Metoprolol Retard-Acrichin, 50 mg 30 pcs

a beta1-adrenoblocker selective.

CodeATH: C07AB02

Pharmacological properties

Pharmacodynamics

A cardioselective beta1-adrenoblocker. It has no membrane stabilizing effect and no intrinsic sympathomimetic activity. It has antihypertensive, antianginal and antiarrhythmic effects.

. By blocking in low doses beta1-adrenoreceptors of heart, it decreases stimulated by catecholamines formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), decreases intracellular calcium ions current, has negative chrono-, dromo-, batmo- and inotropic effects (decreases heart rate (HR), inhibits conduction and excitability, decreases myocardial contractility).

The total peripheral vascular resistance (TPR) at the beginning of administration of beta-adrenoblockers (in the first 24 hours after oral administration) increases (as a result of reciprocal increase of alpha-adrenoreceptor activity and elimination of beta2-adrenoreceptor stimulation) which returns to baseline in 1-3 days and decreases with long-term administration.

The antihypertensive effect is caused by the decrease of the minute blood flow volume and renin synthesis, inhibition of the activity of renin-angiotensin-aldosterone system (of greater importance in patients with initial renin hypersecretion) and central nervous system, restoration of sensitivity of the aortic arch baroreceptors (there is no increase of their activity in response to a decrease of blood pressure (BP) and in result a decrease of peripheral sympathetic effects. Reduces elevated BP at rest, under physical stress and strain. The antihypertensive effect lasts more than 24 hours.

The antianginal effect is determined by decreasing myocardial oxygen demand as a result of decreasing HR (prolongation of diastole and improvement of myocardial perfusion) and contractility and decreasing myocardial sensitivity to sympathetic innervation. It reduces the number and severity of angina attacks and increases exercise tolerance. By increasing left ventricular end-diastolic pressure and increasing ventricular muscle fiber stretch may increase oxygen demand, especially in patients with chronic heart failure (CHF).

. The antiarrhythmic effect is caused by the removal of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased content of CAMF, arterial hypertension), the decrease of spontaneous excitation rate of sinus and ectopic pacemakers and delay of atrioventricular (AV) conduction (mainly in antegrade and, to a lesser degree, in retrograde direction via AV node) and by additional pathways.

In supraventricular tachycardia, atrial fibrillation, sinus tachycardia in functional heart disease and thyrotoxicosis, it reduces HR or may even lead to restoration of sinus rhythm.

Prevent the development of migraine.

In contrast to non-selective beta-adrenoblockers when administered in medium therapeutic doses, it has less pronounced effect on organs containing beta2-adrenoreceptors (pancreas, skeletal muscles, smooth muscle of peripheral arteries, bronchi and uterus) and on carbohydrate metabolism; intensity of atherogenic action does not differ from that of propranolol. When administered for many years, it reduces blood cholesterol concentration. When used in high doses (more than 100 mg/day) it has a blocking effect on both beta-adrenoreceptor subtypes.

Pharmacokinetics

Absorption when ingested is complete (95%). Fat solubility is moderate. It is subjected to intensive presystemic metabolism, bioavailability is 50% during the first use and it increases up to 70% after repeated use. Binding to plasma proteins is 10%. Time of reaching maximum plasma concentration is 6-12 hours after drug administration. Bioavailability increases during the course of treatment. Food intake increases bioavailability by 20-40 %.

Fast distribution in tissues, penetrates through the blood-brain barrier and the placental barrier. It penetrates into breast milk.

It is metabolized in the liver; 2 metabolites have beta-adrenoblocking activity. The CYP2D6 isoenzyme is involved in the metabolism of the drug. The elimination half-life is from 3.5 to 7 hours when administered orally. It is not eliminated by hemodialysis.

Significant accumulation of metabolites is observed in patients with creatinine clearance of 5 ml/min, and the beta-adrenoblocking activity of the drug is not increased.

Bioavailability is increased in liver cirrhosis, while its total clearance is reduced.

Indications

Arterial hypertension.

Chronic heart failure II-IV functional class according to the NYHA classification in the compensation stage (in the complex therapy).

Ischemic heart disease: the prevention of stable angina attacks, reducing mortality and the rate of repeated myocardial infarction after the acute phase of myocardial infarction.

Heart rhythm disorders, including supraventricular tachycardia, reduction of ventricular contraction rate in atrial fibrillation and ventricular extrasystoles.

Functional disorders of cardiac activity accompanied by tachycardia.

Prevention of migraine attacks.

