Bisoprolol-teva

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

Composition:

Active substance: bisoprolol;

1 tablet contains 5 mg or 10 mg of bisoprolol hemifumarate;

Excipients: lactose monohydrate, microcrystalline cellulose, crospovidone, magnesium stearate;

For 5 mg tablets: yellow pigment PV 22812 (containing: lactose monohydrate, yellow iron oxide (E 172));

For 10 mg tablets: beige pigment PV 27215 (containing: lactose monohydrate, yellow iron oxide (E 172), red iron oxide (E 172)).

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets – pale yellow with specks, round, biconvex tablets, marked with "5" and a break line on one side;

10 mg tablets – beige with specks, round, biconvex tablets, marked with "10" and a break line on one side.

Pharmacotherapeutic group. Selective β-adrenoreceptor blockers.

ATC code C07AB07.

Pharmacological Properties

Pharmacodynamics

Bisoprolol is a highly selective β1-adrenoceptor blocker. It has no intrinsic sympathomimetic activity and no clinically significant membrane-stabilizing properties. The drug has very low affinity for β2-receptors in the smooth muscle of bronchi and blood vessels, 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 is maintained throughout the therapeutic dose range.

Bisoprolol does not exhibit a pronounced negative inotropic effect.

The maximum effect of bisoprolol occurs within 3–4 hours after 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 after 2 weeks of continuous 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 treatment, 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 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

After oral administration, more than 90% of bisoprolol is absorbed from the gastrointestinal tract. Absorption is not affected by food intake. First-pass metabolism in the liver is minimal, resulting in high bioavailability of approximately 90%. Plasma protein binding is about 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, while the remaining 50% is excreted unchanged by the kidneys. Total clearance of bisoprolol is 15 L/h. Due to its long elimination half-life (10–12 hours), the drug maintains therapeutic efficacy for 24 hours with once-daily administration.

Bisoprolol kinetics are linear and independent of age.

Since both renal and hepatic pathways contribute approximately equally to the elimination of bisoprolol, dosage adjustment is not required in patients with renal or hepatic impairment. In patients with chronic heart failure of NYHA (New York Heart Association) functional class III, plasma levels of bisoprolol are higher and the 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.

− Hypersensitivity to bisoprolol, other β-blockers, or any component of the medicinal product;

− Acute heart failure or decompensated heart failure requiring intravenous 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 bronchial asthma or severe chronic obstructive pulmonary disease;

− Severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome;

− Metabolic acidosis;

− Untreated pheochromocytoma;

• Concomitant use with floctafénine and sultopride.

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations

Floctafénine: β-blockers may impair compensatory cardiovascular responses to arterial hypotension or shock that may be induced by floctafénine.

Sultopride: concomitant use of bisoprolol with sultopride is not recommended due to an increased risk of ventricular arrhythmias.

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 (careful clinical and ECG monitoring required).

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 receiving β-blockers may lead to marked arterial hypotension and atrioventricular block.

− Centrally-acting antihypertensive agents (clonidine, methyldopa, guanfacine, moxonidine, rilmenidine): possible worsening of heart failure due to reduced central sympathetic tone (reduced heart rate and cardiac output, vasodilation). Abrupt withdrawal, especially if preceded by discontinuation of β-blockers, may increase the risk of rebound hypertension.

− Monoamine oxidase inhibitors (MAOIs) (except MAO-B inhibitors): enhanced hypotensive effect of β-blockers; risk of hypertensive crisis.

Combinations requiring 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. 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.

− Other β-blockers, including 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: reduced reflex tachycardia, increased risk of myocardial depression and arterial hypotension (see section "Special precautions for use").

− Cardiac glycosides: reduced heart rate, prolonged atrioventricular conduction time.

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

− Ergotamine derivatives: worsening of peripheral circulation disorders.

− β-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 β-adrenergic receptors (e.g., adrenaline, noradrenaline): possible manifestation of α-adrenergic-mediated vasoconstrictive effects, leading to increased blood pressure and exacerbation of intermittent claudication. Such interaction is more likely with non-selective β-blockers.

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

Baclofen: enhanced hypotensive effect.

Amifostine: enhanced hypotensive effect.

Consider during concomitant use

− Mefloquine: possible increased risk of bradycardia.

• Corticosteroids: reduced hypotensive effect due to water and sodium retention.
• Rifampicin: possible slight reduction in the elimination half-life of bisoprolol due to induction of hepatic enzymes metabolizing drugs. Dose adjustment is usually not required.

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. In patients with ischemic heart disease, abrupt discontinuation of treatment may increase the risk of myocardial infarction or sudden death (see section "Dosage and administration" for further details). 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 mellitus (insulin-dependent), severe renal impairment, severe hepatic impairment, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant acquired valvular heart disease, or myocardial infarction within the past 3 months.

