Bisotrol 10

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BISOTROL 5 (BISOTROL 5) BISOTROL 10 (BISOTROL 10)

Composition:

Active substance:
bisoprolol;

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

Excipients:
microcrystalline cellulose, calcium hydrogen phosphate, pregelatinized starch, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, titanium dioxide (E 171), polyethylene glycol, polysorbate 80, purified water, red iron oxide (E 172), and yellow iron oxide (E 172) (BISOTROL 5).

Pharmaceutical form.
Film-coated tablets.

Main physicochemical properties:

5 mg tablets: pink-colored, round, biconvex, film-coated, smooth on both sides;

10 mg tablets: white or almost white, round, biconvex, film-coated, smooth on both sides.

Pharmacotherapeutic group.
Selective beta-adrenoceptor blockers.

ATC code: C07AB07.

Pharmacological properties.

Pharmacodynamics.

Bisoprolol is a highly selective β1-adrenoceptor blocker. It has no intrinsic sympathomimetic activity and no clinically significant membrane-stabilizing properties. The drug has very low affinity for β2-receptors in bronchial and vascular smooth muscle, as well as for β2-receptors involved in metabolic regulation. 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 3–4 hours after oral administration. The plasma elimination half-life is 10–12 hours, resulting in 24-hour efficacy after a single dose. Maximum antihypertensive effect is achieved within 2 weeks of treatment.

In intensive therapy of patients with ischemic heart disease without chronic heart failure, bisoprolol reduces cardiac output and myocardial oxygen demand by decreasing heart rate 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 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. First-pass metabolism is ≤ 10%. Bioavailability is approximately 90%.

Distribution.
Volume of distribution is 3.5 L/kg. Plasma protein binding is approximately 30%.

Metabolism and elimination.
Bisoprolol is eliminated from the body via two pathways: 50% is metabolized in the liver into inactive metabolites and excreted by the kidneys; the remaining 50% is excreted unchanged by the kidneys. Total bisoprolol clearance is 15 L/h. Due to its long elimination half-life (10–12 hours), the drug maintains therapeutic efficacy for 24 hours with once-daily administration.

Linearity.
The pharmacokinetics of bisoprolol are linear, and its parameters are independent of age.

Special patient groups.
Since bisoprolol is eliminated equally via the kidneys and the liver, dosage adjustment is not required in patients with hepatic or renal impairment. Pharmacokinetics in patients with stable chronic heart failure and impaired liver or kidney function have not been studied. In patients with chronic heart failure of NYHA functional class III, plasma bisoprolol levels are higher and elimination half-life is prolonged compared to healthy volunteers. Steady-state plasma concentration averages 64+21 ng/mL at a daily dose of 10 mg, with an elimination half-life of 17+5 hours.

Clinical characteristics.

Indications.

• Arterial hypertension;
• Ischemic heart disease (angina pectoris);
• Chronic heart failure with systolic dysfunction of the left ventricle, in combination with ACE inhibitors, diuretics, and, if necessary, cardiac glycosides.

Contraindications.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended.

• Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): possible potentiation of atrioventricular conduction effects and enhancement of negative inotropic effect.

• Calcium antagonists (verapamil group, 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 pronounced arterial hypotension and atrioventricular block.
• Antihypertensive agents with central mechanism of action (clonidine, methyldopa, moxonidine, rilmenidine): possible worsening of heart failure due to reduction in central sympathetic tone (decreased heart rate and cardiac output, vasodilation). Sudden withdrawal, particularly if preceded by discontinuation of β-adrenoceptor blockers, may increase the risk of rebound hypertension.

Combinations requiring caution.

• Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): possible potentiation of atrioventricular conduction effects and enhancement of negative inotropic effect.

• Dihydropyridine calcium antagonists (e.g., nifedipine, felodipine, amlodipine): possible increased risk of arterial hypotension. A potential increase in negative inotropic effect on myocardial function in patients with heart failure cannot be excluded.
• Class III antiarrhythmic agents (e.g., amiodarone): possible potentiation of effects on atrioventricular conduction.
• Locally acting β-blockers (e.g., those contained in 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. β-Adrenoceptor blockade may mask symptoms of hypoglycemia.
• Anesthetic agents: increased risk of myocardial depression and development of arterial hypotension (see section "Special precautions").
• Cardiac glycosides: reduced heart rate, prolonged atrioventricular conduction time.
• Nonsteroidal anti-inflammatory drugs (NSAIDs): possible attenuation of the antihypertensive effect of bisoprolol.
• β-Sympathomimetics (e.g., orciprenaline, isoprenaline, dobutamine): combination with BISOTROL preparation may reduce the therapeutic effect of both agents. Higher doses of adrenaline may be required for treatment of allergic reactions.
• Sympathomimetics activating both α- and β-adrenoceptors (e.g., adrenaline, noradrenaline): possible manifestation of α-adrenoceptor-mediated vasoconstrictive effect, 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 agents exhibiting hypotensive effects (e.g., tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of arterial hypotension.

