Metocor Adipharm (Tablets, Solution) Instructions for Use

ATC Code

C07AB02 (Metoprolol)

Active Substance

Metoprolol (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Beta₁-adrenoblocker

Pharmacotherapeutic Group

Selective beta1-adrenergic blocker

Pharmacological Action

Cardioselective beta1-adrenergic blocker. Metoprolol has a slight membrane-stabilizing effect and does not have intrinsic sympathomimetic activity. It has antihypertensive, antianginal, and antiarrhythmic effects.

By blocking beta1-adrenergic receptors of the heart, it reduces the catecholamine-stimulated formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), reduces the intracellular flow of calcium ions, and has negative chronotropic, dromotropic, bathmotropic, and inotropic effects (slows heart rate), inhibits conductivity and excitability, and reduces myocardial contractility.

The total peripheral vascular resistance (TPVR) at the beginning of the use of beta-blockers (in the first 24 hours after oral administration) increases (as a result of a reciprocal increase in the activity of alpha-adrenergic receptors and elimination of beta2-adrenergic receptor stimulation), which returns to the initial level after 1-3 days, and with long-term use decreases.

The antihypertensive effect is due to a reflex decrease in minute volume of blood and renin synthesis, inhibition of the activity of the renin-angiotensin-aldosterone system (RAAS) (more important in patients with initial hypersecretion of renin) and the central nervous system (CNS), restoration of the sensitivity of the aortic arch baroreceptors (their activity does not increase in response to a decrease in blood pressure) and, ultimately, a decrease in peripheral sympathetic influences.

The antianginal effect is determined by a decrease in myocardial oxygen demand as a result of a decrease in heart rate (prolongation of diastole and improvement of myocardial perfusion) and contractility, as well as a decrease in myocardial sensitivity to the effects of sympathetic innervation.

The antiarrhythmic effect is due to the elimination of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased cAMP content, arterial hypertension), a decrease in the rate of spontaneous excitation of the sinus and ectopic pacemakers and slowing of atrioventricular (AV) conduction (mainly in the antegrade and to a lesser extent in the retrograde directions through the AV node) and through additional pathways.

Unlike non-selective beta-blockers, when prescribed in average therapeutic doses, it has a less pronounced effect on organs containing beta2-adrenergic receptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchi, and uterus). When used in high doses (more than 100 mg/day), it has a blocking effect on both subtypes of beta-adrenergic receptors.

In myocardial infarction, intravenous administration reduces the severity of retrosternal pain and reduces the risk of atrial fibrillation and flutter. At the first symptoms of myocardial infarction (within 24 hours of their appearance), it reduces the risk of further progression of myocardial infarction. Early initiation of treatment improves the further prognosis of myocardial infarction treatment.

With intravenous infusion of metoprolol over 10 minutes or more, the maximum effect develops after 20 minutes; the slowing of the heart rate at doses of 5 and 10 mg is 10% and 15%, respectively.

Pharmacokinetics

The time to reach C_max in blood plasma is 20 minutes – after intravenous administration.

Plasma protein binding – 10%. C_max is reached in blood plasma 1 hour after intravenous administration of 20 mg – 200 nmol/l. It is rapidly distributed in tissues, penetrates the blood-brain and placental barrier. Penetrates into breast milk (concentration is higher than in blood plasma).

It is metabolized in the liver; 2 metabolites have beta-adrenergic blocking activity. The isoenzyme CYP2D6 is involved in the metabolism of the drug. Over 95% of the intravenously administered dose is excreted by the kidneys, 5% – unchanged. T_1/2 – 5-15 minutes – with intravenous administration. Systemic clearance with intravenous administration – 1 l/min. It is not removed by hemodialysis. Significant accumulation of metabolites is observed in patients with a creatinine clearance of 5 ml/min, while the beta-adrenergic blocking activity of the drug does not increase.

Bioavailability increases in liver cirrhosis, while its total clearance decreases (patients with a portacaval anastomosis have a total clearance after intravenous administration of about 300 ml/min, and AUC is 6 times higher than in healthy volunteers).

Indications

• Supraventricular tachycardia;
• Prevention and treatment of myocardial ischemia, tachycardia and pain syndrome in myocardial infarction or suspected myocardial infarction.

ICD codes

Dosage Regimen

Solution

Parenteral administration of Metocor Adipharm should be carried out by specially trained personnel, in the presence of cardiorespiratory monitoring and the possibility of resuscitation. To relieve paroxysmal supraventricular tachycardia, it is administered parenterally, in a hospital setting, intravenously slowly at a dose of 2-5 mg (1-2 mg/min). If there is no therapeutic effect, the administration can be repeated after 5 minutes. Increasing the dose above 15 mg usually does not lead to a greater severity of action.

