Concor® cor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CONCOR® COR (CONCOR® COR)

Composition:

Active substance: bisoprolol;

1 tablet contains 2.5 mg of bisoprolol fumarate;

Excipients: colloidal anhydrous silicon dioxide; magnesium stearate; crospovidone; microcrystalline cellulose; maize starch; anhydrous calcium hydrogen phosphate;

Film coating: hypromellose 2910/15; macrogol 400; simethicone 100; titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical characteristics: almost white, heart-shaped, biconvex film-coated tablets with a line on both sides.

Pharmacotherapeutic group. Selective β-adrenoreceptor blockers.

ATC code C07AB07.

Pharmacological properties.

Pharmacodynamics.

Bisoprolol is a highly selective β1-adrenoblocker. When administered in therapeutic doses, it has no intrinsic sympathomimetic activity and no clinically significant membrane-stabilizing properties.

It exerts antianginal and antihypertensive effects. It reduces myocardial oxygen demand by decreasing heart rate (HR) and cardiac output, and by lowering arterial blood pressure. It improves myocardial oxygen supply by reducing end-diastolic pressure and prolonging diastole.

The drug has very low affinity for β2-receptors in bronchial and vascular smooth muscle, as well as for β2-receptors of the endocrine system. Therefore, bisoprolol rarely affects bronchial and peripheral arterial smooth muscle or glucose metabolism.

Pharmacokinetics.

Absorption.
Bioavailability is approximately 90%.

Distribution.
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 into inactive metabolites and excreted by the kidneys, and 50% is excreted unchanged by the kidneys. Total bisoprolol clearance is 15 L/h. Due to its 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 is linear, and its parameters are independent of age.

Special patient groups.
Since bisoprolol is eliminated equally by the liver and kidneys, dosage adjustment is not required in patients with hepatic or renal impairment. However, the pharmacokinetics of bisoprolol have not been studied in patients with stable chronic heart failure or in those with hepatic or renal dysfunction. In patients with NYHA class III chronic heart failure, plasma levels of bisoprolol are higher and elimination half-life is prolonged compared to healthy volunteers. The steady-state maximum 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.

Treatment of chronic heart failure with left ventricular systolic dysfunction in combination with angiotensin-converting enzyme inhibitors (ACE inhibitors), diuretics, and, if necessary, cardiac glycosides.

Contraindications.

• Acute heart failure or decompensated heart failure requiring intravenous inotropic therapy;
• cardiogenic shock;
• second- or third-degree atrioventricular block;
• sick sinus syndrome;
• sinoatrial block;
• symptomatic bradycardia;
• symptomatic arterial hypotension;
• severe form of bronchial asthma;
• severe form of peripheral arterial occlusive diseases 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 types of interactions.

Combinations not recommended.

• 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 hypotension and atrioventricular block.
• Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): possible potentiation of effects on atrioventricular conduction and enhanced negative inotropic effect.
• Antihypertensive agents with central mechanism of action (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 of these agents, particularly after discontinuation of β-adrenoceptor blockers, may increase the risk of rebound hypertension.

Combinations requiring caution.

• Dihydropyridine calcium antagonists (e.g., 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: blunting of reflex tachycardia and increased risk of arterial hypotension.
• Cardiac glycosides: reduced heart rate, prolonged atrioventricular conduction time.
• Non-steroidal anti-inflammatory drugs (NSAIDs): possible attenuation of the antihypertensive effect of bisoprolol.

-β-Sympathomimetics (e.g., isoprenaline, dobutamine): possible reduction in the therapeutic effect of both agents.

• 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 medicinal products with hypotensive effects (e.g., tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of arterial hypotension.

Combinations possible.

• Mefloquine: possible increased risk of bradycardia.
• MAO inhibitors (except MAO-B inhibitors): increased hypotensive 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 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, 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 respiratory tract diseases);
• Diabetes mellitus with significant 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. Cases of coronary artery spasm have been observed. Despite high β1-selectivity, episodes of angina may not be fully controlled when bisoprolol is administered to patients with Prinzmetal's angina;
• Peripheral arterial occlusive disease (symptoms may worsen at the beginning of therapy);
• General anesthesia.

It is essential to inform the anesthesiologist about the use of β-adrenoreceptor blockers.

In patients scheduled for general anesthesia, the use of β-blockers reduces the incidence of arrhythmias and myocardial ischemia during induction, intubation, and the postoperative period.

Continuation of beta-blocker therapy during the perioperative period is recommended.

The anesthesiologist should consider potential drug interactions that may lead to bradyarrhythmia, reflex tachycardia, and reduced capacity of reflex mechanisms to compensate for blood loss.

If discontinuation of bisoprolol is necessary 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, antiarrhythmic drugs of class I, or 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 effect on lung function compared to non-selective β-blockers, their use, like all β-blockers, should be avoided in obstructive respiratory tract diseases unless there are compelling reasons for therapy.

