Bisoprolol - instructions for use, dose, side effects, contraindications

Excipients: cellulose microcrystalline 93.5 mg, corn starch 43.7 mg, croscarmellose sodium 2.9 mg, magnesium stearate 1.5 mg, silicon dioxide colloid 1,4 mg;

shell: film coating (polyvinyl alcohol 1.80 mg, titanium dioxide 1.03 mg, macrogol 0.91 mg, talc 0.67 mg, iron oxide dye yellow 0.09 mg) 4.5 mg;

dosage 5 mg:

active substance: bisoprolol fumarate 5.0 mg;

helpatFerrous substances: cellulose microcrystalline 91.0 mg, corn starch 43.7 mg, croscarmellose sodium 2.9 mg, magnesium stearate 1.5 mg, silicon dioxide colloid 1,4 mg;

shell: film coating (polyvinyl alcohol 1,8000 mg, macrogol 0.9090 mg, titanium dioxide 0.8770 mg, talc 0.6666 mg, iron oxide dye yellow 0.2475 mg, iron iron oxide oxide 0.0005 mg) 4.5 mg;

dosage of 10 mg:

active substance: bisoprolol fumarate 10.0 mg;

Excipients: cellulose microcrystalline 150.4 mg, corn starch 73.0 mg, croscarmellose sodium 4.9 mg, magnesium stearate 2.4 mg, silicon dioxide colloid 2.3 mg;

shell: film coating (polyvinyl alcohol 2.80 mg, titanium dioxide 1.75 mg, macrogene 1.41 mg, talc 1.04 mg) 7.0 mg.

Description:

Dosage 2.5 mg: Round biconvex tablets with a risk and a facet, covered with a film shell from light yellow to yellow.On a cross-section the nucleus is from white to yellowish white.

Dosage of 5 mg: Round biconvex tablets with a risk and a facet, covered with a film coat from yellow to dark yellow. On a cross-section the nucleus is from white to yellowish white.

Dosage of 10 mg: Round biconvex tablets, covered with a film coating of white color. On a cross-section the nucleus is from white to yellowish white.

Pharmacotherapeutic group:Beta1-blocker selective

ATX: & nbsp

C.07.A.B Selective beta-blockers

C.07.A.B.07 Bisoprolol

Pharmacodynamics:

Bisoprolol - selective beta₁- adrenoblocker, without its own sympathomimetic activity, does not possess membrane-stabilizing action. As for the other beta₁adrenoblockers, the mechanism of action for arterial hypertension is unclear. At the same time, it is known that bisoprolol reduces the activity of renin in the blood plasma, reduces the need for myocardium in oxygen, and reduces the heart rate (heart rate). Has antihypertensive, antiarrhythmic and anti-anginal action. Blocking in low doses of beta₁-adrenoceptors of the heart, reduces catecholamine-stimulated formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), reduces the intracellular current of calcium ions (Ca²⁺), has a negative chrono-, dromo-, batmo- and inotropic effect, inhibits conduction and excitability, reduces atrioventricular (AV) conductivity.

If the therapeutic dose is exceeded, beta₂-adrenoblocking action. The total peripheral vascular resistance at the beginning of the drug application, in the first 24 hours, increases (as a result of the reciprocal increase in the activity of alpha-adrenergic receptors and the elimination of beta stimulation₂-adrenoreceptors), returns to the initial value after 1-3 days, and decreases with prolonged use.

The antihypertensive effect is associated with a decrease in the minute volume of blood, sympathetic stimulation of the peripheral vessels, a decrease in the activity of the sympathetic adrenal system (CAS) (important for patients with initial hypersecretion of renin), restoration of sensitivity in response to lowering blood pressure (BP) and affecting the central nervous system (CNS).With arterial hypertension, the effect develops in 2-5 days, a stable effect is observed after 1-2 months.

The antianginal effect is due to a decrease in myocardial oxygen demand as a result of a decrease in heart rate, a slight decrease in contractility, diastole lengthening, and improvement in myocardial perfusion.

