Metoprolol Organica (Tablets) Instructions for Use

Marketing Authorization Holder

Organika, JSC (Russia)

ATC Code

C07AB02 (Metoprolol)

Active Substance

Metoprolol (Rec.INN registered by WHO)

Dosage Forms

	Metoprolol Organica	Tablets 25 mg: 20, 30, 50 or 60 pcs.
		Tablets 50 mg: 20, 30, 50 or 60 pcs.

Dosage Form, Packaging, and Composition

Tablets white or white with a yellowish tint, flat-cylindrical in shape with a bevel.

Excipients: calcium hydrogen phosphate dihydrate 20 mg, sodium carboxymethyl starch (primogel) 8.9 mg, microcrystalline cellulose 34 mg, povidone K90 (plasdone K90) 1.2 mg.

Magnesium stearate monohydrate 0.9 mg

20 pcs. – jars (1) of light-protective glass – cardboard packs.
30 pcs. – jars (1) of light-protective glass – cardboard packs.
50 pcs. – jars (1) of light-protective glass – cardboard packs.
60 pcs. – jars (1) of light-protective glass – cardboard packs.
10 pcs. – contour cell blisters (2) – cardboard packs.
10 pcs. – contour cell blisters (3) – cardboard packs.
10 pcs. – contour cell blisters (5) – cardboard packs.
10 pcs. – contour cell blisters (6) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
50 pcs. – polymer jars (1) – cardboard packs.
60 pcs. – polymer jars (1) – cardboard packs.

Tablets white or white with a yellowish tint, flat-cylindrical in shape with a bevel.

Excipients: calcium hydrogen phosphate dihydrate 40 mg, sodium carboxymethyl starch (primogel) 17.8 mg, microcrystalline cellulose 68 mg, povidone K90 (plasdone K90) 2.4 mg.

Magnesium stearate monohydrate 1.8 mg

20 pcs. – jars (1) of light-protective glass – cardboard packs.
30 pcs. – jars (1) of light-protective glass – cardboard packs.
50 pcs. – jars (1) of light-protective glass – cardboard packs.
60 pcs. – jars (1) of light-protective glass – cardboard packs.
10 pcs. – contour cell blisters (2) – cardboard packs.
10 pcs. – contour cell blisters (3) – cardboard packs.
10 pcs. – contour cell blisters (5) – cardboard packs.
10 pcs. – contour cell blisters (6) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
50 pcs. – polymer jars (1) – cardboard packs.
60 pcs. – polymer jars (1) – cardboard packs.

Clinical-Pharmacological Group

Beta₁-adrenoblocker

Pharmacotherapeutic Group

Beta-adrenergic blockers; selective beta-adrenergic blockers

Pharmacological Action

Metoprolol Organica is a cardioselective beta₁-adrenergic receptor blocker that does not possess intrinsic sympathomimetic activity or membrane-stabilizing properties. It has antihypertensive, antianginal, and antiarrhythmic effects.

Total peripheral vascular resistance (TPVR) at the beginning of beta-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 baseline after 1-3 days, and with long-term administration, it decreases.

The antihypertensive effect is due to a decrease in cardiac output and renin synthesis in the kidneys, inhibition of the renin-angiotensin-aldosterone system activity (more important in patients with initial renin hypersecretion) 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.

The antianginal effect is determined by a reduction in myocardial oxygen demand resulting from a decrease in heart rate (lengthening diastole and improving 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.

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

After oral administration, the drug is almost completely (approximately 95%) absorbed from the gastrointestinal tract. C_max in blood plasma is reached after 1.5-2 hours. Bioavailability increases by 20-40% when taken with food and increases during course treatment. Plasma protein binding is 10%. It penetrates the blood-brain barrier and placental barrier and is excreted in breast milk. It is intensively biotransformed in the liver with the formation of metabolites; two metabolites of Metoprolol Organica possess beta-adrenergic blocking activity. The isoenzyme CYP2D6 is involved in the metabolism of Metoprolol Organica. T_1/2 from plasma is about 3.5 hours. The total plasma clearance is approximately 1 L/min. It is excreted mainly by the kidneys (95%), about 3% unchanged, the rest as metabolites. In case of impaired renal function, the excretion of metabolites decreases, and the excretion of unchanged Metoprolol Organica practically does not change.

In liver cirrhosis, the bioavailability of Metoprolol Organica increases.

In elderly patients, no significant changes in the pharmacokinetics of Metoprolol Organica are observed compared to younger patients.

Impaired renal function does not require a dose reduction of the drug, but in case of impaired liver function, the dose of the drug should be reduced.

Indications

• Arterial hypertension (in monotherapy or in combination with other antihypertensive agents);
• Functional cardiac disorders accompanied by tachycardia;
• 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 tablets are taken orally simultaneously with food or immediately after a meal, the tablets can be divided in half, but should not be chewed and should be taken with liquid.

Arterial hypertension

The initial daily dose is 50-100 mg in 1-2 doses (morning and evening). If the therapeutic effect is insufficient, the daily dose can be gradually increased to 100-200 mg and/or other antihypertensive agents can be additionally prescribed. The maximum daily dose is 200 mg.

