Эгилок® With

General characteristics. Structure:

Tablets of the prolonged action, film coated 1 table.
active agent:  metoprolola succinate of 23,75      mg 47,5 mg 95 mg 190 mg
(there correspond 25, 50, 100 and 200 mg of a metoprolol of tartrate)  
excipients: MKTs PH 101 — 73,9/147,8/295,6/591,2 mg; methyl cellulose of 15 MPas · with — 11,87/23,75/47,5/95 mg; глицерол — 0,24/0,48/0,95/1,9 mg; starch corn — 1,94/3,87/7,75/15,5 mg; ethyl cellulose 100 мПа.с — 11,43/22,85/45,7/91,4 mg; magnesium stearate — 1,87/3,75/7,5/15 mg  
cover film (a covering Sepifilm LP 770 white — 3,75/7,5/15/30): MKTs of 20 microns (5–15%) — 0,19–0,56/0,38–1,13/0,75–2,25/1,5–4,5 mg, a gipromelloza of 5/15 MPas · with (60–70%) — 2,25–2,63/4,5–5,25/9–10,5/18–21 mg, stearic acid (8–12%) — 0,3–0,45/0,6–0,9/1,2–1,8/2,4–3,6 mg, titanium dioxide (E171) (10–20%) — 0,38–0,75/0,75–1,5/1,5–3/3–6 mg  

Description of a dosage form

Tablets, 25, 50, 100 and 200 mg: oval biconvex tablets of white color, film coated, with risky on both sides.

Pharmacological properties:

Pharmacological action - antiarrhytmic, hypotensive, anti-anginal.
Pharmacodynamics. Metoprolol — the beta1-adrenoblocker blocking beta1-adrenoceptors in doses considerably smaller than the doses which are required for blocking of beta2-adrenoceptors.

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 ChSS, minute volume and strengthening of contractility of heart, and also increase in the ABP called by sharp emission of catecholamines.

Unlike the usual tableted dosage forms of the selection beta1-adrenoblockers (including a metoprolol tartrate), at use of drug of a metoprolol of succinate of the prolonged action constant concentration of drug in a blood plasma is observed and the steady clinical effect (beta1-blockade) during more than 24 h is provided. Owing to absence of significant Cmax in a blood plasma drug is characterized by higher beta1-selectivity in comparison with the usual tableted forms of a metoprolol. Besides, the potential risk of the side effects observed at the maximum concentration of drug in a blood plasma, for example bradycardia and weakness in legs when walking substantially decreases. Patients with symptoms of obstructive diseases of lungs if necessary can appoint a metoprolol succinate of the prolonged action in combination with beta2-adrenomimetika. At combined use from beta2-adrenomimetika of a metoprolol succinate of the prolonged action in therapeutic doses to a lesser extent influences the bronkhodilatation caused by beta2-adrenomimetika, than non-selective beta adrenoblockers. Metoprolol to a lesser extent, than non-selective beta adrenoblockers, influences products of insulin and carbohydrate metabolism. Influence of drug on CCC in the conditions of a hypoglycemia is considerably less expressed in comparison with non-selective beta adrenoblockers.

Use of drug at arterial hypertension leads to considerable decrease in the ABP during more than 24 h, both in a prone position and standing, and at an exercise stress. 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.

Pharmacokinetics. Each tablet of drug of a metoprolol of succinate of the prolonged action contains a large number of microgranules (pellets) allowing to carry out controlled release of a metoprolol of succinate. Outside each microgranule (pellet) is covered with a polymeric cover that allows to provide controlled release of medicinal substance.

Action of the prolonged tablets comes quickly. In a GIT the tablet is desintegrated on separate microgranules (pellets) which work as independent units and provide uniform controlled release of a metoprolol (kinetics of a zero order) during more than 20 h. Speed of release of active agent depends on acidity of the environment. Duration of therapeutic effect after administration of drug in a dosage form of a tablet of the prolonged action makes more 24th p. T1/2 of a free metoprolol averages 3,5–7 h.

