CARDOLAX

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARDOLAX (CARDOLAX)

Composition:

Active substance: metoprolol;

1 ml of solution contains metoprolol (as metoprolol tartrate) 1 mg;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colourless solution.

Pharmacotherapeutic group.

Selective β-adrenoreceptor blockers. ATC code C07AB02.

Pharmacological properties.

Pharmacodynamics.

Intravenous metoprolol therapy in myocardial infarction reduces the intensity of chest pain and decreases the incidence of atrial fibrillation and flutter. Early administration (within 24 hours after the onset of the first symptoms) helps limit the development and spread of the myocardial infarction area. Early initiation of therapy enhances the therapeutic benefits.

In paroxysmal supraventricular tachycardia and atrial fibrillation/flutter, a reduction in ventricular heart rate is observed.

Metoprolol is a selective β1-receptor blocker, meaning it affects cardiac β1-receptors at lower doses than those required to influence β2-receptors in peripheral blood vessels and bronchi. As the dose of metoprolol increases, β1-selectivity may decrease.

Metoprolol lacks intrinsic β-stimulating activity and exhibits minimal membrane-stabilizing activity. β-receptor blockers exert negative inotropic and chronotropic effects.

Metoprolol reduces the effects of catecholamines during physical and psychoemotional stress, decreases heart rate, cardiac output, and arterial blood pressure. In stressful situations associated with increased adrenaline release from the adrenal glands, metoprolol does not interfere with normal physiological vasodilation. At therapeutic doses, metoprolol causes less bronchial smooth muscle contraction than non-selective β-blockers. This property allows metoprolol to be used in combination with β2-receptor agonists in patients with bronchial asthma or other significant obstructive lung diseases. Metoprolol affects insulin release and carbohydrate metabolism to a lesser extent than non-selective β-blockers, making it suitable for use in patients with diabetes mellitus. Cardiovascular responses to hypoglycemia, including tachycardia, are less pronounced with metoprolol, and blood glucose recovery occurs faster compared to non-selective β-receptor blockers.

Pharmacokinetics.

Metoprolol is metabolized in the liver primarily via CYP2D6. Three major metabolites have been identified, none of which exhibit any clinically significant beta-blocking activity. The elimination half-life from plasma is 3–5 hours. Approximately 5% of metoprolol is excreted unchanged by the kidneys, while the remainder is excreted as metabolites.

Clinical characteristics.

Indications.

• Supraventricular tachyarrhythmia.
• Prevention and treatment of myocardial ischemia, tachyarrhythmia, and pain when acute myocardial infarction is suspected or diagnosed.

Contraindications.

• Established hypersensitivity to metoprolol, to other β-blockers, and/or to excipients of the medicinal product.
• Cardiogenic shock.
• Sick sinus syndrome (in the absence of a permanent pacemaker).
• Second- and third-degree atrioventricular block (AV block).
• Unstable, uncompensated heart failure (pulmonary edema, hypoperfusion, or arterial hypotension); ongoing or intermittent inotropic therapy with β-adrenoceptor agonists.
• Symptomatic bradycardia or arterial hypotension. Metoprolol should not be administered to patients with suspected acute myocardial infarction until heart rate is ≥ 45 beats/minute, PQ interval is ≤ 0.24 seconds, and systolic blood pressure is ≥ 100 mm Hg.
• Systolic blood pressure below 110 mm Hg in patients with supraventricular tachyarrhythmia.
• Severe peripheral vascular disease with risk of gangrene.

Interaction with other medicinal products and other forms of interaction.

Metoprolol is a substrate of the CYP2D6 enzyme. Medicinal products that inhibit CYP2D6 activity may affect plasma concentrations of metoprolol: quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone, and diphenhydramine. When initiating treatment with these medicinal products, dose reduction of metoprolol may be necessary.

Concomitant use of metoprolol with the following agents should be avoided.

Barbiturates.

When used concomitantly with metoprolol, barbiturates (investigated for pentobarbital) stimulate metoprolol metabolism via enzyme induction.

Propafenone.

When used concomitantly with metoprolol, propafenone (similarly to quinidine) may inhibit metoprolol metabolism via the cytochrome P450 2D6 system. The outcome of this combination is likely unpredictable, as propafenone also possesses β-blocking properties.

Verapamil.

When used concomitantly with β-blockers (reported for atenolol, propranolol, and pindolol), verapamil may cause bradycardia and reduced arterial blood pressure. Verapamil and β-blockers (including metoprolol) exert additive inhibitory effects on atrioventricular conduction (AV conduction) and sinus node function.

