Bisoprolol-FT

General characteristics. Structure:

Active ingredient: 2,5 mg, 5 mg and 10 mg of a bisoprolol of a fumarat.

Excipients: starch corn, кросповидон, silicon dioxide colloid, magnesium stearate, cellulose microcrystallic, calcium hydrophosphate anhydrous, a gipromelloza, titanium dioxide (E-171), ferrous oxide yellow (E-172 – for a dosage of 10 mg), a macrogoal 400.

The cardial drug having hypotensive, antiarrhytmic and anti-anginal effect.

Pharmacological properties:

Pharmacodynamics. Bisoprolol is the selection beta1-adrenoblocker without own sympathomimetic activity, does not possess membrane stabilizing action. Reduces activity of a renin of a blood plasma, reduces the need of a myocardium for oxygen, reduces the heart rate (HR) at rest and at loading. Has hypotensive, antiarrhytmic and anti-anginal effect. Blocking heart beta1-adrenoceptors in low doses, reduces stimulated catecholamines formation of tsAMF from ATP, reduces intracellular current of calcium ions, renders negative hrono-, dromo-, batmo-and inotropic action (conductivity and excitability oppresses, slows down atrioventricular (AV) conductivity).

At use in average therapeutic doses, unlike non-selective beta adrenoblockers, бисопролол 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 (Na+) in an organism. At increase in a dose is higher than therapeutic development of beta2-adrenoceptor blocking effect can be noted.

The general peripheric vascular resistance at the beginning of drug use (in the first 24 h) increases as a result of reciprocal increase of activity of alpha adrenoceptors a little. Approximately in 1-3 days it is returned to initial level, and at long appointment decreases.

The hypotensive effect is connected with reduction of minute volume of blood, sympathetic stimulation of peripheral vessels, decrease of the activity a system renin-angiotenzinovoy (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 arterial hypertension the effect occurs in 2-5 days, stable action develops - in 1-2 months.

The anti-anginal effect is caused by reduction of need of a myocardium for oxygen as a result of an urezheniye of ChSS, insignificant decrease in contractility, lengthening of a diastole, improvement of perfusion of a myocardium.

The antiarrhytmic effect is caused by elimination of aritmogenny factors (tachycardia, a superactivity of a sympathetic nervous system, the increased maintenance of tsAMF, arterial hypertension), reduction of speed of spontaneous excitement of sinus and ectopic pacemakers and delay of AV-of carrying out (it is preferential in antegrade and, to a lesser extent, in retrograde the directions) and on additional ways.

Unlike non-selective beta adrenoblockers at use of a bisoprolol in average therapeutic doses less expressed its influence on the bodies containing beta2-adrenoceptors (a pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchial tubes and a uterus) and on carbohydrate metabolism is observed, there is no delay of ions of sodium in an organism. At increase in a dose is higher than therapeutic development of beta2-adrenoceptor blocking effect can be noted.

Pharmacokinetics. Absorption. Bisoprolol almost completely (> 90%) is soaked up from digestive tract. Its bioavailability owing to insignificant metabolism "at the first passing" through a liver (about 10%-15%) makes about 85-90% after intake. Meal does not influence bioavailability. Bisoprolol shows linear kinetics, and its concentration in a blood plasma are proportional to the entered dose in the range of doses from 5 to 20 mg. The maximum concentration in a blood plasma is reached in 2-3 hours.

Distribution. Bisoprolol is distributed quite widely. The volume of distribution makes 3,5 l/kg. Communication with proteins of a blood plasma reaches about 35%; capture by blood cells is not observed.

Metabolism. It 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 (about 95%), a CYP2D6 plays a small role in metabolism of a bisoprolol.

Removal. The clearance of a bisoprolol is defined by balance between its removal by kidneys in the form of not changed substance (about 50%) and oxidation in a liver (about 50%) to metabolites which then are also removed by kidneys. The general clearance makes 15,6 ± 3,2 l/hour, and the renal clearance is equal to 9,6±1,6 l/hour. The elimination half-life (Т½) makes 10-12 hours.

Indications to use:

· arterial hypertension;
· coronary heart disease: prevention of attacks of stenocardia;
· chronic heart failure.

