Bisomor (Tablets) Instructions for Use

Marketing Authorization Holder

Edge Pharma Private Limited (India)

ATC Code

C07AB07 (Bisoprolol)

Active Substance

Bisoprolol (Rec.INN registered by WHO)

Dosage Forms

	Bisomor	Film-coated tablets, 2.5 mg: 30 pcs.
		Film-coated tablets, 5 mg: 30 pcs.
		Film-coated tablets, 10 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets orange in color, round, biconvex; a cross-section shows two layers, the core is from white to almost white.

Excipients : mannitol – 141.5 mg, microcrystalline cellulose – 21.1 mg, croscarmellose sodium – 1.8 mg, magnesium stearate – 3.6 mg.

Coating composition dye Vinkout WT-AQ-01620 orange (hypromellose, macrogol 400, titanium dioxide, talc, macrogol 6000, sunset yellow aluminum lake) – 3.6 mg.

10 pcs. – contour cell blisters (3) – cardboard packs.

Film-coated tablets light yellow in color, round, biconvex, with a score on one side; a cross-section shows two layers, the core is from white to almost white.

Excipients : mannitol – 149 mg, microcrystalline cellulose – 21.1 mg, croscarmellose sodium – 1.8 mg, magnesium stearate – 3.6 mg.

Film coating composition: dye Vinkout WT-AQ-01530 yellow (hypromellose, macrogol 400, titanium dioxide, talc, macrogol 6000, quinoline yellow aluminum lake) – 3.6 mg.

10 pcs. – blisters (3) – cardboard packs.

Film-coated tablets light orange in color, round, biconvex; a cross-section shows two layers, the core is from white to almost white.

Excipients : mannitol – 146.5 mg, microcrystalline cellulose – 21.10 mg, croscarmellose sodium – 1.8 mg, magnesium stearate – 3.6 mg.

Coating composition dye Vinkout WT-AQ-01069 orange (hypromellose, macrogol 400, titanium dioxide, talc, macrogol 6000, sunset yellow aluminum lake) – 3.6 mg.

10 pcs. – contour cell blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Beta₁-adrenoblocker

Pharmacotherapeutic Group

Selective beta1-adrenergic blocker

Pharmacological Action

Selective beta₁-adrenergic blocker, without intrinsic sympathomimetic activity, does not have membrane-stabilizing action.

It reduces plasma renin activity, decreases myocardial oxygen demand, and reduces heart rate. It has antihypertensive, antiarrhythmic, and antianginal action. By blocking beta₁-adrenergic receptors of the heart in low doses, it reduces catecholamine-stimulated formation of cAMP from ATP, reduces the intracellular flow of calcium ions, and has negative chronotropic, dromotropic, bathmotropic, and inotropic effects (inhibits conduction and excitability, slows AV conduction). When the dose is increased above the therapeutic level, it exerts beta₂-adrenergic blocking action.

Peripheral vascular resistance at the beginning of drug use (in the first 24 hours) increases slightly (as a result of reciprocal increase in alpha-adrenergic receptor activity and elimination of beta₂-adrenergic receptor stimulation), which returns to the initial value after 1-3 days, and decreases with long-term use.

The antihypertensive effect is associated with a decrease in cardiac output, sympathetic stimulation of peripheral vessels, a reduction in the activity of the sympathoadrenal system (which is important for patients with initial hypersecretion of renin), restoration of sensitivity in response to decreased blood pressure, and an effect on the central nervous system. In arterial hypertension, the effect occurs after 2-5 days, stable action – after 1-2 months.

The antianginal effect is due to a decrease in myocardial oxygen demand as a result of reduced contractility and other myocardial functions, prolonged diastole, and improved myocardial perfusion. Due to an increase in end-diastolic pressure in the left ventricle and increased stretching of the ventricular muscle fibers, myocardial oxygen demand may increase, especially in patients with chronic heart failure.

The antiarrhythmic effect is due to the elimination of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased cAMP levels, arterial hypertension), a decrease in the rate of spontaneous excitation of the sinus and ectopic pacemakers, and slowing of AV conduction (mainly in the antegrade and, to a lesser extent, in the retrograde direction through the AV node) and via accessory pathways.

