Bisoprolol-Vertex, 5 mg 60 pcs.

Pharmacotherapeutic group

Beta1-adrenoblocker selective

ATX code

C07AB

Pharmacodynamics:

Bisoprolol is a selective β1-adrenoblocker with no sympathomimetic activity of its own and has no membrane-stabilizing effects. As with other β1-adrenoblockers, the mechanism of action in arterial hypertension is unclear. At the same time, it is known that bisoprolol reduces plasma renin activity and decreases myocardial oxygen demand and decreases heart rate (HR). It has antihypertensive antiarrhythmic and antianginal effects.

Blocking in low doses β1-adrenoreceptors of heart reduces stimulated by catecholamines formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) reduces intracellular flow of calcium ions depresses all heart functions reduces atrioventricular (AV) conduction and excitability. If the therapeutic dose is exceeded, it has a β2-adrenoblocking effect. Total peripheral vascular resistance increases at the beginning of the drug administration during the first 24 hours (as a result of reciprocal increase of α-adrenoreceptor activity and elimination of β2-adrenoreceptor stimulation). It returns to initial value after 1-3 days and decreases with prolonged use.

The antihypertensive effect is related to the decrease of the minute blood volume by sympathetic stimulation of peripheral vessels decrease of sympathoadrenal system (SAS) activity (of great importance for patients with initial renin hypersecretion) restoration of sensitivity in response to blood pressure (BP) decrease and influence on the central nervous system. In arterial hypertension, the effect develops in 2-5 days, stable effect is noted after 1-2 months.

The antianginal effect is caused by decrease of myocardial oxygen demand as a result of decrease of contractility and other myocardial functions, prolongation of diastole and improvement of myocardial perfusion. By increasing left ventricular end-diastolic pressure and increasing ventricular muscle fiber stretch, oxygen demand may increase especially in patients with chronic heart failure (CHF).

In contrast to non-selective β-adrenoblockers, when used in medium therapeutic doses it has less pronounced effect on organs containing β2-adrenoreceptors (pancreas skeletal muscles smooth muscles of peripheral arteries of 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.

Pharmacokinetics:

Bisoprolol is almost completely (over 90%) absorbed in the gastrointestinal tract food intake does not affect absorption. The effect of “primary passage” through the liver is insignificant (at 10-15%) resulting in high bioavailability (90%). Food intake has no effect on the bioavailability of bisoprolol.

Bisoprolol is metabolized by the oxidative pathway without subsequent conjugation. All metabolites are strongly polar and are excreted by the kidneys. The major metabolites detected in plasma and urine have no pharmacological activity. Experiments with human liver microsomes in vitro show that bisoprolol is metabolized primarily by CYP3A4 isoenzyme (approximately 95%) and CYP2D6 isoenzyme plays only a minor role.

The binding to plasma proteins is about 30%. Volume of distribution is 35 l/kg. Total clearance is approximately 15 l/h. Maximum concentration in blood plasma is determined after 2-3 hours. Blood-brain barrier and placental barrier permeability is low.

The plasma elimination half-life (10-12 hours) provides efficacy for 24 hours after a single daily dose.

Bisoprolol is eliminated from the body in two ways 50% of the dose is metabolized in the liver to form inactive metabolites. About 98% is excreted by the kidneys, of which 50% is excreted unchanged; less than 2% is excreted in the intestine (with the bile).

As excretion takes place in the kidneys and liver equally in patients with impaired liver function or with renal failure the dose adjustment is not required. The pharmacokinetics of bisoprolol are linear and independent of age.

Bisoprolol has higher plasma concentrations and longer half-life in patients with CHF compared to healthy volunteers.

There is no information about the pharmacokinetics of bisoprolol in patients with CHF and concomitant hepatic or renal impairment.

Indications

Active ingredient

Composition

1 tablet contains:

Active ingredient:

bisoprolol fumarate 5 mg.

Associates:

lactose monohydrate,

microcrystalline cellulose,

How to take, the dosage

Bisoprolol is taken orally in the morning on an empty stomach, once without chewing and with a small amount of fluid. The tablets should not be chewed or crushed into a powder.

The treatment of arterial hypertension and angina

In all cases, the regimen and dosage are individually selected by the physician for each patient, taking into account the heart rate and the therapeutic response.

