Bisoprolol, 2,5mg 30 pcs.

Pharmacotherapeutic group: beta₁-adrenoblocker selective

ATC code: C07AB07 Pharmacological properties

Pharmacodynamics

A selective beta₁-adrenoblocker, without intrinsic sympathomimetic activity, has no membrane-stabilizing action.

Limits blood plasma renin activity, reduces myocardial oxygen demand, reduces heart rate (HR) (at rest and under load). It has antihypertensive, antiarrhythmic and antianginal effects. By blocking at low doses of beta₁-adrenoreceptors of the heart, reduces catecholamine-stimulated formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), reduces intracellular calcium ion current, has negative chrono-, dromo-, batmo- and inotropic effects (inhibits conduction and excitability, slows atrioventricular (AV) conduction).

If the therapeutic dose is exceeded, it has beta₂-adrenoblocking effect.

The total peripheral vascular resistance at the beginning of the drug use during the first 24 h is slightly increased (as a result of reciprocal increase of activity of alpha-adrenoreceptors) which returns to baseline after 1-3 days and decreases with prolonged administration.

The antihypertensive effect is associated with reduction of the minute blood volume, sympathetic stimulation of peripheral vessels, reduction of renin-angiotensin-aldosterone system activity (of great importance for patients with initial renin hypersecretion), restoration of sensitivity in response to reduction of blood pressure (BP) and influence on the central nervous system (CNS). In arterial hypertension the effect occurs after
2-5 days, stable effect – after 1-2 months.

The antianginal action is caused by decrease of myocardial oxygen demand as the result of HR shortening, slight decrease of contractility, prolongation of diastole, improvement of myocardial perfusion.

The antiarrhythmic action is caused by the removal of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased content of CAMF, arterial hypertension), the decrease of spontaneous excitation rate of sinus and ectopic pacemakers and AV conduction slowing (mainly in antegrade and to a lesser extent in retrograde direction via AV node) and by additional pathways.

When used at moderate therapeutic doses, unlike non-selective beta-adrenoblockers, it has less pronounced effects on organs containing beta₂– adrenoreceptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchi and uterus) and on carbohydrate metabolism, does not cause retention of sodium ions in the body. The severity of atherogenic action does not differ from that of propranolol.

Bisoprololol decreases heart rate, stroke volume, and consequently myocardial oxygen demand in patients with coronary heart disease (CHD) without evidence of chronic heart failure (CHF) when administered alone.

Pharmacokinetics

Intake

Bisoprolol is almost completely (> 90%) absorbed from the gastrointestinal tract. Its bioavailability due to insignificant metabolism “at primary passage” through the liver (approximately 10%) is about
90% after oral administration. Food intake has no effect on bioavailability. Bisoprolol exhibits linear kinetics, and its plasma concentrations are proportional to the dose taken in the dose range from 5 to 20 mg. Maximum plasma concentrations are reached after 2-3 hours.

Distribution

Bisoprolol is fairly widely distributed. The volume of distribution is
3.5 l/kg. The binding to plasma proteins reaches about 30%.

Metabolism

Metabolized by the oxidative pathway without subsequent conjugation. All metabolites are polar (water-soluble) and are excreted by the kidneys. The major metabolites found in plasma and urine have no pharmacological activity. The data obtained from in vitro experiments with human liver microsomes show that bisoprolol is metabolized primarily by the CYP3A4 isoenzyme (about
95%) and the CYP2D6 isoenzyme plays only a minor role.

The clearance of bisoprolol is determined by a balance between its excretion via the kidneys unchanged (about 50%) and its oxidation in the liver (about 50%) to metabolites, which are then also excreted by the kidneys. Total clearance is 15 l/h. The half-life (T_1/2) is 10-12 h.

There are no data on the pharmacokinetics of bisoprolol in patients with CHF and concomitant hepatic or renal impairment.

Indications

Active ingredient

Composition

1 film-coated tablet contains:

Composition of the core of the tablet

The active ingredient: bisoprolol fumarate – 2.5 mg.

Excipients: calcium hydrophosphate anhydrous – 46.875 mg, microcrystalline cellulose – 18.5 mg, corn starch – 5.625 mg, magnesium stearate – 0.75 mg, colloidal silica – 0.75 mg.

