Bisoprolol sandoz®

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

Composition:

Active substance: bisoprolol fumarate;

One tablet contains 5 mg or 10 mg of bisoprolol fumarate;

Excipients: calcium hydrogen phosphate anhydrous, microcrystalline cellulose, pregelatinized corn starch, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating for 5 mg tablets: coating without dyes (lactose monohydrate, hypromellose, titanium dioxide (E 171), macrogol 4000), yellow iron oxide (E 172);

Film coating for 10 mg tablets: coating without dyes (lactose monohydrate, hypromellose, titanium dioxide (E 171), macrogol 4000), yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: yellow, round, film-coated tablets, with score lines for division into four parts, embossed with «BIS5» on one side;

10 mg tablets: apricot-colored, round, film-coated tablets, with «snap tab» type score lines for division into four parts, embossed with «BIS10» on one side.

Pharmacotherapeutic group.

Selective β-adrenoreceptor blockers. ATC code C07AB07.

Pharmacological Properties.

Pharmacodynamics.

Bisoprolol is a highly selective β1-adrenoblocker. When used in therapeutic doses, it has no intrinsic sympathomimetic activity and no clinically significant membrane-stabilizing properties. It exerts antianginal and antihypertensive effects. In the treatment of patients with ischemic heart disease (IHD) without chronic heart failure, bisoprolol reduces myocardial oxygen demand by decreasing heart rate, cardiac output, and arterial pressure, while improving myocardial oxygen supply due to reduction of end-diastolic pressure and prolongation of diastole. The drug has very low affinity for β2-receptors in bronchial and vascular smooth muscle, as well as for β2-receptors of the endocrine system. Bisoprolol may affect bronchial and peripheral arterial smooth muscle and glucose metabolism only in isolated cases.

Bisoprolol does not have a pronounced negative inotropic effect.

The maximum effect of bisoprolol is achieved within 3–4 hours after oral administration. After single administration, the effect of bisoprolol lasts for 24 hours. The maximum antihypertensive effect of bisoprolol is usually achieved within 2 weeks.

Pharmacokinetics.

Absorption. After oral administration, bisoprolol is well absorbed from the gastrointestinal tract. Bioavailability is approximately 90% and is independent of food intake. The pharmacokinetics of bisoprolol and plasma concentration are linear within the dose range of 5 mg to 20 mg. Maximum plasma concentration (Cmax) is reached within 2–3 hours.

Distribution. Plasma protein binding is approximately 30%, volume of distribution is 3.5 L/kg, and total clearance is approximately 15 L/h.

Metabolism and Elimination. The elimination half-life from plasma is 10–12 hours. Bisoprolol is eliminated from the body via two equal pathways: 50% of the active substance is metabolized into inactive metabolites in the liver and excreted by the kidneys, and 50% is excreted unchanged by the kidneys. In vitro studies using human liver microsomes have shown that bisoprolol metabolism involves CYP3A4 (~95%), while CYP2D6 plays only a minor role. Dose adjustment is not required in patients with mild to moderate hepatic or renal impairment. The pharmacokinetics of bisoprolol are linear and independent of patient age.

Clinical characteristics.

Indications.

Arterial hypertension, ischemic heart disease (IHD) (angina pectoris), chronic heart failure (CHF) 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 syndrome;
• Marked sinoatrial block;
• Symptomatic bradycardia (heart rate less than 60 beats/min);
• Symptomatic arterial hypotension (systolic blood pressure below 100 mm Hg);
• Severe chronic obstructive pulmonary disease;
• Severe form of bronchial asthma;
• Advanced peripheral circulatory disorders, Raynaud's disease;
• Untreated pheochromocytoma;
• Metabolic acidosis;
• Concomitant use with flecainide and sulpiride.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended for use.

Treatment of chronic heart failure.

• Class I antiarrhythmics (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecaine, propafenone): negative effect on atrioventricular conduction and myocardial inotropic function.

All indications.

