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

Excipients (core): lactose monohydrate (milk sugar) 150.0 mg, microcrystalline cellulose 31.5 mg, magnesium stearate 2.0 mg, povidone (polyvinylpyrrolidone) 7.0 mg, croscarmellose sodium 7.0 mg.

Auxiliary substances (shell): hypromellose 3.3 mg, macrogol 4000 0.9 mg, titanium dioxide 1.8 mg.

Each 5.0 mg tablet contains:

Active substance: bisoprolol fumarate 5.0 mg.

Excipients (core): lactose monohydrate (milk sugar) 71.5 mg, microcrystalline cellulose 18.0 mg, magnesium stearate 0.75 mg, pregelatinized starch 1.25 mg, povidone (polyvinylpyrrolidone) 3.5 mg.

Auxiliary substances (shell): hypromellose 1.65 mg, macrogol 4000 0.45 mg, titanium dioxide 0.9 mg.

Each 10.0 mg tablet contains:

Active substance: bisoprolol fumarate 10.0.

Excipients (core): lactose monohydrate (milk sugar) 143.0 mg, microcrystalline cellulose 36.0 mg, magnesium stearate 1.5 mg, pregelatinized starch 2.5 mg, povidone (polyvinylpyrrolidone) 7.0 mg.

Auxiliary substances (shell): hypromellose 3.3 mg, macrogol 4000 0.9 mg, titanium dioxide 1.8 mg.

Description:

Tablets are cylindrical, biconvex, covered with a film coat of white or almost white color.On the fracture, two layers are visible: a white or almost white core and a film shell. Tablets with a dosage of 2.5 mg with a risk on one side.

Pharmacotherapeutic group:Beta1-blocker selective

ATX: & nbsp

C.07.A.B Selective beta-blockers

C.07.A.B.07 Bisoprolol

Pharmacodynamics:

Bisoprolol - selective β₁- adrenoblocker, without its own sympathomimetic activity, does not possess membrane-stabilizing action. As for others β₁adrenoblockers, 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 β₁-adrenoceptors of the heart, reduces catecholamine-stimulated formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), reduces the intracellular current of calcium ions, inhibits all cardiac functions, reduces atrioventricular (AV) conductivity and excitability. If the therapeutic dose is exceeded, β₂-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 α-adrenergic receptor activity and elimination of stimulation β₂-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 the blood, sympathetic stimulation of the peripheral vessels, a decrease in the activity of the sympathoadrenal 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 . 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 decreased contractility and other myocardial functions, diastole lengthening, and improved myocardial perfusion. By increasing the end diastolic pressure in the left ventricle and increasing the tension of the ventricular muscle fibers,increase the need for oxygen, especially in patients with chronic heart failure (CHF).

When used at average therapeutic doses, in contrast to non-selective β-blockers, it exerts a less pronounced effect on organs containing β₂-adrenoreceptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchi and uterus) and 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 (more than 90%) absorbed in the gastrointestinal tract, eating does not affect absorption. The effect of "primary transmission" through the liver is negligible (at the level of 10-15%), which leads to high bioavailability (90%). Eating does not affect the bioavailability of bisoprolol.

Bisoprolol is 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 minor 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. The maximum concentration in the blood plasma is determined after 2-3 hours. Permeability through the blood-brain barrier and the placental barrier is low.

The half-life of blood plasma (10-12 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 than in healthy volunteers.

There is no information on the pharmacokinetics of bisoprolol in patients with CHF and simultaneous impairment of liver or kidney function.

Indications:

- Arterial hypertension;

- ischemic heart disease: prevention of angina attacks;

chronic heart failure.

Contraindications:

- Hypersensitivity to bisoprolol, other components of the drug and to other β-blockers;

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

- shock (including cardiogenic);

- pulmonary edema;

- atrioventricular block (AV) blockade II-III degree, without pacemaker;

- sinoatrial blockade;

- syndrome of weakness of the sinus node;

- bradycardia (heart rate less than 60 beats per minute);

- severe arterial hypotension (systolic blood pressure (BP) 100 mmHg);

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

- severe peripheral circulatory disorders, Raynaud's syndrome;

- metabolic acidosis;

- pheochromocytoma (without simultaneous use αadrenoblockers);

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

- age under 18 years (effectiveness and safety not established);

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Carefully:

Carrying out desensitizing therapy, angina pectoris Prinzmetal, hyperthyroidism, type 1 diabetes mellitus and diabetes mellitus with significant fluctuations in blood glucose concentration, AV blockade of I degree, renal failure (CC less than 20 ml / min), expressed violations of the liver, psoriasis, restrictive cardiomyopathy, congenital heart disease or valvular heart disease with severe hemodynamic disorders, CHF with myocardial infarction during the last 3 months, severe diet, depression (including history), elderly age.

Pregnancy and lactation:

Bisoprolol has pharmacological effects that can have harmful effects on the course of pregnancy and / or on the fetus or newborn. Usually β-adrenoconjugators reduce placental perfusion, which leads to a slowing of fetal growth, intrauterine fetal death, miscarriage or premature birth.The fetus and newborn child may experience pathological reactions (eg, hypoglycemia, bradycardia, arterial hypotension).

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 treatment with bisoprolol is considered necessary, monitoring of uteroplacental blood flow and intrauterine development of the fetus should be carried out. In case of adverse effects on pregnancy or fetus, alternative therapy should be considered. Symptoms of hypoglycemia and bradycardia usually occur within the first 3 days. You should carefully examine the newborn after delivery.