Active ingredient

Composition

One tablet contains:

active ingredient:

metoprolol succinate converted to 100 percent substance 23.83 mg, 47.66 mg and 95.32 mg, equivalent to 25 mg, 50 mg and 100 mg of metoprolol tartrate, respectively;

auxiliary substances :

Hypromellose 155.96 mg, 161.92 mg or 184.84 mg;

Ludipress LCE [lactose monohydrate 94.7-98.3%, povidone 3-4%] 117.21 mg, 87.42 mg or 412.84 mg;

Colloidal silica 1.5 mg, 1.5 mg, or 3.5 mg;

Magnesium stearate 1.5 mg, 1.5 mg, or 3.5 mg, respectively.

Composition of the shell:

For 25 mg and 100 mg dosage tablets, the orange-colored Opadray II ready-mix (polyvinyl alcohol 6 mg or 14 mg, talc 2.22 mg or 5.18 mg, macrogol 3.03 mg or 7.07 mg, titanium dioxide 3,36 mg or 7.84 mg, iron oxide red dye 0.009 mg or 0.021 mg, iron oxide yellow dye 0.378 mg or 0.882 mg, iron oxide black dye 0.003 mg or 0.007 mg) 15 mg or 35 mg respectively.

For 50 mg dosage tablets, the ready mixed Opadray II green (polyvinyl alcohol 6 mg, talc 2.22 mg, macrogol 3.03 mg, titanium dioxide 2.925 mg, quinoline yellow dye (aluminum varnish) 0.268 mg, iron oxide black dye 0.015 mg, indigo carmine dye (aluminum varnish) 0.542 mg) 15 mg.

How to take, the dosage

Metoprolol retard-Acrichine is intended for oral administration once a day, it is recommended to take in the morning, without chewing, with water. Metoprolol retarde-Acrichine may be taken regardless of meals. In order to prevent bradycardia, the dose is adjusted individually and increased gradually.

In arterial hypertension and angina pectoris, the initial dose is 50 mg once daily; if the therapeutic effect is insufficient, the daily dose may be increased to 100-200 mg daily. In case of arterial hypertension, another hypotensive agent may be added at a dose of 100-200 mg per day if the drug is ineffective.

In chronic heart failure II functional class according to NYHA classification (without exacerbations during last 6 weeks and without changes in complex therapy during last 2 weeks), the recommended initial dose is 25 mg once daily. After two weeks, the daily dose may be increased to 50 mg, then after two weeks to 100 mg, and after another two weeks to 200 mg.

In chronic heart failure III-IV functional class according to the NYHA classification, the recommended initial dose for the first 2 weeks is 12.5 mg of the drug once daily. It is possible to use metoprolol in other dosage form, for example, tablets of 25 mg with a rib. During the period of increasing the dose, the patient should be monitored, because in some patients the symptoms of heart failure may worsen.

After 1 to 2 weeks, the dose may be increased to 25 mg once daily. Then after 2 weeks, the dose may be increased to 50 mg once daily. In patients who tolerate the drug well, the dose may be doubled every 2 weeks until a maximum dose of 200 mg of the drug once daily is reached.

Secondary prevention of myocardial infarction and heart rhythm disturbances – the initial dose is 100 mg once daily.

In functional disorders of cardiac activity accompanied with tachycardia, 50 mg daily; if necessary, the dose can be increased to 200 mg daily.

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

Elderly patients, patients with renal insufficiency or patients on hemodialysis do not require dose adjustment.

Hepatic disorders affect excretion of metoprolol, so dose adjustment may be required depending on the clinical condition.

Interaction

Catecholamine-lowering agents (e.g., reserpine, MAO inhibitors) when used concomitantly with metoprolol may increase the hypotensive effect or cause marked bradycardia. There should be a treatment interval of at least 14 days between MAO inhibitors and metoprolol.

Metoprolol is a substrate of CYP2D6 isoenzyme. Medicinal products that inhibit or induce the activity of CYP2D6 isoenzyme may affect the plasma concentration of metoprolol.

The inhibitors of CYP2D6 isoenzyme: some antidepressants and neuroleptics, quinidine, terbinafine, celecoxib, propafenone, difehidramine, hydroxychlorine, cimetidine – increase the plasma concentration of metoprolol.

CYP2D6 isoenzyme inducers: barbituric acid derivatives, rifampicin – decrease the plasma concentration of metoprolol.

Concomitant use with cardiac glycosides, clonidine, “slow” calcium channel blockers (verapamil, diltiazem), amiodarone, class I antiarrhythmic agents, agents for general anesthesia, methyldopa, guanfacine may lead to decreased BP and marked bradycardia.

