Metoprolol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT METOPROLOL (METOPROLOL)

Composition:

Active substance: metoprolol;

1 tablet contains metoprolol tartrate, recalculated to 100 % substance – 25 mg or 50 mg or 100 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; crospovidone; povidone; talc; calcium stearate.

Medicinal form. Tablets.

Main physico-chemical properties: round-shaped tablets with a flat surface, white or white with a creamy shade, with two perpendicular intersecting grooves and bevelled edges.

Pharmacotherapeutic group. Selective β-adrenoreceptor blockers.

ATC code C07AB02.

Pharmacological properties.

Pharmacodynamics.

Metoprolol is a cardioselective β1-adrenoceptor blocker. It has no membrane-stabilizing effect and lacks intrinsic sympathomimetic activity.

It suppresses cardiac effects of increased sympathetic activity, substantially reducing heart rate, myocardial contractility, cardiac output, and arterial pressure.

In arterial hypertension, metoprolol reduces arterial pressure in patients both in the standing and supine positions. The sustained antihypertensive effect of the drug is associated with a gradual reduction in total peripheral vascular resistance.

In patients with arterial hypertension, long-term use of the drug leads to a statistically significant reduction in left ventricular mass and improvement in left ventricular diastolic function.

In men with mild to moderate arterial hypertension, metoprolol reduces mortality due to cardiovascular diseases (primarily by decreasing the incidence of sudden cardiac death, fatal myocardial infarctions, and strokes).

By reducing systemic arterial pressure, heart rate, and myocardial contractility, metoprolol decreases myocardial oxygen demand. By reducing heart rate and thereby prolonging diastole duration, metoprolol improves perfusion and oxygenation of myocardial areas with impaired blood supply.

Additionally, the drug reduces the frequency, duration, and severity of angina attacks, as well as asymptomatic ischemia, and increases exercise tolerance.

In myocardial infarction, metoprolol reduces mortality by decreasing the risk of sudden cardiac death. This effect is primarily associated with prevention of ventricular fibrillation. The reduction in mortality is observed regardless of whether metoprolol was administered early or late in the course of the disease, and also in high-risk patients and in patients with diabetes mellitus.

When administered after myocardial infarction, metoprolol reduces the likelihood of recurrent infarction.

In chronic heart failure resulting from dilated cardiomyopathy, metoprolol, initially prescribed at a low dose (2 × 5 mg daily) and gradually increased, improves cardiac function, quality of life, and physical capacity; it also reduces the number of rehospitalizations due to heart failure and the need for heart transplantation.

In supraventricular tachycardia, atrial fibrillation, and ventricular extrasystoles, metoprolol reduces ventricular rate and the number of extrasystoles.

At therapeutic doses, the peripheral vasoconstrictive and bronchoconstrictive effects of metoprolol are less pronounced than with non-selective β-adrenoceptor blockers.

Compared to non-selective β-adrenoceptor blockers, metoprolol has considerably less effect on insulin production and carbohydrate metabolism. It only slightly alters the cardiovascular response to hypoglycemia or prolongs the duration of a hypoglycemic episode.

In short-term clinical studies, metoprolol induced a slight increase in triglyceride levels and a slight decrease in serum free fatty acid levels. In some cases, a slight decrease in HDL-C (high-density lipoprotein cholesterol) levels was also observed, although this was less pronounced than with non-selective β-adrenoceptor blockers. However, in long-term clinical studies, a significant reduction in total serum cholesterol levels was demonstrated after several years of treatment with metoprolol.

Pharmacokinetics.

Metoprolol is rapidly and almost completely absorbed from the gastrointestinal tract. The pharmacokinetic parameters of metoprolol are linear within the therapeutic dose range.

Maximum plasma concentration is reached within 1.5–2 hours after administration. Following absorption, metoprolol undergoes first-pass metabolism. The bioavailability of metoprolol is approximately 50% after a single dose and nearly 70% after repeated administration.

Concomitant food intake may increase the bioavailability of metoprolol by 30–40%.

Plasma protein binding is low, about 5–10%.

