Coronal (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Saneca Pharmaceuticals, a.s. (Slovakia)

ATC Code

C07AB07 (Bisoprolol)

Active Substance

Bisoprolol (Rec.INN registered by WHO)

Dosage Forms

	Coronal	Film-coated tablets, 5 mg: 10, 30, 60 or 100 pcs.
		Film-coated tablets, 10 mg: 10, 30, 60 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow in color, round, biconvex, with a score line.

Excipients: microcrystalline cellulose, corn starch, sodium lauryl sulfate, colloidal silicon dioxide, magnesium stearate.

Film coating composition: hypromellose, macrogol 400, titanium dioxide, yellow iron oxide dye (E172).

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
15 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (4) – cardboard packs.

Film-coated tablets light pink in color, round, biconvex, with a score line.

Excipients: microcrystalline cellulose, corn starch, sodium lauryl sulfate, colloidal silicon dioxide, magnesium stearate.

Film coating composition: hypromellose, macrogol 400, titanium dioxide, red iron oxide dye (E172).

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
15 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Beta₁-adrenoblocker

Pharmacotherapeutic Group

Beta-adrenergic blockers; selective beta-adrenergic blockers

Pharmacological Action

Selective beta₁-adrenergic blocker. Reduces plasma renin activity, decreases myocardial oxygen demand, reduces heart rate (at rest and under load). It has antihypertensive, antiarrhythmic and antianginal action.

By blocking beta₁-adrenergic receptors of the heart in low doses, it reduces catecholamine-stimulated cAMP formation from ATP, reduces intracellular calcium ion current, and has negative chronotropic, dromotropic, bathmotropic and inotropic effects (slows heart rate, inhibits conduction and excitability, reduces myocardial contractility). At higher doses, it exerts beta₂-adrenergic blocking action.

Total peripheral vascular resistance increases at the beginning of drug use, within the first 24 hours after oral administration (as a result of reciprocal increase in alpha-adrenergic receptor activity and elimination of beta₂-adrenergic receptor stimulation), which returns to baseline after 1-3 days, and decreases with long-term administration.

Antihypertensive action is associated with a decrease in minute volume of blood, sympathetic stimulation of peripheral vessels, reduction in the activity of the renin-angiotensin-aldosterone system (more important for patients with initial hypersecretion of renin) and the central nervous system, restoration of the sensitivity of the aortic arch baroreceptors (their activity does not increase in response to decreased blood pressure) and, ultimately, a reduction in peripheral sympathetic influences. In arterial hypertension, the hypotensive effect develops after 2-5 days, a stable effect – after 1-2 months.

Antianginal action is due to a decrease in myocardial oxygen demand as a result of decreased heart rate and reduced contractility, prolonged diastole, improved myocardial perfusion, as well as reduced myocardial sensitivity to sympathetic innervation. It reduces the number and severity of angina attacks and increases exercise tolerance. Due to an increase in end-diastolic pressure in the left ventricle and increased stretching of the ventricular muscle fibers, oxygen demand may increase, especially in patients with chronic heart failure.

Antiarrhythmic action 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 (mainly in the antegrade and, to a lesser extent, in the retrograde directions through the AV node) and conduction via accessory pathways.

When used in medium therapeutic doses, unlike non-selective beta-adrenergic blockers, it has a less pronounced effect on organs containing beta₂-adrenergic receptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchi and uterus) and on carbohydrate metabolism, does not cause sodium ion retention in the body. When used in high doses (200 mg and more), it exerts a blocking effect on both subtypes of beta-adrenergic receptors, mainly in the bronchi and vascular smooth muscles.

Pharmacokinetics

Absorption

Absorption is 80-90%, food intake does not affect absorption. C_max in blood plasma is observed after 1-3 hours.

Distribution

Binding to blood plasma proteins is about 30%. Permeability through the blood-brain barrier and placental barrier is low, secretion into breast milk is low.

Metabolism

Metabolized in the liver to form inactive metabolites.

Excretion

T_1/2 is 10-12 hours. Excreted by the kidneys about 98% (50% unchanged), less than 2% is excreted in the bile.

Indications

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

ICD codes

Dosage Regimen

For arterial hypertension and coronary artery disease (prevention of stable angina attacks) the initial dose is 2.5-5 mg once/day. If necessary, the dose can be increased to 10 mg once/day. The maximum daily dose is 20 mg.

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

Dose adjustment in elderly patients is not required.

The tablets should be taken orally in the morning on an empty stomach, without chewing, with a small amount of liquid.

Adverse Reactions

The frequency of adverse effects is defined as follows: 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, including isolated reports).