Drug is completely absorbed 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 beta and adrenoceptor blocking effect. About 5% of a dose for intake are removed by kidneys in not changed look, other part of 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;

the stable chronic heart failure (CHF) with existence of clinical manifestations (the II-IV functional class on NYHA classification) and 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:

Inside. Эгилок® With it is intended for daily reception once a day, it is recommended to accept drug in the morning. The tablet Egilok® C should be swallowed, washing down with liquid. Tablets (or the tablets halved) should not be chewed or crumbled. Meal does not influence bioavailability of drug. 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 200 mg a day or to add other antihypertensive, diuretic and BKK are more preferable. The maximum daily dose at AG — 200 mg/days.

Stenocardia: 100–200 mg of Egilok® With once a day. If necessary other anti-anginal drug can be added to therapy.

Stable chronic heart failure with existence of clinical manifestations and disturbance of systolic function of a left ventricle. Patients have to be at a stage of stable chronic heart failure without aggravation episodes during the last 6 weeks and without changes in the main therapy during the last 2 weeks.

Therapy of chronic heart failure beta adrenoblockers can sometimes lead to temporary deterioration in a course of chronic heart failure. 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 of the drug Egilok® About the first 2 weeks — 25 mg once a day. After 2 weeks of therapy the dose can be increased to 50 mg once a day and further double each 2 weeks.

Maintenance dose for prolonged treatment — 200 mg of the drug Egilok® C once a day.

Stable chronic heart failure, III–IV functional class. The recommended initial dose the first 2 weeks — 12,5 mg of the drug Egilok® C (1/2 tab. on 25 mg) once a day. The dose is selected individually. During increase in a dose the patient has to be under observation since at some patients symptoms of chronic heart failure can progress.

In 1–2 weeks the dose can be increased to 25 mg of the drug Egilok® C once a day. Then, in 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 of the drug Egilok® C once a day. In case of arterial hypotension and/or bradycardia correction of doses of the main therapy or a dose decline of the drug Egilok® C can be necessary. Arterial hypotension at the beginning of therapy not necessarily specifies that this dose of the drug Egilok® C will not be transferred at further prolonged treatment. However increase in a dose is possible only after stabilization of a condition of the patient. Control of function of kidneys can be required.

Disturbances of a heart rhythm: 100–200 mg once a day.

The supporting treatment after a myocardial infarction. A target dose — 100–200 mg/days, in one (or two) reception.

The functional disturbances of cordial activity which are followed by tachycardia: 100 mg 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 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 a blood plasma dose adjustment of drug 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.

Features of use:

The patients accepting beta adrenoblockers should not enter into BKK like verapamil.

Patients with an obstructive pulmonary disease are not recommended to appoint beta adrenoblockers. In case of bad portability of other antihypertensives 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 purpose of a beta2-adrenomimetik is possible.

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

At use of beta1-adrenoblockers the risk of their influence on carbohydrate metabolism or a possibility of masking of symptoms of a hypoglycemia is much less, than at use of non-selective beta 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 the drug Egilok® C.

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 the drug Egilok® C needs to be reduced or it is necessary to cancel drug gradually.

Metoprolol can worsen symptoms of disturbance of peripheric circulation generally owing to decrease in the ABP.

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

At the patients accepting beta adrenoblockers, the acute anaphylaxis proceeds in more severe form. Use of adrenaline in therapeutic doses not always leads to achievement of the desirable clinical effect against the background of reception of a metoprolol. Patients with a pheochromocytoma, in parallel with the drug Egilok® C, should appoint alpha adrenoblocker.

In case of surgical intervention it is necessary to inform the anesthesiologist that the patient accepts Egilok® S. Patsiyentam whom surgical intervention is necessary, it is not recommended to stop treatment by beta adrenoblockers.

Data of clinical trials on efficiency and safety at patients with heavy stable heart failure (the IV class on NYHA classification) are limited.

