Concor

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

Composition:

Active substance: bisoprolol;

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

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

Film coating for 5 mg tablets: yellow iron oxide (E 172), simethicone 100, polyethylene glycol 400, titanium dioxide (E 171), hypromellose 2910/15;

Film coating for 10 mg tablets: yellow iron oxide (E 172), red iron oxide (E 172), simethicone 100, polyethylene glycol 400, titanium dioxide (E 171), hypromellose 2910/15.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: yellowish-white, heart-shaped, biconvex film-coated tablets, with a score line on both sides;

10 mg tablets: light orange, heart-shaped, biconvex film-coated tablets, with a score line on both sides.

Pharmacotherapeutic group. Selective beta-adrenoceptor blockers.

ATC code C07AB07.

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 of 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 does not have a pronounced negative inotropic effect.

The maximum effect of bisoprolol occurs 3–4 hours after oral administration. The plasma half-life is 10–12 hours, resulting in 24-hour efficacy after a single dose. 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 and stroke volume. During 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 a reduction in heart rate and 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 into inactive metabolites and excreted by the kidneys, and 50% is excreted unchanged by the kidneys. The total clearance of bisoprolol is 15 L/h. Due to its long elimination half-life (10–12 hours), the drug maintains therapeutic efficacy for 24 hours with once-daily administration.

Linearity.
The pharmacokinetics of bisoprolol are linear, and its parameters are independent of age.

Special patient groups.
Since bisoprolol is eliminated equally via 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 impaired liver or kidney function has not been studied. In patients with NYHA class III chronic heart failure, 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 systolic dysfunction of the left ventricle, in combination with ACE inhibitors, diuretics, and, if necessary, cardiac glycosides.

Contraindications.

Interaction with other medicinal products and other forms of interaction.

Treatment of chronic heart failure.

• Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): possible potentiation of atrioventricular conduction effects and enhanced negative inotropic effect.

All indications.

• Calcium antagonists (verapamil group, to a lesser extent – diltiazem): negative effect on myocardial contractility and atrioventricular conduction. Intravenous administration of verapamil in patients taking β-blockers may lead to marked arterial hypotension and atrioventricular block.
• 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, especially if preceded by discontinuation of β-adrenoreceptor 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 calcium antagonists (e.g., nifedipine, felodipine, amlodipine): possible increased risk of arterial hypotension. A potential increase in the negative effect on myocardial inotropic function cannot be excluded in patients with heart failure.
• 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-Adrenoreceptor blockade may mask symptoms of hypoglycemia.
• Anesthetic agents: increased risk of myocardial depression and arterial hypotension (see section "Special precautions").
• Cardiac glycosides: reduced heart rate, prolonged atrioventricular conduction time.
• Nonsteroidal anti-inflammatory drugs (NSAIDs): possible attenuation of the antihypertensive effect of bisoprolol.
• β-Sympathomimetics (e.g., orciprenaline, isoprenaline, dobutamine): concomitant use with Concor® 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-adrenoreceptors (e.g., adrenaline, noradrenaline): possible manifestation of α-adrenoreceptor-mediated vasoconstrictive effects, 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 drugs exhibiting hypotensive effects (e.g., tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of arterial hypotension.

Combinations that are possible.

• Mefloquine: possible increased risk of bradycardia.
• MAO inhibitors (except MAO type B inhibitors): enhanced 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 without urgent need, 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 diseases and pathological conditions: type 1 diabetes mellitus (insulin-dependent), severe renal impairment, severe hepatic impairment, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant acquired valvular heart diseases, myocardial infarction within the past 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 such cases, symptoms of hypoglycemia (tachycardia, palpitations, 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 with 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-adrenoceptor blockers, as they must consider potential interactions with other drugs that could lead to bradyarrhythmia, reflex tachycardia, and reduced compensatory 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, 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, they should be avoided, as with all β-blockers, in obstructive airway diseases unless there are strong indications for therapy. If such indications exist, the drug Concor® should be used with caution. In patients with obstructive airway diseases, bisoprolol therapy should be initiated at the lowest possible dose. Patients should be monitored for the emergence of new symptoms (such as dyspnea, exercise intolerance, cough).