From the central nervous system uncommon – increased fatigue, asthenia, dizziness, headache, drowsiness or insomnia, depression; rare – hallucinations, nightmares, convulsions.

From the senses rare – visual impairment, decreased tear fluid secretion, dry and painful eyes, hearing impairment; very rare – conjunctivitis.

From the cardiovascular system very common – sinus bradycardia; common – decreased blood pressure, manifestation of angiospasm (worsening of peripheral circulation disorders, cold extremities, paresthesia); uncommon – AV conduction disturbance, orthostatic hypotension, decompensation of chronic heart failure, peripheral edema.

From the digestive system common – dry oral mucosa, nausea, vomiting, diarrhea, constipation; rare – hepatitis, increased activity of liver transaminases.

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

From the endocrine system rare – hyperglycemia (in patients with type 2 diabetes mellitus), hypoglycemia (in patients receiving insulin).

Allergic reactions rare – skin itching, rash, urticaria.

From the skin rare – increased sweating, skin hyperemia; very rare – psoriasiform skin reactions, exacerbation of psoriasis symptoms, alopecia.

From the musculoskeletal system: uncommon – muscle weakness, calf muscle cramps, arthralgia.

From the hematopoietic organs in some cases – thrombocytopenia, agranulocytosis.

Other very rare – impaired potency; rare – hypertriglyceridemia, withdrawal syndrome (increased angina attacks, increased blood pressure).

Contraindications

• Shock (including cardiogenic);
• Acute heart failure;
• Chronic heart failure in the stage of decompensation;
• Second and third degree AV block (without an artificial pacemaker);
• Sinoatrial block;
• Sick sinus syndrome;
• Severe bradycardia;
• Cardiomegaly (without signs of heart failure);
• Arterial hypotension (systolic blood pressure below 100 mm Hg, especially in myocardial infarction);
• History of bronchial asthma and chronic obstructive pulmonary disease;
• Concomitant use of MAO inhibitors (except for MAO-B inhibitors);
• Concomitant use of floctafenine and sultopride;
• Late stages of peripheral circulatory disorders;
• Raynaud’s disease;
• Lactation period;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to the components of the drug and other beta-adrenergic blockers.

With caution the drug should be prescribed for hepatic insufficiency, renal insufficiency (creatinine clearance less than 20 ml/min), metabolic acidosis, pheochromocytoma (with concomitant use of alpha-adrenergic blockers), diabetes mellitus in the stage of decompensation, first degree AV block, Prinzmetal’s angina, restrictive cardiomyopathy, congenital heart defects or heart valve defects with severe hemodynamic disturbances, chronic heart failure with myocardial infarction within the last 3 months, psoriasis, depression (including history), severe allergic reactions in history, during pregnancy, when following a strict diet, undergoing desensitizing immunotherapy with allergens and allergen extracts, as well as in elderly patients.

Use in Pregnancy and Lactation

During pregnancy, Coronal is prescribed only for strict indications if the intended benefit to the mother outweighs the potential risk to the fetus. 72 hours before delivery, Coronal should be discontinued due to the possible development of bradycardia, arterial hypotension, hypoglycemia and respiratory depression in the fetus/newborn.

If Coronal is necessary during lactation, breastfeeding should be discontinued.

When taking bisoprolol during pregnancy, intrauterine growth retardation, hypoglycemia, and bradycardia are possible in the fetus.

Use in Hepatic Impairment

In patients with severe hepatic impairment the maximum daily dose is 10 mg.

Use in Renal Impairment

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

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age (efficacy and safety not established).

Geriatric Use

^{The drug should be prescribed with caution to elderly patients.}

Special Precautions

When prescribing Coronal, heart rate and blood pressure should be regularly monitored (at the beginning of treatment – daily, then – once every 3-4 months), ECG should be performed, blood glucose levels should be determined in patients with diabetes mellitus (once every 4-5 months). In elderly patients, it is recommended to monitor renal function (once every 4-5 months).

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

Before starting treatment, it is recommended to examine the function of external respiration in patients with a burdened bronchopulmonary history.

It should be taken into account that in approximately 20% of patients with angina, beta-adrenergic blockers are ineffective due to severe coronary atherosclerosis with a low ischemia threshold (heart rate less than 100 beats/min) and increased end-diastolic volume of the left ventricle, which impairs subendocardial blood flow.

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

Patients using contact lenses should take into account that during treatment, a decrease in tear fluid production is possible.

When using Coronal in patients with pheochromocytoma, there is a risk of developing paradoxical arterial hypertension (if effective alpha-adrenergic blockade has not been previously achieved).

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

In diabetes mellitus, Bisoprolol may mask tachycardia caused by hypoglycemia. Unlike non-selective beta-adrenergic 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 with clonidine, the latter can be discontinued only a few days after discontinuation of Coronal.