When used in average therapeutic doses, unlike non-selective beta-blockers, it has a less pronounced effect on organs containing beta₂-adrenergic receptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchi, and uterus) and on carbohydrate metabolism, and does not cause sodium ion retention in the body.

Pharmacokinetics

Absorption

Bisoprolol is almost completely (> 90 %) absorbed from the gastrointestinal tract, food intake does not affect absorption. Bisoprolol demonstrates linear kinetics, and its plasma concentrations are proportional to the administered dose in the range from 5 to 20 mg. C_max of bisoprolol in plasma is reached in 2-3 hours.

Distribution

Vd is 3.5 L/kg. Plasma protein binding is about 30%.

Metabolism

It is metabolized via the oxidative pathway without subsequent conjugation; it is minimally metabolized during the “first pass” through the liver (approximately 10-15 %). All metabolites are polar. The main metabolites found in plasma and urine do not exhibit pharmacological activity. Data obtained from experiments with human liver microsomes in vitro show that Bisoprolol is metabolized primarily by the CYP3A4 isoenzyme (about 95 %), and the CYP2D6 isoenzyme plays only a minor role.

Elimination

Bisoprolol is eliminated by two routes, 50% of the dose is metabolized in the liver to form inactive metabolites. About 98% is excreted by the kidneys, of which 50% is unchanged, less than 2% is excreted through the intestines (with bile). Total clearance is 12-18 L/h, with renal clearance being 8-11 L/h, T_1/2 is 10-12 hours. Permeability through the blood-brain barrier and placental barrier is low. The pharmacokinetics of bisoprolol are linear and independent of age. In patients with CHF, the plasma concentration of bisoprolol is higher and the T_1/2 is longer compared to healthy volunteers.

Indications

• Arterial hypertension;
• Coronary artery disease: prevention of attacks of stable angina pectoris;
• Chronic heart failure.

ICD codes

Dosage Regimen

The drug Bisomor should be taken orally with a small amount of fluid in the morning before breakfast, during or after it. The tablets should not be chewed or crushed into powder.

In all cases, the regimen and dose are selected by the doctor individually for each patient, in particular taking into account the heart rate and the patient’s condition.

Treatment of arterial hypertension and stable angina pectoris

As a rule, the initial dose is 5 mg once a day. If necessary, the dose can be increased to 10 mg once a day.

In the treatment of arterial hypertension and angina pectoris, the maximum recommended dose is 20 mg once a day.

For patients with mild or moderate hepatic or renal impairment, as well as for elderly patients, dosage regimen adjustment is generally not required.

For patients with severe renal impairment (creatinine clearance less than 20 ml/min) and patients with severe hepatic impairment, the maximum daily dose is 10 mg.

Chronic heart failure

Initiating treatment for chronic heart failure requires mandatory implementation of a special titration phase and regular medical supervision. A prerequisite for treatment with the drug Bisomor is stable CHF without signs of exacerbation.

Treatment of chronic heart failure is initiated according to the scheme below, and individual adaptation may be required depending on how well the patient tolerates the prescribed dose, i.e., the dose can only be increased if the previous dose was well tolerated.

The recommended initial dose of the drug Bisomor is 1.25 mg (1/2 tablet of 2.5 mg) once a day. Depending on individual tolerance, the dose should be gradually increased to 2.5 mg, 3.75 mg (1.5 tablets of 2.5 mg), 5 mg, 7.5 mg (1 tablet of 5 mg and 1 tablet of 2.5 mg) and 10 mg once a day at intervals of at least 2 weeks or more.

The maximum recommended dose of the drug Bisomor in the treatment of chronic heart failure is 10 mg once a day.

If increasing the dose of the drug is poorly tolerated by the patient, a dose reduction is possible.

During titration, regular monitoring of blood pressure, heart rate, and symptoms of worsening chronic heart failure is recommended. Worsening of chronic heart failure symptoms is possible from the first day of drug use.