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

Amiodarone.

Studies have shown that marked sinus bradycardia may develop in patients receiving amiodarone when used concomitantly with metoprolol. Amiodarone has an extremely long elimination half-life (approximately 50 days); therefore, interaction may occur for a prolonged period after discontinuation of amiodarone.

Class I antiarrhythmic agents.

When used concomitantly, class I antiarrhythmics and β-blockers (including metoprolol) exert additive negative inotropic effects, which may lead to serious hemodynamic adverse reactions in patients with impaired left ventricular function. Concomitant use of these agents should be avoided in patients with sick sinus syndrome and impaired AV conduction. This interaction is best documented for disopyramide.

Non-steroidal anti-inflammatory drugs (NSAIDs) and antirheumatic agents.

NSAIDs have been shown to antagonize the antihypertensive effect of β-blockers (including metoprolol). This interaction has been primarily studied with indomethacin. The interaction is unlikely with sulindac. A negative interaction has been demonstrated with diclofenac.

Diphenhydramine.

When used concomitantly, diphenhydramine reduces (by 2.5-fold) the clearance of metoprolol to α-hydroxy-metoprolol via the CYP2D6 system in individuals who are rapid hydroxylators. The effects of metoprolol are potentiated.

Digitalis glycosides.

When used concomitantly, digitalis glycosides and β-blockers (including metoprolol) may increase AV conduction time and may also cause bradycardia.

Diltiazem.

When used concomitantly, diltiazem and β-blockers (including metoprolol) exert additive inhibitory effects on AV conduction and sinus node function. Marked bradycardia has also been observed (case reports).

Epinephrine.

After administration of epinephrine (adrenaline), pronounced arterial hypertension and bradycardia have been reported in patients receiving non-selective β-blockers (including pindolol and propranolol) (approximately 10 reports). These clinical observations have been confirmed in studies involving healthy volunteers. Additionally, epinephrine used in local anesthesia may provoke such reactions upon intravascular injection. This risk is likely lower with cardioselective β-blockers.

Phenylpropanolamine.

Phenylpropanolamine (norephedrine) at a single dose of 50 mg may cause pathological increase in diastolic blood pressure in healthy volunteers. Propranolol generally counteracts the blood pressure increase induced by phenylpropanolamine. However, concomitant use of β-blockers (including metoprolol) may provoke paradoxical hypertensive reactions in patients receiving high doses of phenylpropanolamine. Hypertensive crisis has been described in several cases during treatment with phenylpropanolamine alone.

Quinidine.

When used concomitantly, quinidine inhibits the metabolism of metoprolol in individuals who are rapid hydroxylators (more than 90% of the Swedish population), resulting in a significant increase in plasma levels and enhanced β-receptor blockade. A similar interaction may occur with other β-blockers metabolized by the same enzyme (cytochrome P450 2D6).

Clonidine.

When used concomitantly, β-blockers (including metoprolol) may potentiate the hypertensive response upon abrupt withdrawal of clonidine. If concomitant treatment with clonidine needs to be discontinued, the β-blocker should be withdrawn several days before stopping clonidine.

Rifampicin.

When used concomitantly, rifampicin may stimulate the metabolism of metoprolol, leading to reduced plasma levels.

Other β-blockers, monoamine oxidase inhibitors (MAO inhibitors).

Patients receiving concomitant treatment with these agents and metoprolol should be under close monitoring.

Inhalational anesthetics.

When used concomitantly with metoprolol, the cardiodepressant effect is enhanced.

Oral antidiabetic agents.

When used concomitantly with metoprolol, dose adjustment of oral antidiabetic agents may be required.

Cimetidine, hydralazine.

When used concomitantly, plasma concentration of metoprolol may increase.

Special precautions for use.

Verapamil should not be administered to patients receiving β-blockers (including metoprolol).

When using the medicinal product in patients with suspected or confirmed heart failure, the patient's haemodynamic status should be carefully monitored after each dose. Treatment must be discontinued if any worsening of dyspnoea or development of cold sweat occurs.

Metoprolol may exacerbate symptoms of peripheral arterial circulation disorders, such as intermittent claudication.

When using the medicinal product in patients with severe renal impairment or concomitant use of cardiac glycosides, the benefit-risk ratio should be carefully considered.

The medicinal product should not be used in patients with latent or manifest heart failure without concomitant therapy.

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

When using the medicinal product in patients with bronchial asthma or other chronic obstructive pulmonary diseases, adequate bronchodilator therapy should be administered concomitantly. An increased dose of β₂-receptor agonists may be required.