After relief of the arrhythmia attack, patients are transferred to oral administration of the drug at a dose of 50 mg 4 times a day, with the first dose taken 15 minutes after the cessation of intravenous administration.

In the acute stage of myocardial infarction, immediately after hospitalization of the patient (with constant monitoring of hemodynamics: ECG, heart rate, AV conduction, blood pressure), 5 mg should be administered intravenously as a bolus; if necessary, the administration is repeated every 2 minutes until a total dose of 15 mg is reached. Fifteen minutes after the last intravenous administration and with good tolerance, it is necessary to prescribe Metoprolol for oral administration – 50 mg of metoprolol every 6 hours for 2 days.

Use in patients with renal insufficiency. Dose adjustment is not required.

Use in patients with hepatic insufficiency. Usually, no dose adjustment is made for patients with liver cirrhosis; in case of severe liver dysfunction, a dose reduction may be necessary.

Use in elderly patients. Dose adjustment is not required.

Tablets

When taken orally, the average dose is 100 mg/day in 1-2 doses. If necessary, the daily dose is gradually increased to 200 mg. With intravenous administration, a single dose is 2-5 mg; if there is no effect, repeated administration is possible after 5 minutes.

Maximum doses when taken orally, the daily dose is 400 mg; with intravenous administration, a single dose is 15-20 mg.

Adverse Reactions

Frequency very common (more than 10%), common (1-10%), uncommon (0.1-1%), rare (0.01-0.1%), very rare (less than 0.1%).

From the cardiovascular system common – bradycardia, orthostatic hypotension (including with fainting), coldness of the lower extremities, palpitations; uncommon – temporary increase in symptoms of heart failure, cardiogenic shock in patients with myocardial infarction, AV block I degree; rare – conduction disorders, arrhythmia; very rare – gangrene (in patients with peripheral circulation disorders).

From the nervous system very common – increased fatigue; common – dizziness, headache; rare – increased nervous excitability, anxiety, impotence/sexual dysfunction; uncommon – paresthesia, convulsions, depression, decreased concentration, drowsiness, insomnia, “nightmare” dreams; very rare – amnesia/memory impairment, depression, hallucinations.

From the senses rare – visual impairment, dryness and/or irritation of the eyes, conjunctivitis; very rare – ringing in the ears, taste disturbance.

From the gastrointestinal tract common – nausea, abdominal pain, constipation or diarrhea; uncommon – vomiting; rare – dryness of the oral mucosa, impaired liver function.

From the skin uncommon – urticaria, increased sweating; rare – alopecia; very rare – photosensitivity, exacerbation of psoriasis.

From the respiratory system common – shortness of breath on physical exertion; uncommon – bronchospasm in patients with bronchial asthma; rare – rhinitis.

Other uncommon – weight gain; very rare – arthralgia, thrombocytopenia.

Contraindications

• Hypersensitivity to the drug;
• Acute myocardial infarction (heart rate less than 45 beats/min, PQ interval more than 0.24 s; systolic blood pressure less than 100 mm Hg);
• Cardiogenic shock;
• Atrioventricular (AV) block II-III degree;
• Sick sinus syndrome;
• Clinically significant sinus bradycardia;
• Chronic heart failure (in the stage of decompensation);
• Arterial hypotension (for the treatment of supraventricular tachycardia – systolic blood pressure less than 110 mm Hg);
• Severe peripheral circulation disorders, threat of gangrene;
• Simultaneous intravenous administration of verapamil;
• Age under 18 years.

With caution AV block I degree, Prinzmetal’s angina, chronic obstructive pulmonary disease, diabetes mellitus, severe renal failure.

Use in Pregnancy and Lactation

During pregnancy, Metocor Adipharm is prescribed only for strict indications if the intended benefit to the mother outweighs the potential risk to the fetus (due to the possible development of bradycardia, arterial hypertension, hypoglycemia in the fetus). In this case, careful monitoring is carried out, especially for the development of the fetus. Strict monitoring of newborns is necessary for 48-72 hours after delivery.

If the use of Metocor Adipharm is necessary during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Usually, no dose adjustment is made for patients with liver cirrhosis; in case of severe liver dysfunction, a dose reduction may be necessary.

Use in Renal Impairment

Use in patients with renal insufficiency: dose adjustment is not required. With caution: severe renal failure.

Pediatric Use

Contraindicated under the age of 18 years.

Geriatric Use

Dose adjustment in elderly patients is not required.

Special Precautions

During combination therapy with clonidine, the latter should be discontinued several days after the withdrawal of Metocor Adipharm to avoid a hypertensive crisis.

If it is necessary to use in patients with concomitant bronchial asthma, beta2-adrenergic agonists should be additionally used; in pheochromocytoma – alpha-adrenergic blockers.

