Metoprolol Retard-Akrikhin (Tablets) Instructions for Use

Marketing Authorization Holder

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

C07AB02 (Metoprolol)

Active Substance

Metoprolol (Rec.INN registered by WHO)

Dosage Forms

	Metoprolol Retard-Akrikhin	Prolonged-release film-coated tablets, 25 mg: 30 pcs.
		Prolonged-release film-coated tablets, 50 mg: 30 pcs.
		Prolonged-release film-coated tablets, 100 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release film-coated tablets of a yellowish-brown color, round, biconvex; on the break – white with a grayish or creamy tint.

Excipients : hypromellose – 155.96 mg, Ludipress LCE (lactose monohydrate – 94.7-98.3%, povidone – 3-4%) – 117.21 mg, colloidal silicon dioxide – 1.5 mg, magnesium stearate – 1.5 mg.

Shell composition ready mixture “Opadry II” orange color (polyvinyl alcohol – 6 mg, talc – 2.22 mg, macrogol – 3.03 mg, titanium dioxide – 3.36 mg, iron oxide red dye – 0.009 mg, iron oxide yellow dye – 0.378 mg, iron oxide black dye – 0.003 mg) – 15 mg.

10 pcs. – contour cell packs (3) – cardboard packs.

Prolonged-release film-coated tablets from light green to green, round, biconvex; on the break – white with a grayish or creamy tint.

Excipients : hypromellose – 161.29 mg, Ludipress LCE (lactose monohydrate – 94.7-98.3%, povidone – 3-4%) – 87.42 mg, colloidal silicon dioxide – 1.5 mg, magnesium stearate – 1.5 mg.

Shell composition ready mixture “Opadry II” green color (polyvinyl alcohol – 6 mg, talc – 2.22 mg, macrogol – 3.03 mg, titanium dioxide – 2.925 mg, quinoline yellow dye (aluminum lake) – 0.268 mg, iron oxide black dye – 0.015 mg, indigo carmine dye (aluminum lake) – 0.542 mg) – 15 mg.

10 pcs. – contour cell packs (3) – cardboard packs.

Prolonged-release film-coated tablets of a yellowish-brown color, round, biconvex; on the break – white with a grayish or creamy tint.

Excipients : hypromellose – 184.84 mg, Ludipress LCE (lactose monohydrate – 94.7-98.3%, povidone – 3-4%) – 412.84 mg, colloidal silicon dioxide – 3.5 mg, magnesium stearate – 3.5 mg.

Shell composition ready mixture “Opadry II” orange color (polyvinyl alcohol – 14 mg, talc – 5.18 mg, macrogol – 7.07 mg, titanium dioxide – 7.84 mg, iron oxide red dye – 0.021 mg, iron oxide yellow dye – 0.882 mg, iron oxide black dye – 0.007 mg) – 35 mg.

30 pcs. – polypropylene jars (1) – cardboard packs.
30 pcs. – plastic bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Beta₁-adrenoblocker

Pharmacotherapeutic Group

Beta-adrenergic blockers; selective beta-adrenergic blockers

Pharmacological Action

Cardioselective beta₁-adrenoblocker. It does not have a membrane-stabilizing effect and does not possess intrinsic sympathomimetic activity. It has antihypertensive, antianginal, and antiarrhythmic action.

By blocking beta₁-adrenergic receptors of the heart in low doses, it reduces catecholamine-stimulated formation of cAMP from ATP, reduces the intracellular flow of calcium ions, and exerts negative chrono-, dromo-, batmo-, and inotropic effects (slows 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 reciprocal increase in alpha-adrenergic receptor activity and elimination of beta₂-adrenergic receptor stimulation), returns to baseline after 1-3 days, and decreases with long-term administration.

The antihypertensive effect is due to a reduction in minute blood volume and renin synthesis, inhibition of the renin-angiotensin-aldosterone system activity (more 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. The antihypertensive effect lasts more than 24 hours.

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 reduction in myocardial sensitivity to sympathetic innervation influence.

It reduces the number and severity of angina attacks and increases exercise tolerance. Due to an increase in end-diastolic pressure in the left ventricle and increased stretching of 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 slowing of AV conduction (mainly in the antegrade and to a lesser extent in the retrograde direction through the AV node) and via accessory pathways.

