Coronal® 5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KORONAL® 5 (CORONAL® 5) KORONAL® 10 (CORONAL® 10)

Composition:

Active substance: bisoprolol;

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

Excipients:

Koronal**®** 5: microcrystalline cellulose, maize starch, sodium lauryl sulfate, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, macrogol 400, titanium dioxide (E 171), yellow iron oxide (E 172);

Koronal**®** 10: microcrystalline cellulose, maize starch, sodium lauryl sulfate, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, macrogol 400, titanium dioxide (E 171), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Koronal**®** 5: light-yellow, biconvex, film-coated tablets with a break line on one side.

Koronal**®** 10: light-pink, biconvex, film-coated tablets with a break line on one side.

Pharmacotherapeutic group. Selective β-adrenoreceptor blockers.

ATC code C07A B07.

Pharmacological properties.

Pharmacodynamics. Bisoprolol is a highly selective β1-adrenoceptor blocker. It has no intrinsic sympathomimetic activity and no clinically significant membrane-stabilizing properties. The drug has very low affinity for β2-receptors in 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 β1-selectivity of bisoprolol extends beyond the therapeutic dose range.

Bisoprolol has no pronounced negative inotropic effect.

The maximum effect of bisoprolol occurs 3–4 hours after oral administration. The elimination half-life from plasma is 10–12 hours, resulting in 24-hour efficacy after single dosing. 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 (HR) and stroke volume. With long-term therapy, elevated peripheral resistance decreases. The antihypertensive effect of β-blockers is also mediated by reduction in plasma renin activity.

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

Pharmacokinetics.

Absorption. After oral administration, more than 90% of bisoprolol is absorbed from the gastrointestinal tract. Absorption is not affected by food intake. The first-pass effect is ≤ 10%. Bioavailability is approximately 90%.

Distribution. The 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 to inactive metabolites and excreted by the kidneys, and 50% is excreted unchanged by the kidneys. Total bisoprolol clearance is 15 L/h. Due to the long elimination half-life (10–12 hours), the drug maintains its therapeutic effect for 24 hours with once-daily administration.

Linearity. The pharmacokinetics of bisoprolol are linear and not influenced by age.

Special patient groups. Since bisoprolol is eliminated equally by the kidneys and the 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 chronic heart failure of NYHA functional class III, plasma levels of bisoprolol are higher and the elimination half-life is longer 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.

• Arterial hypertension;
• Ischemic heart disease (angina pectoris);
• 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 inotropic therapy;
• Cardiogenic shock;
• Second- or third-degree atrioventricular block (except in patients with a permanent pacemaker);
• Sinus node dysfunction;
• 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 of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended for use.

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 enhanced negative inotropic effect.

All indications.

• Calcium antagonists (verapamil group, and to a lesser extent, diltiazem): negative effects on myocardial contractility and atrioventricular conduction. Intravenous administration of verapamil in patients receiving β-blockers may lead to marked arterial hypotension and atrioventricular block.
• Centrally-acting antihypertensive agents (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, particularly if preceded by discontinuation of β-adrenoceptor blockers, may increase the risk of rebound hypertension.

Combinations that should 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 enhanced negative inotropic effect.

All indications.

• Dihydropyridine-type calcium antagonists (e.g., nifedipine, felodipine, amlodipine): possible increased risk of arterial hypotension. An increased negative effect on myocardial inotropic 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 eye drops 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-Adrenoceptor blockade may mask symptoms of hypoglycemia.
• Anesthetic agents: increased risk of myocardial depression and arterial hypotension (see section "Special precautions").
• Cardiac glycosides: decreased heart rate, prolonged atrioventricular conduction time.
• Non-steroidal anti-inflammatory drugs (NSAIDs): possible attenuation of the antihypertensive effect of bisoprolol.
• β-Sympathomimetics (e.g., orciprenaline, isoprenaline, dobutamine): combination use 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 effect, 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 and other 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 antihypertensive effect of β-blockers, but risk of hypertensive crisis exists.

