Vasocardin Retard (Tablets) Instructions for Use

Marketing Authorization Holder

Zentiva, a.s. (Slovakia)

ATC Code

C07AB02 (Metoprolol)

Active Substance

Metoprolol (Rec.INN registered by WHO)

Dosage Form

Vasocardin Retard

Extended-release tablets 200 mg: 30, 60, or 100 pcs.

Dosage Form, Packaging, and Composition

Extended-release tablets round, flat, white to white with a yellowish tint, with a bevel and a score on one side; marbling is allowed.

Excipients: glycerol tribehenate, calcium hydrogen phosphate dihydrate, povidone 25, colloidal anhydrous silica, hydrogenated cottonseed oil, sodium stearyl fumarate.

10 pcs. – blisters (3) – cartons.
10 pcs. – blisters (6) – cartons.
10 pcs. – blisters (10) – cartons.

Clinical-Pharmacological Group

Beta₁-adrenoblocker

Pharmacotherapeutic Group

Selective beta1-adrenergic blocker

Pharmacological Action

Relatively cardioselective beta₁-adrenergic blocker. It does not have a membrane-stabilizing effect and does not possess intrinsic sympathomimetic activity. It has hypotensive, antianginal, and antiarrhythmic effects.

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

Total peripheral vascular resistance increases at the beginning of beta-blocker use (in the first 24 hours after oral administration) (as a result of a reciprocal increase in the activity of alpha-adrenergic receptors and elimination of beta₁-adrenergic receptor stimulation), which returns to the initial level after 1-3 days, and decreases with long-term use.

The hypotensive effect is due to a decrease in cardiac output and renin synthesis, inhibition of the activity of the renin-angiotensin system (more important in patients with initial hypersecretion of renin) and the central nervous system, 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. It reduces elevated blood pressure at rest, during physical exertion, and stress.

The hypotensive effect develops rapidly (systolic blood pressure decreases after 15 minutes, maximally after 2 hours) and lasts for 6 hours; diastolic blood pressure changes more slowly: a stable decrease is observed after several weeks of regular use.

The antianginal effect is determined by a reduction in myocardial oxygen demand due to 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. It reduces the number and severity of angina attacks and increases exercise tolerance. Due to an increase in the left ventricular end-diastolic pressure and an increase in the stretching of the ventricular muscle fibers, it may increase oxygen demand, especially in patients with chronic heart failure.

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 a slowing of AV conduction (mainly 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 thyrotoxicosis, it 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-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; the severity of the atherogenic effect does not differ from that of propranolol. With long-term use, it reduces blood cholesterol concentration. When used in high doses (more than 100 mg/day), it has a blocking effect on both subtypes of beta-adrenergic receptors.

Pharmacokinetics

Absorption after oral administration is 95%. It undergoes intensive first-pass metabolism. Bioavailability is 50% upon first administration and increases to 70% with repeated use. Plasma protein binding is about 10%.

C_max in plasma is reached 6-12 hours after oral administration. Food intake increases bioavailability by 20-40%. The slow release of the active substance from the extended-release tablets ensures a uniform gradual entry into the bloodstream and distribution in tissues and a longer effect, allowing to extend the interval between individual doses. T_1/2 is 3-7 hours.

It is metabolized in the liver. Over 95% of the orally administered dose is excreted by the kidneys, 3-10% unchanged.

It is rapidly distributed in tissues, penetrates the blood-brain barrier, placental barrier, and is excreted in breast milk.

Bioavailability increases in liver cirrhosis.

Indications

• Arterial hypertension (as monotherapy or in combination with other antihypertensive agents);
• Coronary artery disease: secondary prevention after myocardial infarction, prevention of angina attacks; hyperkinetic cardiac syndrome;
• Heart rhythm disorders: sinus tachycardia, supraventricular and ventricular arrhythmias;
• Chronic heart failure (compensated) in combination with diuretics, ACE inhibitors, and cardiac glycosides;
• Prevention of migraine attacks;
• Hyperthyroidism (complex therapy).

ICD codes

Dosage Regimen

The drug should be taken orally at the same time, preferably after meals, with a small amount of liquid, without chewing. The tablets can be divided in half. The dose of the drug is selected individually.

The maximum daily dose is 400 mg.

For arterial hypertension

1 extended-release tablet 200 mg in the morning.

If a positive therapeutic effect is not achieved after using this dose, Vasocardin Retard can be used in combination with other antihypertensive agents or with diuretics.

