Арител® Box

General characteristics. Structure:

Active agent: the bisoprolola fumarates 2,5 mg;

excipients: silicon dioxide colloid (aerosil) of 1,5 mg, starch of potato 18 mg, lactoses monohydrate (sugar milk) 54 mg, povidone of 3 mg, cellulose of microcrystallic 20 mg, magnesium stearate of 1 mg;

structure of a film cover: Selekoat of AQ-02140 3 mg, including: gipromelloz (gidroksipropilmetiltsellyuloz) of 1,8 mg, macrogoal (polyethyleneglycol 400) of 0,33 mg, macrogoal (polyethyleneglycol 6000) of 0,45 mg, titanium dioxide of 0,39 mg, dye sunset of yellow 0,03 mg.

Description

Tablets, film coated light orange color, a heart-shaped form with risky on both parties. On cross section two layers: inside layer of almost white color.

Pharmacological properties:

Pharmacodynamics. The selection beta1-adrenoblocker, without own sympathomimetic activity, does not possess membrane stabilizing action. Has only insignificant affinity to beta2-adrenoceptors of smooth muscles of bronchial tubes and vessels, and also to the beta2-adrenoceptors participating in metabolism regulation. Therefore, бисопролол in general does not influence resistance of respiratory tracts and metabolic processes in which beta2-adrenoceptors are involved.

As a rule, the maximum lowering of arterial pressure (ABP) is reached in 2 weeks after the beginning of therapy.

Bisoprolol reduces activity of sympathoadrenal system, blocking heart beta1-adrenoceptors.

At a single dose inside at patients with coronary heart disease without symptoms of the chronic heart failure (CHF) бисопролол to an urezhayetchastot of cordial reductions (ChSS), the stroke output of blood reduces and, as a result, reduces fraction of emission and the need of a myocardium for oxygen. At long therapy initially increased general peripheric vascular resistance (GPVR) decreases. Decrease of the activity of a renin in a blood plasma, is considered as one of components of hypotensive effect of beta adrenoblockers.

Pharmacokinetics. Absorption. Bisoprolol almost completely (more than 90%) is soaked up from digestive tract. Its bioavailability owing to an insignificant metabolization at "the first passing" through a liver (at about 10%) makes about 90% after intake. Meal does not influence bioavailability. Bisoprolol shows linear kinetics, and its concentration in a blood plasma are proportional to the accepted 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 30%.

Metabolism. It is metabolized on an oxidizing way without the subsequent conjugation. All metabolitypolyarna (vodorastvorima) are also 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 liver microsomes chelovekain vitro show what бисопролол is metabolized first of all by means of CYP3A4 isoenzyme (about 95%), Cyp2d6igrayet aizoferment a lishneznachitelny role.

Removal. The clearance of a bisoprolol is defined by balance between removal by kidneys in not changed look (about 50%) and metabolism in a liver (about 50%) to metabolites which are also removed by kidneys. The general clearance makes 15 l/hour. An elimination half-life — 10 — 12 hours.

There is no information on pharmacokinetics of a bisoprolol at patients with HSN and a simultaneous abnormal liver function or kidneys.

Indications to use:

Chronic Heart Failure (CHF);
arterial hypertension;
coronary heart disease: prevention of attacks of stable stenocardia.

Route of administration and doses:

Pill of the drug Aritel® of Box should be taken with a small amount of liquid, in the morning till a breakfast, in time or after it once a day.

Tablets should not be chewed or pounded in powder.

Chronic heart failure

The initiation of treatment of chronic heart failure the drug Aritel® of Box demands obligatory carrying out a special phase of titration and regular medical control.

Preliminary condition for treatment by the drug Aritel® of Box is stable chronic heart failure without aggravation signs.

Treatment of chronic heart failure the drug Aritel® of Box begins according to the following scheme of titration.

The recommended initial dose makes 1,25 mg (1/2 tablets on 2,5 mg) once a day. Observation for individual an adaptatsiyeypatsiyenta to the appointed dose is necessary. In зависимостиот individual portability it is necessary to increase a dose gradually to 2,5 mg, 3,75 mg, 5 mg, 7,5 mg and 10 mg of 1 times 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.

Most recommended dose at chronic heart failure makes 10 mg of the drug Aritel® of Box of 1 times a day.

