Bisoprolol aurobindo

Ukraine
Brand name Bisoprolol aurobindo
Form tablets, film-coated
Active substance / Dosage
bisoprolol · 10 mg
Prescription type prescription only
ATC code
C07AB07
Registration number UA/16250/01/03
Manufacturer Aurobindo Pharma Limited - Unit III

Table of Contents

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BISOPROLOL AUROBINDO (BISOPROLOL AUROBINDO)

Composition:

Active substance: bisoprolol;

One film-coated tablet contains 2.5 mg or 5 mg or 10 mg of bisoprolol fumarate;

Excipients: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, colloidal anhydrous silicon dioxide, crospovidone, magnesium stearate, Opadry White 03B28796 (hypromellose, titanium dioxide (E 171), polyethylene glycol 400).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

2.5 mg tablets: white, round, biconvex film-coated tablets, marked with "R" and a break line on one side and "2" on the other side;

5 mg tablets: white, round, biconvex film-coated tablets, marked with "R" and a break line on one side and "5" on the other side;

10 mg tablets: white, round, biconvex film-coated tablets, marked with "R" and a break line on one side and "10" on the other side.

Pharmacotherapeutic group. Selective beta-adrenoreceptor blockers.

ATC code C07AB07.

Pharmacological properties.

Pharmacodynamics.

Bisoprolol is an active, highly selective β1-adrenoceptor blocker with no intrinsic sympathomimetic activity and no clinically relevant membrane-stabilizing properties. Bisoprolol 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 should 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 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 β-blockers is also mediated by a 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, which are excreted by the kidneys, and the remaining 50% is excreted unchanged by the kidneys. Total bisoprolol clearance is 15 L/h. The elimination half-life from plasma is 10–12 hours, ensuring 24-hour efficacy after a single dose.

Linearity. Bisoprolol pharmacokinetics are linear and independent of age.

Special patient groups. Since bisoprolol is eliminated equally by the kidneys and liver, dosage adjustment is not required in patients with hepatic or renal impairment. However, the 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 levels of bisoprolol are higher and the elimination half-life is longer compared to healthy volunteers. The steady-state maximum 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.

  • 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 (sick sinus syndrome);
  • Sinoatrial block;
  • Symptomatic bradycardia;
  • Symptomatic arterial hypotension;
  • Severe form of bronchial asthma or severe form of chronic obstructive pulmonary disease (COPD);
  • Severe peripheral circulatory disorders and Raynaud's syndrome;
  • Untreated pheochromocytoma;
  • Metabolic acidosis.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended

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 enhancement of negative inotropic effect.

All indications

Calcium antagonists (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 severe arterial hypotension and atrioventricular block.

Centrally-acting antihypertensive agents (clonidine, methyldopa, guanfacine, moxonidine, rilmenidine): possible worsening of heart failure due to reduction in central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Sudden withdrawal, particularly following 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 enhancement of negative inotropic effect.

All indications

Dihydropyridine calcium antagonists (e.g., nifedipine, felodipine, amlodipine): possible increased risk of arterial hypotension and development of heart failure. A possible increase in the 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 antidiabetic agents: enhanced hypoglycemic effect. β-receptor 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.

Non-steroidal anti-inflammatory drugs (NSAIDs): possible attenuation of the antihypertensive effect of bisoprolol.

β-sympathomimetics (e.g., orciprenaline, isoprenaline, dobutamine): combination 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 β-adrenergic receptors (e.g., noradrenaline, adrenaline): combination with bisoprolol may unmask vasoconstrictive effects mediated by α-adrenergic receptors, 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 agents with hypotensive effects (tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of arterial hypotension.

Combinations that may be used

Mefloquine: increased risk of bradycardia.

MAO inhibitors (except MAO-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 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 diseases and pathological conditions:

  • Type 1 diabetes mellitus (insulin-dependent);
  • Severe renal function impairment;
  • Severe hepatic function impairment;
  • Restrictive cardiomyopathy;
  • Congenital heart defects;
  • Hemodynamically significant acquired valvular heart diseases;
  • 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; 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 (coronary vasospasm has been observed; despite high β1-selectivity, angina attacks cannot be completely controlled with bisoprolol in patients with Prinzmetal's angina);
  • Peripheral arterial occlusive diseases (complaints may worsen at the beginning of therapy);
  • General anesthesia.

It is mandatory to inform the 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. Continuation of β-blocker therapy during the perioperative period is recommended. The anesthesiologist should consider the potential interaction with other medicinal products, which may lead to bradyarrhythmia, reflex tachycardia, and reduced capacity of reflex mechanisms to compensate for blood loss. If discontinuation of bisoprolol is necessary before surgery, the dose should be gradually reduced and the drug discontinued 48 hours prior to 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 types of interactions").

Although cardioselective β1-blockers 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 compelling reasons for therapy. If such reasons exist, the medicinal product Bisoprolol-Aurobindo should be used with caution. In patients with obstructive airway diseases, bisoprolol therapy should be initiated with 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 drug administration.

β-blockers (e.g., bisoprolol) should be prescribed to patients with psoriasis (including in the medical history) only after careful benefit/risk assessment.

In patients with pheochromocytoma, bisoprolol should be prescribed only after initiation of α-adrenoblocker therapy.

