Метозок®

General characteristics. Structure:

Active ingredient: 23,83 mg, 47,66 mg, 95,32 mg or 190,64 mg of a metoprolol of succinate in terms of 100% substance that 25 mg, 50 mg, 100 mg and 200 mg of a metoprolol of tartrate respectively are equivalent.

Excipients: gipromelloza, лудипресс LTsE [lactoses monohydrate of 94,7-98,3%, povidone of 3-4%], silicon dioxide colloid, magnesium stearate.

Structure of a cover. For tablets with dosages of 25 mg and 100 mg – the ready mix "Opadray II" of orange color (polyvinyl alcohol, talc, a macrogoal, titanium dioxide, dye ferrous oxide red, dye ferrous oxide yellow, dye ferrous oxide black). 

For tablets with dosages of 50 mg and 200 mg – the ready mix "Opadray II" of green color (polyvinyl alcohol, talc, a macrogoal, titanium dioxide, dye quinolinic yellow (an aluminum varnish), dye ferrous oxide black, dye indigo carmine (an aluminum varnish)).  

Pharmacological properties:

Pharmacodynamics. Cardioselective beta1-adrenoblocker. Has no membrane stabilizing effect and has no internal sympathomimetic activity. Possesses anti-hypertensive, anti-anginal and antiarrhytmic action.

Blocking heart beta1-adrenoceptors in low doses, reduces stimulated catecholamines formation of cyclic adenosinemonophosphate (tsAMF) from adenosinetriphosphate (ATP), reduces intracellular current of calcium ions, renders negative hrono-, dromo-, batmo-and inotropic action (urezhat the heart rate (HR), conductivity and excitability oppresses, reduces contractility of a myocardium).

The General Peripheric Vascular Resistance (GPVR) at the beginning of use of beta adrenoblockers (in the first 24 h after oral administration) increases (as a result of reciprocal increase of activity of alpha adrenoceptors and elimination of stimulation beta2adrenoretseptorov) which in 1-3 days is returned to initial, and at long appointment decreases.

Anti-hypertensive action is caused by reduction of minute volume of a blood-groove and synthesis of a renin, activity oppression system renin-angiotensin-aldosteronovoy (has bigger value at patients with initial hypersecretion of a renin) and the central nervous system, recovery of sensitivity of baroreceptors of an aortic arch (there is no strengthening of their activity in response to a lowering of arterial pressure (ABP) and as a result reduction of peripheral sympathetic influences. Reduces raised by the ABP at rest, at a physical tension and a stress. The anti-hypertensive effect lasts more than 24 hours.

The anti-anginal effect is defined by decrease in need of a myocardium for oxygen as a result of reduction of ChSS (lengthening of a diastole and improvement of perfusion of a myocardium) and contractility, and also decrease in sensitivity of a myocardium to influence of a sympathetic innervation. Reduces number and weight of attacks of stenocardia and increases portability of an exercise stress. Due to increase in end diastolic pressure in a left ventricle and increases in stretching of muscle fibers of ventricles can increase oxygen requirement, especially at patients with the chronic heart failure (CHF).

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 atrioventricular (AV) 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 supraventricular tachycardia, atrial fibrillation, sinus tachycardia at functional heart diseases and a thyrotoxicosis urezhat ChSS or can even lead to recovery of a sinus rhythm.

Prevents development of migraine.

Unlike non-selective beta adrenoblockers at appointment in average therapeutic doses 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; expressiveness of atherogenous action does not differ from effect of propranolol. At long-term reception reduces concentration of cholesterol in blood. At use in high doses (more than 100 mg/days) renders the blocking effect on both subtypes of beta adrenoceptors.

Pharmacokinetics. Absorption at intake full (95%). Solubility in fats moderate. Is exposed to intensive presistemny metabolism, bioavailability – 50% at the first reception and increases up to 70% at repeated use. Communication with proteins of plasma – 10%. Time of achievement of the maximum concentration in a blood plasma of 6-12 h after administration of drug. During course treatment bioavailability increases. Meal increases bioavailability for 20-40%.

It is quickly distributed in fabrics, gets through a blood-brain barrier, a placental barrier. Gets into breast milk.

It is metabolized in a liver, 2 metabolites have beta and adrenoceptor blocking activity. CYP2D6 isoenzyme takes part in metabolism of drug. An elimination half-life – from 3,5 to 7 h at intake. Is not removed at a hemodialysis.

Considerable accumulation of metabolites is observed at patients with clearance of creatinine of 5 ml/min., at the same time beta and adrenoceptor blocking activity of drug does not increase.

