Dorez

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

Composition:

Active substance: bisoprolol;

One film-coated tablet contains bisoprolol fumarate 5 mg or 10 mg;

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

Coating:

tablets 5 mg – Opadry Yellow 02B32859 (hypromellose, polyethylene glycol 400, titanium dioxide (E 171), iron oxide yellow (E 172));

tablets 10 mg – Opadry Yellow 02F32202 (hypromellose, polyethylene glycol 400, titanium dioxide (E 171), iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets 5 mg: yellow, round, biconvex, film-coated tablets with a break line on one side.

Tablets 10 mg: orange-yellow, round, biconvex, film-coated tablets with a break line on one side.

Pharmacotherapeutic group. Selective ß-adrenoreceptor blockers.

ATC code C07AB07.

Pharmacological properties.

Pharmacodynamics.

Bisoprolol is a highly selective ß1-adrenoblocker. It has no intrinsic sympathomimetic activity and no clinically significant membrane-stabilizing properties. The drug has very low affinity for ß2-receptors of bronchial and vascular smooth muscle, as well as for ß2-receptors involved in metabolic regulation. Thus, bisoprolol does not affect airway resistance or ß2-mediated metabolic effects. The ß1-adrenoceptor 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 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 ß-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 independent of 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. 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. Bisoprolol pharmacokinetics are linear, and its parameters do not depend on 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 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 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 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 channel blockers (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 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 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 for use").
• Cardiac glycosides: reduction in 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): 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 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 other 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.
• MAO inhibitors (except type B MAO 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 discontinued abruptly unless absolutely necessary, as this may lead to transient worsening of the condition. Initiation and discontinuation of bisoprolol therapy require regular monitoring.

There is currently insufficient therapeutic experience in treating chronic heart failure in patients with the following conditions and pathological states: type 1 (insulin-dependent) diabetes mellitus, severe renal impairment, severe hepatic impairment, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant acquired 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 marked 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 cannot be completely excluded when using bisoprolol in patients with Prinzmetal's angina;
• Obstructive peripheral arterial disease (symptoms may worsen at the beginning of therapy);
• General anesthesia.

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. 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 drugs may lead to bradyarrhythmia, reflex tachycardia, and reduced capacity of reflex mechanisms to compensate for 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, their use, like all β-blockers, should be avoided in obstructive airway diseases unless there are strong indications for therapy. If such indications exist, the drug should be used with caution. In patients with obstructive airway diseases, bisoprolol treatment should be initiated at the lowest possible dose. Patients should be monitored for the development 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 the benefit-risk ratio.

In patients with pheochromocytoma, the drug should be administered only after prior treatment with α-adrenoblockers. Symptoms of thyrotoxicosis may be masked during treatment. A positive doping test result may occur during drug 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 labor. 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 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 medical supervision. Hypoglycemia and bradycardia should be expected within the first 3 days.

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

Ability to affect reaction speed when driving or operating machinery.

In clinical studies, the drug did not affect the ability to drive in patients with ischemic heart disease. 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, when changing the dose of the drug, or when combined with alcohol.

Method of Administration and Dosage

Tablets should be swallowed whole, 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 medicinal product containing 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 the medicinal product containing 10 mg) once daily. Further dose increases are justified only in exceptional cases. The maximum recommended dose is 20 mg once daily.

Dose adjustments should be determined individually by a physician, depending 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 intolerance to ACE inhibitors), β-blockers, diuretics, and, if necessary, cardiac glycosides.

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

Therapy should be managed by a physician experienced in treating chronic heart failure.

Treatment of stable chronic heart failure with this medicinal product should be initiated according to the titration schedule below 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.

* At the initiation of therapy for chronic heart failure, a dosage of 2.5 mg is recommended.

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

During the titration phase, 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.

Modification of Therapy.

If the maximum recommended dose is poorly tolerated, gradual dose reduction may be considered. If progressive worsening of heart failure occurs during or after the titration phase, or if arterial hypotension or bradycardia develops, dose adjustment of the drug is recommended, which may require temporary reduction of the bisoprolol dose or, possibly, interruption 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 worsening of the patient's condition. If discontinuation is necessary, the treatment should be tapered gradually (e.g., by halving the dose weekly).

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

The duration of treatment with the medicinal product 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 impairment. In patients with severe renal impairment (creatinine clearance less than 20 mL/min) or severe hepatic impairment, the dose should not exceed 10 mg 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 data on the pharmacokinetics of bisoprolol in patients with chronic heart failure combined with hepatic or renal dysfunction; 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 children are lacking; therefore, the drug should not be used in this patient population.

Overdose.

Symptoms.

Cases of overdose (e.g., administration of a daily dose of 15 mg instead of 7.5 mg) have been associated with third-degree atrioventricular block, bradycardia, and dizziness. 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 arterial hypertension and/or ischemic heart disease (maximum dose – 2000 mg bisoprolol), manifesting as bradycardia and/or arterial hypotension. All patients recovered. There is wide variability in individual 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").

Treatment.

In case of overdose, administration of 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.

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 temporary pacemaker may be required.

Arterial hypotension: intravenous fluid administration and vasopressors. Intravenous glucagon may be effective.

Atrioventricular block of grade II and III: careful monitoring, infusion of isoprenaline, or transvenous insertion of a cardiac pacemaker.

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

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

Hypoglycemia: intravenous glucose administration.

Side effects

Classification of frequency of adverse reactions: 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 (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:

Common: dizziness*, headache*;

Rare: syncope.

Eye disorders:

Rare: decreased lacrimation (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 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: β-blockers may cause exacerbation of psoriasis or induce psoriasiform rashes, alopecia.

Musculoskeletal system:

Uncommon: muscle weakness and cramps.

Hepatic disorders:

Rare: hepatitis.

Vascular disorders:

Common: cold sensation 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: sleep disturbances, depression;

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 any adverse effects or unwanted reactions occur, the physician should be informed immediately.

Reporting of adverse reactions after drug registration is highly important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System 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 5 mg or 10 mg.

10 tablets per blister, 3 blisters per 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.