Possible combinations.

• Mefloquine: possible increased risk of bradycardia.
• MAO inhibitors (except MAO type 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, bisoprolol 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 with bisoprolol treatment of heart failure in patients with the following conditions and pathological states:

• insulin-dependent diabetes mellitus (type I) (insulin-dependent);
• severe renal function impairment;
• severe hepatic function impairment;
• restrictive cardiomyopathy;
• congenital heart defects;
• hemodynamically significant acquired valvular heart disease;
• myocardial infarction within the last 3 months.

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

• bronchospasm (in bronchial asthma, obstructive airway diseases);
• diabetes mellitus with marked fluctuations in blood glucose levels; in such cases, symptoms of hypoglycemia (tachycardia, palpitations, sweating) may be masked;
• 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 (adrenaline) treatment may not always produce a positive therapeutic effect;
• first-degree atrioventricular block;
• Prinzmetal's angina; episodes of coronary artery spasm have been observed. Despite high β1-selectivity, angina attacks cannot be completely controlled with bisoprolol in patients with Prinzmetal's angina.
• peripheral arterial occlusive diseases (worsening of symptoms may occur at the beginning of therapy);
• general anesthesia.

In patients scheduled for general anesthesia, the use of β-blockers reduces the incidence of arrhythmias and myocardial ischemia during induction, intubation, and the postoperative period. It is recommended to continue β-blocker therapy during the perioperative period. The anesthesiologist must be informed about the use of β-adrenoreceptor blockers, as they should consider potential interactions with other drugs that may lead to bradyarrhythmia, reflex tachycardia, and reduced capacity of reflex mechanisms to compensate for blood loss. If bisoprolol is discontinued prior to surgery, the dose should be gradually reduced and the drug discontinued 48 hours before 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 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. In such cases, the drug Concor® should be used with caution. In patients with obstructive airway diseases, bisoprolol therapy should be initiated at the lowest possible dose. Patients should be monitored for the emergence of new symptoms (such as dyspnea, exercise intolerance, cough).

If symptoms of bronchial asthma or other chronic obstructive pulmonary diseases occur, concomitant therapy with bronchodilators is indicated. In some cases, patients with bronchial asthma may require higher doses of β2-sympathomimetics due to increased airway resistance during treatment.

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

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

Symptoms of thyrotoxicosis may be masked during treatment.

A positive doping test result may occur during bisoprolol use.

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 when 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 therapy should be considered.

After delivery, the newborn should be under close observation. Hypoglycemia and bradycardia should be expected within the first 3 days of life.

Breastfeeding period.
There are no data on the excretion of bisoprolol into breast milk; therefore, the drug is not recommended during breastfeeding.

Ability to influence reaction rate when driving or operating machinery.

In clinical studies involving patients with ischemic heart disease, the drug did not affect the ability to drive. However, 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 changes, or when used concomitantly with alcohol.

Method of Administration and Dosage

The BISOTROL 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 stepwise dose increase. The recommended dose is 5 mg (1 tablet of BISOTROL 5 mg) once daily. For mild hypertension (diastolic pressure up to 105 mm Hg), a dose of 2.5 mg* is appropriate.

If necessary, the daily dose may be increased to 10 mg (1 tablet of BISOTROL 10 mg) once daily. Further dose escalation is justified only in exceptional cases. The maximum recommended dose is 20 mg per day.

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

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

Standard therapy for chronic heart failure includes ACE inhibitors (or angiotensin receptor blockers in case of ACE inhibitor intolerance), ß-blockers, diuretics, and, if necessary, cardiac glycosides.

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

Therapy should be administered by a physician experienced in managing chronic heart failure.

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

• 1.25 mg* of bisoprolol fumarate once daily for 1 week; if well tolerated, increase to
• 2.5 mg* of bisoprolol fumarate once daily for the next 1 week; if well tolerated, increase to
• 3.75 mg* of bisoprolol fumarate once daily for the next 1 week; if well tolerated, increase to
• 5 mg of bisoprolol fumarate once daily for the next 4 weeks; if well tolerated, increase to
• 7.5 mg* of bisoprolol fumarate once daily for the next 4 weeks; if well tolerated, increase to
• 10 mg of bisoprolol fumarate once daily as maintenance therapy.