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 abruptly discontinued 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 heart failure in patients with the following conditions and pathological states: type 1 (insulin-dependent) diabetes mellitus, severe renal dysfunction, severe hepatic dysfunction, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant acquired heart valve disorders, myocardial infarction within the last 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 significant fluctuations in blood glucose levels, in which symptoms of hypoglycemia (tachycardia, palpitations, increased sweating) 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; episodes of coronary artery spasm have been observed. Despite high β1-selectivity, angina attacks cannot be completely controlled by bisoprolol in patients with Prinzmetal's angina.
• Peripheral arterial occlusive diseases (symptoms may worsen at the beginning of therapy);
• General anesthesia.

In patients undergoing general anesthesia, the use of β-blockers reduces the incidence of arrhythmias and myocardial ischemia during induction, intubation, and the postoperative period. It is recommended to continue β-blocker therapy during the perioperative period. The anesthesiologist must be informed about the use of β-adrenoreceptor blockers, as potential interactions with other medicinal products must be considered, which may lead to bradyarrhythmia, reflex tachycardia, and reduced compensatory capacity of reflex mechanisms in response to blood loss. If bisoprolol is 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, class I antiarrhythmic drugs, and 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 impact 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 such reasons exist, the drug 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 bronchial asthma or other chronic obstructive lung diseases that may cause symptoms, 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 in medical history) only after careful benefit-risk assessment.

Patients with pheochromocytoma should be prescribed the drug only after prior treatment with α-adrenoblockers. Symptoms of thyrotoxicosis may be masked during treatment. A positive doping control test result may occur during treatment.

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 death, spontaneous abortion, or preterm delivery. Adverse effects in the fetus and newborn (e.g., hypoglycemia, bradycardia) may occur. If treatment with β-blockers is necessary, a β1-selective adrenoblocker is preferred.

The drug 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 treatment should be considered.

After delivery, the newborn should be under close medical supervision. Hypoglycemia and bradycardia should be anticipated during the first 3 days of life.

Lactation period. There are no data on the excretion of bisoprolol in breast milk; therefore, the drug is not recommended during breastfeeding.

Ability to affect reaction rate when driving vehicles or operating machinery.

In clinical studies involving patients with ischemic heart disease, the drug did not affect the ability to drive a car. 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 of the drug, or when interacting with alcohol.

Method of Administration and Dosage.

The drug should be taken without chewing, in the morning on an empty stomach, during or after breakfast, with a small amount of liquid.

Arterial hypertension; ischemic heart disease (angina pectoris).

Treatment should be initiated gradually with low doses, followed by dose escalation. The recommended dose is 5 mg (1 tablet of the 5 mg preparation) once daily. For mild hypertension (diastolic pressure up to 105 mm Hg), a dose of 2.5 mg (½ tablet of the 5 mg preparation) is appropriate.

If necessary, the daily dose may be increased to 10 mg (1 tablet of the 10 mg preparation) once daily. Further dose increases are justified only in exceptional cases. The maximum recommended dose is 20 mg per day.

Dose adjustment should be performed individually by a physician based on pulse rate and therapeutic benefit.

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), \ß-blockers, diuretics, and, if needed, cardiac glycosides.

The drug is indicated for treatment of patients with chronic heart failure without signs of acute decompensation.

Therapy should be administered by a physician experienced in managing chronic heart failure.

Treatment of stable chronic heart failure with this drug should begin according to the titration schedule below, which 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 bisoprol combustible 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 beginning of chronic heart failure treatment, a starting dose of 2.5 mg is recommended. To achieve a 2.5 mg dose, the 5 mg tablet may be divided in half.

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

During the titration phase, monitoring of vital signs such as blood pressure, heart rate, and symptoms of worsening heart failure is essential. Symptoms may develop from the first day of treatment.

Dose Modification.

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

The drug should not be discontinued abruptly, especially in patients with ischemic heart disease, as this may lead to worsening of the patient's condition. If discontinuation is necessary, therapy should be tapered gradually by progressively reducing the dose (e.g., halving the dose weekly).

Treatment of stable chronic heart failure is usually long-term.

The duration of treatment is prolonged and depends on the nature and severity of the disease.

Patients with hepatic and/or renal impairment.