Metoprolol may affect carbohydrate metabolism or mask symptoms of hypoglycaemia, although this risk is lower than with non-selective β-blockers.

Very rarely, the condition of patients with existing moderate-degree AV conduction disturbances may worsen (potentially leading to the development of AV block).

β-blocker therapy (including metoprolol) may impair the effectiveness of treatment for anaphylactic reactions.

If the medicinal product is administered to patients with phaeochromocytoma, concomitant treatment with an α-blocker should be considered.

If discontinuation of the medicinal product is necessary, it should be done gradually over a period of 2 weeks, as abrupt withdrawal may worsen angina symptoms and increase the risk of myocardial infarction.

In case of surgical intervention, the anaesthesiologist should be informed about the use of the medicinal product. Discontinuation of β-blocker therapy in patients undergoing surgery is not recommended. Emergency initiation of high doses of the medicinal product in patients scheduled for non-cardiac surgery should be avoided, as this may lead to bradycardia, arterial hypotension, and stroke, including fatal outcomes, in patients with existing cardiovascular risk factors.

The second or third dose of the medicinal product should not be administered if the heart rate is < 40 beats per minute, systolic blood pressure is < 90 mm Hg, or the P-Q interval is > 0.26 seconds.

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

The medicinal product should not be used during pregnancy and breastfeeding unless absolutely necessary.

In general, β-blockers reduce placental blood flow, which may lead to intrauterine growth retardation, fetal death, miscarriage, and preterm delivery. Therefore, appropriate monitoring of the pregnant woman and fetus is recommended when metoprolol is used during pregnancy. β-blockers may cause bradycardia in the fetus and newborn. This should be taken into account when prescribing these medicinal products in the third trimester of pregnancy and during delivery.

The medicinal product should be gradually discontinued 48–72 hours before the planned delivery. If this is not possible, the newborn should be monitored for 48–72 hours after delivery to detect symptoms of β-adrenoceptor blockade (e.g., cardiac and respiratory complications).

Breastfeeding period.

The concentration of metoprolol in breast milk is approximately three times higher than the plasma concentration in the mother. The risk of adverse reactions in breastfed infants is low when the mother is receiving therapeutic doses of metoprolol. However, monitoring of the breastfed infant should be performed, with attention to signs of β-adrenoceptor blockade.

Ability to affect reaction speed when driving or operating machinery.

Dizziness and fatigue may occur during metoprolol use, which patients should consider when driving or operating machinery.

Method of Administration and Dosage

The medicinal product is intended for parenteral administration.

Parenteral administration of metoprolol should be performed under the supervision of specially trained personnel in facilities where arterial pressure can be measured, ECG recorded, and resuscitation measures carried out.

Supraventricular tachyarrhythmia.

Initially, the medicinal product should be administered intravenously at a dose of 5 mg (= 5 mL) at a rate of 1–2 mg/min. This dose may be repeated every 5 minutes until the desired effect is achieved. Usually, a total dose of 10–15 mg (= 10–15 mL) is sufficient. The recommended maximum dose for intravenous administration is 20 mg (= 20 mL).

Prophylaxis and treatment of myocardial ischemia, tachyarrhythmia, and pain in suspected or diagnosed myocardial infarction.

Acute condition: the medicinal product should be administered intravenously at a dose of 5 mg (= 5 mL). This dose may be repeated every 2 minutes; the maximum dose is 15 mg (= 15 mL). Fifteen minutes after the last injection, 50 mg of metoprolol should be administered orally every 6 hours for 48 hours.

Special Patient Categories.

Patients with impaired renal function.

Renal function has only a minor effect on the elimination rate of metoprolol; therefore, dose adjustment is not necessary in these patients.

Patients with impaired hepatic function.

Generally, patients suffering from liver cirrhosis can receive the same dose of metoprolol as patients with normal liver function. Only in cases of signs of very severe hepatic dysfunction (e.g., patients who have undergone shunt surgery) should a reduction in the dose of the medicinal product be considered.

Elderly patients.

Dose adjustment is not required for these patients.

Children.

Experience with the use of metoprolol in children is limited.

Overdose.

Toxicity.

Administration of metoprolol at a dose of 7.5 g in adults has led to intoxication with a fatal outcome. Administration of 100 mg in a 5-year-old child did not result in any symptoms after gastric lavage. Administration of 450 mg in a 12-year-old child and 1.4 g in an adult caused moderate intoxication; administration of 2.5 g in an adult led to severe intoxication, and administration of 7.5 g in an adult resulted in very severe intoxication.