If surgical intervention is necessary, the anesthesiologist must be informed about the therapy being carried out (choice of a drug for general anesthesia with minimal negative inotropic effect). In patients with initial AV conduction disorders, treatment with metoprolol may lead to deterioration (possible outcome – AV block). If bradycardia develops, its dose should be reduced.

Metocor Adipharm may worsen the symptoms of peripheral circulation disorders, mainly due to a decrease in blood pressure.

A repeated dose should not be administered if the heart rate is less than 40 beats/min, the PQ interval is more than 0.26 s, and the systolic blood pressure is less than 90 mm Hg.

Effect on the ability to drive vehicles and mechanisms. Since dizziness and weakness may develop when using the drug, caution should be exercised when driving vehicles and working with potentially dangerous mechanisms.

Overdose

Symptoms pronounced severe sinus bradycardia, dizziness, AV block (up to the development of complete transverse block and cardiac arrest), pronounced decrease in blood pressure, weak peripheral perfusion, increased fatigue, fainting, arrhythmia, ventricular extrasystole, heart failure, cardiogenic shock, depression of lung function, apnea, asystole, bronchospasm, impaired consciousness, up to its loss, tremor, convulsions, increased sweating, paresthesia, coma, nausea, vomiting, hypo- or hyperglycemia, hyperkalemia, transient muscle weakness. The first signs of overdose appear 20 minutes – 2 hours after administration of the drug.

Treatment symptomatic.

With a pronounced decrease in blood pressure – the patient should be in the Trendelenburg position; in case of an excessive decrease in blood pressure, bradycardia and heart failure – intravenous, at intervals of 2-5 minutes, beta-adrenergic agonists – until the desired effect is achieved or intravenous 0.5-2 mg of atropine. In the absence of a positive effect – dopamine, dobutamine or norepinephrine.

As subsequent measures, the administration of 1-10 mg of glucagon and the installation of a transvenous intracardial pacemaker are possible.

For bronchospasm, intravenous stimulants of beta2-adrenergic agonists should be administered. For convulsions – slow intravenous administration of diazepam. Hemodialysis is ineffective.

Drug Interactions

Barbiturates enhance the metabolism of metoprolol due to the induction of liver microsomal enzymes.

Propafenone increases the plasma concentration of metoprolol by 2-5 times (probably as a result of inhibition of the CYP2D6 isoenzyme by propafenone).

Simultaneous intravenous administration of verapamil can cause bradycardia and a pronounced decrease in blood pressure.

Class I antiarrhythmic drugs can lead to a summation of the negative inotropic effect with the development of pronounced hemodynamic side effects in patients with impaired left ventricular function (this combination should be avoided in patients with sick sinus syndrome and impaired AV conduction).

Amiodarone – risk of developing pronounced sinus bradycardia (including a long time after discontinuation of amiodarone, due to its long half-life).

Diltiazem – risk of developing pronounced bradycardia (mutual enhancement of the inhibitory effect on AV conduction and sinus node function). The hypotensive effect is weakened by non-steroidal anti-inflammatory drugs (sodium retention and blockade of prostaglandin synthesis by the kidneys). Diphenhydramine reduces the clearance of metoprolol, enhancing its effect. Epinephrine – risk of developing a pronounced decrease in blood pressure and bradycardia. Phenylpropanolamine in high doses – paradoxical increase in blood pressure (up to a hypertensive crisis).

Quinidine inhibits the metabolism of metoprolol in rapid acetylators, leading to a significant increase in the plasma concentration of metoprolol and an enhancement of its beta-adrenergic blocking action.

Clonidine – risk of a pronounced increase in blood pressure with abrupt withdrawal of clonidine against the background of simultaneous administration of beta-blockers, therefore, in case of clonidine withdrawal, gradual discontinuation of beta-blockers should be started several days before its withdrawal.

Rifampicin – enhances the metabolism of metoprolol, reducing the plasma concentration.

Cimetidine, hydralazine, selective serotonin reuptake inhibitors (including paroxetine, fluoxetine, sertraline) increase the plasma concentration of metoprolol.

Drugs for inhalation anesthesia enhance the cardiodepressive effect of metoprolol.

Caution should be exercised when using other beta-blockers in eye drops and MAO inhibitors.

Against the background of metoprolol use, dose adjustment of oral hypoglycemic agents may be required.

Cardiac glycosides increase the risk of bradycardia.

Allergens used for immunotherapy, or allergen extracts for skin tests increase the risk of severe systemic allergic reactions or anaphylaxis in patients receiving Metoprolol.

Iodine-containing X-ray contrast agents for intravenous administration increase the risk of anaphylactic reactions.

Storage Conditions

Store in a light-protected place at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life. 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.