Bisoprolol
Producer: CJSC Rafarm Russia
Code of automatic telephone exchange: C07AB07
Release form: Firm dosage forms. Tablets.
General characteristics. Structure:
Active ingredient: 2,5 mg, 5 mg or 10 mg of a bisoprolol of a fumarat.
Excipients: cellulose microcrystallic, starch corn, croscarmellose sodium, magnesium stearate, silicon dioxide colloid.
Cover: film covering (polyvinyl alcohol, titanium dioxide, macrogoal, talc).
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 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 heart beta1-adrenoceptors in low doses, reduces stimulated catecholamines formation of cyclic adenosinemonophosphate (tsAMF) from adenosinetriphosphate (ATP), reduces intracellular current of calcium ions (Sa2+), renders negative hrono-, dromo-, batmo-and inotropic action, oppresses conductivity and excitability, reduces atrioventricular (AV) conductivity.
At exceeding of a therapeutic dose has beta2-adrenoceptor blocking effect. 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 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 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 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 through an AV node) and on additional ways.
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 (Na+) in an organism; expressiveness of atherogenous action does not differ from effect of propranolol.
Pharmacokinetics. Absorption. Bisoprolol almost completely (> 90%) is soaked up from digestive tract. Its bioavailability owing to an insignificant metabolization at "primary passing" through a liver (at about 10-15%) makes about 85-90% after intake. Meal does not influence bioavailability of a bisoprolol. 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 of a bisoprolol blood cells is not observed.
Metabolism. 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.
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 of a bisoprolol makes 15,6 ± 3,2 l/h, and the renal clearance is equal 9,6 ± 1,6 l/h. The elimination half-life of a bisoprolol makes 10-12 hours.
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 the chronic heart failure (CHF) plasma concentration of a bisoprolol are higher, and the elimination half-life is more long in comparison with healthy volunteers.
Indications to use:
- coronary heart disease: prevention of attacks of stable stenocardia;
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 water, 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 hypertension and coronary heart disease drug is appointed on 5 mg of 1 times/days. If necessary the dose is increased to 10 mg of 1 times/days.
At treatment of arterial hypertension and stenocardia the maximum daily dose makes 20 mg of 1 times/days.
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), beta 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 HSN 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, that is the dose can be increased only if the previous dose was well transferred.
For providing the below-mentioned mode of a drug dosing at HSN drug use Bisoprolol in tablets on 2,5 mg with risky is possible.
The recommended initial dose makes 1,25 mg once a day. Depending on individual portability the dose should be raised gradually to 2,5 mg, 3,75 mg (11/2 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 makes 10 mg of drug Bisoprolol once a day.
During titration regular control of the ABP, ChSS and degree of manifestation of symptoms of HSN is recommended. Aggravation of symptoms of a current of HSN is possible from the first day of use of drug.
If the patient badly transfers most recommended drug dose, perhaps gradual dose decline.
During a phase of titration or after it there can be temporary deterioration in a current HSN, arterial hypertension or bradycardia. In this case it is recommended to carry out, first of all, correction of doses of drugs of the accompanying therapy. Also the temporary dose decline of drug Bisoprolol or his cancellation 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.
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 heavy 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.
Elderly patients. Dose adjustment is not required.
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:
Pregnancy and lactation. Pregnancy. 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 on 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.
Breastfeeding period. There are no data on allocation of a bisoprolol in breast milk. Therefore administration of drug Bisoprolol is not recommended to women during feeding by a breast. In need of use of drug during breastfeeding, 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 in 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 arterial hypertension (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 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 50 beats/min), the expressed decrease in the ABP (systolic the ABP less than 100 mm of mercury.), 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 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 cardiovascular system: very often - urezheny ChSS (bradycardia, especially at patients with HSN); 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 AY 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, 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).
Interaction with other medicines:
Simultaneous use of other medicines can affect efficiency and portability of medicines. Such interaction can happen also when two medicines are accepted through a short period. The doctor needs to be informed on use of other medicines, even in case of their reception without appointment of the doctor (that is drugs of non-prescription dispensing).
