Betalok ZOK

General characteristics. Structure:

One tablet Betalok ZOK contains 25 mg:
Active agent: 23,75 mg of a metoprolol of succinate that corresponds to 19,5 mg of a metoprolol and 25 mg of a metoprolol of tartrate.
Excipients: ethyl cellulose of 21,5 mg, a hypro rod of 6,13 mg, a gipromelloza of 5,64 mg, cellulose of microcrystallic 94,9 mg, paraffin of 0,06 mg, a macrogoal of 1,41 mg, silicon dioxide of 14,6 mg, sodium of the stearylfumarating 0,241 mg, titanium dioxide of 1,41 mg.
One tablet Betalok ZOK contains 50 mg:
Active agent: 47,5 mg of a metoprolol of succinate that corresponds to 39 mg of a metoprolol and 50 mg of a metoprolol of tartrate.
Excipients: ethyl cellulose of 23 mg, a hypro rod of 7 mg, a gipromelloza of 6,2 mg, cellulose of microcrystallic 120 mg, paraffin of 0,1 mg, a macrogoal of 1,6 mg, silicon dioxide of 12 mg, sodium of the stearylfumarating 0,3 mg, titanium dioxide of 1,6 mg.
One tablet Betalok ZOK contains 100 mg:
Active agent: 95 mg of a metoprolol of succinate that corresponds to 78 mg of a metoprolol and 100 mg of a metoprolol of tartrate.
Excipients: ethyl cellulose of 46 mg, a hypro rod of 13 mg, a gipromelloza of 9,8 mg, cellulose of microcrystallic 180 mg, paraffin of 0,2 mg, a macrogoal of 2,4 mg, silicon dioxide of 24 mg, sodium of the stearylfumarating 0,5 mg, titanium dioxide of 2,4 mg.
Description
Betalok ZOK of 25 mg: Oval biconvex tablets white or almost white
colors, coated; with a notch on both parties and an engraving
A on one party
β
Betalok ZOK of 50 mg: Round biconvex tablets of white or almost white color,
coated; with a notch on one party and an engraving
A on other party
mo
Betalok ZOK of 100 mg: Round biconvex tablets white or almost white
colors, coated; with a notch on one party and an engraving
A on other party
ms

Pharmacological properties:

Pharmacodynamics. Metoprolol-β1-адреноблокатор, blocking β1-рецепторы in doses considerably smaller, than the doses which are required for blocking β2-рецепторов.

Metoprolol has insignificant membrane stabilizing effect and does not show activity of a partial agonist.

Metoprolol reduces or inhibits agonistic effect which the catecholamines which are allocated at nervous and physical stresses have on cordial activity.

It means what метопролол has ability to interfere with increase in the heart rate (HR), minute volume and strengthening of contractility of heart, and also increase in the arterial pressure (AP), the catecholamines caused by sharp emission.

Unlike the usual tableted dosage forms of the selection β1-адреноблокаторов (including метопролол tartrate), at drug use Betalok ZOK observes constant concentration of drug in a blood plasma and the steady clinical effect (β1-блокада) within more than 24 hours is provided. Owing to lack of explicit peak concentration in plasma, clinically Betalok ZOK is characterized by the best β1-селективностью in comparison with the usual tableted forms β1-адреноблокаторов. Besides, the potential risk of the side effects observed at peak concentration of drug in plasma, for example, bradycardia and weakness in legs when walking substantially decreases. Patients with symptoms of obstructive diseases of lungs if necessary can appoint Betalok ZOK in combination with β2-adrenomimetika. When sharing with β2-adrenomimetikam Betalok of ZOK in therapeutic doses to a lesser extent influences the bronkhodilatation, than non-selective β-adrenoblockers caused β2-by adrenomimetika.......... Metoprolol to a lesser extent, than non-selective β-adrenoblockers, influences products of insulin and carbohydrate metabolism. Influence of drug on reaction of cardiovascular system in the conditions of a hypoglycemia is considerably less expressed in comparison with non-selective β-adrenoblockers..........