Particle film coating: opadray II white (85F18422) (polyvinyl alcohol – 40%, titanium dioxide – 25%, macrogol 3350 – 20.2%, talc – 14.8%) – 3.0 mg.

How to take, the dosage

The tablets should be taken orally in the morning with a small amount of liquid, regardless of the time of the meal. The tablets should not be chewed.

The standard regimen for treatment of CHF includes angiotensin-converting enzyme inhibitors (ACE) or angiotensin II receptor antagonists (if ACE inhibitors are intolerant),
beta-adrenoblockers, diuretics and, optionally, cardiac glycosides. A precondition for treatment with the drug is stable CHF without signs of exacerbation.

A temporary worsening of the course of heart failure, marked BP decrease or bradycardia may be observed during or after the titration phase.

The titration phase

The use of bisoprolol preparations from other manufacturers in the dosage form of 2.5 mg tablets or “double-risk 5 mg tablets” is recommended to provide the dosing regimen indicated below in the initial stages of treatment.

The initiation of treatment of CHF with the drug requires a specific titration phase.

The recommended starting dose is 1.25 mg once daily. Depending on individual tolerance, the dose should be gradually increased to 2.5 mg, 3.75 mg, 5 mg, 7.5 mg, and 10 mg once daily. Each subsequent dose increase should be made after at least two weeks.

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

While in the titration phase, regular monitoring of BP, HR, and severity of CHF symptoms is recommended. Worsening of CHF symptoms is possible from the first day of using the drug.

Changing the regimen

If the patient has difficulty tolerating the maximum recommended dose, the dose can be gradually reduced.

In case of worsening of CHF symptoms, marked BP and bradycardia, first of all, a dose adjustment of the concomitant therapy drugs is recommended. Temporary dosage reduction or drug withdrawal may also be necessary.

After the patient’s condition has stabilized, re-titration should be performed, or treatment should continue.

If discontinuation of the medication is necessary, the dose should be reduced gradually, as abrupt withdrawal may cause a sudden worsening of the patient’s condition.

Treatment with the drug is usually long-term.

Particular patient groups

In severe renal failure (CK < 20 ml/min) and in patients with severe hepatic impairment, the maximum daily dose of the drug is 10 mg. Increasing the dose of the drug in such patients should be carried out with extreme caution.

In mild to moderate hepatic or renal dysfunction, no dose adjustment is usually required.

Dose adjustment is not necessary when using the drug in elderly patients.

Interaction

The efficacy and tolerability of bisoprolol may be affected by concomitant administration of other drugs. Such interaction may also occur when two drugs are taken at short intervals. The physician should be informed about taking other drugs, even if they are taken without a prescription (i.e. over-the-counter drugs).

Unrecommended combinations

The class I antiarrhythmic drugs (e.g., quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) when used concomitantly with bisoprolol may decrease AV conductivity and myocardial contractility.

Slow calcium channel blockers (CMBs) such as verapamil and, to a lesser extent, diltiazem, when used concomitantly with bisoprololol, may lead to decreased myocardial contractility and impaired AV conduction. In particular, intravenous administration of verapamil in patients taking beta-adrenoblockers may result in marked arterial hypotension and AV blockade.

Centrally acting hypotensive agents (such as clonidine, methyldopa, moxonidine, rilmenidine) may result in decreased HR and cardiac output as well as vasodilation due to reduced central sympathetic tone. Abrupt withdrawal, especially before withdrawal of beta-adrenoblockers, may increase the risk of “ricochet” arterial hypertension.

Combinations requiring special caution

Dihydropyridine derivatives (e.g., nifedipine, felodipine, amlodipine) BMCCs may increase the risk of arterial hypotension when used concomitantly with bisoprolol. In patients with CHF the risk of subsequent deterioration of cardiac contractile function cannot be excluded.

The antiarrhythmic agents of class III (e.g., amiodarone) may increase AV conduction disturbances.

The effects of beta-adrenoblockers for topical use (e.g. eye drops to treat glaucoma) may increase the systemic effects of bisoprololol (BP reduction, heart rate slowing).

Parasympathomimetics when used concomitantly with bisoprololol may increase AV conduction impairment and increase the risk of bradycardia.

The hypoglycemic effect of insulin or hypoglycemic agents for oral administration may increase. Signs of hypoglycemia – particularly tachycardia – may be masked or suppressed. These interactions are more likely with non-selective beta-adrenoblockers.

