Bisoprol®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BISOPROLOL® (BISOPROL)

Composition:

Active substance: bisoprolol;

One tablet contains 5 mg or 10 mg of bisoprolol fumarate, calculated as 100% substance;

Excipients: lactose monohydrate, microcrystalline cellulose, calcium hydrogen phosphate, crospovidone, colloidal anhydrous silicon dioxide, sunset yellow FCF (E 110), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: 5 mg tablets are round, biconvex, light pink in color, with or without a score line. Speckles on the tablet surface are permissible;

10 mg tablets are round, flat-faced, with bevelled edges and a score line, light pink in color. Speckles on the tablet surface are permissible.

Pharmacotherapeutic group. Selective β-adrenoreceptor 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 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 is maintained 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 plasma elimination half-life is 10–12 hours, resulting in 24-hour efficacy after a single dose. 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. 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 β1-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. 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 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 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. Steady-state plasma concentration reaches 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.

• Acute heart failure or decompensated heart failure requiring inotropic therapy;
• Cardiogenic shock;
• Second- or third-degree atrioventricular block (except in patients with a pacemaker);
• Sick sinus syndrome;
• 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 increased negative inotropic effect.

All indications.

• Calcium channel antagonists (verapamil group, and to a lesser extent, diltiazem): negative effects on myocardial contractility and atrioventricular conduction. Intravenous administration of verapamil in patients taking β-blockers may lead to severe 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, especially if preceded by discontinuation of β-blockers, may increase the risk of rebound hypertension.

Combinations to 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 increased negative inotropic effect.

All indications.

• Dihydropyridine calcium antagonists (e.g., nifedipine, felodipine, amlodipine): possible increased risk of arterial hypotension. A potential increase in negative inotropic effects on myocardial 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-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.
• Nonsteroidal anti-inflammatory drugs (NSAIDs): possible attenuation of the antihypertensive effect of bisoprolol.
• β-Sympathomimetics (e.g., orciprenaline, isoprenaline, dobutamine): concomitant use with Bisoprol® 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-adrenergic receptors (e.g., adrenaline, noradrenaline): possible manifestation of α-adrenergic receptor-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 or other 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 developing 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 heart failure in patients with the following conditions and pathological states: type 1 diabetes (insulin-dependent), 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, in which 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;
• 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 they 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 is discontinued before surgery, the dose should be gradually reduced and the drug discontinued 48 hours prior to general anesthesia.

Combinations of bisoprolol with calcium antagonists of the verapamil or diltiazem group, with class I antiarrhythmic drugs, and with centrally acting antihypertensive agents are 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 necessary, Bisoprol® 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 lung 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 Bisoprol® only after prior therapy with α-adrenoblockers.

Symptoms of thyrotoxicosis may be masked during treatment.

Use of Bisoprol® may result in a positive doping test.

Bisoprol® 5 mg and 10 mg tablets contain lactose; therefore, this medication is not recommended for patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Bisoprol® 5 mg and 10 mg tablets contain the colorant Yellow FCF (E 110), which may cause allergic reactions.

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 if the expected benefit to the woman 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 should be expected within the first 3 days.

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

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 vehicles or operate complex machinery. Particular attention should be paid at the beginning of treatment, during dose changes, or when combined with alcohol.

Method of Administration and Dosage.

Bisoprol® 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 Bisoprol® 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 Bisoprol® 10 mg) once daily. Further dose increases are justified only in exceptional cases. The maximum recommended dose is 20 mg per day.

Dosage adjustments are determined individually by the 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 ACE inhibitor intolerance), ß-blockers, diuretics, and, if necessary, cardiac glycosides.

Bisoprol® is indicated for the treatment of patients with chronic heart failure without signs of acute decompensation.

Treatment must be initiated and supervised by a physician experienced in managing chronic heart failure.

Treatment of stable chronic heart failure with Bisoprol® should be initiated according to the titration schedule below 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 initiation of chronic heart failure treatment, Bisoprol® 2.5 mg tablets are recommended.

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

During the titration phase, close 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 treatment.

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, interruption of treatment. After stabilization of the patient’s condition, re-initiation of bisoprolol therapy should always be considered.

Treatment with 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, treatment 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 Bisoprol® therapy 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 of Bisoprol® per day. 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 available 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 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 bradycardia: intravenous administration of atropine. If no response, cautious administration of isoprenaline or another agent with positive chronotropic effect. In exceptional cases, transvenous insertion of a temporary pacemaker may be required.

In arterial hypotension: intravenous fluid administration and vasopressor agents. Intravenous glucagon may be beneficial.

In second- or third-degree atrioventricular block: careful monitoring, infusion of isoprenaline, or transvenous cardiac pacing.

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

In bronchospasm: bronchodilators (e.g., isoprenaline), ß2-adrenergic agonists, and/or aminophylline.

In 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), 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: decreased tear production (should be considered in patients wearing contact lenses).

Very rare: conjunctivitis.

Ear and labyrinth disorders.

Rare: hearing impairment.

Respiratory system disorders.

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

Rare: allergic rhinitis.

Gastrointestinal disorders.

Common: nausea, vomiting, diarrhea, constipation.

Skin and subcutaneous tissue disorders.

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

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 in severity, 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.

Do not use the medicinal product 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. 10 tablets in a blister pack. 2, 3 or 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Address of manufacturer and location of business activity.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.