• Calcium antagonists of the verapamil type, and to a lesser extent diltiazem: negative effect on myocardial contractility and atrioventricular conduction. Intravenous administration of verapamil may lead to marked arterial hypotension and atrioventricular block in patients taking β-blockers.
• Concomitant use of antihypertensive agents with central mechanism of action (clonidine, methyldopa, moxonidine, rilmenidine) may lead to decreased heart rate, reduced cardiac output, and vasodilation. Sudden withdrawal of these agents during combination therapy may increase the risk of reflex hypertension.

Combinations to be used with caution.

Treatment of arterial hypertension or ischemic heart disease (angina pectoris).

• Class I antiarrhythmics (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecaine, propafenone): may enhance the negative effect on atrioventricular conduction and myocardial inotropic function.

All indications.

• Dihydropyridine-type calcium antagonists (e.g., nifedipine, felodipine, amlodipine): may increase the 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): may enhance the negative effect on atrioventricular conduction.
• Locally acting β-blockers (e.g., those contained in eye drops for glaucoma treatment): the effect of bisoprolol may be enhanced.
• Parasympathomimetics: may increase atrioventricular conduction time and increase the risk of bradycardia.
• Insulin and oral hypoglycemic agents: the effect of these drugs may be enhanced. Signs of hypoglycemia may be masked. This interaction is more likely with non-selective β-blockers.
• Anesthetic agents: increased risk of myocardial depression and development of arterial hypotension.
• Cardiac glycosides (digitalis preparations): may reduce heart rate and prolong atrioventricular conduction time.
• Nonsteroidal anti-inflammatory drugs (NSAIDs): may attenuate the antihypertensive effect of bisoprolol.
• β-sympathomimetics (e.g., orciprenaline, isoprenaline, 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-receptor-mediated vasoconstrictive effect, leading to increased blood pressure and worsening of intermittent claudication. This interaction is more likely with non-selective β-blockers.
• Antihypertensive agents (e.g., tricyclic antidepressants, barbiturates, phenothiazines): increased risk of arterial hypotension.

Possible combinations.

• Mefloquine: increased risk of bradycardia.
• MAO inhibitors (except MAO-B inhibitors): enhance the hypotensive effect of β-blockers. Risk of hypertensive crisis.
• Rifampicin: possible slight reduction in the elimination half-life of bisoprolol due to induction of hepatic enzymes. Dose adjustment is not required.
• Ergotamine derivatives: exacerbation of peripheral circulatory disorders.

Special precautions for use.

Treatment of chronic heart failure with bisoprolol should be initiated with dose titration. Regular monitoring is required at the beginning of treatment.

Treatment must not be interrupted abruptly; it should be discontinued gradually by slowly reducing the dose of bisoprolol.

Caution is required when treating patients with hypertension or angina pectoris associated with heart failure using bisoprolol.

Particular caution is required when administering bisoprolol in the following cases:

• First-degree atrioventricular block;
• Diabetes mellitus with marked fluctuations in blood glucose levels; symptoms of hypoglycemia may be masked (e.g., tachycardia, palpitations, increased sweating);
• Strict diet;
• Prinzmetal's angina;
• Bronchospasm (bronchial asthma and other moderate obstructive lung diseases). Before initiating treatment, pulmonary function testing is recommended in patients with a history of bronchial asthma;
• 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;
• Peripheral circulatory disorders (symptoms may worsen, especially at the beginning of therapy);
• General anesthesia.

The anesthesiologist must be informed about the use of β-blockers. In patients scheduled for general anesthesia, β-blockers reduce the incidence of arrhythmias and myocardial ischemia during anesthesia, intubation, and the postoperative period. It is recommended to continue β-blocker therapy during the intraoperative period. The anesthesiologist should consider potential interactions with other drugs that may lead to bradyarrhythmia, reflex tachycardia, and reduced capacity of reflex mechanisms to compensate for decreased arterial pressure. If discontinuation of bisoprolol before surgery is deemed necessary, the dose should be tapered gradually and discontinued approximately 48 hours before general anesthesia.

Initiation and discontinuation of bisoprolol treatment for chronic heart failure require regular monitoring of the patient's condition.