An increase in the severity of the hypersensitivity reaction and a lack of effect from usual doses of epinephrine may occur against the background of 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, a drug for general anesthesia with minimal negative inotropic effect should be selected for him.

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

Drugs that reduce catecholamine reserves (including reserpine) may enhance the effect of beta-adrenergic blockers, so patients taking such combinations of drugs should be under constant medical supervision for the detection of a pronounced decrease in blood pressure or bradycardia.

Patients with concomitant bronchospastic 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 elderly patients develop increasing bradycardia (less than 50 beats/min), a pronounced decrease in blood pressure (systolic blood pressure below 100 mm Hg), AV block, the dose should be reduced or treatment should be discontinued.

It is recommended to discontinue therapy if depression develops.

The drug should be discontinued before testing the blood and urine for catecholamines, normetanephrine, vanillylmandelic acid, and antinuclear antibody titers.

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 (the dose is reduced by 25% every 3-4 days).

Use in pediatrics

The use of Coronal in children and adolescents under 18 years of age is contraindicated, as efficacy and safety have not been established.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, 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 arrhythmia, ventricular extrasystole, severe bradycardia, AV block, decreased blood pressure, acute heart failure, acrocyanosis, difficulty breathing, bronchospasm, dizziness, fainting, convulsions.

Treatment gastric lavage is necessary and adsorbent drugs should be prescribed. Symptomatic therapy is carried out: in case of developed AV block – intravenous administration of 1-2 mg of atropine, epinephrine or placement of a temporary pacemaker; for ventricular extrasystole – intravenous lidocaine (class I A drugs are not used); with decreased blood pressure, the patient should be in the Trendelenburg position; in the absence of symptoms of pulmonary edema – intravenous plasma-substituting solutions, if ineffective – administration of epinephrine, dopamine, dobutamine (to maintain chrono- and inotropic action and eliminate a pronounced decrease in blood pressure); in heart failure – cardiac glycosides, diuretics, glucagon; for convulsions – intravenous diazepam; for bronchospasm – inhaled beta₂-adrenergic stimulants.

Drug Interactions

Allergens used for immunotherapy or allergen extracts for skin tests increase the risk of severe systemic allergic reactions or anaphylaxis in patients receiving Bisoprolol.

With simultaneous use with Coronal, iodine-containing radiopaque drugs for intravenous administration increase the risk of anaphylactic reactions.

With simultaneous use with Coronal, intravenous phenytoin, drugs for inhalation general anesthesia (hydrocarbon derivatives) increase the severity of the cardiodepressive effect and the likelihood of decreased blood pressure.

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

With simultaneous use, Coronal 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.

NSAIDs (due to sodium ion retention and blockade of prostaglandin synthesis in the kidneys), corticosteroids and estrogens (due to sodium ion retention) weaken the antihypertensive effect of Coronal.

With simultaneous use with Coronal, cardiac glycosides, methyldopa, reserpine and guanfacine, slow 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.

When used concomitantly with Coronal, nifedipine may lead to a significant decrease in blood pressure.

Concomitant use of Coronal with diuretics, clonidine, sympatholytics, hydralazine, and other antihypertensive medications may lead to an excessive decrease in blood pressure.

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

Concomitant use of Coronal with tricyclic and tetracyclic antidepressants, antipsychotic medications (neuroleptics), ethanol, sedative and hypnotic medications enhances central nervous system depression and may provoke cardiac arrhythmias, bradycardia, and orthostatic hypotension.

Concomitant use of Coronal with MAO inhibitors is not recommended due to a significant enhancement of the antihypertensive effect; the treatment interval between taking MAO inhibitors and Coronal should be at least 14 days.

Concomitant use of Coronal with non-hydrogenated ergot alkaloids and ergotamine increases the risk of peripheral circulatory disorders.

Concomitant use of Coronal with sulfasalazine increases the plasma concentration of bisoprolol.

Concomitant use of Coronal with rifampicin shortens the T_1/2 of bisoprolol.

There is a potential risk of an additive effect with the development of hypotension and/or significant bradycardia when used concomitantly with topically applied beta-adrenergic blockers (eye drops).

A reduction in the antihypertensive effect of the drug is noted during the use of epinephrine and norepinephrine.

The likelihood of disturbances in cardiac automaticity, conduction, and contractility increases (mutually) during therapy with quinidine-like drugs (mefloquine, chloroquine).

In case of shock or arterial hypotension caused by floctafenine, concomitant use may reduce compensatory cardiovascular reactions.

Concomitant use with baclofen or amifostine also enhances the antihypertensive effect.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 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.