Data on the isolation of bisoprolol in breast milk are absent. Therefore, if you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

A drug Bisoprolol take inside, in the morning on an empty stomach, once, without chewing, squeezed a small amount of liquid. Tablets should not be chewed or ground into a powder.

Treatment of arterial hypertension and angina

In all cases, the regimen of taking and dosage is chosen by the doctor for each patient individually, in particular, taking into account the heart rate and the therapeutic response.

With arterial hypertension and coronary heart disease, usually the initial dose is 5 mg 1 time per day. If necessary, increase the dose to 10 mg once a day.

In the treatment of hypertension and angina, the maximum daily dose is 20 mg 1 time / day. It is possible to divide the daily dose into 2 doses.

Treatment of stable chronic heart failure

The standard treatment regimen of CHF includes the use of inhibitors angiotensin-converting enzyme (ACE) or angiotensin II receptor antagonists (in the case of intolerance to ACE inhibitors), β-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 drug treatment Bisoprolol is stable chronic heart failure 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. The recommended initial dose is 1.25 mg (1/2 tablets of 2.5 mg) once a day. Depending on the individual tolerability, the dose should be gradually increased to 2.5 mg, 3.75 mg (1¹/₂2.5 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 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.

Special patient groups

Impaired renal or hepatic function:

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

- PIn severe renal impairment (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.

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 hemodynamicviolations.

Also, there has not been sufficient data on patients with CHF with myocardial infarction in 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 heart and blood vessels: very often - a decrease in the heart rate (bradycardia, especially in patients with CHF); a feeling of palpitations; often a marked decrease in blood pressure (especially in patients with CHF), manifestation of angiospasm (increased peripheral circulatory disturbances, sensation of coldness in the extremities (paresthesia), infrequent infringement AV 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 disturbances, 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, back pain.

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, β-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.

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 P-adrenomimetics, such as epinephrine. If necessary - staging an artificial pacemaker.

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

When bronhospazme - the appointment of bronchodilator, including β₂adrenomimetics and / or aminophylline.

Interaction:

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, with simultaneous application with bisoprolol may 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 withdrawal, especially before the abolition of β-blockers can increase the risk of developing "ricochet" arterial hypertension.

Combinations that require caution

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

The action of β-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.

Simultaneous use of the drug Bisoprolol with β-adrenomimetics (eg, isoprenaline, dobutamine) can lead to a decrease in the effect of both drugs. The combination of bisoprolol with adrenomimetics that affect β- and α-adrenergic receptors (for example, norepinephrine, epinephrine), can enhance the vasoconstrictor effects of these agents that arise with the participation of α-adrenergic receptors, leading to an increase in blood pressure. Similar interactions are more likely when using non-selective β-blockers.

Mefloquine with simultaneous application with bisoprolol may increase the risk of developing 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 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 effectiveness of insulin and hypoglycemic agents for oral administration may change with treatment with bisoprolol (masks the symptoms of developing hypoglycemia: tachycardia, increased 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.

Antihypertensive effect weaken non-steroidal anti-inflammatory drugs (NSAIDs) (sodium ion delay and blockade of prostaglandin synthesis by the kidneys), glucocorticosteroids and estrogens (sodium ion delay).

Cardiac glycosides, methyldopa, reserpine and guanfacine, blockers of "slow" calcium channels (verapamil, diltiazem), amiodarone and other antiarrhythmic drugs increase the risk of developing or worsening bradycardia, AV blockade, cardiac arrest and heart failure.

Nifedipine can lead to a significant reduction in blood pressure.

Diuretics, clonidine, sympatholytics, hydralazine and other antihypertensives can lead to excessive blood pressure lowering.

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

Tricyclic and tetracyclic antidepressants, antipsychotics (antipsychotics), ethanol, sedatives and hypnotics increase the inhibition of the central nervous system.

It is not recommended simultaneous use with MAO inhibitors (except for MAO B inhibitors) due to a significant increase in antihypertensive action. Simultaneous application can also lead to the development of hypertensive crisis. A break in treatment between taking MAO inhibitors and bisoprolol should be at least 14 days.

Unhydrated ergot alkaloids increase the risk of peripheral circulatory disorders.

Ergotamine increases the risk of peripheral circulatory disorders.

Sulfasalazine increases the concentration of bisoprolol in the blood plasma.

Rifampicin shortens the half-life of bisoprolol.

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 heart rate and instruct about the need for medical consultation at heart rate less than 50 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 In patients with pheochromocytoma, there is a risk of developing paradoxical arterial hypertension (unless an effective blockade of α-adrenergic receptors has been 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 β-adrenoblockers, it does not substantially increase insulin-induced hypoglycemia and does not delay the restoration of blood glucose to normal levels.

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 catecholamine depot (incl. reserpine), can increase the action of β-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 β-adrenoblockers in case of intolerance and / or ineffectiveness of other antihypertensive agents.Against the background of taking β-blockers in patients with concomitant bronchial asthma, respiratory tract resistance may 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 60 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 β-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, 25, 30, 50 tablets in contour mesh packaging made of polyvinylchloride film and aluminum foil printed lacquered.

By 10, 20, 30, 40, 50, 60 or 100 tablets in cans of polymeric for medicines.

One bank or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 contour mesh packages together with the instruction for use are placed in a cardboard pack of cardboard.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002065

Date of registration:30.04.2013 / 22.10.2014

Expiration Date:30.04.2018

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Information update date: & nbsp14.02.2017

Illustrated instructions

Instructions

Bisoprolol (Bisoprolol)