Metoprolol is widely distributed in tissues and has a large volume of distribution (5.6 L/kg).

Metoprolol is metabolized in the liver by cytochrome P450 enzymes. The metabolites do not contribute to the clinical effect.

The elimination half-life (t1/2) averages 3.5 hours (ranging from 1 to 9 hours).

Total clearance is approximately 1 L/min.

Over 95% of the administered dose is recovered in urine, with 5% excreted unchanged. In some cases, the unchanged fraction may increase up to 30%.

In elderly patients, the pharmacokinetic parameters of metoprolol are not significantly altered.

Renal impairment does not affect systemic bioavailability or elimination of metoprolol. However, in such cases, metabolite excretion is reduced. Significant accumulation of metabolites has been observed in critically ill patients with renal failure (glomerular filtration rate of 5 mL/min). Nevertheless, metabolite accumulation does not increase the degree of β-blockade.

Hepatic impairment has a minor effect on the pharmacokinetic parameters of metoprolol. However, in cases of severe liver cirrhosis and following portacaval anastomosis surgery, metoprolol bioavailability may increase and total clearance may decrease. In patients after portacaval anastomosis surgery, total body clearance decreased to approximately 0.3 L/min, and the area under the concentration-time curve increased about sixfold compared to healthy individuals.

Clinical characteristics.

Indications.

• Arterial hypertension.
• Angina pectoris (including post-infarction).
• Arrhythmia (including supraventricular tachycardia).
• Prevention of sudden cardiac death and recurrent myocardial infarction after the acute phase of myocardial infarction.
• As part of complex therapy in thyrotoxicosis.
• Prophylaxis of migraine attacks.

Contraindications.

• Hypersensitivity to any component of the medicinal product or to other β-blockers;
• Second- or third-degree atrioventricular block (AV block), sinoatrial block;
• Sick sinus syndrome;
• Decompensated heart failure (pulmonary edema, hypoperfusion syndrome, or arterial hypotension); long-term or periodic inotropic therapy with β-receptor agonists;
• Marked bradycardia (heart rate ≤ 45 beats per minute);
• Cardiogenic shock;
• Severe peripheral circulatory disorders with pain or trophic changes;
• Arterial hypotension (systolic blood pressure < 100 mm Hg);
• Metabolic acidosis;
• Untreated pheochromocytoma;
• Long-term or periodic inotropic therapy with β-receptor agonists;
• Concomitant therapy with monoamine oxidase inhibitors type A (MAO-A inhibitors);
• Severe bronchial asthma, severe form of chronic obstructive bronchopulmonary diseases;
• Metoprolol is contraindicated in patients receiving intravenous administration of calcium antagonists of the verapamil and diltiazem type or other antiarrhythmic agents (such as disopyramide).

Metoprolol should not be administered to patients with suspected acute myocardial infarction if heart rate is less than 45 beats/min, PQ interval > 0.24 sec, or systolic arterial pressure < 100 mm Hg.

Note. Metoprolol may be used in patients with decompensated heart failure who are well-tolerating other medications, provided individual dose titration is performed.

Interaction with other medicinal products and other forms of interactions.

Metoprolol is a substrate of the CYP 2D6 enzyme. Drugs that inhibit CYP 2D6 may affect metoprolol plasma concentrations, e.g.: quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone, and diphenhydramine. At the beginning of treatment with these drugs, it may be necessary to reduce the dose of metoprolol.

Barbituric acid derivatives: barbiturates (including pentobarbital) stimulate metoprolol metabolism via enzyme induction.

Concomitant use of metoprolol with the following medicinal products should be avoided.

Patients should be under close monitoring if metoprolol is used concomitantly with ganglion blockers, other β-blockers (e.g., eye drops), or monoamine oxidase inhibitors (MAO inhibitors).

Propafenone: concomitant administration with propafenone should be avoided. It has been reported that in 4 patients treated with metoprolol, plasma concentrations of metoprolol increased 2–5 times after administration of propafenone, and 2 patients developed adverse effects typical of metoprolol. This interaction has been confirmed in 8 healthy volunteers. The interaction may be explained by the fact that propafenone, like quinidine, inhibits metoprolol metabolism via cytochrome P450 2D6. The outcome of this combination is unpredictable because propafenone also has β-blocking properties.