In arterial hypertension and ischemic heart disease, the usual starting dose is 5 mg once daily. If necessary, the dose is increased to 10 mg once daily.

In the treatment of arterial hypertension and angina pectoris, the maximum daily dose is 20 mg once daily. It is possible to divide the daily dose into 2 doses.

Treatment of stable chronic heart failure

The standard regimen for treatment of CHF includes angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists (if ACE inhibitors are intolerant) β-adrenoblockers diuretics and facultative cardiac glycosides. Initiation of CHF treatment with Bisoprolol requires special titration phase and regular medical monitoring.

The precondition for treatment with Bisoprolol is stable chronic heart failure without signs of exacerbation.

The treatment of chronic heart failure with Bisoprolol starts according to the following titration scheme. Individual adaptation may be necessary depending on how well the patient tolerates the prescribed dose, i.e. the dose may be increased only if the previous dose was well tolerated. The recommended starting dose is 125 mg (1/2 tablet of 25 mg) once a day. Depending on individual tolerance, the dose should be gradually increased to 25 mg 375 mg (11/2 25 mg tablets) 75 mg (3 25 mg tablets) and 10 mg once a day. Each subsequent dose increase should be made after at least two weeks.

If the increased dose is not well tolerated by the patient, the dose may be reduced. The maximum recommended dose in CHF is 10 mg of Bisoprolol once daily.

When titrated, 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.

If the patient does not tolerate the maximum recommended dose of the drug, gradual dose reduction is possible.

A temporary worsening of CHF, such as hypotension or bradycardia, may occur during or after the titration phase. In this case, it is recommended that doses of concomitant therapy drugs be adjusted first. It may also be necessary to temporarily reduce the dose of Bisoprolol or discontinue it.

After the patient’s condition has stabilized, the dose should be titrated again or treatment should continue.

Patient special groups

He has impaired renal or hepatic function:

In mild to moderate hepatic or renal dysfunction, no dose adjustment is usually necessary;

In severe renal dysfunction (CK less than 20 mL/min) and in patients with severe liver disease, the maximum daily dose is 10 mg. Increasing the dose in such patients should be carried out with extreme caution.

To date there are not enough data regarding use of Bisoprololol in patients with CHF associated with type 1 diabetes mellitus with severe renal and/or hepatic impairment restrictive cardiomyopathy congenital heart disease or cardiac valve defect with severe hemodynamic abnormalities.

There are also still insufficient data regarding patients with CHF with myocardial infarction within the past 3 months.

Interaction

Unrecommended combinations

Class I antiarrhythmic drugs (e.g. quinidine disopyramide lidocaine phenytoin; flecainide propafenone) when used concomitantly with bisoprolol may decrease AV conduction and cardiac contractility.

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

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

Combinations requiring caution

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

The action of β-adrenoblockers for topical use (e.g. eye drops to treat glaucoma) may increase the systemic effects of bisoprololol (decreased BP, slower heart rate).

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

The concomitant use of bisoprololol with β-adrenomimetics (e.g. isoprenaline dobutamine) may decrease the effect of both drugs. Combination of bisoprolol with adrenomimetics affecting β- and α-adrenoreceptors (e.g. norepinephrine epinephrine) may increase the vasoconstrictor effects of these drugs arising from α-adrenoreceptors, resulting in increased BP. Similar interactions are more probable when using non-selective β-adrenoblockers.

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

Allergens used for immunotherapy or allergen extracts for skin tests increase the risk of severe systemic allergic reactions or anaphylaxis in patients receiving bisoprolol.

Iodine-containing x-ray contrast diagnostic agents for intravenous administration increase the risk of anaphylactic reactions.

Phenytoin when administered intravenously, inhalation anesthetics (hydrocarbon derivatives) increase the severity of cardiodepressant effects and the likelihood of BP reduction.

The effectiveness of insulin and oral hypoglycemic agents may be altered by treatment with bisoprolol (masks the symptoms of developing hypoglycemia: tachycardia and increased BP).

The clearance of lidocaine and xanthines (except theophylline) may be decreased due to possible increased plasma concentrations, particularly in patients with initially increased clearance of theophylline due to smoking.

The antihypertensive effect is weakened by nonsteroidal anti-inflammatory drugs (NSAIDs) (retention of sodium ions and blockade of prostaglandin synthesis by kidneys) glucocorticosteroids and estrogens (retention of sodium ions).