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

Prevents the development of migraine.

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) 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 exerts a blocking effect on both subtypes of beta-adrenergic receptors.

Pharmacokinetics

Absorption

Absorption after oral administration is complete (95%). Fat solubility is moderate. It undergoes intensive first-pass metabolism, bioavailability is 50% on first administration and increases to 70% with repeated use. Time to reach C_max in blood plasma is 6-12 hours after drug intake. During course treatment, bioavailability increases. Food intake increases bioavailability by 20-40%.

Distribution

Plasma protein binding is 10%. It is rapidly distributed in tissues, penetrates the blood-brain barrier, placental barrier. Penetrates into breast milk.

Metabolism

Metabolized in the liver, 2 metabolites possess beta-adrenergic blocking activity. The isoenzyme CYP2D6 is involved in the drug’s metabolism.

Excretion

T_1/2 is from 3.5 to 7 hours after oral administration. It is not removed by hemodialysis.

Pharmacokinetics in special clinical cases

Significant accumulation of metabolites is observed in patients with creatinine clearance of 5 ml/min, but the beta-adrenergic blocking activity of the drug does not increase.

Bioavailability increases in liver cirrhosis, while its total clearance decreases.

Indications

• Arterial hypertension;
• Chronic heart failure functional class II-IV according to NYHA classification in the compensation stage (as part of combination therapy);
• Coronary artery disease: prevention of stable angina attacks, reduction of mortality and frequency of recurrent myocardial infarction after the acute phase of myocardial infarction;
• Heart rhythm disorders, including supraventricular tachycardia, reduction of ventricular rate in atrial fibrillation and ventricular extrasystoles;
• Functional heart disorders accompanied by tachycardia;
• Prevention of migraine attacks.

ICD codes

Dosage Regimen

The drug Metoprolol Retard-Akrikhin is taken orally once a day. The tablets are recommended to be taken in the morning, without chewing, with water. Metoprolol Retard-Akrikhin can be taken regardless of meals.

To prevent bradycardia, the dose is selected individually and increased gradually.

For arterial hypertension and angina the initial dose is 50 mg once a day; if the therapeutic effect is insufficient, the daily dose can be increased to 100-200 mg/day. For arterial hypertension, if the drug is ineffective at a dose of 100-200 mg/day, another antihypertensive agent can be added.

For chronic heart failure functional class II according to NYHA classification (without exacerbations in the last 6 weeks and without changes in combination therapy in the last 2 weeks) the recommended initial dose is 25 mg once a day. After 2 weeks, the daily dose can be increased to 50 mg, then after 2 weeks to 100 mg, and after another 2 weeks to 200 mg.

For chronic heart failure functional class III-IV according to NYHA classification the recommended initial dose is the first 2 weeks 12.5 mg once a day. It is possible to use metoprolol in another dosage form, for example, 25 mg tablets with a score. During the dose increase period, the patient should be under observation, as in some patients the symptoms of heart failure may worsen.

After 1-2 weeks, the dose can be increased to 25 mg once a day. Then after 2 weeks, the dose can be increased to 50 mg once a day. For patients who tolerate the drug well, the dose can be doubled every 2 weeks until the maximum dose of 200 mg once a day is reached.

For secondary prevention of myocardial infarction and cardiac rhythm disorders the initial dose is 100 mg once a day.

For functional heart disorders accompanied by tachycardia, 50 mg/day is prescribed; if necessary, the dose can be increased to 200 mg/day.

For prevention of migraine attacks, 100-200 mg once a day is prescribed.

Elderly patients, patients with renal impairment or patients on hemodialysis, do not require dose adjustment.

Liver function impairment affects the elimination of metoprolol, so dose adjustment may be required depending on the clinical condition.

Adverse Reactions

Frequency of side effects: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10,000 and <1/1000), very rare (<1/10,000, including isolated reports).

From the cardiovascular system: common – bradycardia, orthostatic hypotension (including with fainting), coldness of the lower extremities, palpitation sensation; uncommon – temporary worsening of heart failure symptoms, cardiogenic shock in patients with myocardial infarction, first-degree AV block; rare – myocardial conduction disorders, arrhythmia; very rare – gangrene (in patients with peripheral circulatory disorders).