Concomitant use of metoprolol with the following medicinal products may require dose adjustment.

Clonidine: abrupt withdrawal of clonidine during β-blocker therapy may lead to increased blood pressure. If concomitant therapy with clonidine needs to be discontinued, the β-blocker should be withdrawn several days before stopping clonidine.

In patients receiving metoprolol concomitantly with calcium antagonists of the verapamil type or diltiazem and/or antiarrhythmic agents, negative inotropic and chronotropic effects may occur. Intravenous verapamil should not be administered to patients taking β-blockers due to the risk of cardiac arrest. β-Blockers may potentiate the negative inotropic and chronotropic effects of antiarrhythmic agents (quinidine analogs or amiodarone).

Amiodarone: clinical case reports confirm that marked sinus bradycardia may develop in patients taking amiodarone when metoprolol is administered concomitantly. Amiodarone has an extremely long elimination half-life (approximately 50 days), meaning that interactions may persist for a long time after discontinuation of the drug.

Class I antiarrhythmic agents: class I antiarrhythmic agents and β-blockers have additive negative inotropic effects, which may lead to serious hemodynamic adverse effects in patients with impaired left ventricular function. This combination should also be avoided in sick sinus syndrome and atrioventricular conduction disturbances. This interaction is best documented with disopyramide.

Nonsteroidal anti-inflammatory/antirheumatic drugs (NSAIDs): NSAIDs have been shown to counteract the antihypertensive effect of β-blockers. Indomethacin has been primarily studied. This interaction is unlikely with sulindac. Negative interaction has been demonstrated with diclofenac.

In patients receiving β-blockers, inhaled anesthetics may enhance the cardiodepressant effect. Inducers or inhibitors of metabolism may affect metoprolol plasma concentrations.

Metoprolol plasma concentration may be reduced by rifampicin or increased by cimetidine, phenytoin, alcohol, hydralazine, and serotonin reuptake inhibitors (paroxetine, fluoxetine, and sertraline).

When used concomitantly with indomethacin or other drugs that inhibit prostaglandin synthase, the antihypertensive effect of β-blockers may be reduced.

Cardioselective β-blockers have a significantly lesser effect on blood pressure when adrenaline is administered compared to non-selective β-blockers.

Diltiazem: diltiazem and β-receptor blockers have additive inhibitory effects on AV conduction and sinus node function, potentially leading to marked bradycardia.

Epinephrine: severe arterial hypertension and bradycardia have been reported in patients (approximately 10 reports) who received non-selective β-receptor blockers (including pindolol and propranolol) after epinephrine (adrenaline) administration. Moreover, epinephrine contained in local anesthetics may provoke these reactions if administered intravascularly. The risk is likely lower when cardioselective β-receptor blockers are used.

Phenylpropanolamine: phenylpropanolamine (norephedrine), in a single dose of 50 mg, may cause pathological increase in diastolic blood pressure in healthy volunteers. Propranolol generally counteracts the blood pressure increase caused by phenylpropanolamine. β-Blockers may provoke paradoxical hypertensive reactions in patients taking high doses of phenylpropanolamine. Two cases of hypertensive crisis have been described during treatment with phenylpropanolamine alone.

Dose adjustment of oral antidiabetic agents may be required in patients receiving β-blockers. Concomitant use of β-blockers with insulin or oral antidiabetic agents may potentiate or prolong their effects. In such cases, symptoms of hypoglycemia (especially tachycardia and tremor) may be masked or absent. Regular monitoring of blood glucose levels is necessary.

Concomitant use with barbiturates should be avoided, as barbiturates (studied with pentobarbital) stimulate metoprolol metabolism via enzyme induction.

Drugs that inhibit CYP 2D6, such as quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone, and diphenhydramine, may affect metoprolol plasma concentrations. At the beginning of treatment with these drugs, dose reduction of metoprolol may be necessary.