Betalok Zok at arterial hypertension leads drug use to a considerable lowering of arterial pressure within more than 24 hours, both in a prone position and standing, and at loading. At the beginning of therapy metoprololy increase in vascular resistance is noted. However at long reception decrease in the ABP owing to reduction of vascular resistance at invariable cordial emission is possible. In MERIT-HF (a survival research at chronic heart failure (a class II-IV on NYHA classification) and reduced fraction of cordial emission (≤ 0,40), including 3991 patients) Betalok showed to ZOK increase in survival and decrease in frequency of hospitalization. At prolonged treatment patients reached the general improvement of symptoms (on the classes NYHA). Also therapy using Betalok showed to ZOK increase in fraction of emission of a left ventricle, decrease final systolic and final a diastolic left ventricle of volumes.

Quality of life during treatment by drug Betalok of ZOK does not worsen or improves. By drug Betalok ZOK observed improvement of quality of life at treatment at patients after a myocardial infarction.

Pharmacokinetics. At contact with tablet liquid quickly break up, at the same time there is dispersion of active agent in digestive tract. Speed of release of active agent depends on acidity of the environment. Duration of therapeutic effect after administration of drug in a dosage form Betalok of ZOK (a tablet with the slowed-down release) makes more than 24 hours, at the same time the constant speed of release of active agent within 20 hours is reached. The elimination half-life averages 3,5 hours.

Betalok is completely absorbed by ZOK after intake. System bioavailability after intake of a single dose makes about 30 - 40%. Metoprolol is exposed to oxidizing metabolism in a liver. Three main metabolites of a metoprolol did not find clinically significant β-blocking effect. About 5% of a peroral dose of drug are removed with urine in not changed look, other part drug is removed in the form of metabolites. Communication with proteins of a blood plasma of low, about 5-10%.

Indications to use:

Arterial hypertension.
Stenocardia.
Stable symptomatic chronic heart failure with disturbance of systolic function of a left ventricle (as auxiliary therapy to the main treatment of chronic heart failure).
Decline in mortality and frequencies of a repeated heart attack after an acute phase of a myocardial infarction.
Disturbances of a cordial rhythm, including supraventricular tachycardia, decrease in frequency of reduction of ventricles at fibrillation of auricles and ventricular extrasystoles.
The functional disturbances of cordial activity which are followed by tachycardia. Prevention of attacks of migraine.

Route of administration and doses:

Betalok is intended to ZOK for daily reception once a day, it is recommended to accept drug in the morning. A tablet Betalok ZOK should be swallowed, washing down with liquid. Tablets (or the tablets halved) should not be chewed or crumbled. Meal does not influence a drug biodostupost.
At selection of a dose it is necessary to avoid development of bradycardia.
Arterial hypertension
50 - 100 mg once a day. If necessary it is possible to increase a dose to 100 mg a day or to add other anti-hypertensive means, diuretic and calcium the antagonist of a dihydropyridinic row is more preferable.
Stenocardia
100-200 mg Betalok ZOK once a day. If necessary other anti-anginal drug can be added to therapy.
Stable symptomatic chronic heart failure with disturbance of systolic function of a left ventricle
Patients have to be in a stage of stable chronic heart failure without aggravation episodes within the last 6 weeks and without changes in the main therapy within the last 2 weeks.
Therapy of heart failure beta adrenoblockers can sometimes lead to temporary deterioration in a symptomatic picture. Continuation of therapy or a dose decline is in certain cases possible, in some cases there can be a need of drug withdrawal.
Stable chronic heart failure, II functional class
The recommended initial dose Betalok ZOK the first 2 weeks of 25 mg once a day. After 2 weeks of therapy the dose can be increased to 50 mg once a day, and further can double each 2 weeks.
Maintenance dose for prolonged treatment of 200 mg Betalok ZOK once a day.
Stable chronic heart failure, III-IV functional class
The recommended initial dose the first 2 weeks of 12,5 mg Betalok ZOK (a half of a tablet of 25 mg) once a day. The dose is selected individually. During increase in a dose the patient has to be under observation as at some patients symptoms of heart failure can worsen.
In 1-2 weeks the dose can be increased to 25 mg Betalok by ZOK once a day. Then after 2 weeks the dose can be increased to 50 mg once a day. Patients who well transfer drug can double a dose each 2 weeks before achievement of the maximum dose of 200 mg Betalok of ZOK once a day.
In case of arterial hypotension and/or bradycardia reduction of the accompanying therapy or a dose decline Betalok can be necessary for ZOK. Arterial hypotension at the beginning of therapy not necessarily specifies that this dose Betalok will not be transferred by ZOK at further prolonged treatment. However the dose should not raise until the state is not stabilized. Monitoring function of kidneys can be required.
Disturbances of a cordial rhythm
100-200 mg Betalok ZOK once a day.
The supporting treatment after a myocardial infarction
200 mg Betalok ZOK once a day.
The functional disturbances of cordial activity which are followed by tachycardia
100 mg Betalok ZOK once a day. If necessary it is possible to increase a dose to 200 mg a day.
Prevention of attacks of migraine
100-200 mg Betalok ZOK once a day.
Renal failure
There is no need to adjust a dose at patients with a renal failure.
Abnormal liver function
Usually because of low extent of communication with proteins of plasma of dose adjustment of a metoprolol it is not required. However at a heavy abnormal liver function (at patients with a severe form of cirrhosis or a porto-caval anastomosis) the dose decline can be required.
Advanced age
There is no need to adjust a dose at patients of advanced age.
Children
Experience of use of drug Betalok is limited by ZOK at children.