Route of administration and doses:

Pill should be taken with a small amount of liquid in the morning before the breakfast, in time or after it. Tablets should not be chewed or pounded in powder.

Treatment of arterial hypertension and stenocardia. In all cases the mode of reception and a dosage are selected by the doctor to each patient individually, in particular, considering ChSS and a condition of the patient. Usually initial dose makes 5 mg (1 tablet of 5 mg) once a day. If necessary it is possible to increase a dosage to 10 mg (2 tablets on 5 mg or 1 tablet of 10 mg) once a day. At treatment of arterial hypertension and stenocardia the maximum recommended dose makes 20 mg of BISOPROLOLA-FT once a day.

Treatment of chronic heart failure. The initiation of treatment of chronic heart failure drug BISOPROLOLOM-FT demands obligatory carrying out a special phase of titration and regular medical control.

Preliminary conditions for treatment following:
· chronic heart failure without aggravation signs in the previous six weeks;
· almost invariable basic therapy in the previous two weeks;
· treatment by optimum doses of APF inhibitors (or other vasodilators, in case of intolerance of APF inhibitors), diuretics and, optionally, cardiac glycosides.

Treatment of chronic heart failure of BISOPROLOLOM-FT 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:

1ya week: 1,25 mg/days - ½ tablets Bisoprolola-FT of 2,5 mg once a day;

2ya week: 2,5 mg/days - 1 tablet Bisoprolola-FT of 2,5 mg once a day;

3ya week: 3,75 mg/days - 1½ the tablets Bisoprolola-FT of 2,5 mg once a day;

4ya-7ya week: 5 mg/days - 1 tablet Bisoprolola-FT of 5 mg once a day;

8ya-11ya week: 7,5 mg/days - 1½ the tablets Bisoprolola-FT of 5 mg once a day or 1 tablet Bisoprolola-FT of 2,5 mg +1   tablet Bisoprolola-FT of 5 mg once a day;

12ya week and further: 10 mg/days - 1 tablet Bisoprolola-FT 10 mg or 2 tablets Bisoprolola-FT of 5 mg once a day as a maintenance therapy.

The maximum recommended dose at treatment of chronic heart failure makes 10 mg of BISOPROLOLA-FT once a day. Patients are recommended to accept the drug dose which is picked up by the doctor if there are no side reactions.

After an initiation of treatment drug in a dose of 1,25 mg (½ tablets BISOPROLOLA-FT of 2,5 mg) of the patient it is necessary to observe within about 4 hours (control of ChSS, the ABP, conductivity disturbance, signs of deterioration in heart failure).

During a phase of titration or after it there can be a temporary deterioration in a course of heart failure, a liquid delay in an organism, arterial hypotension or bradycardia. In this case it is recommended to pay, first of all, attention to selection of a dosage of the accompanying basic therapy (to optimize a dose of diuretic and/or APF inhibitor) before decrease in a dosage of BISOPROLOLA-FT. Treatment should be interrupted only in urgent cases

After stabilization of a condition of the patient it is necessary to carry out repeated titration, or to continue treatment.

Treatment duration at all indications. Treatment by drug BISOPROLOLOM-FT usually is the long-term procedure. If necessary treatment can be interrupted and resumed with observance of certain rules.

Treatment should not be interrupted suddenly, especially at patients with coronary heart disease. If the treatment termination is necessary, then the dosage of drug should be reduced gradually.

Features of use:

It is necessary to warn the patient about that he did not interrupt treatment sharply and did not change the recommended dosage without preliminary consultation with the doctor as it can lead to temporary deterioration in action of the heart. Treatment should not be interrupted suddenly, especially at patients with coronary heart disease. If the termination of treatment is necessary, then the dosage should be reduced gradually.

Control of a condition of the patients accepting BISOPROLOL-FT has to include measurement of ChSS and the ABP (in an initiation of treatment - daily, then 1 time in 3 - 4 months), carrying out an ECG, blood glucose definition at patients with a diabetes mellitus (1 time in 4-5 months). At elderly patients 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 it about need of medical consultation at ChSS less than 50 уд. / 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 have to consider that against the background of treatment reduction of products of the lacrimal liquid is possible.