From the central nervous system: very common – increased fatigue, decreased speed of mental and motor reactions; common – dizziness, headache; uncommon – paresthesia, convulsions, depression, decreased concentration, drowsiness, insomnia, nightmares; rare – asthenia, tremor, increased nervous excitability, anxiety; very rare – amnesia/memory impairment, depression, hallucinations, myasthenia.

From the sensory organs: rare – visual impairment, dry and/or irritated eyes, conjunctivitis; very rare – ringing in the ears, taste disturbance.

From the digestive system: common – nausea, abdominal pain, constipation or diarrhea; uncommon – vomiting; rare – dry oral mucosa, liver function impairment, hepatitis.

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

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

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

From the endocrine system: common – hypoglycemia (in patients with type 1 diabetes), rare – hyperglycemia (in patients with type 2 diabetes), hypothyroid state.

Other: uncommon – weight gain; rare – impotence/sexual dysfunction; very rare – arthralgia, thrombocytopenia.

Contraindications

• Cardiogenic shock;
• Second- and third-degree AV block;
• Sinoatrial block;
• Sick sinus syndrome;
• Severe bradycardia (heart rate <50 beats/min);
• Acute heart failure or chronic heart failure in the decompensation stage;
• Arterial hypotension (systolic blood pressure <100 mm Hg);
• Acute myocardial infarction (heart rate <45 beats/min, PQ interval more than 0.24 s, systolic blood pressure <100 mm Hg);
• Severe bronchial asthma;
• Severe peripheral circulatory disorders;
• Concomitant use of MAO inhibitors or simultaneous intravenous administration of verapamil;
• Pheochromocytoma (without simultaneous use of alpha-blockers);
• Age under 18 years (efficacy and safety not established);
• Lactation period;
• Lactase deficiency, lactose intolerance, glucose/galactose malabsorption syndrome;
• Hypersensitivity to metoprolol and other beta-blockers.

With caution the drug should be prescribed for diabetes mellitus, first-degree AV block, Prinzmetal’s angina, metabolic acidosis, bronchial asthma, COPD, severe renal and/or hepatic impairment, myasthenia gravis, pheochromocytoma (with simultaneous use of alpha-blockers), thyrotoxicosis, depression (including in history), psoriasis, peripheral circulatory disorders (intermittent claudication, Raynaud’s syndrome), pregnancy, as well as to elderly patients.

Use in Pregnancy and Lactation

During pregnancy, the drug Metoprolol Retard-Akrikhin should be used only for strict indications, when the expected benefit to the mother outweighs the potential risk to the fetus/child (due to the possible development of bradycardia, decreased blood pressure, hypoglycemia, and respiratory paralysis in the newborn). In this case, careful monitoring, especially of fetal development, is carried out. Treatment is discontinued 48-72 hours before the onset of labor. If this is not possible, the newborn should be under particularly careful observation for 48-72 hours after birth.

The use of the drug Metoprolol Retard-Akrikhin is contraindicated during lactation. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Liver function impairment affects the elimination of metoprolol, so dose adjustment may be required depending on the clinical condition.

Use in Renal Impairment

Patients with renal impairment or patients on hemodialysis do not require dose adjustment.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Elderly patients do not require dose adjustment.

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

Special Precautions

Monitoring of patients taking beta-blockers includes regular observation of heart rate and blood pressure. 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.

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

In elderly patients, monitoring of renal function is recommended (once every 4-5 months).

Taking the drug Metoprolol Retard-Akrikhin may intensify the symptoms of impaired peripheral arterial circulation.

In angina pectoris, 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 smoking patients, the effectiveness of beta-blockers is lower.

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

In diabetes mellitus, taking Metoprolol Retard-Akrikhin may mask tachycardia caused by hypoglycemia.

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

If surgical intervention is necessary, the anesthesiologist must be informed about taking Metoprolol Retard-Akrikhin (it is necessary to choose an agent for general anesthesia with minimal negative inotropic effect); withdrawal of the drug is not recommended.

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

In case of increasing bradycardia (less than 50 beats/min), arterial hypotension (systolic BP 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.

