Metocard^® (Tablets) Instructions for Use

Marketing Authorization Holder

Polpharma Pharmaceutical Works, Sa (Poland)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

C07AB02 (Metoprolol)

Active Substance

Metoprolol (Rec.INN registered by WHO)

Dosage Forms

	Metocard®	Tablets 50 mg: 30 pcs.
		Tablets 100 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets white, round, biconvex, with a score line.

Excipients: lactose, povidone, talc, magnesium stearate, microcrystalline cellulose, rice starch.

10 pcs. – blisters (3) – cardboard packs.

Tablets white, round, biconvex, with a score line.

Excipients: lactose, povidone, talc, magnesium stearate, microcrystalline cellulose, rice starch.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Beta₁-adrenoblocker

Pharmacotherapeutic Group

Selective beta1-adrenergic blocker

Pharmacological Action

Cardioselective beta₁-adrenergic blocker, devoid of intrinsic sympathomimetic activity and membrane-stabilizing properties. It has antihypertensive, antianginal, and antiarrhythmic effects.

By blocking beta₁-adrenergic receptors in the heart in low doses, it reduces catecholamine-stimulated formation of cAMP from ATP, reduces the intracellular flow of Ca²⁺, and exerts negative chronotropic, dromotropic, bathmotropic, and inotropic effects (reduces heart rate, inhibits conduction and excitability, reduces myocardial contractility).

Total peripheral vascular resistance at the beginning of beta-adrenergic blocker use (within the first 24 hours after oral administration) increases (due to reciprocal increase in alpha-adrenergic receptor activity and elimination of beta₂-adrenergic receptor stimulation), which returns to the initial level after 1-3 days, and with long-term administration, it decreases.

The acute antihypertensive effect is due to a reduction in cardiac output; the stable antihypertensive effect develops within 2-3 weeks and is due to a decrease in renin synthesis and plasma renin accumulation, inhibition of the renin-angiotensin system activity (particularly important in patients with initial hypersecretion of renin) and the central nervous system, restoration of aortic arch baroreceptor sensitivity (their activity does not increase in response to decreased blood pressure), and, ultimately, a reduction in peripheral sympathetic influences. It reduces elevated blood pressure at rest, during physical exertion, and under stress.

Blood pressure decreases after 15 minutes, maximally after 2 hours, and the reduction continues for 6 hours; diastolic blood pressure changes more slowly: a stable reduction is observed after several weeks of regular use.

The antianginal effect is determined by a reduction in myocardial oxygen demand due to decreased heart rate (prolongation of diastole and improvement of myocardial perfusion) and contractility, as well as a decrease in myocardial sensitivity to sympathetic innervation. It reduces the number and severity of angina attacks and increases exercise tolerance.

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

In supraventricular tachycardia, atrial fibrillation, sinus tachycardia in functional heart diseases and hyperthyroidism, the drug reduces heart rate or may even lead to the restoration of sinus rhythm. Prevents the development of migraine.

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

Pharmacokinetics

Absorption

After oral administration, it is rapidly and almost completely (95%) absorbed from the gastrointestinal tract. C_max of metoprolol in blood plasma is reached 1-2 hours after oral administration. Bioavailability is 50% upon first administration and increases to 70% with repeated use. Food intake increases bioavailability by 20-40%.

Distribution

Plasma protein binding averages 10%.

Penetrates the blood-brain barrier and placental barrier. Excreted in breast milk in small amounts.

Metabolism

Biotransformed in the liver. Metabolites do not possess pharmacological activity.

Excretion

T_1/2 averages 3.5 hours (range 1 to 9 hours). About 5% of the drug is excreted unchanged by the kidneys. Not removed by hemodialysis.

Pharmacokinetics in special clinical cases

The bioavailability of metoprolol increases in liver cirrhosis. Impaired liver function slows down the metabolism of the drug.

Indications

• Arterial hypertension (including hyperkinetic type) as monotherapy or in combination with other antihypertensive agents;
• Coronary artery disease: myocardial infarction (secondary prevention – complex therapy), prevention of angina attacks;
• Cardiac arrhythmias (supraventricular tachycardia, ventricular extrasystole);
• Hyperthyroidism (complex therapy);
• Prevention of migraine attacks.