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.
The Blockers of "Slow" Calcium Channels (BSCC) 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 beta 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 beta adrenoblocker cancellation, can increase risk of development of "ricochet" arterial hypertension.
The combinations demanding extra care. BMKK derivative dihydropyridine (for example, nifedipine, фелодипин, амлодипин) at simultaneous use with bisoprololy can increase risk of development of arterial hypotension. At patients with HSN it is impossible to exclude risk of the subsequent deterioration in sokratitelny function of heart.
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.
Hypoglycemic effect of insulin and hypoglycemic means for intake can amplify. Hypoglycemia signs - in particular tachycardia - can mask or be suppressed. Similar interactions are more probable at use of non-selective beta adrenoblockers.
Means for carrying out the general anesthesia can increase risk of cardiodepressive action, leading to arterial hypotension (see the section "Special Instructions").
Cardiac glycosides at simultaneous use with bisoprololy can lead to increase in time of carrying out an impulse, and thus, to development of bradycardia.
Non-steroidal anti-inflammatory drugs (NPVP) can reduce anti-hypertensive effect of a bisoprolol.
Bisoprolol with beta-adrenergic agonists (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 beta and alpha adrenoceptors (for example, Norepinephrinum, Epinephrinum), can strengthen the vasopressor effects of these means arising with participation of alpha adrenoceptors, leading to increase in the ABP. Similar interactions are more probable at use of non-selective beta adrenoblockers.
Antihypertensives as well as other means with possible anti-hypertensive effect (for example, tricyclic antidepressants, barbiturates, fenotiazina), can strengthen hypotensive effect of a bisoprolol.
Meflokhin at simultaneous use with bisoprololy can increase risk of development of bradycardia.
MAO inhibitors (except for MAO inhibitors of V type) can strengthen hypotensive effect of beta adrenoblockers. Simultaneous use can also lead to development of hypertensive crisis.
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.
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.
Contraindications:
- hypersensitivity to components of drug and other beta adrenoblockers;
- the acute heart failure and HSN in a decompensation stage demanding performing inotropic therapy;
- collapse;
- AV blockade of the II-III degree, without pacemaker;
- sinuatrial blockade;
- bradycardia (ChSS prior to treatment less than 60 уд. / mines);
- heavy arterial hypotension (systolic arterial pressure is less than 100 mm of mercury.)
- a cardiomegaly (without symptoms of heart failure);
- severe forms of bronchial asthma and the chronic obstructive pulmonary disease (COPD) in the anamnesis;
- the expressed disturbances of peripheric circulation;
- Reynaud's syndrome;
- a pheochromocytoma (without simultaneous use of alpha adrenoblockers);
- a concomitant use of monoamine oxidase inhibitors (MAO) (except for MAO inhibitors of V type);
- age up to 18 years (efficiency and safety are not established).
With care. Psoriasis, a depression (including in the anamnesis), a diabetes mellitus (can mask hypoglycemia symptoms), allergic reactions (in the anamnesis), a bronchospasm (in the anamnesis), performing the desensibilizing therapy, Printsmetal's stenocardia, AV blockade of the I degree, the expressed renal failures (the clearance of creatinine (CC) less than 20 ml/min.); heavy abnormal liver functions; a hyperthyroidism, advanced age, 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.
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. Sensitivity to a single dose of a high dose of a bisoprolol strongly varies among certain patients and probably patients with HSN have high sensitivity.
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 by beta-adrenergic agonists, 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 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 use after a period of validity.
Issue conditions:
According to the recipe
Packaging:
On 10 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 100 tablets in bank polymeric blown, made of polypropylene and corked by a cover from polypropylene or to bank polymeric, made of polyethylene of low pressure and corked by the cover made of mix of polyethylene of high pressure and polyethylene of low pressure. On 3, 5 or 10 blister strip packagings or 1 bank polymeric together with the application instruction place in a pack from a cardboard.
