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

*Core:*	tab. 5 mg	tab. 10 mg
Active substance:
Bisoprolol fumarate	5,00mg	10.00 mg
Excipients:
Microcrystalline cellulose	55.07 mg	52.57 mg
Corn starch	55.07 mg	52.57 mg
Croscarmellose sodium	3.60 mg	3.60 mg
Silica colloidal dioxide	0.96 mg	0.96 mg
Magnesium stearate	0.30 mg	0.30 mg
Sheath:	Opadrai II 85F 24286	Opadrai II 85F 24297
Polyvinyl alcohol	1,440	1,680
Macrogol 4000	0,727	0,848
Titanium dioxide	0,868	0,931
Talc	0,533	0,622
Iron oxide yellow	0,023	0,077
Iron oxide red	0,007	0,042
Iron oxide black	0,002	-

Description:

Tablets 5 mg: round, biconcave tablets covered with a film coating of beige color.

Tablets 10 mg: round, biconcave tablets, covered with a film shell of dark pink color.

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 (SMA); has antihypertensive and antianginal 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 (it decreases the heart rate (heart rate)), inhibits conduction and excitability, reduces myocardial contractility).

The total peripheral vascular resistance (OPSS) at the beginning of beta-blockers 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), which, after 1-3 days, returns to the original, and with a long-term administration decreases. The antihypertensive effect is associated with a decrease in the minute volume of the circulation, the sympathetic stimulation of the peripheral vessels, a decrease in the activity of the renin-angiotensin-aldosterone system (RAAS) (is of greater importance for patients with initial hypersecretion of renin), restoration of the sensitivity of the aortic arch baroreceptors activity in response to a decrease in blood pressure (BP) and influence on the central nervous system (CNS).

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

Antianginal effect is due to a decrease in myocardial oxygen demand as a result of a decrease in heart rate and a decrease in contractility, diastole lengthening, and improvement in myocardial perfusion. By increasing the end 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 administered at average therapeutic doses, it exerts a less pronounced effect on organs containing beta₂-adrenoceptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchial and uterine) and carbohydrate metabolism, does not cause delays sodium ions (Na⁺) in organism. When used in large doses has a blocking effect on both subtypes of beta adrenoreceptors.

Pharmacokinetics:

Bisoprolol is almost completely absorbed in the gastrointestinal tract, eating does not affect absorption. The effect of "primary passage" through the liver is negligible, which leads to high bioavailability (90%).The maximum concentration of active substance in the blood plasma (C_mOh) is 46.552 ± 7.6 ng / ml. Time to reach the maximum concentration (TC_mOh) - 2-4 hours.

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, first of all, with the help of isoenzyme CYP3A4 (about 95%), and isoenzyme CYP2D6 plays only a small 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 (T_1/2) 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, 50 of them% output in unmodified form; 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.

Indications:

- Arterial hypertension;

- cardiac ischemia:

- prevention of attacks of stable angina pectoris.

Contraindications:

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

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

- cardiogenic shock, collapse;

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

- syndrome of weakness of the sinus node;

- sinoatrial blockade;

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

- cardiomegaly (no signs of heart failure);

- severe arterial hypotension (systolic blood pressure less than 90 mm Hg);

- severe forms of bronchial asthma and chronic obstructive pulmonary disease in anamnesis;

- late stages of peripheral circulation, Raynaud's syndrome;

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

- metabolic acidosis;

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

- simultaneous administration of sultopride and floktaphenin;

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

Carefully:

Take psoriasis, depression (including history), diabetes mellitus (can mask symptoms of hypoglycemia), a history of allergic anamnesis, bronchospasm (in the anamnesis), desensitizing therapy, Prinzmetal angina, AV blockade of the 1st degree, violation of peripheral circulation; severe renal impairment (creatinine clearance (CK) less than 20 ml / min); pheochromocytoma (with simultaneous use of alpha-blockers); severe violations of liver function; thyrotoxicosis; myasthenia gravis; old age; strict diet.