Digitalis glycosides: concomitant use of digitalis glycosides and β-receptor blockers may increase atrioventricular conduction time and cause bradycardia.

Diphenhydramine: diphenhydramine reduces (by 2.5 times) the clearance of metoprolol to α-hydroxymetoprolol via the CYP 2D6 system in individuals with rapid hydroxylation. This leads to enhanced effects of metoprolol. Diphenhydramine may also inhibit the metabolism of other CYP 2D6 substrates.

Rifampicin: rifampicin may stimulate metoprolol metabolism, leading to reduced plasma levels.

Caution is advised when combining with nitrates due to the risk of arterial hypotension and/or bradycardia.

Patients receiving ganglion blockers concomitantly with metoprolol should be under close observation.

Metoprolol may impair lidocaine elimination.

Metoprolol should be prescribed with caution in patients using β2- and β1-receptor stimulants, as well as dihydropyridines.

Caution is required when using metoprolol concomitantly with ergotamine.

Combination of metoprolol with other antihypertensive agents should be done with caution.

Special precautions for use.

When taking metoprolol tartrate, as with other β-blockers, heart rate (HR) and blood pressure (BP) should be monitored (initially daily, then once a month).

Patients receiving β-blockers should not be given intravenous calcium antagonists of the verapamil type.

Generally, patients with asthma who are treated with β-blockers should also receive concomitant β2-agonists (in tablets or aerosol form). When such patients start taking the drug, an increased dose of β2-agonists may be required. The risk of the drug affecting β2-receptors is lower than with conventional non-selective β1-blockers in tablet form.

Particular medical supervision is necessary when treating patients with diabetes mellitus (monitoring blood glucose levels), patients with unstable blood sugar levels, or those on strict diets involving fasting. During treatment with metoprolol, the risk of affecting glucose metabolism or masked hypoglycemia is minimal compared to treatment with non-selective β-blockers.

Metoprolol may mask some clinical signs of thyrotoxicosis (e.g., tachycardia). Abrupt discontinuation of the drug in patients with thyrotoxicosis is contraindicated due to the possible exacerbation of symptoms.

Patients undergoing treatment for heart failure should have their condition stabilized before initiating metoprolol therapy and during such treatment.

Very rarely, pre-existing AV conduction disturbances may progress to more severe degrees of AV block. Patients with first-degree AV block should be treated with this drug very cautiously.

Sudden withdrawal of beta-blockers is dangerous, especially in high-risk patients, and may worsen chronic heart failure, as well as increase the risk of myocardial infarction and sudden death. Therefore, discontinuation of metoprolol for any reason should be done gradually, if possible, over at least 2 weeks, with the dose halved at each step until the final dose of 12.5 mg (half of a 25 mg tablet). The final dose should be taken for at least 4 days before complete discontinuation. If symptoms recur, the dose reduction should be slowed.

Metoprolol should be used with caution in patients with myasthenia gravis.

Metoprolol may exacerbate pre-existing bradycardia. If bradycardia develops during treatment (HR less than 50–55 beats/min), the dose should be reduced and/or the drug gradually discontinued.

Due to its hypotensive effect, the drug may exacerbate symptoms of peripheral circulatory disorders such as intermittent claudication.

If metoprolol is administered to patients with pheochromocytoma, an α-sympatholytic agent should be used concomitantly.

Before general anesthesia, the anesthesiologist must be informed that the patient is taking metoprolol. In case of surgery, the anesthesiologist should be warned that the patient is on metoprolol. Discontinuation of β-blocker therapy in patients scheduled for surgery is not recommended. If discontinuation of metoprolol is considered necessary, it should occur, if possible, at least 48 hours before general anesthesia. Emergency use of high-dose metoprolol in patients after non-cardiac surgery should be avoided, as it may lead to bradycardia, arterial hypotension, and stroke, including fatal outcomes in patients with cardiovascular risk factors.

However, beta-blockers may be beneficial as premedication for certain patients. In such cases, an anesthetic with minimal negative inotropic effect should be selected to minimize the risk of myocardial depression.

