrome;
• Severe bradycardia;
• Prinzmetal’s angina;
• Cardiomegaly (without signs of heart failure);
• Arterial hypotension (systolic blood pressure less than 100 mm Hg, especially in myocardial infarction);
• History of bronchial asthma and chronic obstructive pulmonary disease;
• Concomitant use of MAO inhibitors (except for MAO type B inhibitors);
• Late stages of peripheral circulatory disorders (Raynaud’s disease);
• Pheochromocytoma (without simultaneous use of alpha-blockers);
• Metabolic acidosis;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to the components of the drug and other beta-blockers.

Use with caution in patients with hepatic insufficiency, chronic renal failure, myasthenia gravis, thyrotoxicosis, diabetes mellitus, AV block I degree, depression (including history), psoriasis, as well as in elderly patients.

Use in Pregnancy and Lactation

The use of the drug during pregnancy and lactation is possible if the benefit to the mother outweighs the risk of side effects in the fetus and child.

Use in Hepatic Impairment

Use with caution in patients with hepatic insufficiency.

Use in Renal Impairment

Use with caution in patients with chronic renal failure.

In patients with impaired renal function with creatinine clearance less than 20 ml/min, the maximum daily dose is 10 mg.

Pediatric Use

Contraindication — age under 18 years (efficacy and safety not established).

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Monitoring of patients taking Biprol should include measurement of heart rate and blood pressure (daily at the beginning of treatment, then once every 3-4 months), ECG, blood glucose determination in diabetic patients (once every 4-5 months). In elderly patients, it is recommended to monitor renal function (once every 4-5 months).

Before starting treatment, it is recommended to investigate external respiratory function in patients with a history of respiratory diseases.

The patient should be taught the method of counting heart rate and instructed on the need for medical consultation if the heart rate is less than 50 beats/min.

Approximately 20% of patients with angina do not respond to beta-blockers. The main reasons are severe coronary atherosclerosis with a low ischemia threshold (heart rate less than 100 beats/min) and increased left ventricular end-diastolic volume, which impairs subendocardial blood flow.

In smoking patients, the effectiveness of beta-blockers is lower.

Patients using contact lenses should take into account that tear production may decrease during treatment.

When used in patients with pheochromocytoma, there is a risk of paradoxical arterial hypertension (if effective blockade of α-adrenergic receptors has not been previously achieved).

In thyrotoxicosis, Biprol may mask certain clinical signs of thyrotoxicosis (e.g., tachycardia). Abrupt withdrawal in patients with thyrotoxicosis is contraindicated, as it may exacerbate symptoms.

In diabetes mellitus, the drug may mask tachycardia caused by hypoglycemia. Unlike non-selective beta-blockers, it practically does not enhance insulin-induced hypoglycemia and does not delay the restoration of blood glucose concentration to normal levels.

With simultaneous use of clonidine, its administration can be discontinued only several days after discontinuation of Biprol.

Increased severity of hypersensitivity reactions and lack of effect from usual doses of epinephrine may occur in patients with a burdened allergic history.

If planned surgical treatment is necessary, the drug should be discontinued 48 hours before the start of general anesthesia. If the patient has taken the drug before surgery, an agent for general anesthesia with minimal negative inotropic effect should be selected.

Reciprocal vagus nerve activation can be eliminated by intravenous administration of atropine (1-2 mg).

Drugs that reduce catecholamine reserves (including reserpine) may enhance the effect of beta-blockers, so patients taking such combinations of drugs should be under constant medical supervision for detection of significant hypotension or bradycardia.

Patients with bronchospastic conditions or diseases can be prescribed cardioselective adrenergic blockers in case of intolerance and/or ineffectiveness of other antihypertensive drugs. Overdose is dangerous due to the development of bronchospasm.

If increasing bradycardia (less than 50 beats/min), significant decrease in blood pressure (systolic blood pressure below 100 mm Hg), AV block are detected in elderly patients, the dose should be reduced or treatment discontinued.