Pregnancy and lactation:

During pregnancy bisoprolol should be recommended only if the benefit to the mother exceeds the risk of side effects in the fetus. As a rule, beta-adrenoblockers reduce blood flow in the placenta and can affect the development of the fetus. Care should be taken to monitor blood flow in the placenta and uterus, as well as monitor fetal growth and development, and, in case of dangerous manifestations in pregnancy or fetus, to take alternative therapeutic measures. You should carefully examine the newborn after delivery. In the first three days of life, hypoglycemia and bradycardia may occur. Data on the excretion of bisoprolol in breast milk or safety of bisoprolol exposure to infants are not available.

Dosing and Administration:

With arterial hypertension and for the prevention of stable angina the initial dose of the drug is 5 mg / day, if necessary, increase the dose to 10 mg / day. The maximum daily dose of 20 mg / day.

In patients with impaired renal function with SC less than 20 ml / min or with severe hepatic dysfunction the maximum daily dose is 10 mg.

Side effects:

The frequency of adverse reactions listed below,according to the following criteria: very often (≥ 1/10), often (≥ 1/100 to <1/10), infrequently (≥ 1/1000 to <1/100), rarely (≥ 1/10000 to <1 / 1000), very rarely (<1/10000).

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, marked decrease in blood pressure, especially in patients with CHF; infringement AV conduction, a bradycardia (at patients with an arterial hypertensia or a stenocardia), aggravation of symptoms of current CHF (at patients with an arterial hypertensia or a stenocardia), an orthostatic hypotension is infrequent.

From the central nervous system: often - dizziness, headache; rarely - loss of consciousness.

Mental disorders: infrequently - depression, insomnia; rarely - hallucinations, nightmares.

From the side of the organ of vision: rarely - a decrease in the secretion of tear fluid (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 airway obstruction in anamnesis; rarely allergic rhinitis.

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

From 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 side of the reproductive system: rarely - a violation of potency.

Laboratory indicators: rarely - an increase in the concentration of triglycerides and the 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, severe bradycardia (heart rate less than 50 beats per minute), AV blockade, significant reduction in blood pressure (systolic blood pressure less than 90 mm Hg), worsening of CHF flow (edema increase, decreased heart rate and blood pressure), finger nail cyanosis or palms, difficulty breathing, bronchospasm, dizziness, fainting, convulsions, hypoglycemia.

Treatment:

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

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

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

In hypoglycemia, intravenous administration of a dextrose solution (glucose) can be indicated.

When AV blockade: patients should be under constant supervision; if necessary - the introduction of epinephrine, 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 introduction of bronchodilators, including beta2-adrenomimetics and / or aminophylline.

When hypoglycemia - intravenous dextrose (glucose).

Interaction:

The effectiveness and tolerability of bisoprolol may be influenced by simultaneous intake 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

Blocks of "slow" calcium channels groups of 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) can lead to progression of heart failure due to a decrease in the central sympathetic tone (decrease in heart rate, cardiac output, vasodilation). Abrupt withdrawal of the drug, especially with the previous discontinuation of beta-blockers, may increase the risk of developing "ricochet" arterial hypertension.

Combinations that require special care

Blockers of "slow" calcium channels dihydropyridine series (eg, nifedipine, felodipine, amlodipine) with simultaneous application with bisoprolol increase the risk of developing arterial hypotension. In patients with heart failure, the risk of a subsequent deterioration in the contractile function of the heart can not be ruled out.

Antiarrhythmic drugs I class (e.g., disopyramide, quinidine) with simultaneous use with bisoprolol reduce AV conductivity and enhance the negative inotropic effect.

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 promote bradycardia.

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

Means for anesthesia: weaken the reflex tachycardia and enhance the antihypertensive effect.

Cardiac glycosides: reduce heart rate and reduce AV conductivity.

Nonsteroidal anti-inflammatory drugs: weaken the hypotensive effect of bisoprolol.