ICD codes

Dosage Regimen

The drug is taken orally with meals or immediately after meals. Tablets can be divided in half but should not be chewed and should be taken with liquid.

For arterial hypertension, the initial dose is 50-100 mg/day in 1-2 divided doses. If necessary, the daily dose can be gradually increased to 100-200 mg. If a satisfactory therapeutic effect is not achieved, Metocard^® can be prescribed in combination with other antihypertensive agents. The maximum daily dose is 200 mg.

For angina pectoris, arrhythmia, prevention of migraine attacks, 100-200 mg/day is prescribed in 2 divided doses (morning and evening).

For secondary prevention of myocardial infarction, a dose of 200 mg/day is prescribed in 2 divided doses (morning and evening).

For functional cardiac disorders accompanied by tachycardia, the drug is prescribed at a dose of 100 mg/day in 2 divided doses (morning and evening).

In elderly patients, in cases of renal impairment, and also when hemodialysis is necessary, no dose adjustment of the drug is required.

In cases of hepatic impairment, the drug dose should be reduced depending on the clinical condition.

Adverse Reactions

From the central and peripheral nervous system: increased fatigue, weakness, headache, slowing of mental and motor reactions; rarely – paresthesia in the extremities (in patients with intermittent claudication and Raynaud’s syndrome), depression, anxiety, decreased attention, drowsiness, insomnia, nightmares, confusion or short-term memory impairment, muscle weakness.

From the sensory organs: rarely – decreased vision, decreased tear secretion, dry and painful eyes, conjunctivitis, tinnitus.

From the cardiovascular system: sinus bradycardia, palpitations, decreased blood pressure, orthostatic hypotension, dizziness, sometimes – loss of consciousness; rarely – decreased myocardial contractility, temporary worsening of symptoms of chronic heart failure (edema, swelling of the feet and/or lower legs, shortness of breath), arrhythmias, manifestation of angiospasm (worsening of peripheral circulation disorders, cold lower extremities, Raynaud’s syndrome), impaired myocardial conduction.

From the digestive system: nausea, vomiting, abdominal pain, dry mouth, diarrhea, constipation, taste changes, impaired liver function, increased activity of liver enzymes; very rarely – hyperbilirubinemia.

Dermatological reactions: urticaria, skin itching, rash, exacerbation of psoriasis, psoriasis-like skin reactions, skin hyperemia, exanthema, photodermatosis, increased sweating, reversible alopecia.

From the respiratory system: nasal congestion, difficulty exhaling (bronchospasm when prescribed in high doses – loss of selectivity and/or in predisposed patients), shortness of breath.

From the endocrine system: hyperglycemia in patients with non-insulin-dependent diabetes mellitus, hypothyroidism.

From the hematopoietic system: rarely – thrombocytopenia (unusual bleeding and hemorrhage), agranulocytosis, leukopenia.

Effect on the fetus possible intrauterine growth retardation, hypoglycemia, bradycardia.

Other: back or joint pain; in isolated cases – slight weight gain, decreased libido and/or potency.

Side effects depend on the individual sensitivity of the patient. They are usually mild and disappear after discontinuation of the drug.

Contraindications

• Cardiogenic shock;
• AV block II or III degree;
• Sinoatrial block;
• Sick sinus syndrome;
• Severe bradycardia;
• Chronic heart failure in the decompensation phase;
• Prinzmetal’s angina;
• Arterial hypotension (when used for secondary prevention of myocardial infarction – systolic blood pressure less than 100 mm Hg, heart rate less than 45 beats/min);
• Lactation period;
• Concomitant use with MAO inhibitors;
• Concomitant intravenous administration of verapamil;
• Age under 18 years;
• Hypersensitivity to metoprolol or other components of the drug, other beta-adrenergic blockers.

With caution the drug should be prescribed for diabetes mellitus, metabolic acidosis, bronchial asthma, chronic obstructive pulmonary disease (pulmonary emphysema, chronic obstructive bronchitis), obliterating peripheral vascular diseases (intermittent claudication, Raynaud’s syndrome), chronic hepatic and/or renal failure, myasthenia gravis, pheochromocytoma, AV block I degree, thyrotoxicosis, depression (including history), psoriasis, pregnancy, as well as to elderly patients.