* Use bisoprolol formulations with appropriate dosing.

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

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.

Modifications of Treatment.

If the maximum recommended dose is poorly tolerated, a 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 stabilization of the patient's condition, 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, therapy should be tapered gradually by stepwise dose reduction (e.g., halving the dose weekly).

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

The duration of treatment is prolonged and depends on the nature and severity of the disease.

Patients with hepatic and/or renal impairment.

Arterial hypertension; ischemic heart disease.

Dose adjustment is generally not required in patients with mild to moderate hepatic or renal impairment. In patients with severe renal impairment (creatinine clearance less than 20 mL/min) or severe hepatic impairment, the dose should not exceed 10 mg of the drug per day. Limited data are available on the use of bisoprolol in dialysis patients. No dosage adjustment is necessary.

Chronic heart failure.

There are no pharmacokinetic data on bisoprolol in patients with chronic heart failure and concomitant hepatic or renal impairment; therefore, dose escalation should be performed with caution.

Elderly patients do not require dose adjustment.

Children.

Clinical data on the efficacy and safety of the drug in pediatric patients are lacking; therefore, the drug should not be used in this patient population.

Overdose.

Symptoms.

Cases of third-degree atrioventricular block, bradycardia, and dizziness have been reported following overdose (e.g., administration of a daily dose of 15 mg instead of 7.5 mg). The most common signs of ß-blocker overdose include bradycardia, arterial hypotension, acute heart failure, hypoglycemia, and bronchospasm. Several cases of overdose have been reported in patients with arterial hypertension and/or ischemic heart disease (maximum dose reported: 2000 mg of bisoprolol). Bradycardia and/or arterial hypotension were observed. All patients recovered. There is a 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.

In case of overdose, drug administration should be discontinued and supportive and symptomatic therapy should be initiated. Limited data suggest that bisoprolol is poorly dialyzable. In suspected overdose, based on the expected pharmacological effects and recommendations for other ß-blockers, the following general measures should be considered:

• In case of bradycardia: intravenous administration of atropine. If no response, isoprenaline or another agent with positive chronotropic effect should be administered 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: close monitoring, infusion of isoprenaline, or transvenous cardiac pacing.
• In case of worsening chronic heart failure: intravenous diuretics, inotropic agents, and vasodilators.
• In case of bronchospasm: bronchodilators (e.g., isoprenaline), ß2-adrenergic agonists and/or aminophylline.
• In case of hypoglycemia: intravenous glucose.

Adverse reactions.

Undesirable effects are classified by frequency of occurrence as follows:

very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10,000 and < 1/1000), very rare (< 1/10,000), not known (frequency cannot be determined from available data).

From the cardiovascular system side.

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).

From the nervous system side.

Common: dizziness*, headache*.

Rare: syncope.

From the eye organs side.

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

Very rare: conjunctivitis.

From the ear organs side.

Rare: hearing impairment.

From the respiratory system side.

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

Rare: allergic rhinitis.

From the gastrointestinal tract side.

Common: nausea, vomiting, diarrhea, constipation.

From the skin and connective tissues side.

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

Very rare: alopecia. During treatment with ß-blockers, worsening of psoriasis may occur, manifesting as psoriatic rash.

From the musculoskeletal system side.

Uncommon: muscle weakness, cramps.

From the liver side.

Rare: hepatitis.

From the vascular system side.

Common: feeling of coldness 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).

From the reproductive system side.

Rare: erectile dysfunction.

Psychiatric disorders.

Uncommon: depression, sleep disturbances.

Rare: nightmares, hallucinations.

Laboratory findings.

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

General disorders.

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

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

* Applies only to patients with arterial hypertension or ischemic heart disease. These symptoms usually occur at the beginning of therapy, are mild, and disappear within the first 1–2 weeks.

In case of adverse events or undesirable reactions, a physician must be informed immediately.

Shelf life.
3 years.

Storage conditions.
Store at a temperature not exceeding 25 °C, in the original packaging. Keep out of reach of children.

Packaging.
10 tablets in a blister; 3 blisters in a cardboard pack.

Prescription category.
Prescription only.

Manufacturer.
Ipca Laboratories Ltd.

Manufacturer's address and place of business.
P.O. Segawata, District Ratlam - 457002 (M.P.), India.