Patients with symptoms of 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 heart failure in a stage of a decompensation is contraindicated.

Sharp cancellation of beta adrenoblocker can lead to strengthening of symptoms of HSN and increase in risk of a myocardial infarction and sudden death, especially patients have groups of high risk in this connection it should be avoided. In need of drug withdrawal it should be seen gradually, during at least 2 weeks, with a double dose decline of drug at each stage, to achievement of a final dose of 12,5 mg (1/2 tab. on 25 mg) which it is necessary to accept at least 4 days before full drug withdrawal. At emergence of symptoms slower mode of drug withdrawal is recommended.

Influence on ability to manage vehicles. It is necessary to be careful at control of vehicles and occupations potentially dangerous types of activity demanding the increased concentration of attention because of risk of development of dizziness and increased fatigue at use of the drug Egilok® C.

Side effects:

Drug is well transferred by patients, side effects generally are easy and reversible.

Applied the following criteria to assessment of frequency of cases: very often (> 10%); often (1–9,9%); infrequently (0,1–0,9%); seldom (0,01–0,09%) and it is very rare (<0,01%).

From CCC: often — the bradycardia, orthostatic hypotension (which are very seldom followed by a faint), a cold snap of extremities, heartbeat; infrequently — peripheral hypostases, pains in heart, 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.

From TsNS: very often — increased fatigue; often — dizziness, a headache; infrequently — paresthesias, spasms, a depression, easing of attention, drowsiness or sleeplessness, nightmares; seldom — the increased nervous irritability, uneasiness, impotence / sexual dysfunction; very seldom — memory amnesia/disturbance, depression, hallucinations.

From a GIT: often — nausea, pains in a stomach, diarrhea, a lock; infrequently — vomiting; seldom — dryness of a mucous membrane of an oral cavity.

From a liver: seldom — abnormal liver functions; very seldom — hepatitis.

From integuments: infrequently — rash (in the form of a small tortoiseshell), the increased sweating; seldom — a hair loss; very seldom — a photosensitization, an aggravation of a course of psoriasis.

From a respiratory organs: often — an asthma at physical effort; infrequently — a bronchospasm; seldom — rhinitis.

From 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 — an arthralgia.

From a metabolism: infrequently — increase in body weight.

From blood: very seldom — thrombocytopenia.

Interaction with other medicines:

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

It is necessary to avoid combined use of the drug Egilok® C with the following HP

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. Possibly, interaction is caused by inhibition propafenony, like quinidine, metabolism of a metoprolol by means of an isoenzyme of CYP2D6 of system of P450 cytochrome. In view of the fact that пропафенон has properties of beta adrenoblocker joint purpose of a metoprolol and a propafenona is not recommended.

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

The combination of the drug Egilok® C with the following drugs can demand dose adjustment

Amiodaronum: joint use of Amiodaronum and metoprolol can lead to the expressed sinus bradycardia. In view of extremely long T1/2 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 beta adrenoblockers can lead 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 syndrome of weakness of a sinus node and disturbance of AV of conductivity.

Interaction is described on the example of Disopyramidum.

NPVS: NPVS weaken anti-hypertensive effect of beta 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: дифенгидрамин reduces metabolism of a metoprolol to a α-gidroksimetoprolol by 2,5 times. Strengthening of action of a metoprolol is at the same time observed.

Diltiazem: diltiazem and beta 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: it was reported about 10 cases of the expressed arterial hypertension and bradycardia at the patients who were accepting non-selective beta adrenoblockers (including Pindololum and propranolol) and receiving Epinephrinum. 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 beta adrenoblockers.

Fenilpropanolamin: фенилпропаноламин (норэфедрин) in a single dose of 50 mg can cause increase in DAD to pathological values in healthy volunteers. Propranolol generally interferes with the increase in the ABP caused fenilpropanolaminy. However beta 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 beta адреноблокады. Believe that similar interaction is characteristic also of other beta adrenoblockers in which metabolism the P450 cytochrome CYP2D6 isoenzyme participates.