During the titration phase or after it, temporary worsening of chronic heart failure, arterial hypotension, or bradycardia may occur. In this case, it is recommended, first of all, to pay attention to the selection of the dose of concomitant standard therapy. It may also be necessary to temporarily reduce the dose of the drug Bisomor or discontinue treatment. After the patient’s condition stabilizes, dose re-titration should be performed, or treatment should be continued.

To date, there is insufficient data regarding the use of the drug Bisomor in patients with CHF associated with type I diabetes mellitus, severe renal and/or hepatic impairment, restrictive cardiomyopathy, congenital heart defects, or hemodynamically significant valvular heart disease. Also, sufficient data have not yet been obtained regarding patients with CHF with myocardial infarction within the last 3 months.

Duration of treatment for all indications

Treatment is usually long-term. If necessary, treatment can be interrupted and resumed following certain rules. Treatment should not be interrupted suddenly, especially in patients with coronary artery disease. If it is necessary to discontinue treatment, the dose of the drug should be reduced gradually.

Adverse Reactions

The frequency of occurrence of the adverse reactions listed below was determined according to the following classification: very common ≥ 1/10; common ≥ 1/100, <1/10; uncommon ≥ 1/1000, <1/100; rare ≥ 1/10000, <1/1000; very rare < 1/10000.

From the cardiovascular system: very common – bradycardia (in patients with chronic heart failure (CHF)); common – worsening of CHF symptoms (in patients with CHF), feeling of coldness or numbness in the extremities, marked decrease in blood pressure, especially in patients with CHF; uncommon – AV conduction disturbance; bradycardia (in patients with arterial hypertension or angina pectoris); worsening of CHF symptoms (in patients with arterial hypertension or angina pectoris), orthostatic hypotension.

From the central nervous system common – dizziness*, headache*; rare – loss of consciousness.

Mental disorders uncommon – depression, insomnia; rare – hallucinations, nightmares.

From the organ of vision rare – decreased lacrimation (should be considered when wearing contact lenses); very rare – conjunctivitis.

From the organ of hearing rare – hearing disorders.

From the respiratory system uncommon – bronchospasm in patients with a history of bronchial asthma or airway obstruction; rare – allergic rhinitis.

From the digestive system common – nausea, vomiting, diarrhea, constipation; rare – hepatitis.

From the musculoskeletal system uncommon – muscle weakness, muscle cramps.

From the skin rare – hypersensitivity reactions such as pruritus, rash, skin hyperemia; very rare: alopecia; beta-blockers may exacerbate the symptoms of psoriasis or cause psoriasis-like rash.

From the reproductive system rare – erectile dysfunction.

General disorders common – asthenia (in patients with CHF), increased fatigue*; uncommon – asthenia (in patients with arterial hypertension or angina pectoris).

Laboratory parameters rare – increased concentration of triglycerides and activity of “liver” transaminases in the blood (AST and ALT).

* In patients with arterial hypertension or angina pectoris, these symptoms more often appear at the beginning of the course of treatment, are usually mild and, as a rule, disappear within 1-2 weeks after the start of treatment.

Contraindications

• Hypersensitivity to bisoprolol or any of the components, as well as to other beta-blockers;
• Acute heart failure;
• Chronic heart failure in the stage of decompensation, requiring inotropic therapy;
• Cardiogenic shock;
• Collapse;
• AV block II and III degree without a pacemaker;
• Sinoatrial block;
• Sick sinus syndrome;
• Bradycardia (heart rate less than 60 beats/min);
• Severe arterial hypotension (systolic blood pressure less than 100 mm Hg);
• Severe bronchial asthma and COPD in history;
• Severe peripheral circulatory disorders, Raynaud’s syndrome;
• Pheochromocytoma (without simultaneous use of alpha-blockers);
• Metabolic acidosis;
• Cardiomegaly (without signs of heart failure);
• Concomitant use of MAO inhibitors (except for MAO type B inhibitors);
• Concomitant use of floctafenine and sultopride;
• Age under 18 years (efficacy and safety have not been established).

