Bisoprolol

General characteristics. Structure:

Each tablet of 2,5 mg contains active agent: the bisoprolola fumarates 2,5 mg.

Excipients (kernel): lactoses monohydrate (sugar milk) - 150,0 mg, cellulose microcrystallic - 31,5 mg, magnesium stearate - 2,0 mg, povidone (polyvinylpirrolidone) - 7,0 mg, croscarmellose sodium - 7,0 mg.

Excipients (cover): a gipromelloza - 3,3 mg a macrogoal of 4000 - 0,9 mg, titanium dioxide - 1,8 mg.

Each tablet of 5,0 mg contains active agent: the bisoprolola fumarates 5,0 mg.

Excipients (kernel): lactoses monohydrate (sugar milk) - 71,5 mg, cellulose microcrystallic - 18,0 mg, magnesium stearate - 0,75 mg, starch prezhelatinizirovanny - 1,25 mg, povidone (polyvinylpirrolidone) - 3,5 mg.

Excipients (cover): a gipromelloza - 1,65 mg, a macrogoal of 4000 - 0,45 mg, titanium dioxide - 0,9 mg.
Each tablet of 10,0 mg contains active agent: the bisoprolola fumarates 10,0.

Excipients (kernel): lactoses monohydrate (sugar milk) - 143,0 mg, cellulose microcrystallic - 36,0 mg, magnesium stearate - 1,5 mg, starch prezhelatinizirovanny - 2,5 mg, povidone (polyvinylpirrolidone) - 7,0 mg.

 Excipients (cover): a gipromelloza - 3,3 mg, a macrogoal of 4000 - 0,9 mg, titanium dioxide - 1,8 mg.

Pharmacological properties:

Pharmacodynamics. Bisoprolol - the selection adrenoblocker, without own sympathomimetic activity,  does not possess membrane stabilizing action. As well as for other β-adrenoblockers, the action mechanism at arterial hypertension is not clear. At the same time, it is known what 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 in low doses - heart adrenoceptors, 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 renders β-adrenoceptor blocking action. 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 and - adrenoceptors and elimination of stimulation β2-адренорецепторов), 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. At arterial hypertension 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 a left ventricle 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 β-adrenoblockers, exerts less expressed impact on the bodies containing β2-адренорецепторы (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 almost completely (more than 90%) is soaked up in digestive tract, meal does not influence absorption. The effect of "primary passing" through a liver is insignificant (at the level of 10-15%) that results in high bioavailability (90%). Meal does not influence bioavailability of a bisoprolol.
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 is only of little importance.
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 and a placental barrier - low. Plasma elimination half-life of blood (10-12 hours) 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).
As removal takes place in kidneys and in a liver equally, 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 the elimination half-life is more long in comparison with healthy volunteers.
There is no information on pharmacokinetics of a bisoprolol at patients with HSN and a simultaneous abnormal liver function or kidneys.

Indications to use:

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

Route of administration and doses:

Drug Bisoprolol is accepted inside, in the morning on an empty stomach, once, without chewing, washing down with a small amount of liquid. 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 the heart rate and the therapeutic answer.
At arterial hypertension and coronary heart disease usually initial dose makes 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. Division of a daily dose into 2 receptions is possible.
Treatment of stable chronic heart failure
The standard scheme of treatment of HSN includes use of inhibitors of an angiotensin-converting enzyme (APF) or antagonists of receptors of angiotensin II (in case of intolerance of APF inhibitors), [-adrenoblockers, diuretics and, optionally, cardiac glycosides. HSN initiation of treatment 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 HSN 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. The recommended initial dose makes 1,25 mg (1/2 tablets on 2,5 mg) once a day.
Depending on individual portability the dose should be raised gradually to 2,5 mg, 3,75 mg (1/tablets on 2,5 mg), 7,5 mg (3 tablets on 2,5 mg) and 10 mg once a day.
Each subsequent increase in a dose has to be carried out not less than in two weeks.
If increase in a dose of drug is badly transferred by the patient, the dose decline is possible. The maximum recommended dose at HSN
Bisoprolol makes 10 mg of drug once a day. During titration regular control of the ABP, ChSS is recommended and
degrees of manifestation of symptoms of HSN. Aggravation of symptoms of a current If the patient badly transfers most recommended dose
drug, perhaps gradual dose decline.
During a phase of titration or after it there can be a temporary deterioration in a current HSN, arterial hypotension or bradycardia. In
this case it is recommended to carry out, first of all, correction of doses of drugs of the accompanying therapy.  Also  can be required
temporary dose decline of drug Bisoprolol or his cancellation.
After stabilization of a condition of the patient it is necessary to carry out repeated titration of a dose, or to continue treatment.

Special groups of patients
Renal failure or liver:
• At an abnormal liver function or kidneys of easy or moderate degree usually it is not required to adjust a dose.
• At the expressed renal failures (KK 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.
So far Bisoprolol at patients from HSN interfaced to a diabetes mellitus of 1 type, the expressed renal failures and/or a liver, a restrictive cardiomyopathy, inborn heart diseases or defect of the valve of heart with the expressed hemodynamic disturbances is not enough data on drug use. Also still sufficient data concerning patients with HSN with a myocardial infarction within the last 3 months were not obtained.

Features of use:

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 50 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 arterial hypertension (if effective blockade and - 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 β-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 β-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 β-adrenoblockers in case of intolerance and/or inefficiency of other antihypertensives. Against the background of reception of β-adrenoblockers at patients with the accompanying bronchial asthma resistance of respiratory tracts can amplify. At exceeding 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 уд. / 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, vanilinmindalny acid, credits of antinuclear antibodies.
At smokers efficiency of β-adrenoblockers is lower.

