Bisoprolol-OBL

General characteristics. Structure:

Active ingredient: 2,5 mg, 5 mg or 10 mg of a bisoprolol of a gemifumarat in 1 tablet.

Excipients: cellulose microcrystallic, Mannitolum, кросповидон, silicon dioxide colloid (aerosil), magnesium stearate.

Excipients for a cover: gipromelloz (gidroksipropilmetiltsellyuloz), macrogoal 6000 (polyethyleneglycol 6000), titanium dioxide, dye quinolinic yellow, Ponso's 4R dye, ferrous oxide yellow.

Pharmacological properties:

Pharmacodynamics. Bisoprolol - the selection beta1-adrenoblocker, without own sympathomimetic activity, does not possess membrane stabilizing action. As well as for other beta1-adrenoblockers, the action mechanism at the arterial hypertension (AH) is not clear. At the same time бисопролол reduces activity of a renin in a blood plasma, reduces the need of a myocardium for oxygen, urezhat the heart rate (HR). Has anti-hypertensive, antiarrhytmic and anti-anginal effect.

Blocking heart beta1-adrenoceptors in low doses, reduces stimulated catecholamines formation of cyclic adenosinemonophosphate (tsAMF) from adenosinetriphosphate (ATP), reduces intracellular current of calcium ions, oppresses all functions of heart, reduces atrioventricular (AV) conductivity and excitability. At exceeding of a therapeutic dose has beta2-adrenoceptor blocking effect. The General Peripheric Vascular Resistance (GPVR) at the beginning of drug use, in the first 24 h, increases (as a result of reciprocal increase of activity of alpha adrenoceptors and elimination of stimulation of beta2-adrenoceptors), in 1-3 days is returned to a reference value, and at prolonged use - decreases.

The anti-hypertensive effect is connected with reduction of minute volume of blood, sympathetic stimulation of peripheral vessels, decrease of the activity of sympathoadrenal system (SAS) (is of great importance for patients with initial hypersecretion of a renin), recovery of sensitivity in response to a lowering of arterial pressure (ABP) and influence on the central nervous system (CNS). At AG the effect develops in 2-5 days, stable action is noted in 1-2 months.

The anti-anginal effect is caused by reduction of need of a myocardium for oxygen as a result of decrease in contractility and other functions of a myocardium, lengthening of a diastole, improvement of perfusion of a myocardium. Due to increase in end diastolic pressure in the left ventricle (LV) and increases in stretching of muscle fibers of ventricles oxygen requirement, especially at patients with the chronic heart failure (CHF) can increase.

At use in average therapeutic doses, unlike non-selective beta adrenoblockers, exerts less expressed impact on the bodies containing beta2-adrenoceptors (a pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchial tubes and a uterus) and on carbohydrate metabolism; does not cause a delay of ions of sodium in an organism; expressiveness of atherogenous action does not differ from effect of propranolol.

Pharmacokinetics. Bisoprolol is almost completely soaked up in the digestive tract (DT), meal does not influence absorption. The effect of "primary passing" through a liver is insignificant that results in high bioavailability (90%).

Bisoprolol is metabolized on an oxidizing way without the subsequent conjugation. All metabolites have strong polarity and are removed by kidneys. The main metabolites found in a blood plasma and urine do not show pharmacological activity. The data obtained as a result of experiments with microsomes of a liver of the person of in vitro show what бисопролол is metabolized first of all by means of CYP3A4 isoenzyme (about 95%), and the isoenzyme of CYP2D6 plays only a small role.

Communication with proteins of a blood plasma - about 30%. Distribution volume - 3,5 l/kg. The general clearance - about 15 l/h. The maximum concentration in a blood plasma is defined in 2-3 hours. Permeability through a blood-brain barrier (GEB) and a placental barrier - low.

Plasma elimination half-life of blood (T1/2) (10-12 h) provides efficiency within 24 hours after reception of a single daily dose.

Bisoprolol is brought from an organism in two ways, 50% of a dose are metabolized in a liver with formation of inactive metabolites. About 98% are removed by kidneys, 50% are brought out of them in not changed look; less than 2% - through intestines (with bile).

With an abnormal liver function or with a renal failure of dose adjustment it is not required to patients. The pharmacokinetics of a bisoprolol is linear and does not depend on age.

At patients with HSN plasma concentration of a bisoprolol are higher, and T1/2 is more long in comparison with healthy volunteers.