Features of use:

To the patients accepting β-adrenoblockers, it is not necessary to enter intravenously blockers of "slow" calcium channels like verapamil.

The patients having an obstructive pulmonary disease are not recommended to appoint β-adrenoblockers. In case of bad portability of other anti-hypertensive means or their inefficiency, it is possible to appoint метопролол as it is the selection drug. It is necessary to appoint minimum effective dose, if necessary appointment β2-адреномиметика is possible.

It is not recommended to appoint non-selective β-adrenoblockers to patients with Printsmetal's stenocardia. This group of patients β-should appoint the selection adrenoblockers with care.

When using β1-адреноблокаторов the risk of their influence on carbohydrate metabolism or a possibility of masking of symptoms of a hypoglycemia is much less, than when using non-selective β-adrenoblockers..........

With chronic heart failure in a stage of a decompensation it is necessary to achieve a stage of compensation from patients both to, and during treatment by drug.

Very seldom at patients with disturbance of AV of conductivity there can occur deterioration (a possible outcome - AV blockade). If against the background of treatment bradycardia developed, the dose of drug needs to be reduced or it is necessary to cancel drug gradually.

Metoprolol can worsen symptoms of disturbance of peripheric circulation generally owing to a lowering of arterial pressure.

It is necessary to show care at purpose of drug to the patients having a heavy renal failure at a metabolic acidosis, joint appointment with cardiac glycosides.

At the patients accepting β-adrenoblockers, the acute anaphylaxis proceeds in more severe form. Use of Epinephrinum in therapeutic doses not always leads to achievement of the desirable clinical effect against the background of reception of a metoprolol. The patients suffering from a pheochromocytoma in parallel with drug Betalok ZOK should appoint alpha adrenoblocker.

In case of surgical intervention it is necessary to inform the anesthesiologist that the patient accepts Betalok ZOK. Patients to whom surgical intervention is necessary are not recommended to stop treatment by β-adrenoblockers.

Data of clinical trials on efficiency and safety at patients with heavy stable symptomatic heart failure (the IV class on NYHA classification) are limited. Treatment of such patients has to be carried out by the doctors having special knowledge and experience.

Patients with symptomatic heart failure in combination with an acute myocardial infarction and unstable stenocardia were excluded from researches on the basis of which indications to appointment were defined. Efficiency and safety of drug for this group of patients is not described. Use at unstable heart failure in a stage of a decompensation is contraindicated.