Bioavailability increases at cirrhosis, at the same time its general clearance is reduced.

Indications to use:

Arterial hypertension.

Chronic heart failure of the II-IV functional class on classification of NYHA in compensation stage (as a part of complex therapy).

Coronary heart disease: prevention of attacks of stable stenocardia, decline in mortality and frequencies of a repeated myocardial infarction after an acute phase of a myocardial infarction.

Disturbances of a heart 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:

Метозок® it is intended for intake of 1 times a day, it is recommended to accept in the morning, without chewing, washing down with water. Метозок® it is possible to accept irrespective of meal. For the purpose of prevention of bradycardia the dose is selected individually and increased gradually.

At arterial hypertension and stenocardia an initial dose of 50 mg of 1 times a day, at insufficient therapeutic effect the daily dose can be increased to 100-200 mg a day. At arterial hypertension at inefficiency of drug in a dose of 100-200 mg a day it is possible to add other antihypertensive.

At chronic heart failure of the II functional class on NYHA classification (without aggravations the last 6 weeks and without change in complex therapy within the last 2 weeks) the recommended initial dose – 25 mg once a day. In two weeks the daily dose can be raised to 50 mg, then in two weeks to 100 mg, in two weeks to 200 mg.

At chronic heart failure of the III-IV functional class on NYHA classification the recommended initial dose the first 2 weeks of 12,5 mg of drug once a day. Use of a metoprolol in other dosage form, for example, of a tablet on 25 mg with risky is possible. 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 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 drug once a day.

Secondary prevention of a myocardial infarction and disturbance of a cordial rhythm – an initial dose of 100 mg of 1 times a day.

At the functional disturbances of cordial activity which are followed by tachycardia – on 50 mg a day, if necessary a dose it is possible to increase up to 200 mg a day.

Prevention of attacks of migraine: 100-200 mg of 1 times a day.

At a renal failure or to the patients who are on a hemodialysis, dose adjustment is not required to elderly patients.

Abnormal liver functions influence removal of a metoprolol therefore dose adjustment depending on a clinical state can be required.

Features of use:

Use during pregnancy and the lactation period. During pregnancy the drug Metozok® has to be used only according to strict indications when the expected advantage for mother exceeds potential risk for the fruit/child (in connection with possible development in the newborn of bradycardia, a lowering of arterial pressure, a hypoglycemia and paralysis of breath). At the same time make careful observation especially of fetation. Treatment is stopped in 48-72 hours before childbirth. If it is impossible, then the newborn has to be under especially careful observation within 48-72 hours after the delivery.

Use of the drug Metozok® is contraindicated in the period of a lactation, in case of need uses of drug in the period of a lactation, breastfeeding needs to be stopped.

Control of the patients accepting beta adrenoblockers includes regular heart-rate monitoring and arterial pressure. It is necessary to train the patient in a technique of calculation of ChSS and to instruct about need of medical consultation at ChSS less than 50 beats/min.

Strengthening of expressiveness of allergic reactions (against the background of the burdened allergological anamnesis) and lack of effect of introduction of usual doses of Epinephrinum (adrenaline) is possible.

At elderly patients it is recommended to exercise control of function of kidneys (1 times in 4-5 months). Can strengthen symptoms of disturbance of peripheric arterial circulation.

At an angina of exertion the picked-up dose of drug has to provide ChSS at rest within 55-60 beats/min, at loading – no more than 110 beats/min.

At "smokers" efficiency of beta adrenoblockers is lower.

Метозок® can mask some clinical displays 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 disguise the tachycardia caused by a hypoglycemia.

In need of appointment to patients with bronchial asthma as the accompanying therapy use beta2-adrenomimetik; at a pheochromocytoma – alpha adrenoblockers.

In need of carrying out surgical intervention it is necessary to warn the anesthesiologist about administration of drug of Metozok® (the choice of means is necessary for the general anesthesia with the minimum negative inotropic effect), drug withdrawal is not recommended.

Reciprocal activation of a vagus nerve can be eliminated in/in administration of atropine (1-2 mg).

In case of the accruing bradycardia (less than 50 beats/min), arterial hypotension (systolic the ABP is lower than 100 mm of mercury.), AV of blockade, a bronchospasm, ventricular arrhythmias, heavy abnormal liver functions and kidneys needs to reduce a dose or to stop treatment.

It is recommended to stop therapy at emergence of skin rashes and development of the depression caused by reception of beta adrenoblockers.

Metoprolol can strengthen symptoms of disturbance of peripheric circulation.