It is recommended to discontinue therapy if depression develops.

Treatment should not be abruptly interrupted due to the risk of severe arrhythmias and myocardial infarction. Discontinuation should be gradual, reducing the dose over 2 weeks or more (by 25% every 3-4 days).

The drug should be discontinued before testing blood and urine for catecholamines, normetanephrine, and vanillylmandelic acid; titers of antinuclear antibodies.

Effect on ability to drive vehicles and operate machinery

During treatment, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms arrhythmias, ventricular extrasystole, severe bradycardia, AV block, significant decrease in blood pressure, chronic heart failure, cyanosis of fingernails and palms, difficulty breathing, bronchospasm, dizziness, fainting, convulsions.

Treatment: gastric lavage, administration of adsorbents. If necessary, symptomatic therapy is carried out: in case of developed AV block, intravenous administration of atropine (1-2 mg), epinephrine, or placement of a temporary pacemaker; for ventricular extrasystole – lidocaine (class I A drugs are not used). In case of decreased blood pressure, the patient should be in the Trendelenburg position; if there are no signs of pulmonary edema, intravenous plasma-substituting solutions are administered; if ineffective – administration of epinephrine, dopamine, dobutamine (to maintain chronotropic and inotropic action and eliminate significant decrease in blood pressure). In heart failure, cardiac glycosides, diuretics, glucagon are prescribed; for convulsions – intravenous diazepam; for bronchospasm – beta₂-adrenergic agonists by inhalation.

Drug Interactions

Use against the background of Biprol therapy with allergens used for immunotherapy or allergen extracts for skin tests increases the risk of severe systemic allergic reactions or anaphylaxis.

With simultaneous use of bisoprolol with iodine-containing radiopaque agents for intravenous administration, the risk of anaphylactic reactions increases.

With simultaneous administration of bisoprolol with intravenous phenytoin, agents for inhalational general anesthesia (hydrocarbon derivatives) increase the severity of the cardiodepressive effect and the likelihood of decreased blood pressure.

With simultaneous use, Bisoprolol changes the effectiveness of insulin and oral hypoglycemic drugs, masks the symptoms of developing hypoglycemia (tachycardia, increased blood pressure).

With simultaneous use, Bisoprolol reduces the clearance of lidocaine and xanthines (except diphylline) and increases their plasma concentration, especially in patients with initially increased theophylline clearance due to smoking.

The antihypertensive effect of bisoprolol is reduced by NSAIDs (Na⁺ retention and blockade of prostaglandin synthesis in the kidneys), corticosteroids and estrogens (Na⁺ ion retention).

With simultaneous use, cardiac glycosides, methyldopa, reserpine and guanfacine, calcium channel blockers (verapamil, diltiazem), amiodarone and other antiarrhythmic drugs increase the risk of development or worsening of bradycardia, AV block, cardiac arrest and heart failure.

With simultaneous use with bisoprolol, nifedipine can lead to a significant decrease in blood pressure.

With simultaneous use with bisoprolol, diuretics, clonidine, sympatholytics, hydralazine and other antihypertensive drugs can lead to an excessive decrease in blood pressure.

Bisoprolol prolongs the action of non-depolarizing muscle relaxants and the anticoagulant effect of coumarins.

Tricyclic and tetracyclic antidepressants, antipsychotic drugs (neuroleptics), ethanol, sedatives and hypnotics enhance the depressant effect of bisoprolol on the central nervous system.

Simultaneous use of bisoprolol with MAO inhibitors is not recommended due to a significant enhancement of the antihypertensive effect (the interval between taking MAO inhibitors and bisoprolol should be at least 14 days).

With simultaneous use with bisoprolol, non-hydrogenated ergot alkaloids, ergotamine increase the risk of peripheral circulation disorders.

With simultaneous use, sulfasalazine increases the plasma concentration of bisoprolol.

With simultaneous use, rifampicin reduces the T_1/2 of bisoprolol.

Storage Conditions

List B. The drug should be stored out of the reach of children, in a dry place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.