During titration regular control of the ABP, ChSS and degree of manifestation of symptoms of chronic heart failure is recommended. Aggravation of symptoms of a course of chronic heart failure perhaps 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 a temporary deterioration in a course of chronic heart failure, 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 the temporary dose decline of the drug Aritel® of Box or its cancellation can be required.

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

Arterial hypertension and stable stenocardia

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.

Usually initial dose makes 5 mg of a bisoprolol of 1 times a day. If necessary it is possible to increase a dose to 10 mg of 1 times a day. At treatment of arterial hypertension and stable stenocardia most recommended dozasostavlyat 20 mg of a bisoprolol of 1 times a day.

 

Treatment duration at all indications

Treatment by the Box drug Aritel® usually is long-term therapy.

 

Special groups of patients

Renal failure or liver:
· At an abnormal liver function or kidneys of easy or moderate degree usually does not demand dose adjustment.
· 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. Increase in a dose at such patients has to be carried out with extra care.

Elderly patients:

Dose adjustment is not required.

 So far there are not enough data on use of a bisoprolol for patients with chronic heart failure in combination with 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.

Features of use:

Do not interrupt treatment with drug sharply and do not change the recommended dose 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 dose should be reduced gradually.

Side effects:

Frequency of the side reactions given below, opredelyalassootvetstvenno to the following:

- very much chasto³1/10;

- chasto³1/100, <1/10;

- infrequently ³1/1000, <1/100;

- redko³1/10 000, <1/1000;

- very seldom <1/10 000, including separate messages.

From the central nervous system

Often: dizziness *, head боль*.

Seldom: loss of consciousness.

General disturbances

Often: the adynamy (at patients with HSN) raised утомляемость*.

Infrequently: an adynamy (at patients with an arterialnoygipertenziya or stenocardia).

Mental disturbances

Infrequently: depression, sleeplessness.

Seldom: hallucinations, nightmares.

From an organ of sight

Seldom: reduction of dacryagogue (it is necessary to consider when carrying contact lenses).

Very seldom: conjunctivitis.

From an acoustic organ Seldom: hearing disorder.

From cardiovascular system

Very often: bradycardia (at patients with HSN).

Often: aggravation of symptoms of a current of HSN (at patients with HSN), feeling of a cold snap and numbness in extremities, the expressed decrease in the ABP, especially at patients with HSN.

Infrequently: narusheniyeavprovodimosti; bradycardia (at patients with an arterialnoygipertenziya or stenocardia); aggravation of symptoms of a current of HSN (at patients with an arterialnoygipertenziya or stenocardia), orthostatic hypotension.

From respiratory system

Infrequently: a bronchospasm at patients with bronchial asthma or obstruction of respiratory tracts in the anamnesis.

Seldom: allergic rhinitis.

From digestive tract

Often: nausea, vomiting, diarrhea, lock.

Seldom: hepatitis.

From a musculoskeletal system Infrequently: muscular weakness, myotonia.

From integuments

Seldom: hypersensitivity reactions, such as skin itch, rash, hyperemia of integuments.

Very seldom: alopecia. Beta adrenoblockers can promote an aggravation of symptoms of a course of psoriasis or cause psoriazopodobny rash.

From reproductive system Seldom: disturbance of a potentiality.

Laboratory indicators

Seldom: increase in concentration of triglycerides and activity of "hepatic" transaminases in blood (aspartate aminotransferase (ACT), alaninaminotranspherase (ALT)).

* At patients with an arterialnoygipertenziya or stenocardia these symptoms appear usually at the beginning of a course of treatment, are softly expressed and проходятв a current of 1-2 weeks after a nachalalecheniye.

Interaction with other medicines:

 Not recommended combinations

- at treatment of chronic heart failure:

Antiarrhytmic sredstvaiklassa (for example, quinidine, Disopyramidum, lidocaine, Phenytoinum; флекаинид, пропафенон) at simultaneous use with bisoprololy can snizhatavprovodimost and sokratitelny ability of heart.

- at treatment of chronic heart failure, arterial hypertension, stable stenocardia:

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 narusheniyuavprovodimosti. In particular, intravenous administration of verapamil to the patients accepting beta adrenoblockers can lead to the expressed arterial hypotension iavblokade.