Metoprolol may cause a slight increase in triglyceride levels and a decrease in free fatty acids in the blood. In some cases, a slight reduction in low-density lipoprotein (LDL) levels has been observed, which is significantly less pronounced than with non-selective β2-blockers. However, in one long-term study, a significant reduction in total cholesterol levels was observed after several years of metoprolol treatment.

There is limited experience with the use of metoprolol in patients with heart failure and the following comorbidities: unstable heart failure (NYHA IV, according to the New York Heart Association classification); acute myocardial infarction or unstable angina within the previous 28 days; renal or hepatic impairment; patient age over 80 or under 40 years; hemodynamically significant valvular disease; hypertrophic obstructive cardiomyopathy; during or within 4 months after cardiac surgery. Treatment of such patients should be managed by physicians with specialized skills and experience.

In patients with Prinzmetal's angina, the frequency and severity of angina attacks may increase due to α-receptor-mediated coronary vasoconstriction. Therefore, non-selective β-blockers should not be prescribed to these patients, and selective β1-blockers should be used with caution.

In patients receiving β-blockers, adrenaline may increase blood pressure and cause (reflex) bradycardia; this reaction is less likely with selective β-blockers.

Very rarely, pre-existing moderate atrioventricular conduction disturbances may worsen, sometimes progressing to atrioventricular block.

Anaphylactic shock may be more severe in patients receiving β-blocker therapy.

Patients with a history of severe allergic reactions require caution when treated with metoprolol. Particular attention should also be paid to patients undergoing allergen immunotherapy (desensitization therapy). The effect of standard doses of adrenaline may be absent.

Patients using contact lenses should be aware that the drug may reduce tear secretion.

Metoprolol therapy should be prescribed to patients with psoriasis or a history of depressive disorders only after careful assessment of benefit versus risk.

The bioavailability of metoprolol may be increased in liver cirrhosis.

Special attention should be given to patients with severe renal impairment, serious acute conditions associated with metabolic acidosis, and patients receiving combined therapy with cardiac glycosides.

The drug contains lactose and therefore should not be administered to patients with hereditary lactase deficiency, galactose intolerance, or glucose/galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Metoprolol, like other medicinal products, should not be used during pregnancy or breastfeeding unless absolutely necessary. Like other β-adrenergic blockers, metoprolol may cause adverse effects such as bradycardia and hypoglycemia in the fetus and newborn or in the breastfed infant.

Generally, β-blockers reduce placental blood flow, which may lead to fetal growth retardation. Metoprolol may cause bradycardia, arterial hypotension, hypoglycemia, and respiratory depression in newborns; therefore, its use should be discontinued 48–72 hours before the expected onset of labor. If this is not possible, the newborn should be closely monitored for 48–72 hours after birth.

On the other hand, the amount of metoprolol transferred to the infant through breast milk is generally insufficient to produce significant β-adrenergic blockade effects, provided the mother's dose is within the therapeutic range. However, breastfed infants should be closely monitored for potential signs of β-blockade.

Ability to affect reaction speed when driving or operating machinery. The use of metoprolol may affect activities requiring high speed of mental and physical reactions and quick decision-making (e.g., driving vehicles, operating machinery, working at heights). Therefore, such activities should be avoided during treatment.

Dosage and Administration

Metoprolol is intended for daily use, preferably in the morning. Tablets should be taken independently of food intake. The tablet should be swallowed whole with sufficient amount of drinking water, without chewing. The dose should be individually adjusted and gradually increased to avoid excessive bradycardia. During dose titration, heart rate should be monitored to prevent bradycardia. The maximum daily dose is 400 mg.

Hypertension. The recommended dose is 100 mg (once daily in the morning or divided into two doses – in the morning and evening). If the therapeutic effect is not achieved at this dosage, the daily dose may be increased to 200 mg (once daily in the morning or divided into two doses – in the morning and evening), or the drug may be combined with other antihypertensive agents.

Angina pectoris. The recommended dose is 50–100 mg 2–3 times daily. If necessary, the drug may be combined with other antianginal agents.

Arrhythmia. The recommended dose is 50 mg 2–3 times daily. If necessary, the daily dose may be increased to 300 mg, divided into 2–3 doses.