The agents for inhalation anesthesia (hydrocarbon derivatives) increase the risk of myocardial depression and arterial hypotension.

The concomitant IV administration of verapamil may induce cardiac arrest.

Non-steroidal anti-inflammatory drugs (NSAIDs) and beta-adrenomimetics weaken the antihypertensive effect of beta-adrenoblockers.

The ergot alkaloids increase the risk of peripheral circulatory disorders.

When co-administered with oral hypoglycemic drugs, their effect may be reduced; with insulin – increased risk of hypoglycemia, prolongation and enhancement of its severity, masking of some symptoms of hypoglycemia (tachycardia, sweating, increased blood pressure).

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

Magnifies and prolongs the effect of nondepolarizing myorelaxants; prolongs the anticoagulant effect of coumarins.

The simultaneous use of epinephrine (adrenaline) with beta-adrenoblockers may increase BP and bradycardia.

Phenylpropanolamine (norephedrine) may increase diastolic BP.

Allergens used for immunotherapy or allergen extracts for skin tests, when combined with metoprolol, increase the risk of systemic allergic reactions or anaphylaxis; iodine containing X-ray contrast agents for IV administration increase the risk of anaphylactic reactions.

In co-administration with ethanol the risk of significant BP decrease increases.

Special Instructions

Management of patients taking beta-adrenoblockers includes regular monitoring of heart rate and blood pressure. The patient should be taught how to calculate heart rate and should be instructed to consult a physician if their heart rate is less than 50 bpm.

The severity of allergic reactions may increase (given a history of poor allergy) and the usual doses of epinephrine (adrenaline) may have no effect.

In elderly patients it is recommended to monitor renal function (once every 4-5 months). May exacerbate symptoms of peripheral arterial circulatory disorders.

In tension angina, the selected dose of the drug should provide an HR at rest within 55-60 bpm, and not more than 110 bpm on exertion.

In “smokers,” the effectiveness of beta-adrenoblockers is lower.

Metoprolol retard-Acrichine may mask some clinical manifestations of thyrotoxicosis (e.g., tachycardia). Abrupt withdrawal of the drug in patients with thyrotoxicosis is contraindicated because it may exacerbate the symptoms.

In diabetics, it may mask the tachycardia caused by hypoglycemia.

Beta2-adrenomimetics are used as concomitant therapy in patients with bronchial asthma; alpha-adrenoblockers are used in pheochromocytoma.

If it is necessary to perform surgical intervention, the anesthesiologist must be warned about the use of Metoprolol retard-Acrichine (the choice of general anesthetic agent with minimal negative inotropic effect is necessary); cancellation of the drug is not recommended.

Reciprocal activation of the vagus nerve can be eliminated by IV administration of atropine (1-2 mg).

In case of increasing bradycardia (less than 50 bpm), arterial hypotension (systolic BP below 100 mm Hg), AV blockade, bronchospasm, ventricular arrhythmias, severe hepatic and renal function impairment, the dose should be reduced or treatment should be stopped.

It is recommended that therapy be discontinued if there is a skin rash or if beta-adreno-blocker-induced depression develops.

Methoprolol may increase symptoms of peripheral circulatory disturbances.

If clonidine is abruptly withdrawn, BP may rise sharply if beta-adrenal blockers are taken at the same time. If clonidine is withdrawn, discontinuation of beta-adrenoblockers should be started several days before clonidine withdrawal.

Drugs that reduce catecholamine stores (e.g., reserpine) may potentiate the effects of beta-adrenoblockers, so patients taking these combinations of drugs should be under constant medical monitoring for excessive BP reduction or bradycardia.

When treatment is stopped abruptly, withdrawal syndrome (increased angina pectoris, increased BP) may occur. Particular attention during drug withdrawal should be paid to patients with angina pectoris, CHF, after myocardial infarction. Metoprolol retard-Acrychine is withdrawn gradually, reducing the dose over 10 days.

Patients who wear contact lenses should be aware that treatment with beta-adrenoblockers may decrease lacrimal fluid production.

During treatment, caution should be exercised when driving motor vehicles and engaging in other potentially hazardous activities requiring increased concentration and quick psychomotor reactions.