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 of beta adrenoblockers can increase risk of development of "ricochet" arterial hypertension.

 The combinations demanding extra care

- at treatment of arterial hypertension, stable stenocardia:

Antiarrhytmic sredstvaiklassa (for example, quinidine, Disopyramidum, lidocaine, Phenytoinum; флекаинид, пропафенон) at simultaneous use with bisoprololy can snizhatavprovodimost and sokratitelny ability of a myocardium.

- at treatment of chronic heart failure, arterial hypertension, stable stenocardia:

BMKK derivative dihydropyridine (for example, nifedipine, фелодипин, амлодипин) at simultaneous use with bisoprololy can increase risk of development of arterial hypotension. At patients with chronic heart failure it is impossible to exclude risk of the subsequent deterioration in sokratitelny function of heart.

Antiarrhytmic sredstvaiiiklassa (for example, Amiodaronum) can strengthen narusheniyeavprovodimosti.

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).

Parasimpatomimetikipri simultaneous use with bisoprololy can be strengthened narusheniyeavprovodimosti and increase risk of development of bradycardia.

Hypoglycemic effect of insulin or 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").

Cordial glikozidypr simultaneous use with bisoprololommonut to lead to increase in time of carrying out an impulse, and thus, to a razvitiyubradikardiya.

Non-steroidal anti-inflammatory drugs (NPVP) can reduce hypotensive effect of a bisoprolol.

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

The combination of a bisoprolol to the adrenomimetika influencing on beta and alpha adrenoceptors (for example, Norepinephrinum, Epinephrinum) can usilivatvazokonstriktorny 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, also 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 (-) In) can strengthen hypotensive effect of beta adrenoblockers. Simultaneous use can also lead to development of hypertensive crisis.

Contraindications:

Hypersensitivity to a bisoprolol or to any of excipients and other beta adrenoblockers; deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption; cardiogenic shock; collapse; acute heart failure; the chronic heart failure in a decompensation stage demanding performing inotropic therapy; atrioventricular blokadaiiiiiistepeni, without electrocardiostimulator; sinuatrial blockade; sick sinus syndrome; the expressed bradycardia (ChSS less than 50 beats/min); severe forms of bronchial asthma or chronic obstructive pulmonary disease; the expressed lowering of arterial pressure (systolic the ABP less than 90 mm рт.ст); the expressed disturbances of peripheric circulation or Reynaud's syndrome; a pheochromocytoma (without simultaneous use of alpha adrenoblockers); metabolic acidosis; lactation period; a concomitant use of monoamine oxidase inhibitors (MAO) (except for MAO inhibitors (-) B); age up to 18 years (efficiency and safety are not established).

With care: performing the desensibilizing therapy; Printsmetal's stenocardia; hyperthyroidism; a diabetes mellitus of 1 type and a diabetes mellitus with considerable fluctuations of concentration of glucose in blood; Degree Avblokada I; the expressed renal failure (clearance of creatinine less than 20 ml/min.); the expressed abnormal liver functions; psoriasis; 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; a pheochromocytoma (at the accompanying use of alpha adrenoblockers); rigid diet.

 Use during pregnancy and during feeding by a breast

During pregnancy the drug Aritel® of Box should be recommended for use 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 a blood stream in a placenta and a uterus, and also to watch growth and development of future child, 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. In the first three days of life there can be symptoms of a hypoglycemia and bradycardia.

There are no data on allocation of a bisoprolol in breast milk. Therefore administration of drug of Aritel® of Box is not recommended to women during feeding by a breast. If administration of drug of Aritel® of Box in the period of a lactation is necessary, breastfeeding should be stopped.

Overdose:

Symptoms

Most chastyesimptoma peredozirovki:avblokada, bradycardia, decrease in the ABP, bronchospasm, acute heart failure and hypoglycemia.

Treatment

At overdose emergence first of all it is necessary to stop administration of drug and to begin the supporting 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 purpose of vazopressor.

Priavblokade: patients have to be under constant observation and receive treatment alpha and 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: use of bronchodilators, including beta2-sympathomimetics and/or Aminophyllinum.

At a hypoglycemia: intravenous administration of a dextrose (glucose).

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. In the place, unavailable to children. Period of validity: 2 years. Not to apply after a period of validity.

Issue conditions:

According to the recipe

Packaging:

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