Bisoprolol-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BISOPROLOL-TEVA (BISOPROLOL-TEVA)

Composition:

Active substance: bisoprolol fumarate;

1 tablet contains bisoprolol fumarate 5 mg or 10 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, magnesium stearate, hypromellose, macrogol 6000, titanium dioxide (E 171), mannitol (E 421).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets, odorless, with the imprint «BISOPROLOL 5» (5 mg tablets) or «BISOPROLOL 10» (10 mg tablets) on one side.

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 of bronchial and vascular smooth muscle, as well as for β2-receptors involved in metabolic regulation. Thus, bisoprolol does not affect airway resistance or β2-mediated metabolic effects. The β1-selectivity of bisoprolol extends beyond the therapeutic dose range.

Bisoprolol has no pronounced negative inotropic effect.

The maximum effect of bisoprolol occurs within 3–4 hours after administration. The elimination half-life from blood plasma is 10–12 hours, resulting in 24-hour efficacy after a single dose. The maximum antihypertensive effect is achieved after 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. With prolonged therapy, increased peripheral resistance decreases. The antihypertensive effect of β-blockers is also mediated by reduction of plasma renin activity.

Bisoprolol suppresses the response to sympathetic-adrenergic activity by blocking cardiac β1-receptors. This leads to a slowing of heart rate and reduced contractile function of the myocardium, thereby decreasing myocardial oxygen demand. This mechanism provides the desired therapeutic effect in patients with angina pectoris and ischemic heart disease.

Pharmacokinetics.

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 through the liver is minimal, contributing to high bioavailability—approximately 90%. Plasma protein binding is approximately 30%. The volume of distribution is 3.5 L/kg.

Bisoprolol is eliminated from the body via two pathways: approximately 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 the long elimination half-life (10–12 hours), the drug maintains its therapeutic effect for 24 hours with once-daily administration.

Because the kidneys and liver contribute approximately equally to the elimination of this drug, dosage adjustment is not required in patients with renal or hepatic impairment. The kinetics of bisoprolol are linear and independent of age.

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.

• Hypersensitivity to bisoprolol or to any of the excipients;
• Acute heart failure or decompensated heart failure requiring inotropic therapy;
• Cardiogenic shock;
• Second- or third-degree atrioventricular block (except in patients with a permanent pacemaker);
• Sinus node dysfunction;
• Sinoatrial block;
• Symptomatic bradycardia;
• Symptomatic arterial hypotension;
• Severe bronchial asthma or severe chronic obstructive pulmonary disease;
• Advanced stages of peripheral circulatory disorders or Raynaud's disease;
• Metabolic acidosis;
• Untreated phaeochromocytoma.

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations.

Flocoufenac: beta-blockers may suppress compensatory cardiovascular responses to arterial hypotension or shock that may be induced by flocoufenac.

Sultopride: bisoprolol should not be used concomitantly with sultopride due to an increased risk of ventricular arrhythmia.

Not recommended combinations.

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 effects on myocardial inotropic function and atrioventricular conduction. Intravenous administration of verapamil in patients taking ß-blockers may lead to pronounced arterial hypotension and atrioventricular block.
• Antihypertensives with central mechanism of action (clonidine, methyldopa, guanfacine, moxonidine, rilmenidine): possible worsening of heart failure due to reduction in central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly following discontinuation of ß-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 enhanced negative inotropic effect.

All indications.

• Calcium antagonists (dihydropyridine derivatives, 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 beta-blockers (particularly those contained in ophthalmic solutions 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. ß-blockade may mask symptoms of hypoglycemia.
• Anesthetic agents: increased risk of myocardial depression and arterial hypotension (see section "Special precautions").
• Cardiac glycosides: reduction in heart rate, prolonged atrioventricular conduction time.
• Non-steroidal anti-inflammatory drugs (NSAIDs): possible attenuation of the antihypertensive effect of bisoprolol.
• ß-sympathomimetics (e.g., isoprenaline, orciprenaline, dobutamine): concomitant use with bisoprolol may reduce the therapeutic effect of both agents. Higher doses of adrenaline may be required to treat allergic reactions.
• Sympathomimetics activating both α- and ß-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 ß-blockers.

Concomitant use with antihypertensive agents or other drugs with hypotensive effects (e.g., tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of arterial hypotension.

• Anticholinesterase agents (including tacrine): possible prolongation of atrioventricular conduction time and/or increased bradycardia.
• Baclofen: enhanced antihypertensive effect.
• Amifostine: increased hypotensive effect.

Permitted combinations.

• Mefloquine: possible increased risk of bradycardia.
• MAO inhibitors (except MAO-B inhibitors): increased antihypertensive effect of ß-blockers, but risk of hypertensive crisis exists.

Special precautions for use.

At the beginning of bisoprolol therapy, patients must be monitored regularly, especially elderly individuals.

Treatment of stable chronic heart failure with bisoprolol should be initiated with a titration phase.

In patients with ischemic heart disease, therapy 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 dysfunction, severe hepatic impairment, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant acquired valvular heart disease, or myocardial infarction within the past 3 months.

Concomitant use of bisoprolol with amiodarone should be done with caution due to the risk of developing contractile dysfunction and disturbances in cardiac conduction (due to suppression of compensatory sympathetic responses).

In general, bisoprolol should not be prescribed in combination with calcium antagonists of the verapamil or diltiazem type or with centrally acting antihypertensive agents.

The drug should be used with caution in patients with the following conditions:

• Bronchospasm (bronchial asthma, obstructive respiratory diseases);
• Diabetes mellitus with significant fluctuations in blood glucose levels due to the potential for masking symptoms of hypoglycemia (tachycardia, palpitations, increased sweating);
• 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 disease (symptoms may worsen at the beginning of therapy);
• General anesthesia.