Secondary prevention of myocardial infarction

200 mg/day in two doses (morning and evening).

Angina pectoris, arrhythmias, prevention of migraine attacks

100-200 mg/day in 2 doses (morning and evening).

Functional cardiac disorders accompanied by tachycardia

100 mg/day in 2 doses (morning and evening)

For hyperthyroidism

150-200 mg/day in 3-4 doses.

In elderly patients, with impaired renal function (creatinine clearance less than 40 ml/min), and also when hemodialysis is necessary, the dose is not changed.

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

Adverse Reactions

The side effects listed below were classified as follows: common (≥1%, but <10%), uncommon (≥0.1%, but <1%), rare (≥0.01%, but <0.1%), very rare (<0.01%).

Nervous system disorders common – weakness, dizziness and headache; uncommon – decreased concentration, drowsiness/insomnia, nightmares, depression, muscle cramps, paresthesia in the extremities (in patients with intermittent claudication and Raynaud’s syndrome); rare – nervousness, anxiety, tremor, convulsions, depression, decreased attention; very rare – lethargy, increased fatigue, restlessness, confusion or short-term memory loss, hallucinations, asthenia, myasthenia.

Sensory organ disorders rare – decreased vision, xerophthalmia, decreased tear secretion, dry and painful eyes, conjunctivitis, tinnitus, hearing loss.

Cardiovascular system disorders common – sinus bradycardia, palpitations, decreased blood pressure, orthostatic hypotension (dizziness, sometimes loss of consciousness), coldness of the lower extremities; uncommon – heart failure, AV-block, edematous syndrome, chest pain; rare – decreased myocardial contractility, arrhythmias, manifestation of angiospasm (worsening of peripheral circulation disorders), impaired myocardial conduction, cardialgia; very rare – exacerbation of pre-existing AV conduction disorders.

Digestive system disorders common – nausea, abdominal pain, constipation or diarrhea; uncommon – vomiting; rare – dry oral mucosa, in some cases – impaired liver function (dark urine, jaundice of the sclera or skin, cholestasis), taste disturbance.

Skin and subcutaneous tissue disorders uncommon – rash, dystrophic skin changes; rare – reversible alopecia; very rare – photosensitivity, exacerbation of psoriasis, itching, erythema, urticaria, hyperhidrosis.

Respiratory system disorders common – dyspnea; uncommon – bronchospasm; rare – vasomotor rhinitis, dyspnea.

Endocrine system disorders rare – hyperglycemia (in patients with type 2 diabetes mellitus), hypoglycemia (type 1 diabetes mellitus), hypothyroidism.

Allergic reactions very rare – urticaria, skin itching, rash.

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

Effects on the fetus very rare – intrauterine growth retardation, hypoglycemia, bradycardia.

Other: uncommon – back or joint pain, increase or decrease in body weight, decreased libido and/or potency, upon abrupt discontinuation of treatment – withdrawal syndrome (increased angina attacks, increased blood pressure), rhinitis, arthritis, Peyronie’s disease.

Contraindications

• Cardiogenic shock;
• AV-block II-III degree (without an artificial pacemaker);
• Sinoatrial block;
• Sick sinus syndrome;
• Severe bradycardia (heart rate less than 50 beats/min);
• Chronic heart failure in the stage of decompensation;
• Prinzmetal’s angina;
• Acute myocardial infarction (heart rate less than 45 beats/min, PQ interval more than 0.25 sec, systolic blood pressure less than 100 mm Hg);
• Lactation period;
• Concomitant use of MAO inhibitors;
• Concomitant intravenous administration of slow calcium channel blockers such as verapamil, diltiazem;
• Age under 18 years (efficacy and safety have not been established);
• Pheochromocytoma (without simultaneous use of alpha-adrenergic blockers);
• Severe peripheral circulatory disorders;
• Severe forms of bronchial asthma and chronic obstructive pulmonary disease;
• Hypersensitivity to metoprolol or other components of the drug, other beta-adrenergic blockers.

Use in Pregnancy and Lactation

During pregnancy, it is prescribed after careful weighing of the benefit/risk ratio, especially in early pregnancy (due to the possible development of bradycardia, hypotension, hypoglycemia, and respiratory paralysis in the newborn). Treatment should be discontinued 48-72 hours before delivery. In cases where this is not possible, strict monitoring of the newborn for 48-72 hours after delivery is necessary.

If taking Metoprolol Organica is necessary during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

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

Use in Renal Impairment

In impaired renal function (creatinine clearance less than 40 ml/min), and also when hemodialysis is necessary, the dose is not changed.

Pediatric Use

Contraindicated

• Age under 18 years (efficacy and safety have not been established).

Geriatric Use

In elderly patients, with impaired renal function (creatinine clearance less than 40 ml/min), and also when hemodialysis is necessary, the dose is not changed.