Antiarrhythmic effect is due to the elimination of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased cAMP, arterial hypertension), a decrease in the rate of spontaneous excitation of sinus and ectopic pacemakers and slowing AV conduct (mainly in antegrade and, to a lesser extent, in the retrograde direction through AV node) and on additional paths.

When used in average therapeutic doses, in contrast to non-selective beta-blockers, it exerts a less pronounced effect on organs containing beta₂- adrenergic receptors (pancreas, skeletal muscles, smooth musculature of peripheral arteries, bronchi and uterus) and carbohydrate metabolism, do not cause delay of sodium ions (Na⁺) in organism; the severity of atherogenic action does not differ from that of propranolol.

Pharmacokinetics:

Suction. Bisoprolol almost completely (> 90%) is absorbed from the gastrointestinal tract. Its bioavailability due to minor metabolization during "primary passage" through the liver (at about 10-15%) is approximately 85-90% after ingestion. Eating does not affect the bioavailability of bisoprolol. Bisoprolol demonstrates linear kinetics, and its concentrations in the blood plasma are proportional to the administered dose in the dose range of 5 to 20 mg. The maximum concentration in the blood plasma is achieved in 2-3 hours.

Distribution. Bisoprolol distributed fairly widely. The volume of distribution is 3.5 l / kg. The connection with blood plasma proteins reaches approximately 35%; seizure of bisoprolol with blood cells is not observed.

Metabolism. Bisoprolol metabolized along the oxidative pathway without subsequent conjugation. All metabolites have a strong polarity and are excreted by the kidneys. The main metabolites found in blood plasma and urine, do not show pharmacological activity.Data obtained as a result of experiments with microsomes of human liver in vitro, show that bisoprolol is metabolized primarily by isoenzyme CYP3A4 (about 95%), and isoenzyme CYP2D6 plays only a small role.

Excretion. Bisoprolol clearance is determined by the balance between excretion through the kidneys in the form of unchanged substance (about 50%) and oxidation in the liver (about 50%) to metabolites, which are then excreted by the kidneys. The total clearance of bisoprolol is 15.6 ± 3.2 l / h, with a kidney clearance of 9.6 ± 1.6 l / h. The half-life of bisoprolol is 10-12 hours.

Since excretion takes place in the kidneys and in the liver equally, patients with a dysfunction of the liver or with renal insufficiency do not need to adjust the dose. The pharmacokinetics of bisoprolol is linear and does not depend on age.

In patients with chronic heart failure (CHF), plasma concentrations of bisoprolol are higher, and the half-life is longer than in healthy volunteers.

Indications:

- Arterial hypertension;

- ischemic heart disease: prevention of attacks of stable angina pectoris;

- chronic heart failure.

Contraindications:

- Hypersensitivity to the components of the drug and other beta-blockers;

- acute heart failure and CHF in the stage of decompensation, requiring inotropic therapy;

- cardiogenic shock;

- collapse;

- AV blockade II-III degree, without a pacemaker;

- sinoatrial blockade;

- syndrome of weakness of the sinus node;

- bradycardia (heart rate before treatment less than 60 bpm);

- severe arterial hypotension (systolic blood pressure less than 100 mm Hg)

- cardiomegaly (no signs of heart failure);

- severe forms of bronchial asthma and chronic obstructive pulmonary disease (COPD) in history;

- severe peripheral circulatory disturbances;

- Raynaud's syndrome;

- metabolic acidosis;

- pheochromocytoma (without simultaneous use of alpha-blockers);

- simultaneous administration of monoamine oxidase inhibitors (MAO) (with the exception of MAO type B inhibitors);

- age to 18 years (efficacy and safety not established).

Carefully:

Psoriasis, depression (including history), diabetes mellitus (can mask symptoms of hypoglycemia), allergic reactions (in the anamnesis), bronchospasm (in the anamnesis), desensitizing therapy, prinzmetal angina, AV blockade of the I degree, expressed disturbances of kidney function (creatinine clearance (CC) less than 20 ml / min); severe violations of liver function; hyperthyroidism, elderly age, restrictive cardiomyopathy, congenital heart disease or heart valve disease with severe hemodynamic disorders, CHF with myocardial infarction during the last 3 months, strict diet.

