Corvitol^® (Tablets) 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 without intrinsic sympathomimetic activity. It has antihypertensive, antianginal, and antiarrhythmic effects. It lowers the automaticity of the sinus node, reduces heart rate, slows AV conduction, decreases myocardial contractility and excitability, reduces cardiac output, and lowers myocardial oxygen demand.

It suppresses the stimulating effect of catecholamines on the heart during physical and psychoemotional stress. The antihypertensive effect stabilizes by the end of the 2nd week of course use. In angina pectoris, Metoprolol reduces the frequency and severity of attacks. It normalizes heart rhythm in supraventricular tachycardia and atrial fibrillation. In myocardial infarction, it helps limit the area of myocardial ischemia and reduces the risk of fatal arrhythmias, lowering the possibility of recurrent myocardial infarction. It prevents the development of migraine.

When used in average therapeutic doses, unlike non-selective beta-blockers, it has a less pronounced effect on organs containing β₂-adrenergic receptors (pancreas, skeletal muscles, smooth muscles of peripheral arteries, bronchi, and uterus) and on carbohydrate metabolism. With long-term use, it reduces the concentration of cholesterol in the blood. When used in high doses (more than 100 mg/day), it has a blocking effect on both subtypes of β-adrenergic receptors.

Pharmacokinetics

After oral administration, Metoprolol is rapidly and almost completely absorbed from the gastrointestinal tract. The C_max of the active substance in blood plasma is reached after 1-2 hours. After absorption, Metoprolol undergoes a significant first-pass effect through the liver. Plasma protein binding is low, about 5-10%. The V_d is 5.6 L/kg. It is rapidly distributed in tissues, penetrates the blood-brain barrier, and the placental barrier. It is excreted in breast milk.

Metoprolol undergoes oxidative metabolism in the liver (mainly with the participation of the CYP2D6 isoenzyme) with the formation of 3 main metabolites, none of which has a clinically significant beta-adrenergic blocking effect. The T_1/2 of metoprolol from plasma is 3-4 hours and does not change during the course of treatment. More than 95% of the administered dose is excreted by the kidneys, about 5% of the administered dose is excreted by the kidneys unchanged.

Indications

Arterial hypertension, prevention of angina attacks, heart rhythm disorders (supraventricular tachycardia, extrasystole), secondary prevention after myocardial infarction, hyperkinetic cardiac syndrome (including in hyperthyroidism, neurocirculatory dystonia). Prevention of migraine attacks.

ICD codes

Dosage Regimen

For arterial hypertension and angina pectoris, initiate treatment with 50-100 mg once daily. Titrate the dose gradually at weekly intervals based on heart rate and blood pressure response.

The maintenance dose is 100-200 mg per day, administered in one or two divided doses. Do not exceed the maximum daily dose of 400 mg.

For secondary prevention after myocardial infarction, initiate therapy as soon as the patient’s condition is stable. The recommended maintenance dose is 200 mg per day, given in two divided doses of 100 mg each.

For cardiac arrhythmias and hyperkinetic cardiac syndrome, administer 50 mg two to three times daily. Adjust the dose as needed for adequate control.

For the prophylaxis of migraine, the typical dose is 100-200 mg per day, given in divided doses.

In elderly patients or those with significant hepatic impairment, initiate therapy at the lower end of the dosage range. A starting dose of 50 mg once daily is recommended. Monitor patients closely for excessive bradycardia or hypotension.

For intravenous administration in acute settings, administer 2-5 mg at a rate of 1-2 mg per minute. Repeat this dose at 5-minute intervals up to a maximum total IV dose of 10-15 mg. Monitor ECG and blood pressure continuously during administration.

Following IV therapy, initiate oral treatment. The first oral dose should be given within 15-30 minutes after the last intravenous injection.

When discontinuing long-term therapy, gradually reduce the dose over a period of 1-2 weeks. Abrupt withdrawal may exacerbate angina or precipitate myocardial infarction. Monitor the patient closely during this period.

Adverse Reactions

From the cardiovascular system often – sinus bradycardia, decreased blood pressure, orthostatic hypotension (dizziness, sometimes loss of consciousness), postural disorders (very rarely accompanied by fainting); rarely – decreased myocardial contractility, development (worsening) of chronic heart failure (edema, swelling of the feet and/or lower legs, shortness of breath), heart rhythm disorders, impaired myocardial conduction, cardialgia, manifestation of angiospasm (worsening of peripheral circulation disorders, cold extremities, Raynaud’s syndrome); very rarely – worsening of pre-existing AV conduction disorders, gangrene in patients with previous severe peripheral circulation disorders.