Indications to use:

- arterial hypertension;

- coronary heart disease: prevention of attacks of stable stenocardia;

- chronic heart failure.

Route of administration and doses:

Drug Bisoprolol is accepted inside, in the morning on an empty stomach, 1 time a day with a small amount of liquid, in the morning till a breakfast, in time or after it. Tablets should not be chewed or pounded in powder. In all cases the mode of reception and a dose are selected by the doctor to each patient individually, in particular considering ChSS and a condition of the patient.

At arterial hypertensia and coronary heart disease drug is appointed on 5 mg of 1 times a day. If necessary the dose is increased to 10 mg of 1 times a day.

At treatment of arterial hypertension and stenocardia the maximum daily dose makes 20 mg of 1 times/days.

Treatment bisoprololy chronic heart failure. An initiation of treatment of chronic heart failure drug Bisoprolol demands obligatory carrying out a special phase of titration and regular medical control.

Preliminary condition for treatment by drug Bisoprolol is stable chronic heart failure without aggravation signs.

Treatment of chronic heart failure drug Bisoprolol begins according to the following scheme of titration. At the same time individual adaptation depending on that can be required, how well the patient transfers the appointed dose, i.e. the dose can be increased only if the previous dose was well transferred.

For ensuring the corresponding process of titration at initial stages of treatment it is recommended to use drug in smaller doses.

The recommended initial dose makes 1,25 mg (1/2 tablets on 2,5 mg) once a day. Depending on individual portability it is necessary to raise a dose gradually to 2,5 mg, 3,75 mg (1,5 tablets of drug бисопролол on 2,5 mg), 5 mg, 7,5 mg (1 tablet on 5 mg and 1/2 tablets on 2,5 mg), and 10 mg with an interval not less than 2 or more weeks once a day.

If increase in a dose of drug is badly transferred by the patient, the dose decline is possible.

The maximum daily dose at treatment of chronic heart failure makes 10 mg once a day.

During titration regular control of the ABP, ChSS and symptoms of chronic heart failure is recommended. Aggravation of symptoms of chronic heart failure is possible from the first day of use of drug.

During a phase of titration or after it there can be a temporary deterioration in a course of chronic heart failure, arterial hypotension or bradycardia. In this case it is recommended to pay first of all attention to selection of a dose of the accompanying standard therapy. Also the temporary dose decline of drug Bisoprolol or cancellation of his reception can be required. After stabilization of a condition of the patient it is necessary to carry out repeated titration of a dose, or to continue treatment.

Treatment bisoprololy at a renal failure or a liver. At an abnormal liver function or kidneys of easy or moderate degree correction of a dose usually is not required.

At the expressed renal failures (the clearance of creatinine (CC) less than 20 ml/min.) and at patients with a serious illness of a liver the maximum daily dose makes 10 mg. Increase in a dose at such patients has to be carried out with extra care.

Treatment bisoprololy elderly patients. Dose adjustment is not required.

So far Bisoprolol at patients with the chronic heart failure interfaced to a diabetes mellitus of 1 type, heavy renal failures and/or a liver, a restrictive cardiomyopathy, inborn heart diseases or hemodynamically caused heart disease is not enough data on drug use.

Also still sufficient data concerning patients with chronic heart failure with the myocardial infarction (MI) within the last 3 months were not obtained.

Features of use:

Pregnancy and lactation. Bisoprolol does not render direct cytotoxic, mutagen and teratogenic action, but has pharmacological effects which can make harmful effects on the course of pregnancy and/or on a fruit, or the newborn. Usually beta adrenoblockers reduce placental perfusion that leads to delay of growth of a fruit, pre-natal death of a fruit, abortions or premature births. The fruit and the newborn child can have pathological reactions, such as a pre-natal arrest of development, a hypoglycemia, bradycardia.

Bisoprolol it is not necessary to apply during pregnancy, use is possible if the advantage for mother exceeds risk of development of side effects in a fruit and/or the child. In that case when treatment by drug Bisoprolol is considered as necessary, it is necessary to trace a blood stream in a placenta and a uterus, and also to watch growth and development of future child and, in case of the undesirable phenomena concerning pregnancy and/or a fruit, to accept alternative methods of therapy. It is necessary to inspect carefully the newborn after the delivery. Symptoms of a hypoglycemia and bradycardia, as a rule, arise during the first 3 days of life.