Myocardial infarction (treatment should preferably begin within the first 12 hours after onset of chest pain). The recommended dose is 50 mg every 6 hours for 48 hours, followed by a maintenance dose of 200 mg daily, divided into two doses. The treatment course should last at least 3 months.

Hyperthyroidism (thyrotoxicosis). The recommended dose is 50 mg four times daily. After achieving the therapeutic effect, the dose should be gradually reduced.

Migraine prophylaxis. The recommended daily dose is 100–200 mg, divided into two doses.

Patients with renal impairment. Dose adjustment is not required.

Patients with hepatic impairment. Dose adjustment (reduction of metoprolol dose) is usually necessary for patients with impaired liver function (e.g., patients with liver cirrhosis).

Elderly patients. Dose adjustment is not required.

Hypertension: in mild to moderate hypertension, the initial dose is 25 mg.

Children. The use of the drug is contraindicated in children.

Overdose.

Toxicity. In adults, ingestion of a 7.5 g dose has caused fatal intoxication. Ingestion of 100 mg by a 5-year-old child did not result in symptoms of intoxication after gastric lavage. A dose of 450 mg caused moderate intoxication in a 12-year-old child, and a dose of 1.4 g caused moderate intoxication in an adult. A dose of 2.5 g caused severe intoxication in an adult, and a dose of 7.5 g caused very severe intoxication.

Symptoms. The most severe symptoms are cardiovascular; however, in some cases, especially in children and young individuals, central nervous system symptoms and respiratory depression may predominate. Arterial hypotension, sinus bradycardia, AV block of I–III degree, QT interval prolongation (rare), heart failure, cardiogenic shock, asystole, nausea, vomiting, bronchospasm, cyanosis, hypoglycemia, loss of consciousness, coma, and in some cases, hypokalemia may occur. Respiratory depression and respiratory arrest may also occur.

Other symptoms: fatigue, confusion, fine tremor, seizures, sweating, paresthesia, bronchospasm, nausea, vomiting, possible esophageal spasm, hypoglycemia (especially in children) or hyperglycemia, hyperkalemia. Renal effects. Transient myasthenic syndrome. Initial signs of overdose may appear 20 minutes to 2 hours after ingestion of an excessive dose.

Concomitant alcohol consumption, use of antihypertensive drugs, quinidine, or barbiturates may worsen the patient's condition.

Treatment. Intensive therapy and close monitoring of the patient are required (circulatory and respiratory parameters, renal function, blood glucose, serum electrolytes). If the drug was recently ingested, further absorption can be reduced by gastric lavage, induction of emesis, and administration of activated charcoal.

NB! Atropine (0.25–0.5 mg intravenously for adults, 10–20 mcg/kg body weight for children) should be administered prior to gastric lavage (due to the risk of vagal stimulation). Intubation and mechanical ventilation may be necessary; adequate volume restoration; glucose infusion; ECG monitoring; repeated intravenous administration of atropine 1–2 mg (mainly for vagal symptoms). In case of myocardial depression: infusion of dobutamine or dopamine and calcium gluconate 9 mg/mL, 10–20 mL.

Glucagon 50–150 mcg/kg body weight may be administered intravenously over 1 minute, as well as amrinone. In some cases, epinephrine (adrenaline) has been effective.

Infusion of sodium (chloride or bicarbonate) in case of QRS complex widening and arrhythmia. A cardiac pacemaker may be used. In case of circulatory arrest, resuscitation measures may be required for several hours. In case of bronchospasm, terbutaline (injection or inhalation) should be administered. Symptomatic therapy.

Adverse reactions.

Metoprolol is well tolerated by patients, and adverse effects that occur are usually mild and transient.

In the table below, adverse reactions to metoprolol are listed according to the MedDRA organ classification:

Table

*The frequency of such adverse effects as skin reactions or eye irritation is low, and symptoms usually disappear after discontinuation of therapy.

Shelf life. 5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets in a blister pack. 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's name and address of business location. 139 Saksaganskogo Street, Kyiv, 01032, Ukraine.