When using patients with a pheochromocytoma have a risk of development of paradoxical arterial hypertension (if it is previously not reached effective alpha адреноблокада). At a thyrotoxicosis of BISOPROLOL-FT can disguise 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 level does not detain.

At a concomitant use of a clonidine its reception can be stopped only in several days after cancellation of BISOPROLOLA-FT.

Strengthening of expressiveness of hypersensitivity reaction and lack of effect of usual doses of Epinephrinum 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 operation, 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).

The medicines reducing stocks 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 cardioselective adrenoblockers in case of intolerance and/or inefficiency of other antihypertensives. At exceeding of a dose of drug there is a danger of development of a bronchospasm.

In case of identification at patients of advanced age of the accruing bradycardia (ChSS less than 50 уд. / min.), the expressed decrease in the ABP (systolic the ABP is lower than 100 mm hg), an atrioventricular block, it is necessary to reduce a dose or to stop treatment. It is recommended to stop therapy at development of a depression.

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 research of content in blood and urine of catecholamines, a normetanefrin and vanilinmindalny acid; credits of antinuclear antibodies.

Management of transport and mechanisms. Bisoprolol does not influence ability to drive the car at a research of the patients having diseases of coronary vessels of heart. However owing to individual reactions ability to drive the car 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 determined by results of performing treatment by other bisoprolol-containing drugs and corresponded to the following indicators characterizing the frequency of their occurrence:
- very often: ≥1/10;
- often:> 1/100 <1/10;
- infrequently:> 1/1000 <1/100;
- seldom:> 1/10 000 <1/1000;
- very seldom: <1/10 000, including separate messages.

Cardiovascular system. Very often: decrease in ChSS (bradycardia, especially at patients with chronic heart failure); often: arterial hypotension (especially at patients with chronic heart failure), emergence of a vasomotor spasm (strengthening of disturbance of peripheric circulation, a cryesthesia in extremities (paresthesia); infrequently: AV conductivity disturbance, orthostatic hypotension, a decompensation of heart failure with development of peripheral hypostases.

Nervous system. At the beginning of a course of treatment frustration of TsNS, infrequently can temporarily appear: dizziness, a headache, an adynamy, increased fatigue, sleep disorders, and also mental disorders (it is not frequent - a depression, it is rare: hallucinations, nightmares, spasms). Usually these phenomena have easy temper and disappear, as a rule, within 1 - 2 weeks after an initiation of treatment.

Organs of sight. Seldom: a vision disorder, reduction of a slezootdeleniye (it is necessary to consider when carrying contact lenses); very seldom: conjunctivitis.

Respiratory system. Seldom: allergic rhinitis. Infrequently: a bronchospasm at patients with bronchial asthma or obstructive respiratory diseases.

Digestive tract. Often: nausea, vomiting, diarrhea, lock, dryness of a mucous membrane of an oral cavity; seldom: hepatitis.

Musculoskeletal system. Infrequently: muscular weakness, spasms in gastrocnemius muscles, an arthralgia.

Allergic reactions. Seldom: hypersensitivity reactions, such as skin itch, erubescence, perspiration, rash. Very seldom: allopecia. Beta adrenoblockers can aggravate the course of psoriasis.

Urinogenital system. Very seldom: disturbance of a potentiality.

Laboratory indicators. Seldom: increase in level of enzymes of a liver in blood (ACT, ALT), increase in level of triglycerides in blood. In some cases: thrombocytopenia, agranulocytosis.

Interaction with other medicines:

Its concomitant use with other medicines can affect efficiency and portability of BISOPROLOLA-FT even then when two or more drugs are accepted through a short period. It is necessary to learn from the patient what he accepts other medicines even if and without instruction.

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 administration, medicines for inhalation general anesthesia (derivatives of hydrocarbons) increase expressiveness of cardiodepressive action and probability of decrease in the ABP.

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

The clearance of lidocaine and xanthines (except Diphyllinum) 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. Non-steroidal anti-inflammatory drugs, glucocorticosteroids and estrogen weaken hypotensive effect of a bisoprolol (Na+ delay, prostaglandin synthesis blockade by kidneys).