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

Sympathomimetic drugs acting on beta and alpha receptors (for example, adrenaline, norepinephrine): induce and enhance alpha-adrenomimeticheskim vasoconstrictor effect of these drugs, which leads to an increase in blood pressure and exacerbation of intermittent claudication. These interactions are more common when combined with nonselective beta-blockers.

Hypotensive drugs and drugs that have an antihypertensive effect (eg, tricyclic antidepressants, barbiturates, phenothiazines): increase the hypotensive effect.

Combinations that need to be considered

Mefloquine: with simultaneous admission with bisoprolol increases the risk of developing bradycardia.

MAO inhibitors (except for MAO type B inhibitors): may increase the hypotensive effect.Simultaneous application can also lead to the development of hypertensive crisis.

Derivatives of ergotamine: strengthen the symptoms of peripheral circulatory disorders.

Rifampicin: shortens the half-life of bisoprolol.

Special instructions:

After the start of treatment with bisoprolol in the minimal dose prescribed by the doctor, the patient should be observed for about 4 hours (control of blood pressure, heart rate, conduction disorders, signs of worsening of heart failure). Monitoring the status of patients receiving bisoprolol, should include measurement of blood pressure and heart rate (at the beginning of treatment - daily, then - once every 3-4 months), ECG, blood glucose in diabetic patients (1 every 4-5 months). In elderly patients it is recommended to follow the function of the kidneys (once every 4-5 months).

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

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 consulting the doctor in advance. 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 IHD.

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 / min) and an increased end diastolic volume (BDW) of the left ventricle, which disrupts the subendocardial blood flow.

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

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

When used in patients with pheochromocytoma, there is a risk of developing paradoxical arterial hypertension (unless an effective alpha-adrenoblockade is previously achieved).

With thyrotoxicosis bisoprolol can mask certain clinical signs of thyrotoxicosis (eg, tachycardia). Sharp abolition in patients with thyrotoxicosis is contraindicated, as 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 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 hypersensitivity reaction and the lack of effect from the usual doses of epinephrine against the background of a burdened 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 the operation, he should choose a preparation 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).

Drugs that reduce the supply of catecholamines (for example, reserpine), can enhance the action of beta-blockers, so patients who take such combinations of drugs should be under constant observation of the doctor for the diagnosis of arterial hypotension or bradycardia.

Patients with bronchospastic diseases can be assigned 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.

Like other beta-blockers, bisoprolol can increase the sensitivity of patients to allergens and the severity of anaphylactic reactions. Treatment with adrenaline does not always lead to the expected therapeutic effect.

Patients with psoriasis can be assigned beta-blockers only after a careful balance between benefit and risk.

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

If elderly patients develop an increasing bradycardia (heart rate less than 60 / min), arterial hypotension (systolic blood pressure below 90 mmHg) 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.

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

Drugs that reduce catecholamine stores (for example, reserpine), can enhance the action of beta-blockers, so patients who take such combinations of drugs should be under constant observation of the doctor for the diagnosis of arterial hypotension or bradycardia.

Before the study of the blood and urine content of catecholamines, normetanephrine and vanillylmandelic acid, as well as titers of antinuclear antibodies, bisoprolol should be canceled.

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

Taking bisoprolol, care should be taken when driving vehicles and complex machinery.

Form release / dosage:Tablets, film-coated, 5 mg and 10 mg.

Packaging:

For 10 tablets, film-coated, 5 and 10 mg, in a blister of Al / PVC.

2, 3, 5, 6 or 10 blisters are placed in a cardboard box together with the instruction for use.

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-002129

Date of registration:05.07.2013 / 05.09.2016

Expiration Date:05.07.2018

The owner of the registration certificate:PROTEK-SVM, LLC PROTEK-SVM, LLC Russia

Manufacturer: & nbsp

PROTEK-SVM, LLC Russia

Antibiotice, S.A. Romania

Information update date: & nbsp14.02.2017

Illustrated instructions

Instructions

Bisoprolol-LEXMM® (Bisoprolol-LEKSVM®)