The cardiac glycosides methyldopa reserpine and guanfacine slow calcium channel blockers (verapamil diltiazem) amiodarone and other antiarrhythmic agents increase the risk of developing or worsening bradycardia AV cardiac arrest blockade and heart failure.

Nifedipine can lead to a significant decrease in BP.

The diuretics clonidine sympatholytics hydralazine and other hypotensive agents may cause excessive BP reduction.

The effects of nondepolarizing myorelaxants and the anticoagulant effect of coumarins may be prolonged during treatment with bisoprolol.

Tricyclic and tetracyclic antidepressants antipsychotics (neuroleptics) ethanol sedatives and hypnotics increase central nervous system depression.

The concomitant use with MAO inhibitors (except MAO B inhibitors) is not recommended due to a significant increase in antihypertensive effect. Concomitant use may also lead to the development of a hypertensive crisis. A treatment break of at least 14 days should be taken between MAO inhibitors and bisoprolol.

Non-hydrogenated ergot alkaloids increase the risk of peripheral circulatory disorders.

Ergotamine increases the risk of peripheral circulatory disorders.

Sulfasalazine increases the plasma concentration of bisoprolol.

Rifampicin shortens the half-life of bisoprolol.

Special Instructions

Monitoring of patients taking Bisoprolol should include measurement of HR and BP ECG determination of blood glucose concentration in patients with diabetes mellitus (once every 4-5 months). In elderly patients it is recommended to monitor kidney function (once every 4-5 months).

The patient should be trained on how to calculate heart rate and instructed to consult a physician if the heart rate is less than 50 bpm.

Patients with a history of bronchopulmonary problems should have an external respiratory function study before starting treatment.

Patients who wear contact lenses should note that there may be a decrease in lacrimal fluid production during treatment with the drug.

In patients with pheochromocytoma, there is a risk of paradoxical arterial hypertension when using Bisoprolol (unless effective α-adrenoreceptor blockade has first been achieved).

In thyrotoxicosis, bisoprolol may mask certain clinical signs of thyrotoxicosis (e.g., tachycardia). Abrupt withdrawal of the drug in patients with thyrotoxicosis is contraindicated because it may exacerbate the symptoms.

In diabetic patients may mask tachycardia caused by hypoglycemia. Unlike non-selective β-adrenoblockers, it practically does not increase insulin-induced hypoglycemia and does not delay recovery of blood glucose concentration to normal values.

If clonidine is used concomitantly, it should not be discontinued until several days after discontinuation of Bisoprolol.

The severity of hypersensitivity reactions and lack of effect of usual doses of epinephrine (adrenaline) with a history of allergy may increase.

If it is necessary to perform elective surgical treatment, the drug should be discontinued 48 hours before general anesthesia. If the patient has taken the drug prior to surgical intervention he should choose a general anesthesia drug with minimal negative inotropic effect.

Reciprocal activation of the vagus nerve may be relieved by intravenous administration of atropine (1-2 mg).

Drugs which deplete catecholamine depots (including reserpine) can potentiate the effects of β-adrenoblockers, so patients taking these combinations of drugs should be monitored closely for any significant decrease in BP or bradycardia.

Patients with bronchospastic disorders may be cautiously prescribed cardioselective β-adrenoblockers if other hypotensive agents are intolerant and/or ineffective. Against the background of taking β-adrenoblockers in patients with concomitant bronchial asthma, airway resistance may increase. If the dose of Bisoprolol is exceeded in such patients, there is a risk of bronchospasm.

If patients show increasing bradycardia (HR less than 60 bpm) or markedly decreased BP (systolic BP less than 100 mm Hg) of AV blockade, the dose should be reduced or treatment stopped.

It is recommended to discontinue therapy with Bisoprolol if depression develops.

Bisoprolol should not be stopped abruptly because of the risk of severe arrhythmias and myocardial infarction. The drug should be withdrawn gradually over a period of 2 weeks or more (25% reduction every 3 to 4 days).

The drug should be discontinued before blood and urine catecholamine concentrations of normetanephrine vanillinmindalic acid antinuclear antibody titers are investigated.

In smokers, the effectiveness of β-adrenoblockers is lower.