Pregnancy and lactation:

Pregnancy

Bisoprolol does not have direct cytotoxic, mutagenic and teratogenic effects, but it has pharmacological effects that can have harmful effects on the course of pregnancy and / or on the fetus or on the newborn. Usually beta-adrenoblockers reduce placental perfusion, which leads to a slowing of fetal growth, fetal death, miscarriage or premature birth. The fetus and the newborn child may experience pathological reactions, such as intrauterine growth retardation, hypoglycemia, bradycardia.

Bisoprolol should not be used during pregnancy, use is possible if the benefit to the mother exceeds the risk of side effects in the fetus and / or the child.In the event that the drug treatment Bisoprolol is considered necessary, blood flow in the placenta and uterus should be monitored, and the growth and development of the unborn child should be monitored, and in the event of undesirable pregnancy and / or fetal events, alternative therapies. You should carefully examine the newborn after delivery. Symptoms of hypoglycemia and bradycardia usually arise during the first 3 days of life.

Breastfeeding period

There is no data on the isolation of bisoprolol in breast milk. Therefore, taking the drug Bisoprolol is not recommended for women during lactation.

If you need to use the drug during breastfeeding, breastfeeding should be discontinued.

Dosing and Administration:

A drug Bisoprolol taken in the morning on an empty stomach, once a day with a small amount of water, in the morning before breakfast, during or after it. Tablets should not be chewed or ground into a powder.

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

When Arterial hypertension and ischemic heart disease the drug is prescribed 5 mg once a day. If necessary, increase the dose to 10 mg 1 time / day.

In the treatment of hypertension and angina, the maximum daily dose is 20 mg 1 time / day.

Chronic heart failure

The standard treatment regimen for CHF includes the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists II (in case of intolerance to ACE inhibitors), beta-adrenoblockers, diuretics and, optionally, cardiac glycosides. Initiation of CHF treatment with a drug Bisoprolol requires mandatory conduct of a special phase of titration and regular medical supervision.

A prerequisite for drug treatment Bisoprolol is stable CHF without signs of exacerbation.

Treatment of CHF with a drug Bisoprolol starts according to the following titration scheme. Individual adaptation may be required depending on how well the patient tolerates the prescribed dose, that is, the dose can be increased only if the previous dose is well tolerated.

To ensure the following dosage regimen of the drug for CHF, it is possible to use the drug Bisoprolol in tablets of 2.5 mg with a risk.

The recommended initial dose is 1.25 mg once a day. Depending on the individual tolerability, the dose should be gradually increased to 2.5 mg, 3.75 mg (1¹/₂ 2.5 mg tablets), 7.5 mg (3 tablets of 2.5 mg) and 10 mg once a day. Each subsequent increase in dose should be carried out not less than two weeks later. If the increase in the dose of the drug is poorly tolerated by the patient, a dose reduction is possible.

The maximum recommended dose for CHF is 10 mg of the drug Bisoprolol 1 per day.

During titration, regular monitoring of blood pressure, heart rate and severity of CHF symptoms is recommended. The aggravation of the symptoms of CHF is possible from the first day of the drug.

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

During the titration phase or after it, temporary worsening of the course of CHF, arterial hypertension or bradycardia may occur. In this case, it is recommended, first of all, to correct the doses of concomitant therapy. It may also be necessary to temporarily reduce the dose of the drug Bisoprolol or its cancellation.

After stabilization of the patient's condition, a repeated titration of the dose should be performed, or the treatment should be continued.

Special patient groups

Impaired renal or hepatic function:

- if there is a mild or moderate degree of liver or kidney failure, you usually do not need to adjust the dose;

- with severe renal dysfunction (CC less than 20 ml / min) and in patients with severe liver disease the maximum daily dose is 10 mg. Increase in the dose in such patients should be carried out with extreme caution.