If necessary, the medicinal product Concor® Cor should be used with caution.

In patients with obstructive respiratory tract 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, 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 assessment of benefit/risk ratio.

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

Symptoms of thyrotoxicosis may be masked during bisoprolol therapy.

Use during pregnancy or breastfeeding.

Pregnancy
Bisoprolol has pharmacological properties that may cause harmful effects on 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 β-blocker therapy is necessary, a β1-selective adrenoblocker is preferred. Bisoprolol 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 options should be considered. After delivery, the newborn should be under close observation. Hypoglycemia and bradycardia should be anticipated during the first 3 days of life.

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

Ability to influence reaction speed when driving vehicles or operating machinery.

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

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 used concomitantly with alcohol.

Method of Administration and Dosage.

Concor® Cor should be taken in the morning with breakfast, without chewing, and swallowed with a small amount of liquid.

Standard therapy for chronic heart failure includes ACE inhibitors or angiotensin II antagonists, β-blockers, diuretics, and, if necessary, cardiac glycosides. Patients should not show signs of acute exacerbation at the start of bisoprolol treatment.

Transient worsening of heart failure, arterial hypotension, or bradycardia may occur during and after the titration period.

Dosage Titration Period.

Treatment of chronic heart failure with bisoprolol should be initiated according to the following titration schedule, 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 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.

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

Close monitoring of vital signs (arterial pressure, heart rate) and symptoms of worsening heart failure is required during the titration period. Symptoms may develop from the first day of treatment initiation.

Modification of Treatment.

If the maximum recommended dose is poorly tolerated, gradual dose reduction may be considered.

If worsening of heart failure, arterial hypotension, or bradycardia occurs during or after the titration period, dosage adjustment is recommended, which may require temporary reduction of bisoprolol dose or interruption of treatment.

After patient's condition stabilizes, re-initiation of bisoprolol treatment should always be considered.

Treatment of stable chronic heart failure with bisoprolol is long-term.

Treatment should not be discontinued abruptly or the recommended dosage changed without consulting a physician, as this may lead to worsening of the patient's condition.

If discontinuation is necessary, treatment should be terminated gradually by tapering the dose.

Patients with Hepatic or Renal Impairment.

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

Elderly Patients

do not require dose adjustment.

Children.

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

Overdose.

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 β-blocker overdose include bradycardia, arterial hypotension, acute heart failure, hypoglycemia, and bronchospasm.

Several cases of bisoprolol overdose have been reported to date (maximum dose – 2000 mg).

Bradycardia or arterial hypotension were observed. All patients recovered. There is wide 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").

In case of overdose, immediate medical attention is required.

Treatment with the drug should be discontinued and supportive and symptomatic therapy initiated.

Limited data suggest that bisoprolol is not easily dialyzable. In suspected overdose, based on the expected pharmacological effects and recommendations for other β-blockers, the following general measures should be considered:

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

For arterial hypotension: intravenous fluid administration and vasoconstrictor agents. Intravenous glucagon may be beneficial.

For second- or third-degree atrioventricular block: careful monitoring and infusion of isoprenaline or transvenous pacemaker insertion.

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

For bronchospasm: bronchodilators (e.g., isoprenaline), β2-adrenergic agonists, and/or aminophylline.

For 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).

Cardiovascular system.

Very common: bradycardia.

Common: worsening of heart failure, sensation of cold or numbness in extremities, arterial hypotension.

Uncommon: atrioventricular conduction disturbances, orthostatic hypotension.

Nervous system.

Common: dizziness, headache.

Rare: syncope.

Eye disorders.

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

Very rare: conjunctivitis.

Ear disorders.

Rare: hearing impairment.

Respiratory system.

Uncommon: bronchospasm in patients with bronchial asthma or obstructive respiratory diseases in medical history.

Rare: allergic rhinitis.

Gastrointestinal tract.

Common: nausea, vomiting, diarrhea, constipation.

Skin and subcutaneous tissue.

Rare: hypersensitivity reactions (itching, erythema, rash), angioneurotic edema.

Very rare: alopecia. During treatment with β-blockers, worsening of psoriasis, manifested as psoriatic rash, may occur.

Musculoskeletal system.

Uncommon: muscle weakness, cramps.

Liver.

Rare: hepatitis.

Reproductive system.

Rare: erectile dysfunction.

Psychiatric disorders.

Uncommon: depression, sleep disturbances.

Rare: nightmares, hallucinations.

Laboratory findings.

Rare: increased blood triglyceride levels, increased plasma liver enzyme activity (aspartate aminotransferase (AST), alanine aminotransferase (ALT)).

General disorders.

Common: asthenia, fatigue.

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 in a blister; 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Merck Healthcare KGaA, Germany.

Manufacturer's address and place of business.

Frankfurter Strasse 250, 64293 Darmstadt, Germany.