Abrupt withdrawal of clonidine can cause a sharp increase in BP when taking beta-blockers simultaneously. In case of clonidine withdrawal, discontinuation of beta-blockers should begin several days before discontinuing clonidine.

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

Abrupt discontinuation of treatment may cause withdrawal syndrome (increased frequency of angina attacks, increased BP). Special attention during drug withdrawal should be given to patients with angina pectoris, chronic heart failure, and after myocardial infarction. Withdrawal of Metoprolol Retard-Akrikhin is carried out gradually, reducing the dose over 10 days.

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

Effect on the ability to drive vehicles and mechanisms

During treatment, 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: marked bradycardia, AV block (up to the development of complete heart block and cardiac arrest), excessive decrease in BP, impaired peripheral circulation, increased symptoms of heart failure, cardiogenic shock, respiratory depression, apnea, cyanosis, increased fatigue, dizziness, loss of consciousness, coma, tremor, convulsions, increased sweating, paresthesia, bronchospasm, nausea, vomiting, possible development of esophageal spasm, hypoglycemia or hyperglycemia, hyperkalemia, transient myasthenia. The first signs of overdose appear 20 minutes to 2 hours after taking the drug.

Treatment: if the drug was taken recently – gastric lavage and intake of adsorbents; in case of impaired AV conduction and/or bradycardia – intravenous administration of 1-2 mg of atropine, epinephrine or placement of a temporary pacemaker; in case of decreased BP, the patient should be placed in the Trendelenburg position. If there are no signs of pulmonary edema – intravenous plasma-substituting solutions, if ineffective – administration of epinephrine, dopamine, dobutamine; in acute heart failure – cardiac glycosides, diuretics; in case of convulsions – intravenous diazepam; in case of bronchospasm – inhaled or parenteral beta₂-adrenergic agonists.

Drug Interactions

Agents that reduce catecholamine reserves (e.g., reserpine, MAO inhibitors) when used concomitantly with metoprolol may enhance the hypotensive effect or cause marked bradycardia. The break in treatment between taking MAO inhibitors and metoprolol should be at least 14 days.

Metoprolol is a substrate of the CYP2D6 isoenzyme. Drugs that inhibit or induce CYP2D6 activity may affect the plasma concentration of metoprolol.

CYP2D6 inhibitors (some antidepressants and antipsychotics, quinidine, terbinafine, celecoxib, propafenone, diphenhydramine, hydroxychloroquine, cimetidine) increase the plasma concentration of metoprolol.

CYP2D6 inducers (barbituric acid derivatives, rifampicin) decrease the plasma concentration of metoprolol.

Concomitant administration of metoprolol with cardiac glycosides, clonidine, slow calcium channel blockers (verapamil, diltiazem), amiodarone, class I antiarrhythmic agents, agents for general anesthesia, methyldopa, guanfacine may lead to decreased BP and marked bradycardia.

Inhalational anesthetics (hydrocarbon derivatives) when used concomitantly with metoprolol increase the risk of myocardial function depression and development of arterial hypotension.

Concomitant intravenous administration of verapamil may provoke cardiac arrest.

NSAIDs and beta-adrenergic agonists weaken the antihypertensive effect of beta-blockers.

Ergot alkaloids when used concomitantly with metoprolol increase the risk of peripheral circulation disorders.

When metoprolol is taken concomitantly with oral hypoglycemic drugs, a decrease in their effect is possible; with insulin – an increased risk of hypoglycemia, prolongation and intensification of its severity, masking of some symptoms of hypoglycemia (tachycardia, sweating, increased BP).

Metoprolol reduces the clearance of xanthines (except dyphylline), especially in patients with initially increased theophylline clearance due to smoking.

Metoprolol reduces the clearance of lidocaine, increases the plasma concentration of lidocaine.

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

When epinephrine is taken concomitantly with beta-blockers, an increase in BP and bradycardia are possible.

Phenylpropanolamine (norephedrine) when used concomitantly with metoprolol may increase diastolic BP.

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 radiopaque agents for intravenous administration when used concomitantly with metoprolol increase the risk of anaphylactic reactions.

When metoprolol is used concomitantly with ethanol, the risk of a marked decrease in BP increases.

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 2 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.