From the nervous system very often – increased fatigue; often – weakness, headache, slowing of mental and motor reactions; rarely – paresthesia, convulsions, tremor, seizures, depression, anxiety, decreased attention, drowsiness, insomnia, nightmares, confusion or short-term memory loss, hallucinations, asthenia, myasthenia, impotence/sexual dysfunction, Peyronie’s disease; very rarely – amnesia/memory impairment, depression, hallucinations.

From the respiratory system often – nasal congestion; infrequently – bronchospasm when prescribed in high doses (loss of selectivity in predisposed patients), shortness of breath; rarely – rhinitis.

From the digestive system: often – nausea, vomiting, abdominal pain, dry mouth, constipation or diarrhea; rarely – dryness of the oral mucosa; very rarely – taste change.

From the liver and biliary tract rarely – impaired liver function (dark urine, jaundice of the sclera or skin, cholestasis), increased activity of liver transaminases.

From the organ of vision rarely – decreased vision, decreased tear secretion, dry and painful eyes, conjunctivitis.

From the organ of hearing and labyrinthine disorders rarely – tinnitus, hearing loss.

From the endocrine system rarely – hyperglycemia (in patients with non-insulin-dependent diabetes mellitus), hypoglycemia (in patients receiving insulin), hypothyroid state.

From the skin and subcutaneous tissues infrequently – skin rashes (exacerbation of psoriasis), psoriasis-like skin reactions, skin hyperemia, exanthema, photodermatosis, increased sweating, reversible alopecia.

Allergic reactions infrequently – urticaria.

General reactions rarely – back or joint pain, weight gain, decreased libido and/or potency; with abrupt discontinuation of treatment – withdrawal syndrome (increased angina attacks, increased blood pressure).

Laboratory data rarely – thrombocytopenia (unusual bleeding and hemorrhage), agranulocytosis, leukopenia, hyperbilirubinemia.

Contraindications

Hypersensitivity to metoprolol or other beta-blockers; AV block II and III degree (without a pacemaker); decompensated heart failure; patients receiving long-term or intermittent therapy with inotropic agents and agents acting on β-adrenergic receptors; clinically significant sinus bradycardia; sick sinus syndrome; cardiogenic shock; severe peripheral circulation disorders, including threat of gangrene; arterial hypotension (systolic blood pressure less than 100 mm Hg); patients with acute myocardial infarction (heart rate less than 45 beats/min, PQ interval duration more than 0.24 sec or systolic blood pressure less than 100 mm Hg); for the treatment of supraventricular tachycardia with systolic blood pressure less than 110 mm Hg; IV administration of calcium channel blockers such as verapamil and diltiazem; simultaneous use of MAO inhibitors; severe forms of bronchial asthma and COPD; pheochromocytoma (without simultaneous use of alpha-blockers); breastfeeding period; children under 18 years of age.

With caution

AV block I degree; Prinzmetal’s angina; COPD and mild bronchial asthma; diabetes mellitus; severe renal failure.

Use in Pregnancy and Lactation

Use during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus. Metoprolol crosses the placental barrier. Due to the possible development of bradycardia, arterial hypotension, hypoglycemia, and respiratory arrest in the newborn, Metoprolol must be discontinued 48-72 hours before the planned delivery date. After delivery, strict monitoring of the newborn’s condition for 48-72 hours is necessary.

It is excreted in breast milk. Contraindicated for use during breastfeeding.

Use in Hepatic Impairment

Use with caution in patients with severe liver dysfunction.

Use in Renal Impairment

Use with caution in patients with severe renal failure.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

In elderly patients, it is recommended to start treatment with a dose of 50 mg/day, because a sharp decrease in blood pressure or increasing bradycardia may be more pronounced.

Special Precautions

Use with caution in patients with chronic obstructive respiratory diseases, diabetes mellitus (especially with unstable course), Raynaud’s disease and obliterating peripheral arterial diseases, pheochromocytoma (should be used in combination with alpha-blockers), severe renal and hepatic impairment.

During treatment with metoprolol, a decrease in tear production is possible, which is important for patients using contact lenses.