At sharp cancellation of a clonidine the ABP can sharply raise, at a concomitant use of betaadrenoblokator. In case of cancellation of a clonidine, the termination of reception of beta adrenoblockers should be begun some days before cancellation of a clonidine.

The drugs reducing stocks of catecholamines (for example, Reserpinum) can strengthen effect of beta adrenoblockers therefore the patients accepting such combinations of drugs have to be under constant medical observation regarding identification of excessive decrease in the ABP or bradycardia.

At the sharp termination of treatment there can be a syndrome of "cancellation" (strengthening of attacks of stenocardia, increase in the ABP). Special attention at drug withdrawal needs to be paid to patients with stenocardia, HSN, after the postponed myocardial infarction. Drug withdrawal of Metozok® is carried out gradually, reducing a dose within 10 days.

The patients using contact lenses have to consider that against the background of treatment by beta adrenoblockers reduction of products of the lacrimal liquid is possible.

During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Frequency of side effects: very often – more than 1/10, it is frequent – more than 1/100 and less than 1/10, infrequently – more than 1/1000 and less than 1/100, is rare – more than 1/10000 and less than 1/1000, is very rare – less than 1/10000, including separate messages.

From cardiovascular system: often – bradycardia, orthostatic hypotension (including with a faint), a cold snap of the lower extremities, a heart consciousness; infrequently – temporary strengthening of symptoms of heart failure, cardiogenic shock at patients with a myocardial infarction, AV blockade of the I degree; seldom – disturbances of conductivity of a myocardium, arrhythmia; very seldom – gangrene (at patients with disturbances of peripheric circulation).

From the central nervous system: very often – increased fatigue, reduction of speed of mental and motor reactions; often – dizziness, a headache; infrequently – paresthesias, spasms, a depression, decrease in concentration of attention, drowsiness, sleeplessness, "dreadful" dreams; seldom – an adynamy, a tremor, the increased nervous irritability, alarm; very seldom – memory amnesia/disturbance, depression, hallucinations, a myasthenia.

From sense bodys: seldom – a vision disorder, dryness and/or irritation of eyes, conjunctivitis; very seldom – a ring in ears, disturbance of flavoring feelings.

From the alimentary system: often – nausea, an abdominal pain, a lock or diarrhea; infrequently – vomiting; seldom – dryness of a mucous membrane of an oral cavity, an abnormal liver function, hepatitis.

From integuments: infrequently – a small tortoiseshell, sweating strengthening; seldom – an alopecia; very seldom – a photosensitization, an aggravation of a course of psoriasis, psoriazopodobny skin reactions.

From respiratory system: often – an asthma; infrequently – a bronchospasm at patients with bronchial asthma; seldom – rhinitis.

Laboratory indicators: very seldom – thrombocytopenia (unusual bleedings and hemorrhages), an agranulocytosis, a leukopenia, increase in activity of "hepatic" enzymes, a hyperbilirubinemia.

From endocrine system: often – a hypoglycemia (at patients with a diabetes mellitus of the I type), it is rare – a hyperglycemia (at patients with a diabetes mellitus of the II type), a hypothyroid state.

Others: infrequently – increase in body weight; seldom – impotence / sexual dysfunction; very seldom – an arthralgia, thrombocytopenia.

Interaction with other medicines:

The means reducing stocks of catecholamines (for example, Reserpinum, MAO inhibitors) at simultaneous use with metoprololy can strengthen hypotensive action or cause the expressed bradycardia. Having rummaged in treatment between reception of MAO inhibitors and a metoprolola has to make not less than 14 days.

Metoprolol is CYP2D6 isoenzyme substrate. Medicines which inhibit or induce activity of an isoenzyme of CYP2D6, can influence plasma concentration of a metoprolol.

CYP2D6 isoenzyme inhibitors: some antidepressants and neuroleptics, quinidine, тербинафин, целекоксиб, пропафенон, дифегидрамин, hydroxychlorine, Cimetidinum – increase concentration of a metoprolol in a blood plasma.

CYP2D6 isoenzyme inductors: derivatives of barbituric acid, rifampicin – reduce concentration of a metoprolol in a blood plasma.

The concomitant use with cardiac glycosides, a clonidine, blockers of "slow" calcium channels (verapamil, diltiazem), Amiodaronum, antiarrhytmic means of the I class, means for the general anesthesia, metildopy, guanfatsiny can lead to decrease in the ABP and the expressed bradycardia.

Means for an inhalation anesthesia (derivatives of hydrocarbons) increase risk of oppression of function of a myocardium and development of arterial hypotension.

Simultaneous in/in administration of verapamil can provoke a cardiac standstill.

