Dorez®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOREZ® (DOREZ®)

Composition:

Active substance: bisoprolol;

One film-coated tablet contains 2.5 mg of bisoprolol fumarate;

Excipients: siliconized microcrystalline cellulose (microcrystalline cellulose 98 % / anhydrous colloidal silicon dioxide 2 %); crospovidone; glycerol dibehenate;

Coating: Opadry White Y-1-7000 (hypromellose, polyethylene glycol 400, titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets with a break line on one side.

Pharmacotherapeutic group. Selective β-adrenoreceptor blockers.

ATC code C07AB07.

Pharmacological properties.

Pharmacodynamics.

Bisoprolol is a highly selective β1-adrenoceptor blocker. 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), cardiac output, and arterial pressure, and 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 to inactive metabolites and excreted by the kidneys, and 50% is excreted unchanged by the kidneys. Total clearance of bisoprolol 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. Bisoprolol pharmacokinetics are linear, and its parameters do not depend on 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 NYHA class III chronic heart failure, plasma bisoprolol levels are higher and elimination half-life is prolonged 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.

Chronic heart failure with systolic dysfunction of the left ventricle, used in combination with 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 forms of interaction.

Combinations not recommended for use.

Calcium antagonists of the verapamil group and, to a lesser extent, diltiazem: negative effects on myocardial contractility and AV conduction. Intravenous administration of verapamil in patients receiving β-blockers may lead to the development of pronounced arterial hypotension and AV 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 reduced central sympathetic tone (decreased heart rate and cardiac output, vasodilation).

Sudden withdrawal of the drug, especially if β-blockers have previously been discontinued, may lead to rebound hypertension.

Combinations that should be used with caution.

Dihydropyridine calcium antagonists (e.g., nifedipine, felodipine, amlodipine): may increase the 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., ophthalmic solutions for glaucoma treatment): enhance systemic effects of bisoprolol.

Parasympathomimetics: negatively affect AV conduction and promote bradycardia.

Insulin or oral antidiabetic agents: enhanced hypoglycemic effect.

β-receptor blockade may mask symptoms of hypoglycemia.

Anesthetic agents: reduce reflex tachycardia and increase the risk of arterial hypotension.

Cardiac glycosides: reduce heart rate and prolong atrioventricular conduction time.

Nonsteroidal anti-inflammatory drugs (NSAIDs): may reduce the antihypertensive effect of bisoprolol.

β-sympathomimetics (e.g., isoprenaline, dobutamine): lead to attenuation of effects of both drugs.

Sympathomimetics acting on α- and β-adrenergic receptors (e.g., adrenaline, noradrenaline): possible manifestation of α-adrenergic-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 with hypotensive effects (e.g., tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of arterial hypotension.

Combinations that should be taken into account.

Mefloquine: increases the risk of bradycardia.

Monoamine oxidase inhibitors (except MAO type B inhibitors): enhance the hypotensive effect of β-blockers or increase the risk of hypertensive crisis.

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 stopped abruptly 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 impairment, 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 airway 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 vasospasm have been observed. Despite high β1-selectivity, angina attacks cannot be completely ruled out when using bisoprolol in patients with Prinzmetal's angina;
• Peripheral arterial occlusive diseases (symptoms may worsen at the beginning of therapy);
• General anesthesia.

It is essential to inform the anesthesiologist about the use of β-receptor 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 interactions with other drugs that may lead to bradyarrhythmia, reflex tachycardia, and reduced capacity of reflex mechanisms to compensate for blood loss.

If bisoprolol must be 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 interactions").

Although cardioselective β-blockers (β1) have less effect on lung function compared to non-selective β-blockers, their use, as with all β-blockers, should be avoided in obstructive airway diseases unless there are strong reasons for therapy.

If necessary, bisoprolol should be used with caution.

In patients with obstructive airway diseases, treatment with bisoprolol should be initiated at the lowest possible dose, and patients should be monitored for the emergence of new symptoms (such as dyspnea, exercise intolerance, cough).

In bronchial asthma or other chronic obstructive lung diseases that may cause symptoms, bronchodilators should be prescribed concomitantly with β-blockers. 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 the medical history) only after careful benefit-risk assessment.

Patients with pheochromocytoma should not be prescribed bisoprolol until treatment with α-adrenoblockers is completed.

Bisoprolol therapy may mask symptoms of thyrotoxicosis.

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 may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. If bisoprolol treatment is considered necessary, 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 within the first 3 days.