Completion of a long course of treatment with metoprolol should be carried out gradually (for at least 10 days) under medical supervision.

Simultaneous use of metoprolol with MAO inhibitors is not recommended.

During combination therapy with clonidine, the latter should be discontinued several days after discontinuation of metoprolol to avoid a hypertensive crisis. When used simultaneously with hypoglycemic agents, adjustment of their dosage regimen is required.

A few days before anesthesia, it is necessary to stop taking metoprolol or select an anesthetic agent with minimal negative inotropic effect.

Effect on the ability to drive vehicles and mechanisms

In patients whose activities require increased attention, the issue of outpatient use of metoprolol should be decided only after assessing the individual patient’s response.

Drug Interactions

When used simultaneously with antihypertensive agents, diuretics, antiarrhythmic agents, nitrates, there is a risk of developing pronounced arterial hypotension, bradycardia, AV block.

When used simultaneously with barbiturates, the metabolism of metoprolol is accelerated, which leads to a decrease in its effectiveness.

When used simultaneously with hypoglycemic agents, the effect of hypoglycemic agents may be enhanced.

When used simultaneously with NSAIDs, the antihypertensive effect of metoprolol may be reduced.

When used simultaneously with opioid analgesics, the cardiodepressive effect is mutually enhanced.

When used simultaneously with peripheral muscle relaxants, neuromuscular blockade may be enhanced.

When used simultaneously with agents for inhalation anesthesia, the risk of myocardial function depression and arterial hypotension development increases.

When used simultaneously with oral contraceptives, hydralazine, ranitidine, cimetidine, the concentration of metoprolol in blood plasma increases.

When used simultaneously with amiodarone, arterial hypotension, bradycardia, ventricular fibrillation, asystole are possible.

When used simultaneously with verapamil, the C_max in blood plasma and AUC of metoprolol increase. Cardiac output and stroke volume, heart rate, and arterial hypotension decrease. The development of heart failure, dyspnea, and sinus node block is possible.

When verapamil is administered IV while taking metoprolol, there is a threat of cardiac arrest.

When used simultaneously, bradycardia caused by digitalis glycosides may be enhanced.

When used simultaneously with dextropropoxyphene, the bioavailability of metoprolol increases.

When used simultaneously with diazepam, a decrease in clearance and an increase in the AUC of diazepam are possible, which may lead to an enhancement of its effects and a decrease in the speed of psychomotor reactions.

When used simultaneously with diltiazem, the concentration of metoprolol in blood plasma increases due to inhibition of its metabolism under the influence of diltiazem. The effect on heart activity is additively depressed due to the slowing of impulse conduction through the AV node caused by diltiazem. There is a risk of developing pronounced bradycardia, a significant decrease in stroke and minute volume.

When used simultaneously with lidocaine, the excretion of lidocaine may be impaired.

When used simultaneously with mibefradil in patients with low activity of the CYP2D6 isoenzyme, an increase in the concentration of metoprolol in blood plasma and an increase in the risk of toxic effects are possible.

When used simultaneously with norepinephrine, epinephrine, other adreno- and sympathomimetics (including in the form of eye drops or as part of antitussives), some increase in blood pressure is possible.

When used simultaneously with propafenone, the concentration of metoprolol in blood plasma increases and toxic effects develop. It is believed that propafenone inhibits the metabolism of metoprolol in the liver, reducing its clearance and increasing serum concentrations.

When used simultaneously with reserpine, guanfacine, methyldopa, clonidine, the development of pronounced bradycardia is possible.

When used simultaneously with rifampicin, the concentration of metoprolol in blood plasma decreases.

Metoprolol may cause a slight decrease in the clearance of theophylline in smoking patients.

Fluoxetine inhibits the CYP2D6 isoenzyme, which leads to inhibition of metoprolol metabolism and its accumulation, which may enhance the cardiodepressive effect and cause bradycardia. A case of lethargy development has been described.

Fluoxetine and mainly its metabolites are characterized by a long T_1/2, so the likelihood of drug interaction persists even several days after discontinuation of fluoxetine.

There are reports of a decrease in the clearance of metoprolol from the body when used simultaneously with ciprofloxacin.

When used simultaneously with ergotamine, an increase in peripheral circulation disorders is possible.

When used simultaneously with estrogens, the antihypertensive effect of metoprolol decreases.

When used simultaneously, Metoprolol increases the concentration of ethanol in the blood and prolongs its excretion.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.