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

Excipients: cellulose microcrystalline 10,000 mg, starch corn 15,000 mg, silicon dioxide colloidal anhydrous (Aerosil) 1,500 mg, magnesium stearate 0.425 mg, sodium carboxymethyl starch (type A) 5,500 mg, calcium hydrophosphate dihydrate up to 170,000 mg:

shell: opedrai II white (polyvinyl alcohol, partially hydrolyzed - 40.00%, talcum - 14.80%, macrogol 3350 (polyethylene glycol 3350) - 20.20%, titanium dioxide, E 171 -25,000%) 6,000 mg.

dosage of 5.0 mg:

active substance: bisoprolol fumarate 5,000 mg;

Excipients: cellulose microcrystalline 10,000 mg, corn starch 14,500 mg, silicon dioxide colloidal anhydrous (Aerosil) 1,500 mg, magnesium stearate 0.425 mg, sodium carboxymethyl starch (type A) 5,500 mg, calcium hydrophosphate dihydrate up to 170,000 mg:

sheath: opahedra II blue (polyvinyl alcohol, partially hydrolyzed 40.00%, talc 14.80%, macrogol 3350 (polyethylene glycol 3350) 20.20% titanium dioxide, E 171 24.640%, aluminum lacquer based on indigo carmine, E 132 - 0.350%, aluminum varnish based on yellow quinoline, E 104 - 0.010%) 6,000 mg.

dosage of 10.0 mg:

active substance: bisoprolol fumarate 10,000 mg;

Excipients: cellulose microcrystalline 10,000 mg, starch corn 14,000 mg, silicon dioxide colloidal anhydrous (Aerosil) 1,500 mg, magnesium stearate 0.425 mg, sodium carboxymethyl starch (type A) 5,500 mg, calcium hydrophosphate dihydrate up to 170,000 mg:

shell: opedrai II pink (polyvinyl alcohol, partially hydrolysed 40.00%, talc - 14.80%, macrogol 3350 (polyethylene glycol 3350) - 20.20%, titanium dioxide, E 171 - 24.940%, aluminum lacquer based on indigo carmine, E 132 - 0.010%, carmine, E 120 - 0.04%, iron oxide black, E 172 - 0.010%) 6,000 mg.

Description:

The film coated tablets are white, 2.5 mg, light-blue - 5 mg, pink - 10 mg, with a biconvex surface, with a risk. Two layers are visible on the transverse section - for dosages of 5 mg and 10 mg.

Pharmacotherapeutic group:Beta1-blocker selective

ATX: & nbsp

C.07.A.B Selective beta-blockers

C.07.A.B.07 Bisoprolol

Pharmacodynamics:

Selective beta₁- adrenoblocker, without its own sympathomimetic activity; has antihypertensive and antianginal action. Blocking in low doses of beta₁-adrenoceptors of the heart, reduces stimulated catecholamines the formation of cyclic adenosine monophosphate from adenosine triphosphate, reduces the intracellular current of calcium ions (Ca²⁺), has a negative chrono-, dromo-, batmo- and inotropic effect (reduces heart rate (heart rate), inhibits conduction and excitability, reduces myocardial contractility).

Total peripheral vascular resistance in the early use of beta-blockers in the first 24 hours is increased (as a result of reciprocal increase in the activity of alpha-adrenoceptor stimulation and removal of beta₂-adrenorets), which returns to the initial one after 1-3 days, and decreases with long-term administration.

Antihypertensive effect is associated with a decrease in minute volume of blood circulation, sympathetic stimulation of peripheral blood vessels, reduction in activity of the renin-angiotensin-aldosterone system (RAAS) (higher for patients with initial hypersecretion renin) reduction baroreceptor sensitivity of the aortic arch (not going to increase their activity in response to a decrease AD) and influence on the central nervous system.

With hypertension, the antihypertensive effect occurs after 2-5 days, stable effect - after 1-2 months.

Antianginal effect due to a decrease in myocardial oxygen demand as a result of deceleration in heart rate and decrease contractility, lengthening of diastole, improving myocardial perfusion. By increasing the final diastolic pressure in the left ventricle and increasing the stretching of the muscle fibers, the ventricles can increase the need for oxygen,especially in patients with chronic heart failure (CHF).

In contrast to non-selective beta-blockers, when used in average therapeutic doses, it has a less pronounced effect on organs containing beta₂-adrenoceptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchi and uterus) and on carbohydrate metabolism, does not cause delay of sodium ions (Na⁺) in organism. When used in high doses has a blocking effect on both subtypes of beta-adrenergic receptors.

Pharmacokinetics:

Bisoprolol is almost completely absorbed into the gastrointestinal tract (80-90%). Eating does not affect absorption. The maximum concentration of the active substance in the blood plasma is 46.552 ± 7.6 ng / ml. The time to reach the maximum concentration is 2-4 hours.