Elderly patients:

Correction of the dose is not required.

To date, there is insufficient data on the use of the drug Bisoprolol in patients with CHF associated with type 1 diabetes mellitus, marked renal and / or liver dysfunction, restrictive cardiomyopathy, congenital heart disease or heart valve disease with severe hemodynamic disorders. Also, sufficient data have not yet been obtained regarding patients with CHF with myocardial infarction during the last 3 months.

Side effects:

The frequency of adverse reactions listed below,was determined according to the following (classification of the World Health Organization): very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely - less than 0.01%, including individual reports.

From the side of the cardiovascular system: very often - a decrease in heart rate (bradycardia, especially in patients with CHF); a feeling of palpitations; often marked decrease in blood pressure (especially in patients with CHF), manifestation of angiospasm (increased peripheral circulatory disorders, cold sensation in the extremities (paresthesia), infrequent - violation AY conduction (up to the development of complete transverse blockade and cardiac arrest), arrhythmias, orthostatic hypotension, aggravation of CHF with development of peripheral edema (swelling of the ankles, stop, shortness of breath), chest pain.

From the nervous system: often - dizziness, headache, asthenia, fatigue, sleep disorders, depression, anxiety; rarely - confusion or short-term memory loss, "nightmarish" dreams, hallucinations, myasthenia gravis, tremor, muscle cramps. Usually, these phenomena are of an easy nature and usually pass within 1-2 weeks after the start of treatment.

From the sense organs: rarely - impaired vision, reduced tearing (should be taken into account when wearing contact lenses), tinnitus, hearing loss, ear pain; very rarely - dryness and soreness of the eyes, conjunctivitis, taste disorders.

From the respiratory system: infrequently bronchospasm in patients with bronchial asthma or obstructive airway disease; rarely - allergic rhinitis, nasal congestion.

From the digestive system: often - nausea, vomiting, diarrhea, constipation, dryness of the oral mucosa, abdominal pain; rarely - hepatitis, increased activity of liver enzymes (alanine aminotransferase, aspartate aminotransferase), increased bilirubin concentration, change in taste.

From the side of the musculoskeletal system: infrequently - arthralgia, pain in the back.

From the genitourinary system: very rarely - a violation of potency, a weakening of the libido.

Laboratory indicators: rarely - an increase in the concentration of triglycerides in the blood; in some cases - thrombocytopenia, agranulocytosis, and leukopenia.

Allergic reactions: rarely - skin itching, rash, hives.

From the skin: rarely - increased sweating, skin hyperemia, exanthema, psoriasis-like skin reactions; very rarely - alopecia, beta-adrenoblockers can aggravate the course of psoriasis.

Other: syndrome of "withdrawal" (increased frequency of angina attacks, increased blood pressure).

Overdose:

Symptoms: arrhythmia, ventricular extrasystole, pronounced bradycardia, AV blockade, marked decrease in blood pressure, acute heart failure, hypoglycemia, acrocyanosis, difficulty breathing, bronchospasm, dizziness, fainting, convulsions. The sensitivity to a single dose of a high dose of bisoprolol varies greatly among individual patients and, probably, patients with CHF are highly sensitive.

Treatment: if an overdose occurs, first of all, stop taking the drug, rinse the stomach, prescribe adsorptive drugs, and conduct symptomatic therapy.

With severe bradycardia - intravenous atropine. If the effect is insufficient, with caution, you can enter a drug that has a positive chronotropic effect. Sometimes it may be necessary to temporarily set up an artificial pacemaker.

With a pronounced decrease in blood pressure - intravenous injection of plasma-substituting solutions and vasopressors.

In hypoglycemia, intravenous dextrose (glucose) can be indicated.

When AV blockade: patients should be under constant supervision, and receive treatment with beta-adrenomimetics, such as epinephrine. If necessary - staging an artificial pacemaker.

With an exacerbation of the course of CHF - intravenous injection of diuretics, drugs with a positive inotropic effect, as well as vasodilators.