Angina pectoris

At the initial stage of therapy, 1 extended-release tablet 200 mg/day. If necessary, the dose can be increased to 400 mg (2 tablets of 200 mg). Improvement in exercise tolerance and reduction in the number of pain attacks usually appears after a dose of 200 mg.

In elderly patients, there is generally no need for dose adjustment. However, caution should be exercised during treatment with Vasocardin Retard in elderly individuals in whom a sharp decrease in blood pressure and heart rate negatively affects the function of vital organs.

Adverse Reactions

From the cardiovascular system sinus bradycardia, pronounced decrease in blood pressure, orthostatic hypotension (dizziness, sometimes loss of consciousness); rarely – decreased myocardial contractility, development or worsening of chronic heart failure, heart rhythm disorders, manifestation of angiospasm (worsening of peripheral circulation disorders, coldness of the lower extremities, Raynaud’s syndrome), impaired myocardial conduction, cardialgia; very rarely – worsening of pre-existing AV conduction disorders.

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), tremor, convulsions, depression, anxiety, decreased attention, drowsiness, insomnia, nightmares, confusion or short-term memory loss, hallucinations, asthenia, myasthenia.

From the digestive system nausea, vomiting, dry mouth, constipation or diarrhea; in some cases — impaired liver function.

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

From the skin skin rashes (exacerbation of psoriasis), psoriasis-like skin reactions, skin hyperemia; rarely – photodermatosis, increased sweating, reversible alopecia.

From the respiratory system shortness of breath, sometimes bronchospasm (when prescribed in high doses); rarely – nasal congestion.

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

Allergic reactions urticaria, skin itching, rash.

Laboratory parameters in some cases – thrombocytopenia, increased activity of liver enzymes.

Other weight gain, rarely – decreased libido and/or potency, arthralgia.

Upon abrupt discontinuation of treatment – withdrawal syndrome (increased angina attacks, increased blood pressure).

Contraindications

• Sinoatrial and AV block II-III degree;
• Sick sinus syndrome;
• Prinzmetal’s angina;
• Acute heart failure;
• Severe bradycardia;
• Cardiogenic shock;
• Arterial hypotension (in case of use for secondary prevention of myocardial infarction, systolic blood pressure less than 100 mm Hg)
• Concomitant use of MAO inhibitors or simultaneous intravenous administration of verapamil;
• Lactation period;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to the drug and other beta-blockers;

Caution should be exercised when using the drug in diabetes mellitus, thyrotoxicosis, COPD (chronic obstructive pulmonary disease) and bronchial asthma, obliterating peripheral vascular diseases (intermittent claudication), Raynaud’s syndrome, metabolic acidosis, hepatic insufficiency, chronic renal failure, myasthenia gravis, pheochromocytoma, psoriasis, pregnancy, old age, AV block I degree.

Use in Pregnancy and Lactation

During pregnancy, it is prescribed only for strict indications (due to the possible development of bradycardia, arterial hypotension, hypoglycemia, and respiratory arrest in the newborn). Treatment should be discontinued 48-72 hours before delivery. In cases where this is not possible, strict monitoring of the newborn is necessary for 48-72 hours after delivery.

Contraindication – lactation period.

Use in Hepatic Impairment

Caution should be exercised when using the drug in hepatic insufficiency.

Use in Renal Impairment

Caution should be exercised when using the drug in chronic renal failure.

Pediatric Use

Contraindication: age under 18 years (efficacy and safety not established).

Geriatric Use

In elderly patients, it is recommended to monitor renal function (once every 4-5 months).

Special Precautions

Monitoring of patients taking beta-blockers includes observation of heart rate and blood pressure (at the beginning of administration – daily, then once every 3-4 months), blood glucose concentration in patients with diabetes mellitus (once every 4-5 months). The patient should be taught the method of counting heart rate and instructed about the need for medical consultation if the heart rate is less than 50 beats/min.

Sudden discontinuation of beta-blockers is unacceptable (if possible, treatment with metoprolol should be discontinued gradually, reducing the dose over 10 days, while the patient should be under constant medical supervision).

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

In elderly patients, it is recommended to monitor renal function (once every 4-5 months).

Metoprolol may intensify the symptoms of impaired peripheral arterial circulation.

In arterial hypertension, the effect occurs 2-5 days after the start of metoprolol administration, a stable effect is noted after 1-2 months.

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

In smokers, the effectiveness of beta-blockers is lower.

When combined therapy with clonidine, the latter should be discontinued several days after the withdrawal of metoprolol to avoid a hypertensive crisis.