Special Precautions

With caution: diabetes mellitus, metabolic acidosis, bronchial asthma, chronic obstructive pulmonary disease, emphysema, chronic obstructive bronchitis, impaired liver function, renal function (creatinine clearance less than 40 ml/min), myasthenia gravis, pheochromocytoma (with simultaneous use of alpha-adrenergic blockers), thyrotoxicosis, depression (including history), psoriasis, peripheral circulatory disorders (intermittent claudication, Raynaud’s syndrome), pregnancy, childhood (efficacy and safety not determined), old age, burdened allergic history, AV-block I degree.

Monitoring of patients taking beta-adrenergic 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.

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

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

It may intensify the symptoms of peripheral arterial circulation disorders.

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.

The effectiveness of beta-blockers is lower in smokers.

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

In diabetes mellitus, it may mask tachycardia caused by hypoglycemia. Unlike non-selective beta-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 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 taking Metoprolol Organica (choice of a drug for general anesthesia with minimal negative inotropic effect), discontinuation of the drug is not recommended.

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

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

The drug should be withdrawn gradually, reducing the dose over 10 days. With abrupt discontinuation of treatment, a “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 fluid production is possible.

Effect on ability to drive vehicles and operate machinery

During the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

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

Treatment gastric lavage and administration of adsorbent medications, symptomatic therapy: in case of a pronounced decrease in BP — the patient should be in the Trendelenburg position; in case of an excessive decrease in BP, bradycardia, and heart failure – IV administration at 2-5 min intervals of beta-adrenergic stimulants – until the desired effect is achieved or IV administration of 0.5-2 mg of atropine sulfate. In the absence of a positive effect — dopamine, dobutamine, or norepinephrine. As subsequent measures, placement of a transvenous intracardiac pacemaker may be considered. For bronchospasm, IV beta-adrenergic agonists should be administered. For convulsions – slow IV administration of diazepam. Hemodialysis is not effective.

Drug Interactions

With simultaneous use:

• With antiarrhythmic drugs (quinidine-like agents and amiodarone) an increase in inotropic and dromotropic effects is possible;
• With calcium channel blockers (verapamil, diltiazem, nifedipine) or other antiarrhythmics, a decrease in cardiac minute and stroke volume, heart rate occurs, and with IV administration of verapamil, there is a threat of cardiac arrest;
• With barbiturates, the metabolism of Metoprolol Organic is accelerated, which leads to a decrease in its effectiveness;
• With inducers or inhibitors of microsomal enzymes, a change in the plasma concentration of Metoprolol Organic is possible – a decrease when taking rifampicin, – an increase when taking cimetidine, ethanol, hydralazine, serotonin reuptake inhibitors (paroxetine, fluoxetine, sertraline), oral contraceptives;
• With indomethacin and other NSAIDs, COX inhibitors, a decrease in the antihypertensive effect is possible;
• With calcium channel blockers, cardiac glycosides, reserpine, nitrates, the risk of arterial hypotension, bradycardia, AV block, negative inotropic action increases;
• With insulin and oral antidiabetic agents, an increased risk of hypoglycemia;
• With narcotic drugs, inhalational anesthetics, and some other drugs affecting the CNS, particularly hypnotics (bromazepam, lorazepam), tranquilizers (chlordiazepoxide, trimetozine, tofisopam), tri- and tetracyclic antidepressants, mutual potentiation of the cardiodepressant effect;
• With allergens used for immunotherapy, or allergen extracts for skin tests, an increased risk of severe systemic reactions and anaphylaxis;
• With iodine-containing radiopaque contrast agents for IV administration, an increased risk of anaphylactic reactions;
• With norepinephrine, epinephrine, and other sympathomimetics, an increased risk of arterial hypertension;
• With phenylpropanolamine in high doses – a paradoxical increase in BP (up to a hypertensive crisis);
• With clonidine – the risk of a significant increase in BP upon abrupt withdrawal of clonidine during simultaneous use of Metoprolol Organic, therefore, in case of clonidine withdrawal, gradual discontinuation of Metoprolol Organic should be started several days before its withdrawal;
• With sympathomimetic agents, ganglion blockers, other beta-adrenergic receptor blockers (for example, eye drops), MAO-B inhibitors, careful monitoring of the patient’s condition is necessary;
• With diazepam, a decrease in clearance and an increase in the AUC of diazepam is possible, which may lead to an enhancement of its effects and a decrease in the speed of psychomotor reactions;
• With lidocaine, a possible impairment of lidocaine excretion;
• With fluoxetine leads to inhibition of Metoprolol Organic metabolism and its accumulation, which may enhance the cardiodepressant action and cause bradycardia, the likelihood of drug interaction persists even several days after withdrawal;
• With fluoxetine. A case of lethargy has been described;
• With ciprofloxacin – a decrease in the clearance of Metoprolol Organic from the body;
• With ergotamine, an increase in peripheral circulation disorders is possible;
• With estrogens, the antihypertensive effect of Metoprolol Organic decreases;
• With mibefradil in patients with low activity of the CYP2D6 isoenzyme, an increase in the plasma concentration of Metoprolol Organic and an increased risk of toxic effects are possible.

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

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.