It is necessary to avoid sharp drug withdrawal. In need of drug withdrawal, cancellation should be carried out gradually. At most of patients administration of drug can be cancelled in 14 days. The dose of drug is reduced gradually, in stages, to achievement of a final dose of 25 mg once a day.

Side effects:

Betalok ZOK is well had by patients, side effects generally are easy and reversible.

Applied the following criteria to assessment of frequency of cases: very often (> 10%), it is frequent (1-9,9%), is not frequent (0,1-0,9%), is rare (0,01-0,09%) and is very rare (<0,01%).

Cardiovascular system
Often: the bradycardia, orthostatic hypotension (which are very seldom followed by a faint), a cold snap of extremities, heartbeat;
Not often: temporary strengthening of symptoms of heart failure, AV blockade of the I degree; cardiogenic shock at patients with an acute myocardial infarction;
Seldom: other disturbances of cordial conductivity, arrhythmia;
Very seldom: gangrene at patients with the previous heavy disturbances of peripheric circulation.

Central nervous system
Very often: increased fatigue;
Often: dizziness, headache;
Seldom: the increased nervous irritability, uneasiness, impotence / sexual dysfunction;
Not often: paresthesias, spasms, depression, easing of attention, drowsiness or sleeplessness, nightmares;
Very seldom: memory amnesia/disturbance, depression, hallucinations.

Digestive tract
Often: nausea, pains in a stomach, diarrhea, a lock;
Not often: vomiting;
Seldom: dryness in a mouth.

Liver
Seldom: abnormal liver functions;
Very seldom: hepatitis.

Integuments
Not often: rash (in the form of a small tortoiseshell), the increased perspiration;
Seldom: hair loss;
Very seldom: photosensitization, exacerbation of psoriasis.

Respiratory organs
Often: an asthma at physical effort;
Not often: bronchospasm;
Seldom: rhinitis.

Sense bodys
Seldom: vision disorders, dryness and/or irritation of eyes, conjunctivitis;
Very seldom: a ring in ears, disturbances of flavoring feelings.

From skeletal and muscular system:
Very seldom: arthralgia

Metabolism
Not often: increase in body weight.

Blood
Very seldom: thrombocytopenia.

Interaction with other medicines:

Metoprolol is CYP2D6 substrate in this connection, the drugs inhibiting CYP2D6 (quinidine, тербинафин, пароксетин, fluoxetine, sertraline, целекоксиб, пропафенон and дифенгидрамин) can influence plasma concentration of a metoprolol.

It is necessary to avoid combined use Betalok of ZOK with the following medicines:

Derivatives of barbituric acid: barbiturates (the research was conducted with pentobarbital) strengthen metabolism of a metoprolol, owing to induction of enzymes.

Propafenon: at purpose of a propafenon to four patients receiving treatment metoprololy increase in plasma concentration of a metoprolol by 2-5 times was noted, at the same time at two patients the side effects characteristic of a metoprolol were noted. This interaction was confirmed during the research on 8 volunteers. Possibly, interaction is caused by inhibition propafenony, like quinidine, metabolism of a metoprolol by means of system of P4502D6 cytochrome. In view of the fact that пропафенон has properties of β-adrenoblocker, joint purpose of a metoprolol and a propafenona is not advisable.

Verapamil: the combination of β-adrenoblockers ((((((((((an atenolola, propranolol and Pindololum) and verapamil can cause bradycardia and lead to decrease in the ABP. Verapamil and β-adrenoblockers have the complementary inhibiting effect on atrioventricular conductivity and function of a sinus node.

The drug combination Betalok of ZOK with the following drugs can demand dose adjustment:

Amiodaronum: Combined use of Amiodaronum and metoprolol can lead to the expressed sinus bradycardia. In view of extremely long elimination half-life of Amiodaronum (50 days), it is necessary to consider possible interaction later long time after cancellation of Amiodaronum.

Antiarrhytmic means of the I class: Antiarrhytmic means of the I class and β-can lead adrenoblockers to summing of a negative inotropic effect which can result in serious hemodynamic side effects at patients with the broken function of a left ventricle. Also it is necessary to avoid a similar combination at patients with a sick sinus syndrome and disturbance of AV of conductivity.
Interaction is described on the example of Disopyramidum.