Patients must be advised to inform their anesthesiologist about the use of β-adrenoreceptor blockers. 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. It is essential to inform the anesthesiologist about the use of β-adrenoreceptor blockers, as the physician must consider potential interactions with other drugs that could 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 tapered and the drug discontinued 48 hours before general anesthesia.

Combinations of bisoprolol with calcium antagonists of the verapamil or diltiazem group, class I antiarrhythmic agents, or 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 respiratory diseases unless there are strong indications for therapy. If necessary, bisoprolol should be used with caution. In patients with obstructive respiratory diseases, bisoprolol therapy 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, 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 versus risk.

In patients with pheochromocytoma, bisoprolol should be prescribed only after initiating therapy with α-adrenoreceptor blockers.

Symptoms of thyrotoxicosis may be masked during treatment.

Use of bisoprolol may lead to a positive result in doping control tests.

Use during pregnancy or breastfeeding.

Pregnancy. Bisoprolol has pharmacological properties that may cause harmful effects on pregnancy and/or fetal/neonatal development. Generally, β-adrenoreceptor blockers reduce placental blood flow, which may lead to intrauterine growth retardation, intrauterine fetal 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 β-blocker is preferred.

Bisoprolol should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. Placental and uterine blood flow must 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 in breast milk. Therefore, the use of the drug is not recommended during breastfeeding.

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

It has been reported that in patients with ischemic heart disease, the drug does 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, when changing the dose of the drug, or when used in combination with alcohol.

Method of Administration and Dosage

Bisoprolol-Teva tablets should be taken without chewing, in the morning or with breakfast, swallowed 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 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. Further dose increases are justified only in exceptional cases. The maximum recommended dose is 20 mg once daily.

Dose adjustments should be individually determined by the 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 necessary, cardiac glycosides.

Bisoprolol should be prescribed for the treatment of patients with chronic heart failure without signs of acute decompensation.

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

Treatment of chronic heart failure with bisoprolol should be initiated according to the titration scheme below and may be adjusted based on individual patient response.

• 1.25 mg* of bisoprolol fumarate once daily for 1 week, then increased to
• 2.5 mg* of bisoprolol fumar combustible once daily for the next 1 week, then increased to
• 3.75 mg* of bisoprolol fumarate once daily for the next 1 week, then increased to
• 5 mg of bisoprolol fumarate once daily for the next 4 weeks, then increased to
• 7.5 mg of bisoprolol fumarate once daily for the next 4 weeks, then increased to
• 10 mg of bisoprolol fumarate once daily as maintenance therapy.

* Use bisoprolol at the corresponding dosage strength.

A dose of 2.5 mg of bisoprolol is recommended at the beginning of therapy for chronic heart failure.

The maximum recommended dose 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, temporary discontinuation of treatment. After patient stabilization, re-initiation of bisoprolol therapy should always be considered.

Bisoprolol therapy should not be stopped abruptly, especially in patients with ischemic heart disease, as this may lead to clinical deterioration. If discontinuation is necessary, the 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 bisoprolol therapy is prolonged and depends on the nature and severity of the disease.

Patients with impaired renal or hepatic function

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 dysfunction (creatinine clearance < 20 mL/min) or severe hepatic impairment, the daily dose should not exceed 10 mg. 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 and/or renal impairment; therefore, dose escalation should be performed cautiously.

For elderly patients, dose adjustment of bisoprolol is not required.

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 β-blocker overdose include bradycardia, arterial hypotension, acute heart failure, bronchospasm, and hypoglycemia. There is considerable individual variability in 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 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, administer isoprenaline or another agent with positive chronotropic effect cautiously. In exceptional cases, transvenous insertion of a temporary pacemaker may be required.

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

For second- or third-degree atrioventricular block: close monitoring, 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.

Side effects.

Immune system: development of antinuclear antibodies with specific clinical symptoms such as lupus-like syndrome, which resolves after discontinuation of treatment.

Nutritional and metabolic disorders: hypoglycemia.

Psychiatric disorders: sleep disturbances, depression, nightmares, hallucinations.

Nervous system disorders: dizziness*, headache*, loss of consciousness.

Eye disorders: decreased tear production (should be considered in contact lens wearers), conjunctivitis.

Ear disorders: hearing impairment.

Cardiac disorders: bradycardia, atrioventricular conduction disturbances, signs of worsening heart failure.

Vascular disorders: cold sensation or numbness in extremities, Raynaud's phenomenon, exacerbation of pre-existing intermittent claudication, arterial hypotension, orthostatic hypotension.

Respiratory system disorders: bronchospasm in patients with history of bronchial asthma or obstructive respiratory diseases, allergic rhinitis.

Gastrointestinal disorders: nausea, vomiting, diarrhea, constipation, abdominal pain.

Hepatic disorders: hepatitis.

Skin and subcutaneous tissue disorders: hypersensitivity reactions including itching, redness, rash, hair loss; β-blockers may cause or exacerbate psoriasis, psoriatic rashes.

Musculoskeletal system disorders: muscle weakness, cramps.

Reproductive system disorders: erectile dysfunction.

General disorders: increased fatigue*, asthenia.

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

* Refers 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.

In case of adverse events or unwanted reactions, inform your doctor immediately.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 10 tablets per blister; 3 blisters per carton.

Prescription category. Prescription only.

Manufacturer. Teva Pharmaceutical Factory JSC.

Manufacturer's location and address of business premises.

Site 1; H-4042 Debrecen, Pallagi Street 13, Hungary.