When bronhospazme - the appointment of bronchodilators, including beta₂adrenomimetics and / or aminophylline.

Interaction:

The effectiveness and tolerability of drugs can be affected by the simultaneous use of other drugs. This interaction can also occur when two drugs are taken in a short time. The doctor should be informed about the use of other medicines, even if they are taken without the doctor's prescription (that is, OTC drugs).

Unrecommended combinations

Antiarrhythmic drugs of the first class (for example, quinidine, disopyramide, lidocaine, phenytoin; flecainide, propafenone) with simultaneous application with bisoprolol may reduce AV conduction and contractility of the heart.

Blockers of "slow" calcium channels (BCCC) such as verapamil and, to a lesser extent, diltiazem when used with bisoprolol can lead to a decrease in myocardial contractility and disruption AV conductivity. In particular, intravenous administration of verapamil to patients taking beta-blockers can lead to severe arterial hypotension and AV blockade.

Hypotensive agents of central action (such as clonidine, methyldopa, moxonidine, rilmenidine) can lead to a decrease in heart rate and a decrease in cardiac output, as well as to vasodilation due to a decrease in the central sympathetic tone. Abrupt cancellation, especially before the abolition of the beta-blocker, may increase the risk of developing "ricochet" hypertension.

Combinations requiring special care

BCCC derivatives of dihydropyridine (for example, nifedipine, felodipine, amlodipine) with simultaneous application with bisoprolol may increase the risk of developing arterial hypotension.In patients with heart failure, the risk of subsequent deterioration of the contractile function of the heart can not be ruled out.

Antiarrhythmic drugs of the III class (for example, amiodarone) can increase the violation AV conductivity.

The action of beta-blockers for topical application (eg, eye drops for the treatment of glaucoma) can enhance the systemic effects of bisoprolol (lowering blood pressure, decreasing heart rate).

Parasympatomimetics with simultaneous use with bisoprolol may increase the disruption AV conductivity and increase the risk of developing a bradycardia.

The hypoglycemic action of insulin and hypoglycemic agents for oral ingestion may be enhanced. Symptoms of hypoglycemia - in particular tachycardia - can be masked or suppressed. Such interactions are more likely when using nonselective beta-blockers.

Means for general anesthesia may increase the risk of cardiodepressive action, leading to hypotension (see section "Special instructions").

Cardiac glycosides with simultaneous application with bisoprolol may lead to an increase in the timing of the impulse, and thus to the development of bradycardia.

Non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the antihypertensive effect of bisoprolol.

Simultaneous use of the drug Bisoprolol with beta-adrenomimetics (for example, isoprenaline, dobutamine) can lead to a decrease in the effect of both drugs. The combination of bisoprolol with adrenomimetics, affecting beta and alpha-adrenoreceptors (for example, norepinephrine, epinephrine), may enhance the vasoconstrictor effects of these agents that occur with alpha-adrenergic receptors, leading to an increase in blood pressure. Such interactions are more likely when using nonselective beta-blockers.

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

Mefloquine with simultaneous application with bisoprolol may increase the risk of developing bradycardia.

MAO inhibitors (except MAO type B inhibitors) can enhance the antihypertensive effect of beta-blockers. Simultaneous application can also lead to the development of hypertensive crisis.

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 radiopaque diagnostic tools for intravenous administration increase the risk of anaphylactic reactions.

Phenytoin with intravenous administration, means for inhalation anesthesia (derivatives of hydrocarbons) increase the severity of cardiodepressive action and the likelihood of lowering blood pressure.

The clearance of lidocaine and xanthines (except theophylline) may decrease due to a possible increase in their concentration in the blood plasma, especially in patients with initially elevated clearance of theophylline under the influence of smoking.

Special instructions:

Monitoring the status of patients taking the drug Bisoprolol, should include measurement of heart rate and blood pressure, ECG, determination of blood glucose concentration in patients with diabetes mellitus (1 time in 4-5 months). In elderly patients it is recommended to monitor the kidney function (1 time in 4-5 months).