Non-steroidal anti-inflammatory drugs (NPVP): NPVP weaken anti-hypertensive effect of β-adrenoblockers.......... This interaction is documented for indometacin. Possibly, the described interaction will not be noted at interaction with sulindaky. Negative interaction was noted in researches with diclofenac.

Difengidramin: Difengidramin reduces clearance of a metoprolol to α-a gidroksimetoprolola by 2,5 times. Strengthening of action of a metoprolol is at the same time observed.

Diltiazem: Diltiazem and β-adrenoblockers mutually strengthen the inhibiting effect on AV conductivity and function of a sinus node. At a combination of a metoprolol with diltiazem cases of the expressed bradycardia were noted.

Epinephrinum (adrenaline): It was reported about 10 cases of the expressed arterial hypertension and bradycardia at the patients who were accepting non-selective β-adrenoblockers ((((((((((including Pindololum and propranolol) and receiving Epinephrinum (adrenaline). Interaction is noted also in group of healthy volunteers. It is supposed that similar reactions can be observed also at use of Epinephrinum together with local anesthetics at accidental hit in a vascular bed. It is supposed that this risk is much lower at use of cardioselective β-adrenoblockers..........

Fenilpropanolamin: Fenilpropanolamin (норэфедрин) in a single dose of 50 mg can cause increase in the diastolic ABP to pathological values in healthy volunteers. Propranolol generally interferes with the increase in the ABP caused fenilpropanolaminy. However, β-adrenoblockers can cause reactions of paradoxical arterial hypertension in the patients receiving high doses of a fenilpropanolamin. It was reported about several cases of development of hypertensive crisis against the background of reception of a fenilpropanolamin.

Quinidine: Quinidine inhibits metabolism of a metoprolol at special group of patients with a bystry hydroxylation (in Sweden about 90% of the population), causing, mainly, significant increase in plasma concentration of a metoprolol and strengthening β-blockade. Believe that similar interaction is characteristic also of others β-adrenoblockers in which metabolism P4502D6 cytochrome participates.

Clonidine: Hypertensive reactions at sharp cancellation of a clonidine can amplify at joint reception of β-adrenoblockers.......... At combined use, in case of cancellation of a clonidine, the termination of reception of β-adrenoblockers should be begun some days before cancellation of a clonidine.

Rifampicin: Rifampicin can strengthen metabolism of a metoprolol, reducing plasma concentration of a metoprolol.

The patients who are at the same time accepting метопролол and other β-adrenoblockers ((((((((((eye drops) or inhibitors of a monoaminooxidase (MAO), have to be under careful observation. Against the background of reception of β-adrenoblockers inhalation anesthetics strengthen cardiodepressive action. Against the background of reception of β-adrenoblockers dose adjustment of the last can be required by the patients receiving hypoglycemic means for intake.

Plasma concentration of a metoprolol can increase at reception of Cimetidinum or gidralazin.

Cardiac glycosides at combined use with β-adrenoblockers can increase time of atrioventricular conductivity and cause bradycardia.

Influence on ability to drive the car and to work with technical devices

When driving motor transport and occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions it is necessary to consider that at use Betalok can be observed by ZOK dizziness and fatigue.

Contraindications:

Atrioventricular block of II and III degrees, heart failure in a decompensation stage, the patients receiving long or intermittent therapy by inotropic means and acting on beta adrenoceptors, clinically significant sinus bradycardia, a sick sinus syndrome, cardiogenic shock, the expressed disturbances of peripheric circulation, arterial hypotension.

Betalok is contraindicated to patients with an acute myocardial infarction at ChSS less than 45 beats per minute, PQ interval more than 0,24 seconds or with a systolic arterial pressure less than 100 mm hg.

The known hypersensitivity to a metoprolol and its components or to others β-to adrenoblockers.

At serious peripheral vascular diseases at threat of gangrene.