Symptoms of thyrotoxicosis may be masked during bisoprolol use. Use of the medicinal product Bisoprolol-Aurobindo may result in a positive doping test.

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 reactions 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 when 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 the excretion of bisoprolol in breast milk; therefore, Bisoprolol-Aurobindo 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.

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 used concomitantly with alcohol.

Method of Administration and Dosage

Bisoprolol Aurubindo 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 a gradual dose increase. The recommended dose is 5 mg (1 tablet of Bisoprolol Aurubindo 5 mg) once daily. For mild hypertension (diastolic pressure up to 105 mm Hg), a dose of 2.5 mg may be appropriate.

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

Dosage adjustments should be determined individually by the physician, depending on pulse rate and therapeutic response.

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 Aurubindo is indicated for treatment of patients with chronic heart failure without signs of acute decompensation.

The treating physician must have experience in managing chronic heart failure.

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

Dose Titration Period

Treatment of chronic heart failure with bisoprolol requires dose titration, initiated according to the following titration scheme, 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, vital signs (heart rate, blood pressure) and symptoms of worsening heart failure must be closely monitored. Symptoms may appear from the first day of treatment.

Modifications in Treatment

If the maximum recommended dose is poorly tolerated, a gradual dose reduction may be considered.

In case of temporary worsening of heart failure, or development of arterial hypotension or bradycardia, the doses of concomitantly administered medications should be reviewed. Temporary reduction of bisoprolol dose or interruption of treatment may also be necessary.

After stabilization of the patient's condition, re-initiation of bisoprolol therapy and/or dose adjustment should always be considered. Abrupt discontinuation of the drug should be avoided, especially in patients with ischemic heart disease, as this may lead to clinical deterioration.

If discontinuation of the drug is necessary, it should be done gradually, with a stepwise dose reduction (e.g., halving the dose weekly). Treatment of stable chronic heart failure with bisoprolol is typically long-term.

The duration of treatment with Bisoprolol-Aurubindo is prolonged and depends on the nature and severity of the disease.

Patients with Hepatic 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 Bisoprolol-Aurubindo 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 available on bisoprolol in patients with chronic heart failure and concomitant hepatic or renal impairment. Therefore, dose escalation in these patients should be performed with particular 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 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, hypoglycemia, and bronchospasm. Several cases of overdose have been reported in patients with arterial 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 wide 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, the drug should be discontinued and supportive and symptomatic therapy initiated. Limited data suggest that bisoprolol is not easily dialyzable. Based on expected pharmacological effects and recommendations for other β-blockers, the following general measures should be considered:

In case of bradycardia: intravenous administration of atropine. If there is no response, administer isoprenaline or another agent with positive chronotropic effect cautiously. In exceptional cases, transvenous insertion of a temporary pacemaker may be required.

In case of arterial hypotension: intravenous fluid administration and vasoconstrictors. Intravenous glucagon may be beneficial.

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

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

In case of bronchospasm: administration of bronchodilators (e.g., isoprenaline), β2-adrenergic agonists and/or aminophylline.

In case of hypoglycemia: intravenous glucose administration.

Side effects

Adverse reactions 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), unknown (frequency cannot be determined from available 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).

Laboratory findings

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

Nervous system

Common: dizziness*, headache*.

Rare: loss of consciousness.

Eye disorders

Rare: reduced tear production (should be considered in contact lens wearers).

Very rare: conjunctivitis.

Ear and labyrinth disorders

Rare: hearing impairment.

Respiratory, thoracic and mediastinal disorders

Uncommon: bronchospasm in patients with bronchial asthma or obstructive respiratory diseases in medical history.

Rare: allergic rhinitis.

Gastrointestinal disorders

Common: gastrointestinal disturbances such as nausea, vomiting, diarrhea, constipation.

Skin and subcutaneous tissue disorders

Rare: hypersensitivity reactions (itching, erythema, rash), angioneurotic edema.

Very rare: alopecia; treatment with β-blockers may worsen psoriasis in patients with psoriasis, manifesting as psoriatic rash.

Musculoskeletal and connective tissue disorders

Uncommon: muscle weakness, cramps.

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).

General disorders

Common: asthenia (in patients with chronic heart failure), fatigue*.

Uncommon: asthenia (in patients with arterial hypertension or ischemic heart disease).

Hepatic disorders

Rare: hepatitis.

Reproductive system disorders

Rare: erectile dysfunction.

Psychiatric disorders

Uncommon: sleep disturbances, depression.

Rare: nightmares, hallucinations.

* 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.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is an important step. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any adverse reactions to the national health authorities.

Shelf life. 2 years.

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

Packaging. 14 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

  1. Aurobindo Pharma Limited – Unit III / Aurobindo Pharma Limited – Unit III.
  2. Aurobindo Pharma Ltd, Formulation Unit XV / Aurobindo Pharma Ltd, Formulation Unit XV.

Manufacturer's address and place of business.

  1. Survey no: 313, 314 – Block I, II, III, IV, Bachupally Village, Quthubullapur Mandal, Medchal District, Telangana, 500090, India.
  2. Plot No.17A, E.Bonangi (Village), Parawada (Mandal), Visakhapatnam, Andhra Pradesh, 531021, India.