Metoprolol may mask some clinical manifestations of thyrotoxicosis (e.g., tachycardia).

In diabetes mellitus, the drug may mask tachycardia caused by hypoglycemia. Unlike non-selective beta-blockers, Metoprolol 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 metoprolol to patients with bronchial asthma, beta₂-adrenergic stimulants are used as concomitant therapy; in pheochromocytoma – alpha-blockers.

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

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

In case of increasing bradycardia (less than 50 beats/min), arterial hypotension (systolic blood pressure below 100 mm Hg), AV block, bronchospasm, ventricular arrhythmia, severe impairment of liver or kidney function in elderly patients, it is necessary to reduce the dose of the drug or discontinue treatment.

It is recommended to discontinue therapy if skin rashes appear and if depression caused by taking a beta-blocker develops.

Discontinuation of metoprolol therapy should be carried out gradually, reducing the dose over 10 days.

Upon abrupt discontinuation of treatment, withdrawal syndrome may occur (increased angina attacks, increased blood pressure). Special attention during drug withdrawal should be paid to patients with angina pectoris.

Patients using contact lenses should take into account that during treatment with beta-blockers, a decrease in tear production is possible.

Effect on ability to drive vehicles and mechanisms

Due to the fact that there are individual differences in the reaction to taking metoprolol, the question of the possibility of engaging in potentially hazardous activities that require increased attention and speed of psychomotor reactions should be decided after assessing the individual patient’s response to the drug.

Overdose

Symptoms pronounced severe sinus bradycardia, dizziness, AV block (up to the development of complete transverse block and cardiac arrest), decreased blood pressure, fainting, heart rhythm disorders, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, loss of consciousness, coma, nausea, vomiting, cyanosis.

The first signs of overdose appear 20 minutes-2 hours after taking the drug.

Treatment gastric lavage and administration of adsorbent drugs. Symptomatic therapy: in case of a pronounced decrease in blood pressure, the patient should be in the Trendelenburg position; in case of excessive decrease in blood pressure, bradycardia and development of heart failure – intravenous administration of beta-adrenergic stimulants at intervals of 2-5 minutes until the desired effect is achieved or intravenous administration of 0.5-2 mg of atropine sulfate. In the absence of a positive effect – dopamine, dobutamine or norepinephrine. As subsequent measures, the administration of 1-10 mg of glucagon, placement of a transvenous intracardial pacemaker may be prescribed. For bronchospasm, intravenous beta₂-adrenergic receptor stimulants should be administered. For convulsions – slow intravenous administration of diazepam. Hemodialysis is not effective.

Drug Interactions

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 radiopaque contrast agents for intravenous administration increase the risk of anaphylactic reactions.

Phenytoin with intravenous administration, drugs for general anesthesia (hydrocarbon derivatives) increase the severity of the cardiodepressive effect and the likelihood of decreased blood pressure.

Metoprolol alters the effectiveness of insulin and oral hypoglycemic drugs, masks the symptoms of developing hypoglycemia (tachycardia, increased blood pressure).

It reduces the clearance of lidocaine and xanthines (except dyphylline) and increases their plasma concentration, especially in patients with initially increased theophylline clearance due to smoking.

The hypotensive effect of metoprolol is weakened by NSAIDs (sodium retention and blockade of prostaglandin synthesis in the kidneys), corticosteroids and estrogens (sodium retention).

Cardiac glycosides, methyldopa, reserpine and guanfacine, slow calcium channel blockers (verapamil, diltiazem), amiodarone and other antiarrhythmic drugs increase the risk of development or worsening of bradycardia, AV block, cardiac arrest and heart failure. Nifedipine may lead to a significant decrease in blood pressure.

Diuretics, clonidine, sympatholytics, hydralazine and other antihypertensive agents may lead to an excessive decrease in blood pressure.

Metoprolol prolongs the action of non-depolarizing muscle relaxants and the anticoagulant effect of coumarins.

Tricyclic and tetracyclic antidepressants, antipsychotic drugs (neuroleptics), ethanol, sedatives and hypnotics enhance central nervous system depression.

Concomitant use with MAO inhibitors is not recommended due to a significant enhancement of the hypotensive effect; the treatment interval between taking MAO inhibitors and metoprolol should be at least 14 days. Non-hydrated ergot alkaloids increase the risk of peripheral circulation disorders.

Storage Conditions

List B. Store at a temperature of 15-25°C (-13°F) in a dry place, protected from light and out of reach of children.

Shelf Life

The shelf life is 2 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.