Influence on ability to manage vehicles and to work with the equipment demanding the increased concentration of attention
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:

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%; rarely 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 - an urezheniye of heart rate (bradycardia, especially at patients with HSN); a heart consciousness, often expressed lowering of arterial pressure (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; asthma), stethalgia.
- From a nervous system: often - dizziness, a headache, an adynamy, increased fatigue, sleep disorders, a depression, concern; seldom - confusion of consciousness or short-term loss of memory, "dreadful" dreams, hallucinations, a myasthenia, a 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; 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 - the increased sweating, a dermahemia, a dieback, psoriazopodobny skin reactions; very seldom - an alopecia, [-adrenoblockers can aggravate the course of psoriasis.
- Other: syndrome of "cancellation" (increase of attacks of stenocardia, increase in the ABP).

Interaction with other medicines:

Not recommended combinations
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 heart.
Blockers of "slow" calcium channels (BMKK) like verapamil and to a lesser extent, diltiazem, at simultaneous use with bisoprololy can lead to decrease in sokratitelny ability of a myocardium and disturbance of AV of conductivity. In particular, intravenous administration of verapamil to the patients accepting [-adrenoblockers, can lead to the blockade expressed to arterial hypotension and AV. Antihypertensives of the central action (such as clonidine, Methyldopum, моксонидин, рилменидин) can lead to an urezheniye of ChSS and decrease in cordial emission, and also to a vazodilatation owing to decrease in the central sympathetic tone. Sharp cancellation, especially before cancellation [-adrenoblockers can increase risk of development of "ricochet" arterial hypertension. The combinations demanding care
Antiarrhytmic means of the III class (for example, Amiodaronum) can strengthen disturbance of AV of conductivity.
Action [-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 [-adrenomimetikam (for example, изопреналин, Dobutaminum) can lead simultaneous use of drug to decrease in effect of both drugs. The combination of a bisoprolol to the adrenomimetika influencing on [-and and - adrenoceptors (for example, Norepinephrinum, Epinephrinum), can strengthen vasopressor effects of these means arising with participation and - adrenoceptors, leading to increase in the ABP. Similar interactions are more probable at use non-selective  [-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 administration, means for inhalation anesthesia (derivatives of hydrocarbons) increase 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.
Nifedipine can lead to considerable decrease in the ABP. Diuretics, a clonidine, sympatholytics, гидралазин and other antihypertensives can lead to excessive decrease in the ABP. Action of nedepolyarizuyushy  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 (except for MAO B inhibitors) owing to considerable strengthening of anti-hypertensive action is not recommended.
Simultaneous use can also lead to development of hypertensive crisis.
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 of a bisoprolol.

Contraindications:

- hypersensitivity to a bisoprolol, other components of drug and to others [-to adrenoblockers,
- the acute heart failure or HSN in a decompensation stage demanding performing inotropic therapy
- shock (including cardiogenic),
- fluid lungs,
- an atrioventricular block (AV) blockade of degree, without electrocardiostimulator,
- sinuatrial blockade,
- sick sinus syndrome,
- bradycardia (ChSS less than 60 уд. / min.),
- heavy arterial hypotension (the systolic arterial pressure (AP) is 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 and - adrenoblockers).
- a concomitant use of inhibitors of a monoaminooxidase (MAO) (except for MAO inhibitors of V type),
- age up to 18 years (efficiency and safety are not established),
- lactose intolerance, insufficiency of lactase or syndrome of glyukozo-galaktozny malabsorption.

With CARE: 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 renal failure (KK less than 20 ml/min.), the expressed abnormal liver functions, psoriasis, a restrictive cardiomyopathy, inborn heart diseases or defect of the valve of heart with the expressed hemodynamic disturbances, HSN with a myocardial infarction within the last 3 months, a rigid diet, a depression (including in the anamnesis), advanced age.

USE  AT  PREGNANCY  AND   DURING BREASTFEEDING
Bisoprolol has pharmacological effects which can make harmful effects on the course of pregnancy and/or on a fruit or the newborn. Usually [-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 (for example, a hypoglycemia, bradycardia, arterial hypotension). Bisoprolol it is not necessary to apply at 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 Bisoprolol is considered as necessary, it is necessary to make observation of an uteroplacental blood-groove and pre-natal fetation. In case of negative impact on pregnancy or a fruit it is necessary to consider alternative therapy. Symptoms of a hypoglycemia and bradycardia, as a rule, arise during the first 3 days. It is necessary to inspect carefully the newborn after the delivery.
Data on allocation of a bisoprolol in breast milk are absent. Therefore in need of use of drug in the period of a lactation, breastfeeding needs to be stopped.

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 dextrose (glucose) can be shown.
At AV to blockade: patients have to be under constant observation and receive treatment of a β-adrenomimetikama, such as Epinephrinum. In case of need - statement of an artificial pacemaker.
At an aggravation of a current of HSN - intravenous administration of diuretics, drugs with positive inotropic effects, and also vazodilatator.
At a bronchospasm - purpose of bronchodilators, including β-adrenomimetik and/or Aminophyllinum.

Storage conditions:

In the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated on 2,5 mg, 5 mg and 10 mg. On 10, 30 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 10, 20, 30, 40, 50, 60 or 100 tablets in banks polymeric for medicines.
One bank or 1, 2, 3, 4, 5, 6, 8 or 10 blister strip packagings together with the application instruction place in a pack from a cardboard.