If symptoms of bronchial asthma or other chronic obstructive pulmonary diseases occur, 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.

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

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 β-blocker therapy 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 therapy should be considered.

After delivery, the newborn should be under close observation. Hypoglycemia and bradycardia may be expected during the first 3 days of life.

Breastfeeding period.
There are no data on the excretion of bisoprolol in human breast milk; therefore, the use of Concor® during breastfeeding is not recommended.

Ability to influence reaction speed when driving 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 or operate complex machinery. Particular attention should be paid at the beginning of treatment, during dose adjustments, or when combined with alcohol.

Method of Administration and Dosage

Concor® tablets should be swallowed whole, without chewing, in the morning on an empty stomach, during or after breakfast, with a small amount of liquid.

Hypertension; ischemic heart disease (angina pectoris)

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

If necessary, the daily dose may be increased to 10 mg (1 tablet of Concor® 10 mg) once daily. Further dose escalation is justified only in exceptional cases. The maximum recommended dose is 20 mg once daily.

Dose adjustments should be made 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), β-blockers, diuretics, and, if needed, cardiac glycosides.

Concor® 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 Concor® should be initiated according to the following titration schedule and 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.

* At the beginning of therapy for chronic heart failure, Concor® Cor, film-coated tablets 2.5 mg, is recommended.

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

During the titration phase, close monitoring of vital signs (blood pressure, heart rate) and symptoms of worsening heart failure is required. 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 stabilization of the patient's condition, 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 clinical deterioration. If discontinuation is necessary, therapy should be tapered gradually by reducing the dose (e.g., halving the dose weekly).

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

The duration of Concor® therapy is prolonged and depends on the nature and severity of the disease.

Patients with hepatic and/or renal impairment

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 <20 mL/min) or severe hepatic impairment, the dose should not exceed 10 mg of Concor® once daily. Limited data are available on the use of bisoprolol in dialysis patients. No dosage adjustment is necessary. Chronic heart failure There are no pharmacokinetic data on bisoprolol in patients with chronic heart failure and concomitant hepatic or renal impairment; therefore, dose escalation should be performed with 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, 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 15 mg daily 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 overdose have been reported in patients with hypertension and/or ischemic heart disease (maximum dose reported: 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, discontinue the drug and initiate supportive and symptomatic therapy. Limited data suggest that bisoprolol is poorly dialyzable. In suspected overdose, based on expected pharmacological effects and recommendations for other β-blockers, the following general measures should be considered:

• For bradycardia: intravenous atropine. If no response, cautiously administer isoprenaline or another agent with positive chronotropic effect. In exceptional cases, transvenous pacemaker insertion may be required.
• For arterial hypotension: intravenous fluid administration and vasoconstrictor agents. Intravenous glucagon may be beneficial.
• For atrioventricular block of grade II or III: careful monitoring, infusion of isoprenaline, or transvenous cardiac pacing.
• For acute exacerbation of chronic heart failure: intravenous diuretics, inotropic agents, vasodilators.
• For bronchospasm: bronchodilators (e.g., isoprenaline), β2-adrenergic agonists, and/or aminophylline.
• For hypoglycemia: intravenous glucose.

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 (> 1/10,000 and < 1/1000), very rare (< 1/10,000), unknown (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: decreased 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 bronchial asthma or obstructive airway diseases in medical history.

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 β-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 and breast disorders.

Rare: erectile dysfunction.

Psychiatric disorders.

Uncommon: depression, sleep disturbances.

Rare: nightmares, hallucinations.

Investigations.

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 disappear within the first 1–2 weeks.

In case of adverse events or undesirable reactions, inform your physician immediately.

Shelf life.
5 years.

Storage conditions.
Store at a temperature not exceeding 30 °C. Keep out of reach of children!

Packaging.
30 tablets in a blister; 1 blister per cardboard box.
25 tablets in a blister; 2 blisters per cardboard box.

Prescription status.
Prescription only.

Manufacturer.
Merck Healthcare KGaA, Germany.

Manufacturer's address and place of business.
Frankfurter Strasse 250, 64293 Darmstadt, Germany.