Currently, there is insufficient therapeutic experience in treating chronic heart failure (CHF) in patients with the following conditions and pathological states: type 1 diabetes mellitus, severe renal and/or hepatic dysfunction, restrictive cardiomyopathy, congenital heart defects, hemodynamically significant acquired valvular heart disease, myocardial infarction within the last 3 months.

Combinations of bisoprolol with calcium antagonists of the verapamil or diltiazem type, class I antiarrhythmic agents, and centrally-acting antihypertensive drugs are not recommended (see section "Interaction with other medicinal products and other forms of interaction").

β-Adrenoblockers should be prescribed to patients with psoriasis (including family history) only after careful assessment of benefit/risk ratio.

Bisoprolol should be administered to patients with pheochromocytoma only after prior treatment with α-adrenoblockers.

Treatment with bisoprolol may mask symptoms of thyrotoxicosis.

Although cardioselective β-blockers (β1) have less impact 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, the drug should be used with caution. In patients with obstructive airway diseases, bisoprolol treatment 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 moderate chronic obstructive lung diseases, concomitant therapy with bronchodilators is indicated. In some cases, patients with bronchial asthma may require higher doses of β2-sympathomimetics due to increased airway tone during bisoprolol treatment.

The use of this drug may result in a positive doping test.

If a patient has a known intolerance to certain sugars, they should consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

The pharmacological action of bisoprolol may have harmful effects on pregnancy and/or the fetus/newborn. Bisoprolol should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. Generally, β-adrenoblockers reduce placental blood flow and may affect fetal development, cause intrauterine death, abortion, or premature delivery. Adverse effects in the fetus/newborn (e.g., hypoglycemia and bradycardia) may occur. If β-blocker therapy is necessary, a β1-selective blocker is preferred. 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. Symptoms of hypoglycemia and bradycardia may be expected during the first 3 days of life.

There are no data on the excretion of bisoprolol in breast milk or on the safety of its effects on breastfed infants.

Breastfeeding is not recommended during bisoprolol treatment.

Effect on ability to drive vehicles or operate 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. This should be taken into account, especially at the beginning of treatment, when changing the dose, or when used concomitantly with alcohol.

Method of Administration and Dosage

The drug should be taken whole in the morning, regardless of food intake, with a small amount of liquid. Tablets of 5 mg and 10 mg may be divided into four parts.

Arterial hypertension; ischemic heart disease (angina pectoris).

The recommended dose is 5 mg (1 tablet) once daily. In cases of mild arterial hypertension (diastolic pressure up to 105 mm Hg), a starting dose of 2.5 mg once daily (½ of a 5 mg tablet) may be prescribed.

If necessary, the daily dose may be increased to 10 mg (1 tablet) once daily. The maximum recommended dose is 20 mg once daily.

Dose adjustments are determined individually by the physician depending on the patient's condition.

Use with caution in patients with arterial hypertension or ischemic heart disease associated with heart failure.

Chronic heart failure with systolic dysfunction of the left ventricle, in combination with ACE inhibitors, diuretics, and, if necessary, cardiac glycosides.

Standard therapy for CHF: ACE inhibitors (or angiotensin receptor blockers in case of ACE inhibitor intolerance), β-blockers, diuretics, and, if necessary, cardiac glycosides.

Bisoprolol is indicated for treatment of patients with CHF without signs of acute decompensation.

Treatment of chronic heart failure should be initiated according to the following titration scheme, which 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 initial treatment of stable chronic heart failure, regular monitoring is required. During the titration phase, vital signs (arterial pressure, heart rate) and symptoms of worsening heart failure must be closely monitored. Symptoms may develop from the first day of treatment.

Dose Modification.

If 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 stabilization of the patient's condition, treatment should be continued.

Treatment with this drug is long-term. The duration of therapy depends on the nature and course of the disease.

Do not discontinue treatment abruptly or alter the recommended dose without consulting a physician, especially in patients with ischemic heart disease, as this may lead to deterioration of the patient's condition. If discontinuation is necessary, treatment should be tapered gradually by slowly reducing the dose.

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 daily dose of bisoprolol 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 dysfunction; therefore, dose escalation should be performed with caution.