Non-steroidal anti-inflammatory drugs (NPVP) and beta-adrenergic agonists weaken anti-hypertensive effect of beta adrenoblockers.

Alkaloids of an ergot increase risk of disturbances of peripheric circulation.

At joint reception with peroral hypoglycemic drugs decrease in their effect is possible; with insulin – increase in risk of development of a hypoglycemia, lengthening and strengthening of its expressiveness, masking of some symptoms of a hypoglycemia (tachycardia, perspiration, increase in arterial pressure).

Reduces clearance of xanthines (except Diaphyllinum), especially at patients with initially increased clearance of theophylline under the influence of smoking. Reduces clearance of lidocaine, increases concentration of lidocaine in plasma.

Strengthens and prolongs action of not depolarizing muscle relaxants; extends anticoagulating effect of coumarins.

At a concomitant use of Epinephrinum (adrenaline) with beta adrenoblockers increase in the ABP and bradycardia is possible.

Fenilpropanolamin (норэфедрин) can raise the diastolic ABP.

The allergens used for an immunotherapy or extracts of allergens for skin tests at combined use with metoprololy, increase risk of emergence of system allergic reactions or an anaphylaxis; iodinated X-ray contrast means for in/in introductions increase risk of development of anaphylactic reactions.

At combined use with ethanol the risk of the expressed decrease in the ABP increases.

Contraindications:

Hypersensitivity to a metoprolol and other beta adrenoblockers, cardiogenic shock, AV blockade of the II-III degree, sinuatrial blockade, a sick sinus syndrome, the expressed bradycardia (ChSS less than 50 beats/min), an acute heart failure or HSN in a decompensation stage, arterial hypotension (systolic the ABP less than 100 mm of mercury.), an acute myocardial infarction (ChSS less than 45 beats/min, an interval PQ more than 0,24 with, systolic the ABP less than 100 mm of mercury.), the lactation period, a concomitant use of monoamine oxidase inhibitors (MAO) or simultaneous in/in administration of verapamil, a pheochromocytoma (without concomitant use of alpha adrenoblockers), age up to 18 years (efficiency and safety are not established), deficit of lactase, a lactose intolerance, glyukozo-galaktozny malabsorption, heavy bronchial asthma, heavy disturbances of peripheric circulation.

With care. A diabetes mellitus, an atrioventricular block of the I degree, Printsmetal's stenocardia, a metabolic acidosis, bronchial asthma, a chronic obstructive pulmonary disease, a renal and/or heavy liver failure, a myasthenia, a pheochromocytoma (at a concomitant use of alpha adrenoblockers), a thyrotoxicosis, a depression (including in the anamnesis), psoriasis, disturbances of peripheric circulation (the "alternating" lameness, Reynaud's syndrome), pregnancy, advanced age.

Overdose:

Symptoms: the expressed bradycardia, AV blockade (up to development of total cross block and a cardiac standstill), the expressed decrease in the ABP, disturbance of peripheric circulation, strengthening of symptoms of heart failure, cardiogenic shock, respiratory depression, an apnoea, cyanosis, increased fatigue, dizziness, a loss of consciousness, a coma, a tremor, spasms, increase in sweating, paresthesia, a bronchospasm, nausea, vomiting, is possible development of an esophagism, a hypoglycemia or a hyperglycemia, a hyperpotassemia, a passing myasthenia. The first signs of overdose are shown in 20 min.-2 the h after administration of drug.

Treatment: If drug is accepted recently – a gastric lavage and reception of the adsorbing means; at disturbance of atrioventricular conductivity and/or bradycardia – in/in introduction of 1-2 mg of atropine, Epinephrinum (adrenaline) or statement of a temporary pacemaker; at a lowering of arterial pressure – the patient has to be in the provision of Trendelenburga. If there are no fluid lungs signs – in/in plasma substituting solutions, at inefficiency – introduction of Epinephrinum, dopamine, Dobutaminum; at an acute heart failure – cardiac glycosides, diuretics; at spasms – in/in diazepam; at a bronchospasm – it is inhalation or parenterally beta2-adrenomimetik.

Storage conditions:

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

Issue conditions:

According to the recipe

Packaging:

Tablets of the prolonged action, film coated, 25 mg, 50 mg, 100 mg and 200 mg. On 30 tablets in a bottle for medicines from plastic. On 10 tablets with dosages of 25 mg and 50 mg in a blister strip packaging. On 30 tablets with dosages of 100 mg and 200 mg in bank from polypropylene (polyethylene). Each can or a bottle, or 3 blister strip packagings together with the application instruction in a pack from a cardboard.