It is necessary to teach the patient how to calculate the heart rate and instruct him about the need for medical consultation at a heart rate of less than 60 beats per minute.

Before the start of treatment, it is recommended to perform an external respiration function in patients with a history of bronchopulmonary anamnesis.

Patients who use contact lenses should take into account that against the background of drug treatment, a decrease in the production of tear fluid is possible.

When using the drug Bisoprolol patients with pheochromocytoma have a risk of developing paradoxical arterial hypertension (unless an effective blockade of alpha-adrenergic receptors is previously achieved).

With thyrotoxicosis bisoprolol can mask certain clinical signs of thyrotoxicosis (eg, tachycardia). Abrupt withdrawal of the drug in patients with thyrotoxicosis is contraindicated, since it can strengthen symptoms.

In diabetes mellitus can mask tachycardia caused by hypoglycemia. In contrast to non-selective beta-blockers, it does not substantially increase insulin-induced hypoglycemia and does not delay the restoration of glucose concentration in the blood to a normal value.

With the simultaneous use of clonidine, his reception may be discontinued only a few days after drug withdrawal Bisoprolol.

It is possible to increase the severity of the reaction of hypersensitivity and the lack of effect from the usual doses of epinephrine (adrenaline) against the background of a weighed allergic anamnesis.

If it is necessary to conduct routine surgical treatment, the drug should be discontinued 48 hours before the general anesthesia. If the patient has taken the drug before surgery, he should choose a drug for general anesthesia with a minimum negative inotropic effect.

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

Medicines that deplete the depots of catecholamines (including reserpine), can enhance the action of beta-blockers, so patients who take such combinations of drugs should be under constant medical supervision to detect a marked decrease in blood pressure or bradycardia.

Patients with bronchospastic diseases can be cautiously prescribed cardioselective beta-blockers in the case of intolerance and / or ineffectiveness of other antihypertensive agents.Against the background of taking beta-blockers in patients with concomitant bronchial asthma, airway resistance can increase. If the dose is exceeded Bisoprolol in such patients there is a risk of developing bronchospasm.

If patients develop an increasing bradycardia (heart rate less than 50 beats per minute), a marked decrease in blood pressure (systolic blood pressure less than 100 mm Hg) AV blockade, it is necessary to reduce the dose or stop treatment.

It is recommended to stop drug therapy Bisoprolol with the development of depression. Do not abruptly interrupt treatment because of the risk of developing severe arrhythmias and myocardial infarction. Cancellation of the drug is carried out gradually, reducing the dose for 2 weeks or more (reduce the dose by 25% in 3-4 days).

It is necessary to cancel the drug before examining the concentration in the blood and urine of catecholamines, normetanephrine, vanillin-mandelic acid, antinuclear antibody titers.

In smokers, the effectiveness of beta-blockers is lower.

Effect on the ability to drive transp. cf. and fur:

Application of the drug Bisoprolol does not affect the ability to drive vehicles according to the results of the study in patients with IHD.However, due to individual reactions, the ability to drive vehicles or work with technically complex mechanisms can be disrupted. This should be paid special attention at the beginning of treatment, after changing the dose, as well as with the simultaneous use of alcohol.

Form release / dosage:

Film coated tablets, 2.5 mg, 5 mg and 10 mg.

Packaging:

For 10 tablets in a planar cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

100 tablets per can polymer blown, made of polypropylene and capped with polypropylene lid or polymer jar made of low pressure polyethylene and capped with a lid made of a mixture of high pressure polyethylenes and low pressure polyethylenes.

For 3, 5 or 10 contour mesh packages or 1 can of polymer, together with the instruction for use, is placed in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002491

Date of registration:06.06.2014 / 07.10.2015

Expiration Date:06.06.2019

The owner of the registration certificate:RAFARMA, CJSC RAFARMA, CJSC Russia

Manufacturer: & nbsp

RAFARMA, JSC Russia

Information update date: & nbsp14.02.2017

Illustrated instructions

Instructions

Bisoprolol (Bisoprolol)