Contraindications

High sensitivity to metoprolol and other beta-adrenoblockers, cardiogenic shock, II-III degree AV block, sinoatrial block, sinus node weakness syndrome, severe bradycardia (HR less than 50 bpm), acute heart failure or decompensated CHF, arterial hypotension (systolic BP less than 100 mm Hg), acute myocardial infarction (HR less than 45 bpm, PQ interval less than 0.24.24. sts), acute myocardial infarction (heart rate less than 45 bpm, PQ interval more than 0.24 s, systolic BP less than 100 mm Hg), lactation period.

Lactation, concomitant use of monoamine oxidase inhibitors (MAOIs) or concomitant intravenous administration of verapamil, pheochromocytoma (without simultaneous use of alpha-adrenoblockers), age under 18 years (effectiveness and safety not established), lactase deficiency, lactose intolerance, glucose-galactose malabsorption, severe bronchial asthma, severe peripheral circulatory disorders.

With caution

. Diabetes mellitus, 1st degree atrioventricular block, Prinzmetal angina, metabolic acidosis, bronchial asthma, chronic obstructive pulmonary disease, renal and/or severe liver failure, myasthenia, pheochromocytoma (while taking alpha-adrenoblockers), thyrotoxicosis, depression (includingIn anamnesis), psoriasis, peripheral circulatory disorders (“intermittent” claudication, Raynaud’s syndrome), pregnancy, old age.

Side effects

Frequency of side effects: very common – more than 1/10, common – more than 1/100 and less than 1/10, infrequent – more than 1/1000 and less than 1/100, rare – more than 1/10000 and less than 1/1000, very rare – less than 1/10000, including individual reports.

Cardiovascular system: often – bradycardia, orthostatic hypotension (including With fainting), coldness of lower extremities, palpitations; infrequent – temporary increase of cardiac insufficiency symptoms, cardiogenic shock in patients with myocardial infarction, 1st degree AV block; rare – myocardial conduction disorders, arrhythmia; very rare – gangrene (in patients with peripheral circulatory disorders).

Central nervous system disorders: very common – increased fatigue, decreased speed of mental and motor reactions; common – dizziness, headache; infrequent – paresthesias, seizures, depression, reduced concentration, drowsiness, insomnia, “nightmares” dreams; rare – asthenia, tremor, increased nervous excitability, anxiety; very rare – amnesia / memory impairment, depression, hallucinations, myasthenia.

Senses: rare – visual impairment, dry and/or irritated eyes, conjunctivitis; very rare – ringing in the ears, impaired sense of taste.

The digestive system: frequently – nausea, abdominal pain, constipation or diarrhea; rarely – vomiting; rarely – dry mucous membrane of the mouth, impaired liver function, hepatitis.

The skin: infrequent urticaria, increased sweating, rarely alopecia, very rare photosensitivity, exacerbation of psoriasis, psoriasis-like skin reactions.

The respiratory system: often – shortness of breath; infrequently – bronchospasm in patients with bronchial asthma; rarely – rhinitis.

Laboratory parameters: very rare – thrombocytopenia (unusual bleeding and hemorrhage), agranulocytosis, leukopenia, increased activity of “liver” enzymes, hyperbilirubinemia.

Endocrine system disorders: often – hypoglycemia (in patients with diabetes mellitus type I), rarely – hyperglycemia (in patients with diabetes mellitus type II), hypothyroidism.

Others: infrequent – weight gain; rarely – impotence/sexual dysfunction; very rare – arthralgia, thrombocytopenia.

Overdose

Symptoms:

. pronounced bradycardia, AV blockade (up to the development of complete transverse blockade and cardiac arrest), pronounced BP decrease, peripheral circulation disorder, increased symptoms of heart failure, cardiogenic shock, respiratory depression, apnea, cyanosis, increased fatigue, dizziness, loss of consciousness, coma, tremor, convulsions, increased sweating, paresthesias, bronchospasm, nausea, vomiting, possible development of esophagospasm, hypoglycemia or hyperglycemia, hyperkalemia, transient myasthenia. The first signs of overdose occur 20 minutes to 2 hours after taking the drug.

Treatment:

If the drug is taken recently – gastric lavage and administration of adsorptive agents; if atrioventricular conduction and/or bradycardia is impaired – IV injection of 1-2 mg of atropine, epinephrine (adrenaline) or placement of temporary pacemaker; if blood pressure decreases – the patient should be in Trendelenburg position. If there are no signs of pulmonary edema – IV plasma substitute solutions, if ineffective – injection of epinephrine, dopamine, dobutamine; in acute heart failure – cardiac glycosides, diuretics; in convulsions – IV diazepam; in bronchospasm – inhaled or parenterally beta2-adrenomimetics.

Similarities