There are no data on allocation of a bisoprolol in breast milk. Therefore administration of drug бисопролол is not recommended to women during feeding by a breast. In need of use of drug during feeding by a breast, breastfeeding needs to be stopped.

Control of a condition of the patients accepting drug Bisoprolol has to include measurement of ChSS and the ABP, carrying out an ECG, definition of concentration of glucose of blood at patients with a diabetes mellitus (1 time in 4-5 months). At patients of advanced age it is recommended to monitor function of kidneys (1 times in 4-5 months).

It is necessary to train the patient in a technique of calculation of ChSS and to instruct about need of medical consultation at ChSS less than 60 beats/min.

Before an initiation of treatment it is recommended to conduct a research of function of external respiration at patients with the burdened bronchopulmonary anamnesis.

The patients using contact lenses should consider that against the background of treatment by drug reduction of products of the lacrimal liquid is possible.

At drug use Bisoprolol with a pheochromocytoma is available for patients risk of development of paradoxical AG (if effective blockade of alpha adrenoceptors is previously not reached).

At a thyrotoxicosis бисопролол can mask certain clinical signs of a thyrotoxicosis (for example, tachycardia). Sharp drug withdrawal at patients with a thyrotoxicosis is contraindicated as it is capable to strengthen symptomatology.

At a diabetes mellitus can mask the tachycardia caused by a hypoglycemia. Unlike non-selective beta adrenoblockers, practically does not strengthen the hypoglycemia caused by insulin and recovery of concentration of glucose in blood to normal value does not detain.

At simultaneous use of a clonidine its reception can be stopped only in several days after drug withdrawal Bisoprolol.

Strengthening of expressiveness of hypersensitivity reaction and lack of effect of usual doses of Epinephrinum (adrenaline) against the background of the burdened allergological anamnesis is possible. In case of need performing planned surgical treatment drug should be cancelled for 48 h before carrying out the general anesthesia. If the patient accepted drug before surgical intervention, it should pick up medicine for the general anesthesia with minimum negative inotropic effect.

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

Medicines which exhaust depot of catecholamines (including Reserpinum) can strengthen effect of beta adrenoblockers therefore the patients accepting such combinations of medicines have to be under constant observation of the doctor regarding identification of the expressed decrease in the ABP or bradycardia.

Patients with bronkhospastichesky diseases can appoint with care cardioselective beta adrenoblockers in case of intolerance and/or inefficiency of other antihypertensives. Against the background of reception of beta adrenoblockers at patients with the accompanying bronchial asthma resistance of respiratory tracts can amplify. At excesses of a dose of drug Bisoprolol at such patients arises danger of development of a bronchospasm.

In case of identification at patients of the accruing bradycardia (ChSS less than 60 beats/min), the expressed decrease in the ABP (systolic the ABP less than 100 mm hg), AV of blockade, it is necessary to reduce a dose or to stop treatment.

Bisoprolol at development of a depression is recommended to stop therapy by drug.

It is impossible to interrupt sharply treatment because of danger of development of heavy arrhythmias and a myocardial infarction. Drug withdrawal is carried out gradually, reducing a dose within 2 weeks and more (lower a dose by 25% in 3-4 days).

It is necessary to cancel drug before a concentration research in blood and urine of catecholamines, a normetanefrina, vanililmindalny acid, credits of antinuclear antibodies.

At smokers efficiency of beta adrenoblockers is lower.

Influence on ability to manage vehicles and mechanisms. Drug use Bisoprolol does not influence ability to manage vehicles according to results of a research at patients with an ischemic heart disease. However owing to individual reactions ability to manage vehicles or work with technically difficult mechanisms can be broken. On it it is necessary to pay special attention in an initiation of treatment, after change of a dose, and also at simultaneous alcohol intake.

Side effects:

Frequency of the side reactions given below was defined according to the following (classification of 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%; seldom - not less than 0,01%; but less than 0,1%; very seldom - less than 0,01%, including separate messages.

From heart and vessels: very often - urezheny ChSS (bradycardia, especially at patients with HSN), a heart consciousness; often - the expressed decrease in the ABP (especially at patients with HSN), manifestation of a vasomotor spasm (strengthening of disturbances of peripheric circulation, a cryesthesia in extremities (paresthesia); infrequently - disturbance of AV of conductivity (up to development of total cross block and a cardiac standstill), arrhythmias, orthostatic hypotension, aggravation of a current of HSN with development of peripheral hypostases (puffiness of anklebones, feet, an asthma), a stethalgia.