Arterial hypertension; ischemic heart disease. Dose adjustment is generally not required in patients with mild to moderate hepatic or renal dysfunction. In patients with severe renal impairment (creatinine clearance <20 ml/min) or severe hepatic impairment, the dose should not exceed a daily dose of 10 mg of the drug. Limited data are available on the use of bisoprolol in dialysis patients. No dosage regimen adjustment is necessary.

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

Elderly patients do not require dose adjustment.

Children.

Clinical data on the efficacy and safety of the drug in children are lacking; therefore, the drug should not be used in this patient population.

Overdose.

Symptoms.

Cases of third-degree atrioventricular block, bradycardia, and dizziness have been reported following overdose (e.g., administration of a daily dose of 15 mg instead of 7.5 mg). The most common signs of ß-blocker overdose include bradycardia, arterial hypotension, acute heart failure, hypoglycemia, and bronchospasm. Several cases of overdose have been reported in patients with arterial hypertension and/or ischemic heart disease (maximum dose – 2000 mg of bisoprolol). 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 "Method of Administration and Dosage").

Treatment.

In case of overdose, treatment with the drug 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 ß-blockers, the following general measures should be considered:

In case of bradycardia: intravenous administration of atropine. If no response, administer isoprenaline or another agent with positive chronotropic effect cautiously. In exceptional cases, transvenous insertion of a temporary pacemaker may be required.

In case of arterial hypotension: intravenous fluid administration and vasopressors. Intravenous glucagon may be beneficial.

In case of second- or third-degree atrioventricular block: careful monitoring and infusion of isoprenaline or transvenous insertion of a cardiac pacemaker.

In case of acute exacerbation of chronic heart failure: intravenous administration of diuretics, inotropic agents, and vasodilators.

In case of bronchospasm: bronchodilator agents (e.g., isoprenaline), ß2-adrenergic agonists and/or aminophylline.

In case of 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 (> 1/10000 and < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be determined from available data).

Cardiac disorders.

Very common: bradycardia (in patients with chronic heart failure).

Common: signs of worsening heart failure (in patients with chronic heart failure).

Uncommon: 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).

Nervous system disorders.

Common: dizziness*, headache*.

Rare: syncope.

Eye disorders.

Rare: reduced tear production (should be considered in contact lens wearers).

Very rare: conjunctivitis.

Ear and labyrinth disorders.

Rare: hearing impairment.

Respiratory system disorders.

Uncommon: bronchospasm in patients with asthma or a history of obstructive respiratory diseases.

Rare: allergic rhinitis.

Gastrointestinal disorders.

Common: nausea, vomiting, diarrhea, constipation.

Skin and subcutaneous tissue disorders.

Rare: hypersensitivity reactions including pruritus, erythema, rash, angioneurotic edema.

Very rare: alopecia. Treatment with ß-blockers may exacerbate psoriasis in patients with psoriasis, manifesting as psoriatic rash.

Musculoskeletal and connective tissue disorders.

Uncommon: muscle weakness, cramps.

Hepatic disorders.

Rare: hepatitis.

Vascular disorders.

Common: sensation of cold or numbness in extremities, arterial hypotension (in patients with chronic heart failure).

Uncommon: orthostatic hypotension (in patients with chronic heart failure), arterial hypotension (in patients with arterial hypertension or ischemic heart disease).

Reproductive system disorders.

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 (in patients with chronic heart failure), fatigue*.

Uncommon: asthenia (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 resolve within the first 1–2 weeks.

If adverse events or undesirable reactions occur, a physician must be informed immediately.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Packaging.

10 tablets in a blister; 3 or 6 blisters in a cardboard box.

15 tablets in a blister; 2 or 4 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

1. JSC "Saneka Pharmaceuticals".
2. C.C. "Zentiva S.A.".

Manufacturer's address and place of business.

1. Nitrianska 100, 920 27 Glogovec, Slovak Republic.
2. Bd. Theodor Pallady, 50, Sector 3, Bucharest, postal code 032266, Romania.

Marketing Authorization Holder.

LLC "Sanofi-Aventis Ukraine".

Address of the Marketing Authorization Holder.

48-50A Zhylianska Street, Kyiv, 01033, Ukraine.