Elderly patients do not require dose adjustment.

Children.

Do not use. Clinical data on the efficacy and safety of the drug in pediatric patients are lacking.

Overdose.

Symptoms. In cases of overdose (e.g., daily dose of 15 mg instead of 7.5 mg), third-degree atrioventricular block, bradycardia, and dizziness have been reported. The most common manifestations of overdose are typically bradycardia, arterial hypotension, bronchospasm, acute heart failure, and hypoglycemia. Several cases of overdose (maximum 2000 mg of bisoprolol) have been reported, presenting with bradycardia and/or arterial hypotension; all patients recovered. There is wide 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. Discontinue the drug and seek medical attention immediately. Supportive and symptomatic therapy should be administered depending on the severity of the overdose. Limited data suggest that bisoprolol is poorly dialyzable.

In case of bradycardia: intravenous administration of atropine. If bradycardia is unresponsive to treatment, isoprenaline or other agents with positive chronotropic effects may be cautiously administered; if necessary, cardiac pacing should be considered. In certain circumstances, transvenous pacemaker insertion may be required.

In case of arterial hypotension: administration of vasoconstrictive agents, intravenous glucagon.

In case of second- or third-degree atrioventricular block: careful patient monitoring is required during isoprenaline infusion; cardiac pacing may be necessary.

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

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

In case of hypoglycemia: intravenous glucose administration.

Adverse reactions.

Undesirable effects are classified according to frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated due to lack of data).

Psychiatric disorders: uncommon – depression, sleep disturbances; rare – nightmares, hallucinations.

Nervous system disorders: common – dizziness, headache; rare – syncope.

Eye disorders: rare – decreased lacrimation (should be considered in contact lens wearers); very rare – conjunctivitis.

Ear and labyrinth disorders: rare – hearing impairment.

Cardiovascular disorders: very common – bradycardia (in patients with chronic heart failure); common – signs of worsening of pre-existing heart failure (in patients with CHF), cold sensation or numbness in extremities, arterial hypotension; uncommon – atrioventricular conduction disturbances, especially in patients with heart failure, orthostatic hypotension, worsening of heart failure (in patients with arterial hypertension or angina pectoris); bradycardia (in patients with arterial hypertension or angina pectoris).

Respiratory system disorders: uncommon – bronchospasm in patients with a history of bronchial asthma and chronic obstructive pulmonary diseases; rare – allergic rhinitis.

Gastrointestinal disorders: common – nausea, vomiting, diarrhea, constipation.

Hepatobiliary disorders: rare – hepatitis.

Skin and subcutaneous tissue disorders: rare – hypersensitivity reactions (itching, erythema, rash), angioneurotic edema; very rare – worsening of psoriasis (manifested as psoriatic rash), alopecia (observed during treatment with β-blockers).

Musculoskeletal and connective tissue disorders: uncommon – myasthenia, muscle spasms, cramps.

Reproductive system and breast disorders: rare – erectile dysfunction.

General disorders and administration site conditions: common – asthenia (in patients with CHF), increased fatigue (especially at the beginning of treatment), usually mild and transient, resolving within 1–2 weeks; uncommon – asthenia (in patients with arterial hypertension and ischemic heart disease).

Investigations: rare – increased blood triglyceride levels, increased plasma liver enzyme activity (AST, ALT).

If adverse effects or undesirable reactions occur, a physician should be informed immediately.

Shelf life. 5 years.

Storage conditions.

No special storage conditions required.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 (10 × 3) blisters in a cardboard box.

15 tablets in a blister; 2 (15 × 2), 4 (15 × 4), 6 (15 × 6) blisters in a cardboard box.

Prescription category. Prescription-only.

Manufacturer.

Salyutas Pharma GmbH (full-cycle production).

Manufacturer's location and address of its business activity.

Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.

Manufacturer.

LEK S.A. (alternative manufacturer).

Manufacturer's location and address of its business activity.

95-010 Strzegom, Podlipie Street 16, Poland (full-cycle production).

Domaniewska 50C, Warsaw, 02-672, Poland (primary and secondary packaging, batch release).