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, an atrioventricular block, cardiac standstill and heart failure.

Nifedipine can lead to considerable decrease in the ABP.

Diuretics, clonidine, sympatholytics, гидралазин and other hypotensive drugs 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.

Rub - and tetracyclic antidepressants, antipsychotic means (neuroleptics), ethanol, sedative and somnolent medicines strengthen oppression of TsNS. Simultaneous use with MAO inhibitors owing to considerable strengthening of hypotensive 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 an elimination half-life.

Contraindications:

BISOPROLOL-FT medicine should not be applied to treatment of patients with the following states:
· hypersensitivity to a bisoprolol or to any of drug components (see the section "Structure") and to other beta adrenoblockers;
· an acute heart failure, chronic heart failure in a decompensation stage;
· the shock caused by disturbance of cordial functions (cardiogenic shock), a collapse;
· an atrioventricular block of II and III degrees without use of an electrocardiostimulator;
· sick sinus syndrome;
· sinuatrial blockade;
· the expressed bradycardia (ChSS less than 50 уд. / min.);
· the expressed decrease in the ABP (systolic the ABP less than 90 mm of mercury.);
· severe forms of bronchial asthma and chronic obstructive pulmonary disease in the anamnesis;
· late stages of disturbance of peripheric circulation, Raynaud's disease;
· a pheochromocytoma (without simultaneous use of alpha adrenoblockers);
· metabolic acidosis;
· a concomitant use of inhibitors of a monoaminooxidase (MAO) except for MAO-B;
· age up to 18 years (efficiency and safety are not established).

With care: a liver failure, a chronic renal failure, Printsmetal's stenocardia, a myasthenia, a thyrotoxicosis, a diabetes mellitus, an atrioventricular block of the I degree, a depression (including in the anamnesis), psoriasis, advanced age.

Special groups of patients. Renal failure or liver. Treatment of arterial hypertension or stenocardia.
· At an abnormal liver function or kidneys of easy or moderate degree usually are not required corrections of a dose.
· At the expressed renal failures (clearance of creatinine less than 20 ml/min.) and at patients with a serious illness of a liver the maximum daily dose makes 10 mg.

Elderly patients. Dose adjustment is not required.

Pregnancy and lactation. During pregnancy of BISOPROLOL-FT it is necessary to recommend only if the advantage for mother exceeds risk of development of side effects in a fruit. As a rule, beta adrenoblockers reduce a blood stream in a placenta and can affect fetation. It is necessary to trace attentively a blood stream in a placenta and a uterus, and also to monitor growth and development of future child, and in case of dangerous manifestations concerning pregnancy or a fruit, to take alternative therapeutic measures. It is necessary to inspect carefully the newborn after the delivery. In the first three days of life there can be symptoms of decrease in level of glucose in blood and ChSS. There are no data on excretion of a bisoprolol in breast milk or safety of impact of a bisoprolol on babies. Therefore administration of drug of BISOPROLOL-FT is not recommended to women during feeding by a breast.

Overdose:

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

Treatment: a gastric lavage and purpose of the adsorbing medicines; symptomatic therapy: at the developed atrioventricular block - intravenous administration of 1-2 mg of atropine, Epinephrinum or statement of a temporary pacemaker; at ventricular premature ventricular contraction - lidocaine (the drugs IA of a class are not used); at the expressed lowering of arterial pressure - the patient has to be in the provision of Trendelenburga; if there are no fluid lungs signs - plasma substituting solutions intravenously, at inefficiency - introduction of Epinephrinum, dopamine, Dobutaminum (for maintenance of chronotropic and inotropic action and elimination of the expressed decrease in the ABP); at heart failure - cardiac glycosides, diuretics, a glucagon; at spasms - intravenously diazepam; at a bronchospasm - beta2 - adrenostimulyator it is inhalation.

Storage conditions:

To store in the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 2 years.

Issue conditions:

According to the recipe

Packaging:

Tablets on 2,5 mg, 5 mg and 10 mg in a blister strip packaging No. 10х3 and No. 10х5 and in banks No. 100. Together with a leaf insert blister strip packagings and banks are located in packs from a cardboard.