Lactation period. There are no data on the excretion of bisoprolol into breast milk or on the safety of its effects on infants. Therefore, the use of the drug during breastfeeding is not recommended.

Ability to affect reaction speed when driving or operating machinery.

During studies in 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.

Tablets should be taken whole, without chewing, in the morning with breakfast, and swallowed with a small amount of liquid.

Standard therapy for chronic heart failure includes ACE inhibitors (or angiotensin receptor blockers in case of intolerance to ACE inhibitors), β-blockers, diuretics, and, if necessary, cardiac glycosides.

At the start of bisoprolol treatment, the patient should not have signs of decompensation.

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

Dosage titration period.

Treatment of chronic heart failure with bisoprolol should be initiated according to the following titration schedule and may be adjusted based on individual patient response:

• 1.25 mg bisoprolol fumarate once daily for 1 week; if well tolerated, increase to
• 2.5 mg bisoprolol fumarate once daily for the next 1 week; if well tolerated, increase to
• 3.75 mg bisoprolol fumarate once daily for the next 1 week; if well tolerated, increase to
• 5 mg bisoprolol fumarate once daily for the next 4 weeks; if well tolerated, increase to
• 7.5 mg bisoprolol fumarate once daily for the next 4 weeks; if well tolerated, increase to
• 10 mg bisoprolol fumarate once daily as maintenance therapy.

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

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

Treatment modification.

If the maximum recommended dose is poorly tolerated, gradual dose reduction may be necessary. If worsening of heart failure, arterial hypotension, or bradycardia occurs during or after the titration phase, adjustment of the drug dosage is recommended, which may require temporary reduction of the bisoprolol dose or, possibly, interruption of treatment. After the patient's condition has stabilized, re-initiation of bisoprolol therapy should always be considered.

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

Treatment should not be stopped abruptly or the recommended dose changed without consulting a physician, as this may lead to deterioration of the patient's condition. If discontinuation is necessary, the treatment should be tapered gradually by slowly reducing the dose.

Patients with hepatic or renal impairment.

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

No dose adjustment is required when administering the drug to elderly patients.

Children.

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

Overdose.

Cases of overdose (e.g., administration of a daily dose of 15 mg instead of 7.5 mg) have been reported, resulting in third-degree atrioventricular block, bradycardia, and dizziness. The most common signs of β-blocker overdose are bradycardia, arterial hypotension, acute heart failure, hypoglycemia, and bronchospasm.

Several cases of overdose (up to 2000 mg of bisoprolol) have been reported, with symptoms including bradycardia and/or hypotension; all patients recovered. There is wide individual variability in sensitivity to a single high dose of bisoprolol, and 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.

In case of overdose, treatment with the drug should be discontinued and supportive and symptomatic therapy should be initiated.

Limited data suggest that bisoprolol is poorly 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 there is no response, isoprenaline or another agent with positive chronotropic effect should be administered cautiously. In exceptional cases, transvenous insertion of a pacemaker may be required.

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

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

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

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

For hypoglycemia: intravenous glucose administration.

Adverse Reactions

Classification of adverse reaction frequencies: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (insufficient data).

Cardiovascular system:

Very common: bradycardia;

Common: worsening of heart failure, sensation of coldness or numbness in extremities, arterial hypotension;

Uncommon: atrioventricular conduction disturbances, orthostatic hypotension.

Nervous system:

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:

Uncommon: bronchospasm in patients with a history of bronchial asthma or chronic obstructive airway diseases;

Rare: allergic rhinitis.

Gastrointestinal disorders:

Common: nausea, vomiting, diarrhea, constipation.

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions (skin itching, erythema, rash) and angioneurotic edema;

Very rare: alopecia; β-adrenergic blockers may exacerbate psoriasis or induce psoriasiform rashes.

Musculoskeletal and connective tissue disorders:

Uncommon: muscle weakness and cramps.

Hepatic disorders:

Rare: hepatitis.

Reproductive system disorders:

Rare: erectile dysfunction.

Psychiatric disorders:

Uncommon: sleep disturbances, depression;

Rare: nightmares, hallucinations.

Laboratory findings:

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

General disorders:

Common: asthenia, fatigue.

If any adverse events or unwanted reactions occur, inform a physician immediately.

Reporting of adverse reactions after drug registration is highly important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: http://aisf.dec.gov.ua

Shelf life.

3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

Tablets of 2.5 mg.

10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ALKALOID AD Skopje.

Manufacturer's address and location of business activity.

Boulevard of Alexander the Great, 12, Skopje, 1000, Republic of North Macedonia.