With caution: bronchial asthma and COPD; simultaneous desensitizing therapy; Prinzmetal’s angina; hyperthyroidism; diabetes mellitus; AV block I degree; severe renal failure (creatinine clearance less than 20 ml/min); severe hepatic impairment; psoriasis; restrictive cardiomyopathy; congenital heart defects or valvular heart disease with significant hemodynamic disturbances; CHF with myocardial infarction within the last 3 months; strict diet; depression (including in history).

Use in Pregnancy and Lactation

During pregnancy, the drug should be recommended for use only if the benefit of treatment for the mother outweighs the risk of side effects in the fetus and/or child.

As a rule, beta-blockers reduce blood flow in the placenta and may affect fetal development. Blood flow in the placenta and uterus should be monitored, and the growth and development of the unborn child should be observed, and if adverse events occur in relation to pregnancy and/or the fetus, alternative therapy methods should be switched to.

If beta-blockers are used during pregnancy, the newborn should be carefully examined after delivery. Symptoms of bradycardia and hypoglycemia may occur in the first three days of life.

There are no data on the excretion of bisoprolol into breast milk. Therefore, the use of the drug Bisomor is not recommended during breastfeeding. If it is necessary to take the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

With caution severe hepatic impairment.

Use in Renal Impairment

With caution: severe renal failure (creatinine clearance less than 20 ml/min).

Pediatric Use

Contraindicated under 18 years of age (efficacy and safety have not been established).

Special Precautions

Monitoring of patients taking the drug Bisomor should include measurement of heart rate and blood pressure (at the beginning of treatment – daily, then once every 3-4 months), ECG, determination of blood glucose levels in patients with diabetes (once every 4-5 months). In elderly patients, it is recommended to monitor renal function (once every 4-5 months).

The patient should be taught the method of counting heart rate and instructed on the need for medical consultation if the heart rate is less than 60 beats/min.

Before starting treatment, it is recommended to examine the function of external respiration in patients with a burdened bronchopulmonary history.

In diabetes mellitus, it may mask tachycardia caused by hypoglycemia. Unlike non-selective beta-blockers, it practically does not enhance insulin-induced hypoglycemia and does not delay the restoration of blood glucose concentration to normal levels.

With simultaneous use of clonidine, its administration can be discontinued only a few days after discontinuation of the drug Bisomor.

If increasing bradycardia (less than 60 beats/min), marked decrease in blood pressure (systolic blood pressure below 100 mm Hg), or AV block is detected in elderly patients, it is necessary to reduce the dose or discontinue treatment.

It is recommended to discontinue therapy if depression develops.

Treatment should not be abruptly interrupted due to the risk of severe arrhythmias and myocardial infarction. The drug should be withdrawn gradually, reducing the dose over 2 weeks or more (reduce the dose by 25% every 3-4 days).

At the initial stages of treatment with the drug Bisomor, patients require constant monitoring.

Patients with bronchospastic diseases can be prescribed cardioselective beta-blockers in case of intolerance and/or ineffectiveness of other antihypertensive agents. If the dose of the drug Bisomor is exceeded, there is a risk of bronchospasm development.

It is possible to increase the severity of hypersensitivity reactions and lack of effect from usual doses of epinephrine against the background of a burdened allergic history.

Patients using contact lenses should be aware that treatment with Bisomor may reduce tear fluid production.

When performing general anesthesia during treatment with the drug, the risk of β-adrenoreceptor blockade should be considered. If it is necessary to discontinue therapy with Bisomor before surgery, the drug should be withdrawn gradually and completed 48 hours before general anesthesia. If the patient has taken the drug before surgery, an agent for general anesthesia with minimal negative inotropic effect should be selected for them. The anesthesiologist should be informed about the treatment with Bisomor.

In patients with pheochromocytoma, the drug can only be prescribed while using alpha-blockers.

During treatment with Bisomor, symptoms of hyperthyroidism (for example, tachycardia) may be masked. Abrupt withdrawal in patients with thyrotoxicosis is contraindicated, as it may worsen the symptoms.

The drug should be discontinued before testing the blood and urine levels of catecholamines, normetanephrine, and vanillylmandelic acid, and titers of antinuclear antibodies.

The effectiveness of beta-blockers is lower in smokers.