Bisoprolol is metabolized along the oxidative pathway without subsequent conjugation. All metabolites have a strong polarity (water-soluble) 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 an insignificant role.

The connection with blood plasma proteins is about 30%. The volume of distribution is 3.5 l / kg. The total ground clearance is approximately 15 l / h.

Permeability through the blood-brain barrier and the placental barrier is low. Half-life of blood plasma is 9-12 hours, provides efficacy within 24 hours after taking a single daily dose. Bisoprolol is excreted from the body in two ways, 50% of the dose is metabolized in the liver with the formation of inactive metabolites. About 98% is excreted by the kidneys, of which 50% is excreted unchanged; less than 2% - through the intestines (with bile).

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 CHF, plasma concentrations of bisoprolol are higher, and the half-life is longer compared to healthy volunteers.

Indications:

- Arterial hypertension;

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

- chronic heart failure.

Contraindications:

- Hypersensitivity to bisoprolol or to any of the components of the drug (see section "Composition") and to other beta-blockers;

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

- cardiogenic shock, collapse;

- atrioventricular (AV) blockade of II and III degree, without an electrocardiostimulator;

- sinoatrial blockade;

- syndrome of weakness of the sinus node;

- bradycardia (heart rate less than 60 beats / min);

- 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 (XOBL) in the anamnesis;

- severe peripheral arterial circulation or 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 18 years (insufficient efficacy and safety data in this age group).

Carefully:

Psoriasis, depression (including history), type 1 diabetes mellitus and diabetes mellitus with significant fluctuations in blood glucose concentration (can mask symptoms of hypoglycemia), allergic reactions (in the anamnesis), bronchospasm (in the anamnesis), desensitizing therapy, angina Prinzmetal, hyperthyroidism; AV blockade I degree, severe renal failure (creatinine clearance (CC) less than 20 ml / min); pheochromocytoma (with simultaneous use of alpha-blockers); severe violations of liver function; restrictive cardiomyopathy; Congenital heart disease or heart valve disease with severe hemodynamic disorders; CHF with myocardial infarction during the last 3 months; hyperthyroidism or thyrotoxicosis; 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 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 with a proven safety profile during pregnancy. 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 penetration of bisoprolol into breast milk. Therefore, taking the drug Bisoprolol is not recommended for women during lactation. If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Tablets of the drug Bisoprolol should be taken once a day with a small amount of liquid, swallow whole in the first half of the day, regardless of the time of eating.

Tablets should not be chewed or ground into 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.

With arterial hypertension and ischemic heart disease, for the prevention of attacks of stable angina the initial dose of the drug is 5 mg / day. The maximum daily dose of 20 mg / day.

Treatment for chronic heart failure

The condition of patients should be stable at the beginning of treatment with bisoprolol (acute heart failure is eliminated). Dose titration starts from 1.25 mg / day (for 1 week), then, with good tolerability, the dose is increased to 2.5 mg / day (for 1 week), 3.75 mg / day (for 1 week), 5 mg / day (for 4 weeks), 7.5 mg / day (for 4 weeks), then 10 mg / day (the target dose).During and after dose titration may occur temporary worsening of heart failure, hypotension and bradycardia. If the patient's condition does not improve thereafter for 1 week, the gradual reduction in the dose should be carried out after the stabilization of the patient titration can be repeated again.

Standard treatment of CHF scheme involves the use of inhibitors of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor antagonists II (in the case of intolerance to ACE inhibitors), beta-blockers, 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 treatment with the drug is a stable CHD 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, i. E.The dose can be increased only if the previous dose is well tolerated.

To ensure the appropriate titration process in the subsequent stages of treatment, it is possible to use Bisoprolol in the dosage form of a tablet of 2.5 mg and 5 mg. 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 or 1¹/₂ 5 mg bisoprolol tablets with a risk) 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 CAS 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 deterioration of the course of CHF, arterial hypotension 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.

Duration of treatment for all indications for the use of the drug Bisoprolol

Treatment with drug Bisoprolol is usually a long-term therapy.

Special patient groups

Impaired renal or hepatic function:

If the liver or kidney function is mild or moderate, you usually do not need to adjust the dose.

In patients with severe renal dysfunction (CC less than 20 ml / min) or with severe impairment of liver function, the maximum daily dose is 10 mg. Increasing the dose in such patients should be carried out with extreme caution.

Elderly patients:

Correction of the dose is not required.

Children:

Since there is insufficient data on the use of the drug Bisoprolol in children, it is not recommended to prescribe the drug to children under 18 years of age.

Side effects:

The frequency of side effects is given in accordance with the classification of the World Health Organization: very often - not less than 10%; often - not less than 1% and less than 10%; infrequently - not less than 0.1% and less than 1%; rarely - not less than 0.01% and less than 0.1%; very rarely - less than 0.01%,including isolated cases; the frequency is unknown - according to the available data, the frequency can not be determined.