Use in Pregnancy and Lactation

During pregnancy, Metocard^® should be used only if the expected benefit to the mother outweighs the potential risk to the fetus.

Metoprolol crosses the placental barrier. If it is necessary to use the drug during pregnancy, due to the possible development of bradycardia, arterial hypotension, and hypoglycemia in the newborn, careful monitoring of fetal development should be ensured. After delivery, strict monitoring of the newborn’s condition for 48-72 hours is necessary.

Metoprolol is excreted in breast milk. The effect of metoprolol on the newborn has not been studied, so if it is necessary to use Metocard^® during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

The drug should be used with caution in severe hepatic impairment.

Use in Renal Impairment

The drug should be used with caution in severe renal impairment.

Special Precautions

Monitoring of patients taking Metocard^® includes regular observation of heart rate and blood pressure, blood glucose levels in patients with diabetes mellitus. If necessary, the dose of insulin or oral hypoglycemic drugs for diabetic patients should be individually adjusted.

The patient should be taught the method of counting heart rate and instructed to consult a doctor if the heart rate is less than 50 beats/min. When taking a dose above 200 mg/day, cardioselectivity decreases.

In heart failure, treatment with metoprolol is started only after the compensation stage is reached.

An increase in the severity of hypersensitivity reactions (against the background of a burdened allergic history) and the absence of an effect from the administration of usual doses of epinephrine (adrenaline) are possible.

While taking Metocard^®, symptoms of peripheral arterial circulation disorders may intensify.

Discontinuation of the drug should be gradual, reducing the dose over 10 days.

Abrupt cessation of treatment may cause withdrawal syndrome (increased angina attacks, increased blood pressure). Special attention during drug withdrawal should be paid to patients with angina pectoris.

In exertional angina, the selected dose of the drug should ensure a resting heart rate within 55-60 beats/min, and during exercise – no more than 110 beats/min.

Patients using contact lenses should consider that during treatment with beta-adrenergic blockers, a decrease in tear fluid production is possible.

Metoprolol may mask some clinical manifestations of hyperthyroidism (e.g., tachycardia). Abrupt withdrawal in patients with thyrotoxicosis is contraindicated, as it can exacerbate symptoms.

In diabetes mellitus, Metocard^® may mask tachycardia caused by hypoglycemia. Unlike non-selective beta-adrenergic blockers, it practically does not enhance insulin-induced hypoglycemia and does not delay the restoration of blood glucose concentration to normal levels.

If it is necessary to prescribe to patients with bronchial asthma, beta₂-adrenergic receptor stimulants are used as concomitant therapy; in pheochromocytoma – alpha-adrenergic blockers.

If surgical intervention is necessary, the anesthesiologist must be informed about the ongoing therapy (choice of general anesthesia agent with minimal negative inotropic effect); discontinuation of the drug is not recommended.

Drugs that reduce catecholamine stores (e.g., reserpine) may enhance the effect of beta-adrenergic blockers, so patients taking such drug combinations should be under constant medical supervision for the detection of excessive blood pressure reduction and bradycardia.

In elderly patients, regular monitoring of liver function is recommended. Adjustment of the dosage regimen is required only if the elderly patient develops increasing bradycardia (less than 50 beats/min), pronounced decrease in blood pressure (systolic blood pressure below 100 mm Hg), AV block, bronchospasm, ventricular arrhythmias, severe liver function disorders; sometimes it is necessary to stop treatment.

Patients with severe renal failure are recommended to have their kidney function monitored.

Special monitoring of the condition of patients with depressive disorders taking Metoprolol should be carried out; in case of depression developing due to the intake of beta-adrenergic blockers, it is recommended to discontinue therapy.

Use in pediatrics

The safety and efficacy of the drug in children and adolescents under 18 years of age have not been established.

Effect on ability to drive vehicles and mechanisms

At the beginning of treatment with metoprolol, patients may experience dizziness and fatigue. In this case, they should refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions. Subsequently, this issue should be resolved after assessing the individual patient’s response to the therapy.