Clonidine: hypertensive reactions at sharp cancellation of a clonidine can amplify at joint reception of beta adrenoblockers. At combined use, in case of cancellation of a clonidine, the termination of reception of beta 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 beta adrenoblockers (in a dosage form of eye drops) or MAO inhibitors, have to be under careful observation. Against the background of reception of beta adrenoblockers inhalation anesthetics strengthen cardiodepressive action. Against the background of reception of beta 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 beta adrenoblockers can increase time of AV of conductivity and cause bradycardia.

Contraindications:

hypersensitivity to a metoprolol, other components of drug or other beta adrenoblockers;

atrioventricular block of II and III degrees, heart failure in a decompensation stage, the patients receiving long or course therapy the inotropic means and in HP operating on beta adrenoceptors, clinically significant sinus bradycardia (ChSS less than 50 уд. / mines), a syndrome of weakness of a sinus node, cardiogenic shock, heavy disturbances of peripheric circulation with threat of a gangrenosis, arterial hypotension (the GARDEN less than 90 mm hg), a pheochromocytoma without concomitant use of alpha adrenoblockers;

suspicion of an acute myocardial infarction at ChSS less than 45 уд. / mines, an interval PQ more than 0,24 with, the GARDEN less than 100 mm hg;

simultaneous use of MAO inhibitors (except for MAO-B of inhibitors);

intravenous administration of BKK 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, simultaneous use with cardiac glycosides, a myasthenia, a pheochromocytoma (with a concomitant use of alpha adrenoblockers), a thyrotoxicosis, a depression, psoriasis, obliterating diseases of peripheral vessels (the alternating lameness, Reynaud's syndrome), advanced age.

Use at pregnancy and feeding by a breast

As well controlled researches on use of a metoprolol during pregnancy were not conducted, use of the drug Egilok® C at treatment of pregnant women is possible only if the advantage for mother exceeds risks for an embryo/fruit.

As well as other antihypertensives, beta adrenoblockers can cause side effects, for example bradycardia in a fruit, the newborn or the child who is on breastfeeding. The quantity of a metoprolol which is marked out in breast milk, and beta and adrenoceptor blocking action at the child who is on breastfeeding (at reception by mother of a metoprolol in therapeutic doses), are insignificant. In spite of the fact that at the children who are on breastfeeding at purpose of therapeutic doses of drug the risk of development of side effects is low (an exception children with metabolic disturbances make), it is necessary to monitor emergence of signs of blockade of beta adrenoceptors in them carefully.

Overdose:

Symptoms: at overdose of a metoprolol by the most serious symptoms are from CCC, 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, an apnoea, and also increased fatigue, consciousness disturbance, a loss of consciousness, a tremor, spasms, the increased sweating, paresthesias, a bronchospasm, nausea, vomiting, the ezofagialny spasm, a hypoglycemia (especially at children) or a hyperglycemia, a hyperpotassemia is possible; renal failure; tranzitorny myasthenic syndrome; the accompanying alcohol intake, antihypertensives, quinidine or barbiturates can worsen a condition of the patient. The first signs of overdose can be observed in 20 min. — 2 h after administration of drug.

Treatment: purpose of absorbent carbon, in case of need — a gastric lavage.

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 OTsK and infusion of glucose. Control of an ECG. Atropine of 1-2 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 min. Addition to therapy of Epinephrinum (adrenaline) can be in certain cases effective. At arrhythmia and an extensive ventricular (QRS) complex solution of sodium of chloride or Natrii hydrocarbonas infusionally enter 0,9%. Statement 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:

Period of validity of 5 years. List B.: At a temperature of 15-25 °C.

Issue conditions:

According to the recipe

Packaging:

Tablets of the prolonged action, film coated, 25 mg, 50 mg, 100 mg, 200 mg. According to 10 tab. in the blister from PVH/PE/PVDH//aluminum foil. 3 or 10 blisters in a cardboard pack.