Influence on the ability to drive vehicles and mechanisms

During treatment with Bisomor, caution must be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms AV block, pronounced bradycardia, marked decrease in BP, bronchospasm, acute heart failure, and hypoglycemia.

Sensitivity to a single high dose of bisoprolol varies greatly among individual patients, and patients with CHF are likely to have higher sensitivity.

Treatment supportive and symptomatic therapy.

For pronounced bradycardia: intravenous administration of atropine. If its effect is insufficient, an agent with a positive chronotropic effect can be administered with caution. Temporary placement of a pacemaker may sometimes be required.

For marked decrease in BP: intravenous administration of plasma-substituting solutions and vasopressor drugs.

For AV block: patients should be under constant observation and receive treatment with beta-adrenergic agonists such as epinephrine. If necessary, placement of a pacemaker.

For acute heart failure: intravenous administration of diuretics, drugs with a positive inotropic effect, and vasodilators. For bronchospasm: administration of bronchodilators, including beta₂-adrenergic agonists and/or aminophylline.

For hypoglycemia: intravenous administration of dextrose (glucose).

Drug Interactions

Not recommended combinations

Treatment of CHF

Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) when used concomitantly with bisoprolol may reduce AV conduction and myocardial contractility.

For all indications

Slow calcium channel blockers of the verapamil type and, to a lesser extent, diltiazem, when used concomitantly with bisoprolol, may lead to reduced myocardial contractility and impaired AV conduction. In particular, intravenous administration of verapamil to patients taking beta-blockers may lead to marked arterial hypotension and AV block.

Centrally acting hypotensive agents (such as clonidine, methyldopa, moxonidine, rilmenidine) may lead to a decrease in heart rate and cardiac output, as well as vasodilation due to reduced central sympathetic tone. Abrupt withdrawal, especially before discontinuation of beta-blockers, may increase the risk of “rebound” arterial hypertension.

Combinations requiring caution

Treatment of arterial hypertension and stable angina

Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin; flecainide, propafenone) when used concomitantly with bisoprolol may reduce AV conduction and myocardial contractility.

For all indications

CCB derivatives of dihydropyridine (e.g., nifedipine, felodipine, amlodipine) may increase the risk of arterial hypotension. In patients with chronic heart failure, the risk of subsequent worsening of myocardial contractile function cannot be excluded. Class III antiarrhythmic agents (e.g., amiodarone) may enhance the impairment of AV conduction.

Topically applied beta-blockers (e.g., eye drops for glaucoma treatment) may enhance the systemic effects of bisoprolol (decreased BP, reduced heart rate).

Parasympathomimetics when used concomitantly with bisoprolol may enhance the impairment of AV conduction and increase the risk of bradycardia. The hypoglycemic effect of insulin or oral hypoglycemic agents may be enhanced. Signs of hypoglycemia – particularly tachycardia – may be masked or suppressed. Such interactions are more likely with the use of non-selective beta-blockers.

Agents for general anesthesia may increase the risk of cardiodepressive effects, leading to a marked decrease in BP (see section “Special Instructions”).

Cardiac glycosides when used concomitantly with bisoprolol may lead to prolonged impulse conduction time and thus to the development of bradycardia.

NSAIDs may reduce the hypotensive effect of bisoprolol.

Concomitant use of bisoprolol with beta-adrenergic agonists (e.g., isoprenaline, dobutamine) may lead to a reduction in the effect of both drugs. The combination of bisoprolol with adrenergic agonists affecting both β- and α-adrenoreceptors (e.g., norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these agents mediated by α-adrenoreceptors, leading to increased BP. Such interactions are more likely with the use of non-selective beta-blockers. Hypotensive agents, as well as other agents with possible antihypertensive effects (e.g., tricyclic antidepressants, barbiturates, phenothiazines) may enhance the antihypertensive effect of bisoprolol.

Mefloquine when used concomitantly with bisoprolol may increase the risk of bradycardia.

MAO inhibitors (except for MAO B inhibitors) may enhance the hypotensive effect of beta-blockers. Concomitant use may also lead to the development of a hypertensive crisis.

Storage Conditions

Store in a dry place, out of reach of children and protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

Dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.