From a nervous system: often - dizziness, a headache, an adynamy, increased fatigue, sleeplessness, a depression, concern; seldom - confusion of consciousness or short-term loss of memory, "dreadful" dreams, hallucinations, a myasthenia; tremor, myotonia. Usually these phenomena have easy temper and pass, as a rule, within 1-2 weeks after an initiation of treatment.

From sense bodys: seldom - a vision disorder, reduction of a slezootdeleniye (it is necessary to consider when carrying contact lenses), a sonitus, decrease in hearing, ear pain; very seldom - dryness and morbidity of eyes, conjunctivitis, taste disturbances.

From respiratory system: infrequently - a bronchospasm at patients with bronchial asthma or obstructive respiratory diseases; seldom - allergic rhinitis, a nose congestion.

From the alimentary system: often - nausea, vomiting, diarrhea, a lock, dryness of a mucous membrane of an oral cavity, an abdominal pain; seldom - hepatitis, increase in activity of enzymes of a liver (alaninaminotranspherase, aspartate aminotransferase), increase in concentration of bilirubin, taste change.

From a musculoskeletal system: infrequently - an arthralgia, a dorsodynia.

From urinogenital system: very seldom - disturbance of a potentiality, weakening of a libido.

Laboratory indicators: seldom - increase in concentration of triglycerides in blood; in some cases - thrombocytopenia, an agranulocytosis, a leukopenia.

Allergic reactions: seldom - a skin itch, rash, a small tortoiseshell.

From integuments: seldom - sweating strengthening, a dermahemia, a dieback, psoriazopodobny skin reactions; very seldom - the alopecia, beta adrenoblockers can aggravate the course of psoriasis.

Others: syndrome of "cancellation" (increase of attacks of stenocardia, increase in the ABP).

If any of the side effects specified in the instruction are aggravated, or you noticed any other side effects which are not specified in the instruction, report about it to the doctor.

Interaction with other medicines:

Antiarrhytmic means of the I class (for example, quinidine, Disopyramidum, lidocaine, Phenytoinum; флекаинид пропафенон) at simultaneous use with bisoprololy can reduce AV conductivity and sokratitelny ability of a myocardium.

Antiarrhytmic means of the III class (for example, Amiodaronum) can strengthen disturbance of AV of conductivity.

Effect of beta adrenoblockers for topical administration (for example, eye drops for treatment of glaucoma) can strengthen system effects of a bisoprolol (decrease in the ABP, urezheny ChSS).

Parasympathomimetics at simultaneous use with bisoprololy can strengthen disturbance of AV of conductivity and increase risk of development of bradycardia.

Bisoprolol with beta-adrenergic agonists (for example, изопреналин, Dobutaminum) can lead simultaneous use of drug to decrease in effect of both drugs.

Combination of a bisoprolol to the adrenomimetika influencing on beta and alpha adrenoceptors (for example; Norepinephrinum, Epinephrinum (adrenaline), can strengthen vasopressor effects of these means arising with participation an alpha of adrenoceptors, leading to increase in the ABP. Similar interactions are more probable at use of non-selective beta adrenoblockers.

Meflokhin at simultaneous use with bisoprololy can increase risk of development of bradycardia.

The allergens used for an immunotherapy or extracts of allergens for skin tests increase risk of emergence of heavy system allergic reactions or an anaphylaxis at the patients receiving бисопролол.

Yodosoderzhashchy X-ray contrast diagnostic intravenous agents increase risk of development of anaphylactic reactions.

Phenytoinum at intravenous introductions, means for inhalation anesthesia (derivatives of hydrocarbons) is raised by expressiveness of cardiodepressive action and probability of decrease in the ABP.

Efficiency of insulin and hypoglycemic means for intake can change at treatment bisoprololy (masks symptoms of the developing hypoglycemia: tachycardia, increase in the ABP).

The clearance of lidocaine and xanthines (except theophylline) can decrease in connection with possible increase in their concentration in a blood plasma, especially at patients with initially increased clearance of theophylline under the influence of smoking.

Anti-hypertensive effect non-steroidal anti-inflammatory drugs (NPVP) (a delay of ions of sodium and blockade of synthesis of prostaglandins kidneys) weaken, glucocorticosteroids and estrogen (a delay of ions of sodium).