Overdose

Symptoms pronounced severe sinus bradycardia, dizziness, nausea, vomiting, cyanosis, marked decrease in blood pressure, arrhythmia, ventricular extrasystole, bronchospasm, fainting, in acute overdose – cardiogenic shock, loss of consciousness, coma, AV block (up to the development of complete transverse block and cardiac arrest), cardialgia. The first signs of overdose appear 20 minutes to 2 hours after taking the drug.

Treatment gastric lavage and administration of adsorbents, symptomatic therapy: in case of marked decrease in blood pressure, the patient should be in the Trendelenburg position; in case of excessive decrease in blood pressure, bradycardia, and heart failure – intravenous administration (at 2-5 minute intervals) of beta-adrenergic stimulants – until the desired effect is achieved or intravenous administration of 0.5-2 mg of atropine sulfate. In the absence of a positive effect – administration of dopamine, dobutamine, or norepinephrine (noradrenaline). As subsequent measures, administration of 1-10 mg of glucagon, placement of a transvenous intracardial pacemaker may be considered. For bronchospasm, intravenous administration of beta₂-adrenergic receptor stimulants should be administered.

Metoprolol is poorly removed by hemodialysis.

Drug Interactions

Concomitant use with MAO inhibitors is not recommended due to a significant increase in the hypotensive effect. The interval between taking MAO inhibitors and metoprolol should be at least 14 days.

Concomitant intravenous administration of verapamil may provoke cardiac arrest. Concomitant use of nifedipine leads to a significant decrease in blood pressure.

When used concomitantly with Metocard^®, agents for inhalational general anesthesia (hydrocarbon derivatives) increase the risk of myocardial function depression and the development of arterial hypotension.

Beta-adrenergic stimulants, theophylline, cocaine, estrogens (sodium retention), indomethacin and other NSAIDs (sodium retention and inhibition of prostaglandin synthesis in the kidneys) weaken the hypotensive effect.

An increase in the depressant effect on the central nervous system is noted with concomitant use with ethanol; summation of the cardiodepressive effect – with agents for general anesthesia; increased risk of peripheral circulation disorders – with ergot alkaloids.

When taken concomitantly with oral hypoglycemic agents, their effect may be reduced; with insulin – the risk of hypoglycemia increases, its severity and duration increase, and some symptoms of hypoglycemia (tachycardia, sweating, increased blood pressure) are masked.

When combined with antihypertensive agents, diuretics, nitroglycerin, or slow calcium channel blockers, a sharp decrease in blood pressure may develop (special caution is required when combined with prazosin).

When Metocard^® is used with verapamil, diltiazem, antiarrhythmic agents (amiodarone), reserpine, alpha-methyldopa, clonidine, guanfacine, general anesthetics, and cardiac glycosides, an increase in the severity of heart rate reduction and suppression of AV conduction is observed.

If Metoprolol and clonidine are taken simultaneously, then when discontinuing metoprolol, clonidine should be discontinued a few days later (due to the risk of withdrawal syndrome).

Inducers of liver microsomal enzymes (rifampicin, barbiturates) lead to increased metabolism of metoprolol, decreased plasma concentration of metoprolol, and reduced effect. Inhibitors of liver microsomal enzymes (cimetidine, oral contraceptives, phenothiazines) increase the plasma concentration of metoprolol.

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

Metoprolol, when used concomitantly, reduces the clearance of xanthines (except for diphylline), especially with an initially increased theophylline clearance due to smoking; reduces the clearance of lidocaine, increases the plasma concentration of lidocaine.

Metocard^®, when used concomitantly, enhances and prolongs the action of non-depolarizing muscle relaxants and prolongs the anticoagulant effect of coumarins.

When Metocard^® is used concomitantly with ethanol, the risk of a pronounced decrease in blood pressure increases.

Tricyclic and tetracyclic antidepressants, antipsychotic agents (neuroleptics), sedatives and hypnotic drugs, when used concomitantly with metoprolol, enhance depression of the central nervous system.

Storage Conditions

The drug should be stored in a dry, light-protected place, out of reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

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.