From the side of the cardiovascular system: very often bradycardia (in patients with CHF); often - exacerbation of CHF symptoms (in patients with CHF), sensation of cooling and numbness in the extremities, expressed by a decrease in blood pressure, especially in patients with CHF; infrequently infringement AV conduction, bradycardia (in patients with hypertension or angina pectoris), aggravation of symptoms of CHF flow (in patients with arterial hypertension or angina pectoris), orthostatic hypotension.

From the central nervous system: often - dizziness, headache; infrequently - depression, insomnia; rarely - loss of consciousness, hallucinations, nightmares.

From the side of the organ of vision: rarely - reduced tearing (should be considered when wearing contact lenses); very rarely - conjunctivitis.

From the side of the hearing organ: rarely - hearing impairment.

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

From the digestive system: often - nausea, vomiting, diarrhea, constipation; rarely hepatitis.

From the side of the musculoskeletal system: infrequently - muscle weakness, muscle cramps.

From the skin: rarely - hypersensitivity reactions, such as skin itching, flushing of skin; very rarely - alopecia. Beta-blockers can exacerbate the symptoms of psoriasis or cause a psoriasis-like rash.

From the genitourinary system: rarely - a violation of potency.

Laboratory indicators: rarely increases in triglyceride concentrations and activity of "hepatic" transaminases in the blood (aspartate aminotransferase (ACT) and alanine aminotransferase (ALT)).

Common violations: often - asthenia (in patients with CHF), increased fatigue; infrequently - asthenia (in patients with arterial hypertension or angina pectoris).

Overdose:

Symptoms: arrhythmia, ventricular extrasystole, pronounced bradycardia (Heart rate less than 50 beats per minute), AV blockade, marked decrease in blood pressure (systolic blood pressure less than 90 mm Hg), worsening of CHF flow (edema development, heart rate reduction or bradycardia, lowering blood pressure), cyanosis of fingernails or palms, hypoglycemia , difficulty breathing, bronchospasm, dizziness, fainting, convulsions.

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

With pronounced bradycardia - intravenous (iv) 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 administration of glucagon or intravenous dextrose (glucose) may be indicated.

When AV blockade: patients should be under constant supervision, and receive treatment with beta-adrenomimetics, such as epinephrine (adrenalin). 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. It is necessary to inform the doctor about taking other medicines, even if they are taken without a doctor's prescription (ie, OTC drugs).

Unrecommended combinations

Antiarrhythmic drugs I class (eg, quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone) with simultaneous application with bisoprolol may reduce AV conduction and contractility of the myocardium.

Blockers of "slow" calcium channels such as verapamil and, to a lesser extent, diltiazem can have a negative effect on the contractility of the myocardium and AV conductivity. Intravenous administration of verapamil in patients on beta-blocker therapy may lead to severe arterial hypotension and AV blockade.

Hypotensive means of central action (such as clonidine, methyldopa, moxonidine, rilmenidine). The simultaneous use of antihypertensive drugs of central action can further reduce the sympathetic tone of the central nervous system and, as a result, reduce the heart rate and cardiac output, and also cause symptoms of vasodilation. A sharp cessation of therapy, especially in conditions of the preliminary cancellation of beta-blockers, may increase the risk of developing "ricochet" arterial hypertension.

Combinations that require special care

Blockers of "slow" calcium channels dihydropyridine type (eg, felodipine and amlodipine). It can not be ruled out that simultaneous use may increase the risk of arterial hypotension and reduce the pumping function of the ventricle in patients with heart failure.

Antiarrhythmic drugs of III class (eg, amiodarone) increase AV conductivity.

Beta-blockers for topical use (eg, eye drops for the treatment of glaucoma) can enhance the systemic effects of bisoprolol.

Parasympathomimetics may lead to a decrease AV conductivity and increase the risk of developing a bradycardia.

Insulin and hypoglycemic agents for oral administration: the hypoglycemic effect. Blockade of beta-adrenoreceptors can mask the symptoms of developing hypoglycemia (tachycardia, increased blood pressure).

Means for general anesthesia: means for general anesthesia can increase the risk of cardiodepressive action, leading to arterial hypotension.

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

Non-steroidal anti-inflammatory drugs (NSAIDs): weaken antihypertensive effect of bisoprolol.

Beta-adrenomimetics (e.g., isoprenaline, dobutamine): simultaneous administration with bisoprolol may lead to a weakening effect of these drugs.

Adrenomimetics, acting on both beta and alpha-adrenergic receptors (for example, norepinephrine, epinephrine): cause and intensify alpha-adrenomimetic vasoconstrictor effect of these drugs, which leads to an increase in blood pressure and aggravation of "intermittent" lameness.Such interaction is more likely when using non-selective beta-blockers.