To the patients receiving β-adrenoblockers, contraindicated intravenous administration of blockers of "slow" calcium channels like verapamil.

Age up to 18 years (efficiency and safety are not established)

With care: an atrioventricular block of the I degree, Printsmetal's stenocardia, bronchial asthma, a chronic obstructive pulmonary disease, a diabetes mellitus, a heavy renal failure, a heavy liver failure, a metabolic acidosis, joint appointment with cardiac glycosides.

Use at pregnancy and during chest feeding

As well as Betalok ZOK should not appoint the majority of drugs during pregnancy and during chest feeding unless the expected advantage for mother exceeds potential risk for a fruit and/or the child. As well as other anti-hypertensive means, β-adrenoblockers can cause side effects, for example, bradycardia in a fruit, the newborns or children who are on breastfeeding. The quantity of a metoprolol which is marked out in breast milk, and β-the blocking action at the child who is on breastfeeding (at reception by mother of a metoprolol in therapeutic doses), are insignificant.

Overdose:

Toxicity: метопролол in a dose of 7,5 g caused intoxication with a lethal outcome in the adult. At 5 summer children who accepted 100 mg of a metoprolol after a gastric lavage symptoms of intoxication were not noted. Reception of 450 mg of a metoprolol by the teenager of 12 years led to moderate intoxication. Reception of 1,4 g and 2,5 g of a metoprolol by adults caused moderate and heavy intoxication, respectively. Reception of 7,5 g adult led to extremely heavy intoxication.

Symptoms: at overdose metoprololy the most serious are symptoms from cordial vascular system, however sometimes, especially at children and teenagers, symptoms from TsNS can prevail and suppression of pulmonary function, bradycardia, AV blockade of the I-III degree, an asystolia, the expressed decrease in the ABP, weak peripheral perfusion, heart failure, cardiogenic shock; oppression of function of lungs, the apnoea, and also, the increased fatigue, consciousness disturbance, a loss of consciousness, a tremor, spasms, the increased sweating, paresthesias, a bronchospasm, nausea, vomiting, is possible an ezofagialny spasm, a hypoglycemia (especially at children) or a hyperglycemia, a hyperpotassemia; impact on kidneys; tranzitorny myasthenic syndrome; the accompanying alcohol intake, anti-hypertensive means, quinidine or barbiturates can worsen a condition of the patient. The first signs of overdose can be observed in 20 min. - 2 hours after administration of drug.

Treatment: purpose of absorbent carbon, in case of need gastric lavage. IMPORTANT! Atropine (0,25-0,5 mg in/in for adults, 10-20 mkg/kg for children) has to be appointed to a gastric lavage (because of risk of stimulation of a vagus nerve). If necessary maintenance of passability of respiratory tracts (intubation) and adequate ventilation of the lungs. Completion of volume of the circulating blood and infusion of glucose. Control of an ECG. Atropine of 1,0-2,0 mg in/in, if necessary repeat introduction (especially in case of vagal symptoms). In case of (suppression) of a depression of a myocardium infusional introduction of Dobutaminum or dopamine is shown It is also possible to apply a glucagon of 50 - 150 mkg/kg in/in at an interval of 1 minute. Addition to adrenaline therapy can be in certain cases effective. At arrhythmia and an extensive ventricular (QRS) complex infusionally enter sodium solutions (chloride or bicarbonate). Installation of an artificial pacemaker is possible. At a cardiac standstill owing to overdose resuscitation actions within several hours can be necessary. To stopping of a bronchospasm it can be applied тербуталин (injektsionno or by means of inhalations). The symptomatic treatment is carried out.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children. Period of validity 3 years. Not to apply after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets with the slowed-down release, coated, on 25 mg, 50 mg and 100 mg.
Tablets of 25 mg: 14 tablets in aluminum/PVC the blister, in a cardboard pack with the application instruction.
Tablets of 50 mg and 100 mg: 30 tablets in a plastic bottle with the screwing-up plastic cover with control of the first opening, place 1 bottle in a cardboard pack with the application instruction.