Symptoms.

Cardiovascular symptoms are the most significant; however, in some cases, particularly in children and young individuals, symptoms from the central nervous system (CNS) and respiratory depression may predominate. Observed symptoms include bradycardia, I–III degree AV block, QT interval prolongation (rare cases), asystole, drop in arterial pressure, inadequate peripheral perfusion, heart failure, cardiogenic shock, respiratory depression, apnea.

Other symptoms: fatigue, confusion, loss of consciousness, fine tremor, seizures, increased sweating, paresthesia, bronchospasm, nausea, vomiting, possible esophageal spasm, hypoglycemia (especially in children) or hyperglycemia, hyperkalemia. Renal effects. Transient myasthenic syndrome. Concomitant alcohol consumption, use of antihypertensive agents, quinidine, or barbiturates may worsen the patient's condition. Initial signs of overdose may appear 20 minutes to 2 hours after oral intake of metoprolol.

Treatment.

Treatment of overdose should be carried out in a department capable of providing appropriate therapeutic interventions, monitoring, and observation.

Atropine, adrenergic stimulants, or a pacemaker are used to correct bradycardia and conduction disturbances.

Therapeutic measures for arterial hypotension, acute myocardial infarction, and shock should include adequate increase in circulating blood volume, administration of glucagon (with subsequent intravenous glucagon infusion if necessary), intravenous administration of an adrenergic stimulant such as dobutamine, with addition of α1-receptor agonists until vasodilation occurs. Intravenous Ca2+ administration may also be performed.

Intubation and artificial ventilation of the lungs should be performed with very broad indications. A cardiac pacemaker may be used. In case of circulatory arrest due to overdose, resuscitation measures may be required for several hours.

Bronchospasm can usually be relieved by the use of bronchodilators.

Adverse reactions.

Adverse reactions occur in approximately 10% of patients and are usually dose-dependent.

The adverse reactions associated with the use of metoprolol are listed below by system organ class and frequency.

The following frequency definitions are used: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated from the available data).

Blood and lymphatic system disorders:

rare – thrombocytopenia.

Psychiatric disorders:

uncommon – depression, nightmares, sleep disorders; rare – memory impairment, confusion, nervousness, anxiety, hallucinations; frequency not known – attention disorders.

Nervous system disorders:

common – headache, dizziness; uncommon – paraesthesia.

Eye disorders:

rare – visual disturbances, dryness and/or eye irritation; frequency not known – conjunctivitis.

Ear and labyrinth disorders:

rare – tinnitus.

Respiratory, thoracic and mediastinal disorders:

common – dyspnea on exertion; uncommon – bronchospasm in patients with bronchial asthma or asthmatic conditions; frequency not known – rhinitis.

Cardiac disorders:

common – bradycardia, palpitations; uncommon – chest pain, transient exacerbations of heart failure, cardiogenic shock in patients with acute myocardial infarction; rare – prolonged AV conduction time, cardiac arrhythmia.

Vascular disorders:

common – cold extremities; rare – syncope; frequency not known – gangrene in patients with severe peripheral vascular disorders.

Gastrointestinal disorders:

common – abdominal pain, nausea, vomiting, diarrhea, constipation; rare – taste disturbances; frequency not known – dry mouth.

Skin and subcutaneous tissue disorders:

uncommon – skin hypersensitivity reactions; rare – exacerbation of psoriasis, photosensitivity reactions, increased sweating, alopecia.

Musculoskeletal and connective tissue disorders:

frequency not known – muscle cramps, joint pain.

General disorders and administration site conditions:

very common – increased fatigue; uncommon – edema, weight gain.

Hepatobiliary disorders:

rare – increased transaminase levels; frequency not known – hepatitis.

Reproductive system and breast disorders:

rare – reversible libido dysfunction.

Metoprolol administered intravenously may rarely cause clinically significant hypotension.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C, protected from light and kept out of the reach of children.

Incompatibilities.

40 ml (8 ampoules) of the injection solution, corresponding to 40 mg of metoprolol tartrate, may be added to 1000 ml of one of the following infusion solutions: sodium chloride 9 mg/ml, mannitol 150 mg/ml, glucose 100 mg/ml, glucose 50 mg/ml, fructose 200 mg/ml, invertose 100 mg/ml, Ringer's solution, Ringer's solution with glucose, Ringer's solution with acetate.

The medicinal product must not be added to Macodex.

Packaging.

5 ml in ampoules; 10 ampoules in a blister pack; 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Mefar Ilac San. A.S., Turkey.

Manufacturer's address.

Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.