MAO inhibitors (except for MAO type B inhibitors) can increase the severity of the decrease in blood pressure of beta-blockers. Simultaneous application can also lead to the development of hypertensive crisis.

The simultaneous use of antihypertensive drugs or other drugs that lower blood pressure (for example, tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of developing arterial hypotension.

Special instructions:

Monitoring the status of patients receiving Bisoprolol, should include a measurement of heart rate and blood pressure (at the beginning of treatment - every day, then - every 3-4 months), ECG, blood glucose in patients with diabetes mellitus (once every 4-5 months). Older patients need control of 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.

Approximately in 20% of patients with angina pectoris beta-blockers are ineffective. The main causes are severe coronary atherosclerosis with a low threshold of ischemia (heart rate less than 90 beats per minute) and an increased end-diastolic volume of the left ventricle, which breaks the subendocardial blood flow. In "smokers" the effectiveness of beta-blockers is lower.

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.

With the simultaneous administration of clonidine, its administration can be stopped only a few days after the withdrawal of 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 can be withdrawn 48 hours before the start of the general anesthesia. If the patient has taken the drug before surgery, he should choose a medicine for general anesthesia with a minimum negativeinotropic action. Reciprocal activation of the vagus nerve can be eliminated by intravenous administration of atropine (1-2 mg).

Drugs that reduce catecholamine stocks (incl. reserpine), can enhance the action of beta-blockers, so patients taking such a combination of drugs should be under constant medical supervision to detect a marked decrease in blood pressure or arterial hypotension, or bradycardia.

If older bradycardia is detected in elderly patients (heart rate less than 60 beats per minute), marked decrease in blood pressure or arterial hypotension (systolic blood pressure below 100 mm Hg) AV blockade, bronchospasm, ventricular arrhythmias, severe impairment of liver and kidney function, it is necessary to reduce the dose or stop treatment. It is recommended to stop therapy with the development of depression caused by the use of beta-blockers.

Do not abruptly interrupt treatment because of the risk of developing severe arrhythmias and myocardial infarction. Abolition is carried out gradually, reducing the dose for 2 weeks or more (reduce the dose by 25% in 3-4 days).

The drug should be withdrawn before the study of blood and urine content of catecholamines, normeganephrine and vanillylmandelic acid, as well as titers of antinuclear antibodies.

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

When using the drug Bisoprolol in patients with pheochromocytoma, there is a risk of developing paradoxical arterial hypertension (unless an effective alpha-adrenoblockade has been previously achieved).

In diabetes mellitus can mask tachycardia caused by hypoglycemia. Unlike nonselective beta-blockers, it does not actually increase insulin-induced hypoglycemia and does not delay the restoration of blood glucose to normal levels.

Patients are advised to take a dose of the drug chosen by the doctor, if no adverse reactions occur.

If necessary, treatment can be interrupted. Treatment should not be interrupted abruptly and the recommended dosage should be changed without first consulting a physician, t. this can lead to a temporary worsening of the heart. If discontinuation of treatment is necessary, the dosage should be reduced gradually, reducing the dose for 2 weeks or more (by 25% in 3-4 days) because of the risk of developing severe arrhythmias and myocardial infarction, especially in patients with ischemic heart disease.

Patients with bronchospastic diseases can be prescribed cardioselective adrenoblockers in case of intolerance and / or ineffectiveness of other antihypertensive drugs, but strict monitoring of dosage should be carried out. Overdosing is dangerous by the development of bronchospasm.

With bronchial asthma or COPD, simultaneous use of bronchodilating agents is indicated. In patients with bronchial asthma, an increase in airway resistance may be required, which requires a higher dose of beta₂-adrenomimetics.

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

A drug Bisoprolol does not affect the ability to drive vehicles according to the results of the study in patients with ischemic heart disease. However, due to individual reactions, the ability to drive vehicles or work with technically complex machinery can be compromised. 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:

10 tablets per contour cell pack.

3, 5 or 6 contour mesh packages together with the instruction for medical use are placed in a pack of cardboard.

Storage conditions:

In a place protected from light and moisture, at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003221

Date of registration:28.09.2015

Expiration Date:28.09.2020

The owner of the registration certificate:BORISOVSKIY FACTORY OF MEDPREPARATES, OJSC BORISOVSKIY FACTORY OF MEDPREPARATES, OJSC Republic of Belarus

Manufacturer: & nbsp

BORISOVSKIY FACTORY OF MEDPREPARATES, OJSC Republic of Belarus

Representation: & nbspBORISOVSKIY FACTORY OF MEDPREPARATES, OJSCBORISOVSKIY FACTORY OF MEDPREPARATES, OJSC

Information update date: & nbsp06.04.2017

Illustrated instructions

Instructions

Bisoprolol (Bisoprolol)