The medicinal product should be used with caution in the following cases:

− bronchospasm (bronchial asthma, obstructive respiratory diseases);

• concomitant treatment with cholinesterase inhibitors (including tacrine): possible prolongation of atrioventricular conduction time or increased bradycardia;
• use of iodine-containing contrast agents: β-blockers may impair compensatory cardiovascular responses in cases of arterial hypotension or shock induced by iodine-containing contrast agents;

− diabetes mellitus with marked fluctuations in blood glucose levels – due to the potential masking of hypoglycemia symptoms (tachycardia, palpitations, increased sweating). Blood glucose levels should be monitored during bisoprolol treatment;

− strict diet;

− undergoing desensitization therapy. Like other β-blockers, bisoprolol may enhance sensitivity to allergens and increase the severity of anaphylactic reactions. In such cases, epinephrine treatment 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.

The anesthesiologist must be informed about the use of β-adrenoreceptor blockers. In patients undergoing general anesthesia, β-blockers reduce 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 the physician must consider potential interactions with other drugs that may lead to bradyarrhythmia, reflex tachycardia, and reduced compensatory capacity for blood loss. If bisoprolol is to be discontinued 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, antiarrhythmic drugs of class I, 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 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 pulmonary 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 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 treatment.

Use of bisoprolol may result in a positive doping test.

The product contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

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 mother 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 treatment should be considered.

The newborn should be under close observation after delivery. Hypoglycemia and bradycardia should be anticipated during the first 3 days of life.

Breastfeeding period. There are no data on bisoprolol excretion in human breast milk. Therefore, the use of the drug is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

It has been reported that the medicinal product does 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 caution is required at the beginning of treatment, when changing the dose, or when used concomitantly with alcohol.

Dosage and Administration

The tablets are intended for oral administration. Bisoprolol-Teva tablets should be taken in the morning on an empty stomach, during or after breakfast, swallowed whole without chewing, with a small amount of liquid. The tablet may be divided into equal doses.

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 a physician based 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 should be prescribed for the 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 chronic heart failure with bisoprolol should be initiated according to the titration schedule below and may be adjusted based on individual patient response.

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

* Use bisoprolol at the corresponding dosage strength.

A dose of 2.5 mg 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.

Dose Modification

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 patient stabilization, 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 clinical deterioration. If discontinuation is necessary, it is recommended to taper the dose gradually (e.g., halving the dose weekly).

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

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 dose 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 with caution.

Elderly patients do not require dose adjustment of bisoprolol.

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 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 "Dosage and Administration").

Treatment

In case of overdose, discontinue the drug and provide supportive and symptomatic therapy. Limited data suggest that bisoprolol is poorly dialyzable. In suspected overdose, based on 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, cautiously administer isoprenaline or another agent with positive chronotropic effect. 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: careful monitoring, infusion of isoprenaline, or transvenous insertion of a cardiac pacemaker.

For worsening of chronic heart failure: intravenous diuretics, inotropic agents, and vasodilators.

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

For hypoglycemia: intravenous glucose administration.

Adverse Reactions

Adverse reactions are categorized by frequency as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Immune system

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

Metabolism and nutrition

Rare: hypoglycemia.

Psychiatric

Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

Nervous system

Common: fatigue, exhaustion, dizziness*, headache*.

Rare: loss of consciousness.

Eye

Rare: decreased lacrimation (should be considered in contact lens wearers).

Very rare: conjunctivitis.

Ear and labyrinth

Rare: hearing disturbances.

Cardiac

Very common: bradycardia (in patients with chronic heart failure).

Common: signs of worsening of pre-existing heart failure (in patients with chronic heart failure).

Uncommon: bradycardia (in patients with arterial hypertension or ischemic heart disease), atrioventricular conduction disturbances, signs of worsening of pre-existing heart failure (in patients with arterial hypertension or ischemic heart disease).

Vascular

Common: sensation of cold or numbness in extremities, exacerbation of pre-existing intermittent claudication, arterial hypotension (especially in patients with heart failure).

Uncommon: orthostatic hypotension.

Respiratory system

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

Rare: allergic rhinitis.

Gastrointestinal

Common: gastrointestinal complaints such as nausea, vomiting, diarrhea, abdominal pain, constipation.

Hepatic

Rare: hepatitis.

Skin and subcutaneous tissue

Rare: hypersensitivity reactions including pruritus, erythema, rash.

Very rare: β-blockers may induce or exacerbate psoriasis, psoriatic rash, alopecia.

Musculoskeletal system

Uncommon: muscle weakness, cramps, arthropathy.

Reproductive system

Rare: erectile dysfunction.

General disorders

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

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

Investigations

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

* 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 adverse effects or unwanted reactions occur, a physician must be informed immediately.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging to protect from moisture. Keep out of reach of children.

Packaging. 10 tablets per blister, 3, 5, or 9 blisters per carton.

Prescription category. Prescription only.

Manufacturer. Merckle GmbH.

Manufacturer's address and place of business.
Ludwig-Merckle-Straße 3, 89143 Blaubeuren, Germany.