Cardiac glycosides, Methyldopum, Reserpinum and гуанфацин, blockers of "slow" calcium channels (verapamil, diltiazem), Amiodaronum and other antiarrhytmic means increase risk of development or aggravation of bradycardia, AV of blockade, a cardiac standstill and heart failure.

Simultaneous use with the drug Nifedipine can result in risk of strengthening of anti-hypertensive action of a bisoprolol.

Diuretics, clonidine, sympatholytics, гидралазин and other antihypertensives can lead to excessive decrease in the ABP.

Action of not depolarizing muscle relaxants and anticoagulating effect of coumarins during treatment bisoprololy can be extended.

Tricyclic and tetracyclic antidepressants, antipsychotic means (neuroleptics), ethanol, sedative and hypnagogues strengthen oppression of the central nervous system.

Simultaneous use with MAO inhibitors owing to considerable strengthening of anti-hypertensive action is not recommended. Having rummaged in treatment between reception of MAO inhibitors and a bisoprolola has to make not less than 14 days.

Not hydrogenated alkaloids of an ergot increase risk of development of disturbances of peripheric circulation.

Ergotamine increases risk of development of disturbance of peripheric circulation.

Sulfasalazinum increases concentration of a bisoprolol in a blood plasma.

Rifampicin shortens T1/2 of a bisoprolol.

Contraindications:

- hypersensitivity to components of drug and other beta adrenoblockers;
- the acute heart failure and chronic heart failure in a decompensation stage demanding performing inotropic therapy;
- cardiogenic shock;
- collapse;
- an atrioventricular block of the II-III degree, without pacemaker;
- sinuatrial blockade;
- sick sinus syndrome (SSS);
- bradycardia (ChSS prior to treatment less than 60 beats/min);
- heavy arterial hypotension (systolic ABP less than 100 mm hg);
- severe forms of bronchial asthma and the chronic obstructive pulmonary disease (COPD) in the anamnesis;
- the expressed disturbances of peripheric circulation;
- Reynaud's syndrome;
- metabolic acidosis;
- a pheochromocytoma (without simultaneous use of alpha adrenoblockers);
- a concomitant use of monoamine oxidase inhibitors (MAO), except for MAO inhibitors of V type);
- the accompanying use of a floktafenin and sultoprid;
- age up to 18 years (efficiency and safety are not established).

With care. With care apply Bisoprolol in the following cases: performing the desensibilizing therapy, Printsmetal's stenocardia, a hyperthyroidism, a diabetes mellitus of 1 type and a diabetes mellitus with considerable fluctuations of concentration of glucose in blood, AV blockade of the I degree, a heavy renal failure (the clearance of creatinine (CC) less than 20 ml/min.), heavy abnormal liver functions, psoriasis, a restrictive cardiomyopathy, inborn heart diseases or defect of the valve of heart with the expressed hemodynamic disturbances, chronic heart failure with a myocardial infarction within the last 3 months, heavy allergic reactions (in the anamnesis), a depression (including in the anamnesis), pregnancy, the breastfeeding period, a rigid diet.

Overdose:

Symptoms: arrhythmia, ventricular premature ventricular contraction, the expressed bradycardia, AV blockade, the expressed decrease in the ABP, an acute heart failure, a hypoglycemia, a Crocq's disease, breath difficulty, a bronchospasm, dizziness, a syncope, spasms.

Treatment: at overdose emergence first of all it is necessary to stop administration of drug, to carry out a gastric lavage, to appoint the adsorbing means, to carry out symptomatic therapy.

At the expressed bradycardia intravenous administration of atropine. If effect insufficient, with care it is possible to enter the means possessing positive chronotropic action. Temporary statement of an artificial pacemaker can sometimes be required.

At the expressed decrease in the ABP - intravenous administration of plasma substituting solutions and vazopressor.

At a hypoglycemia intravenous administration of a glucagon or intravenous administration of a dextrose (glucose) can be shown.

At AV to blockade: patients have to be under constant observation and receive treatment by beta-adrenergic agonists, such as Epinephrinum (adrenaline). In case of need statement of an artificial pacemaker.

At an aggravation of a current of HSN - intravenous administration of diuretics, drugs with a positive inotropic effect, and also vazodilatator.

At a bronchospasm - purpose of bronchodilators, including beta2-adrenomimetik and/or Aminophyllinum.

Storage conditions:

In the dry, protected from light place, at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 10, 15, 20 or, 30 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1, 2, 3, 5, 10 blister strip packagings together with the application instruction in a pack from a cardboard.