The agents for general anesthesia may increase the risk of cardiodepressant effects, leading to arterial hypotension (see section “Special Precautions”).

The cardiac glycosides, when used concomitantly with bisoprolol, may increase pulse conduction time and thereby lead to bradycardia.

Non-steroidal anti-inflammatory drugs (NSAIDs) may decrease the hypotensive effect of bisoprolol.

The concomitant use of bisoprolol with beta-adrenomimetics (e.g., isoprenaline, dobutamine) may decrease the effect of both drugs.

The combination of bisoprolol with adrenomimetics affecting beta- and alpha-adrenoreceptors (e.g. norepinephrine (noradrenaline), epinephrine (adrenaline)) may enhance the vasoconstrictor effects of these agents occurring with alpha-adrenoreceptors, leading to increased BP. Such interactions are more likely when using non-selective beta-adrenoblockers.

Antihypertensive agents, as well as other agents with possible antihypertensive effects (e.g., tricyclic antidepressants, barbiturates, phenothiazines), may increase the hypotensive effect of bisoprolol.

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

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

Special Instructions

Bisoprolol treatment should not be abruptly interrupted or the recommended dose changed without first consulting a physician, as this may lead to a temporary worsening of heart function. Treatment should not be abruptly interrupted, especially in patients with CHD. If discontinuation of treatment is necessary, the dose should be reduced gradually.

In the initial stages of bisoprolol treatment, patients require continuous monitoring.

The drug should be used with caution in the following cases:

– severe forms of COPD and nonsevere forms of bronchial asthma;

– diabetes mellitus with significant fluctuations in blood glucose concentrations: symptoms of marked decreases in glucose concentration (hypoglycemia), such as tachycardia, palpitations, or increased sweating, may be masked;

– strict diet;

– conducting desensitization therapy;

p> – 1st degree AV blockade;

– Prinzmetal angina;

– mild to moderate peripheral arterial circulatory disorders (worsening of symptoms may occur at the start of therapy);

– psoriasis (including history

– Psoriasis (including history).

Respiratory system: in bronchial asthma or COPD concomitant use of bronchodilators is indicated. Patients with bronchial asthma may have increased airway resistance, requiring a higher dose of beta2-adrenomimetics. In patients with COPD, bisoprololol administered in combination therapy to treat heart failure should be started at the lowest possible dose, and patients should be closely monitored for the appearance of new symptoms (e.g., dyspnea, exercise intolerance, cough).

Allergic reactions: beta-adrenoblockers, including bisoprolol, may increase sensitivity to allergens and the severity of anaphylactic reactions due to impairment of adrenergic compensatory regulation by beta-adrenoblockers. Therapy with epinephrine (adrenaline) does not always give the expected therapeutic effect.

General anesthesia: In general anesthesia, the risk of beta-adrenoreceptor blockade should be considered. If bisoprolol therapy has to be discontinued before surgery, this should be done gradually and completed 48 h before general anesthesia. The anesthesiologist should be warned about bisoprolol therapy.

Pheochromocytoma: In patients with adrenal tumor (pheochromocytoma), bisoprololol may be administered only with the use of alpha-adrenoblockers.

Hyperthyroidism: When treated with bisoprololol, symptoms of thyroid hyperfunction (hyperthyroidism) may be masked.

Impact on driving and operating ability

Bisoprolol does not affect the ability to drive according to the results of studies in patients with CHD. However, due to individual reactions, the ability to drive motor transport or operate technically complex mechanisms may be impaired. Special attention should be paid to this at the beginning of therapy, after changing the dose, as well as with the simultaneous use of alcohol.

Synopsis

Contraindications

– hypersensitivity to bisoprolol or any of the excipients;

– acute heart failure, decompensated chronic heart failure requiring inotropic therapy;

– cardiogenic shock;

– Atrioventricular (AV) block of II and III degree (without pacemaker);

– sinoatrial block;

– sinus node weakness syndrome;

– marked bradycardia (HR < 60 bpm);

– severe arterial hypotension (systolic BP < 100 mmHg. Hg);

– severe arterial hypotension (systolic BP);

– severe bronchial asthma;

– marked peripheral arterial circulatory disorders or Raynaud’s syndrome;

– metabolic acidosis;

– pheochromocytoma (without concomitant use of alpha-adrenoblockers);

– childhood and adolescence under 18 years of age (efficacy and safety not established).