The use of Bisoprolol has no effect on the ability to drive vehicles according to the results of a study in patients with CHD. However, due to individual reactions, the ability to drive vehicles or operate technically complex mechanisms may be impaired. Special attention should be paid to this when starting treatment after changing the dose, as well as in case of concomitant alcohol consumption.

Contraindications

Side effects

The incidence of adverse reactions were determined according to the following (World Health Organization classification): very common – at least 10%; common – at least 1% but less than 10%; infrequent – at least 01% but less than 1%; rare – at least 001% but less than 01%; very rare – less than 001% including individual reports.

Heart and vascular disorders: very often – reduced heart rate (bradycardia especially in patients with CHF); sensation of palpitations; often – marked decrease in blood pressure (especially in patients with CHF) manifestation of angiospasm (increased peripheral circulatory disorders feeling of cold in the extremities (paresthesias); infrequent – abnormal AV conduction (up to complete transverse blockage and cardiac arrest) arrhythmias orthostatic hypotension – worsening of CHF course with the development of peripheral edema (edema of ankles of feet; dyspnea) chest pain.

Nervous system disorders: frequently – dizziness headache asthenia increased fatigability sleep disorders depression anxiety; rarely – confusion or short-term memory loss “nightmare” dreams hallucinations myasthenia tremor muscle cramps. Usually these phenomena are mild and usually go away within 1-2 weeks after the start of treatment.

Sensory organs: rare – vision disorders decreased tear production (should be considered when wearing contact lenses) tinnitus decreased hearing pain in the ear; very rare – dry and painful eyes conjunctivitis taste disorders.

Respiratory system disorders: infrequent – bronchospasm in patients with bronchial asthma or obstructive airways disease; rare – allergic rhinitis; nasal congestion.

The digestive system: frequently – nausea vomiting diarrhea constipation dry oral mucosa abdominal pain; rarely – hepatitis increased liver enzyme activity (alanine aminotransferase aspartate aminotransferase) increased bilirubin concentration changes in taste.

Musculoskeletal system: infrequent – arthralgia back pain.

Urogenital system disorders: very rare – impaired potency impaired libido.

Laboratory indices: rare – increase of triglycerides concentration in blood; in single cases – thrombocytopenia agranulocytosis leukopenia.

Allergic reactions: rare – skin itching rash urticaria.

Skin reactions: rare – increased sweating skin hyperemia exanthema psoriasis-like skin reactions; very rare – alopecia β-adrenoblockers may worsen the course of psoriasis.

Others: withdrawal syndrome (increased frequency of attacks of angina pectoris and increased BP).

Overdose

Symptoms: arrhythmia ventricular extrasystole marked bradycardia AV blockade marked BP decrease acute heart failure hypoglycemia acrocyanosis difficult breathing bronchospasm dizziness fainting convulsions.

Treatment: in case of overdose first of all it is necessary to stop taking the drug, gastric lavage, administer adsorptive agents, conduct symptomatic therapy.

In case of marked bradycardia – intravenous injection of atropine. If the effect is insufficient, a drug with positive chronotropic action may be administered with caution. Occasionally, temporary placement of an artificial pacer may be necessary.

In case of significant decrease in BP – intravenous administration of plasma exchange solutions and vasopressors.

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

In AV blockade: patients should be kept under constant observation and treated with P-adrenomimetics such as epinephrine. If necessary, insertion of artificial pacemaker.

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

In case of bronchospasm – administration of bronchodilators including β2-adrenomimetics and/or aminophylline.

Pregnancy use

Bisoprolol has pharmacological effects that can have harmful effects on pregnancy and/or the fetus or newborn. Typically, β-adrenoblockers reduce placental perfusion, which leads to fetal growth retardation, intrauterine fetal death, miscarriage, or preterm birth. The fetus and the newborn child may have abnormal reactions (e.g. hypoglycemia, bradycardia, arterial hypotension).

Bisoprolol should not be used during pregnancy if the benefit to the mother exceeds the risk of side effects in the fetus and/or child. If treatment with Bisoprololol is considered necessary, uteroplacental blood flow and fetal development should be monitored. Alternative therapy should be considered if the pregnancy or fetus is adversely affected. Symptoms of hypoglycemia and bradycardia usually occur within the first 3 days. The newborn should be carefully evaluated after delivery.

There are no data on excretion of bisoprolol into breast milk. Therefore, if it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Similarities