With caution

– conducting desensitization therapy;

– hyperthyroidism;

p> – type I diabetes mellitus and diabetes mellitus with significant fluctuations in blood glucose concentration;

– severe renal insufficiency (creatinine clearance (CK) less than
20 ml/min);

– severe liver function impairment;

– psoriasis;

– 1st degree AV blockade;

– Prinzmetal angina;

– restrictive cardiomyopathy;

– congenital heart disease or heart valve malformation with significant hemodynamic abnormalities;

– chronic heart failure with myocardial infarction within the last 3 months;

– peripheral circulatory disorders;

– severe forms of chronic obstructive pulmonary disease;

– bronchospasm (history);

– allergic reactions (history);

– general anesthesia;

– strict diet.

Side effects

The frequency of adverse reactions below was distributed as follows (WHO classification): very common (≥ 1/10), common (≥ 1/100, < 1/10), infrequent (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000); very rare (< 1/10000, including individual reports).

Cardiovascular system disorders: very frequently – bradycardia; frequently – worsening of symptoms of CHF course, sensation of coldness or numbness in extremities, marked BP decrease; infrequently – AV conduction disorders, orthostatic hypotension.

Nervous system disorders: frequently – dizziness, headache; rarely – loss of consciousness.

Psychiatric disorders: infrequent – depression, insomnia; rare – hallucinations, nightmares.

Sensory system disorders: rare – decreased tear production (should be considered when wearing contact lenses), hearing disorders; very rare – conjunctivitis.

Respiratory system: infrequent – bronchospasm in patients with bronchial asthma or obstructive airway disease in the anamnesis; rarely – allergic rhinitis.

The digestive system: frequently – nausea, vomiting, diarrhea, constipation; rarely – hepatitis.

Muscular system: infrequent – muscle weakness, muscle cramps.

Urogenital system disorders: rarely – impaired potency.

Skin disorders: rare – hypersensitivity reactions such as skin itching, skin rash, skin hyperemia; very rare – alopecia, beta-adrenoblockers may contribute to exacerbation of psoriasis symptoms or cause psoriasis-like rash.

In the laboratory data: rarely – increase of triglycerides concentration and “liver” transaminases activity in blood (aspartate aminotransferase (AST), alanine aminotransferase (ALT)).

General disorders and disorders at the site of administration: often – asthenia, increased fatigue.

Overdose

Symptoms: marked bradycardia, AV blockade, marked BP decrease, acute heart failure, hypoglycemia, bronchospasm.

Sensitivity to single-dose high-dose bisoprolol varies widely among individual patients and is likely to be highly sensitive in patients with CHF.

Treatment: first of all, discontinue the drug and initiate supportive symptomatic therapy. In marked bradycardia – intravenous injection of atropine. If the effect is insufficient, drugs with positive chronotropic effect may be administered with caution. Sometimes a temporary artificial pacer may be necessary.

In case of a marked decrease in BP – intravenous administration of plasma replacement solutions and vasopressor drugs.

In case of hypoglycemia intravenous administration of dextrose (glucose), glucagon may be indicated.

In case of AV-blockade – patients should be constantly monitored and receive treatment with beta-adrenomimetics, such as epinephrine (adrenaline). If necessary, placement of an artificial pacemaker.

In case of exacerbation of CHF, intravenous administration of diuretics, drugs with positive inotropic effect, and vasodilators.

In case of bronchospasm – administration of bronchodilators, including beta2-adrenomimetics and/or aminophylline.

Pregnancy use

The use of the drug in pregnancy is possible only when the estimated benefit to the mother outweighs the potential risk to the fetus.

Beta-adrenoblockers decrease blood flow in the placenta and may affect fetal development. Blood flow in the placenta and uterus should be monitored carefully, and the growth and development of the unborn child should be monitored and alternative therapeutic measures should be taken if there are adverse events in relation to pregnancy and/or fetus.

The newborn should be carefully examined after delivery. Symptoms of bradycardia and hypoglycemia may occur in the first 3 days of life.

There are no data on the excretion of bisoprolol with breast milk or on the safety of exposure of breastfed infants to bisoprolol. If it is necessary to use the drug during breastfeeding, discontinuation of breastfeeding should be considered.

Similarities