Amiodarone concentrate for the preparation of solution for intravenous administration “Borisovsky. Amiodarone injections: instructions for use Synonyms of nosological groups

Antiarrhythmic drug

Active substance

Release form, composition and packaging

Solution for intravenous administration transparent, light yellow.

Excipients: benzyl alcohol - 60 mg, polysorbate 80 - 300 mg, water for injection - up to 3 ml.

3 ml - colorless glass ampoules (type I) with a breaking point and two marking rings on the top (6) - contour plastic cell packaging (1) - cardboard packs.

pharmachologic effect

Antiarrhythmic drug. Amiodarone belongs to class III (class of repolarization inhibitors) and has a unique mechanism of antiarrhythmic action, because in addition to the properties of class III antiarrhythmics (potassium channel blockade), it has the effects of class I antiarrhythmics (sodium channel blockade), class IV antiarrhythmics (calcium channel blockade) and a non-competitive beta-blocker effect.

In addition to the antiarrhythmic effect, the drug has antianginal, coronary dilation, alpha and beta adrenergic blocking effects.

Antiarrhythmic action:

an increase in the duration of phase 3 of the action potential of cardiomyocytes, mainly due to blocking the ion current in potassium channels (the effect of class III antiarrhythmics according to the Williams classification);
decreased automatism of the sinus node, leading to a decrease in heart rate;
non-competitive blockade of α- and β-adrenergic receptors;
slowing of sinoatrial, atrial and AV conduction, more pronounced with tachycardia;
no changes in ventricular conductivity;
an increase in refractory periods and a decrease in the excitability of the myocardium of the atria and ventricles, as well as an increase in the refractory period of the AV node;
slowing down conduction and increasing the duration of the refractory period in additional AV conduction bundles.

Other effects:

reduction of oxygen consumption by the myocardium due to a moderate decrease in peripheral resistance and heart rate, as well as a decrease in myocardial contractility due to the beta-adrenergic blocking effect;
an increase in coronary blood flow due to a direct effect on the smooth muscle of the coronary arteries;
preservation of ejection, despite a slight decrease in myocardial contractility, due to a decrease in pressure in the aorta and a decrease in peripheral resistance;
influence on the exchange of thyroid hormones: inhibition of the conversion of T3 to T4 (blockade of thyroxine-5-deiodinase) and blocking the uptake of these hormones by cardiocytes and hepatocytes, leading to a weakening of the stimulating effect of thyroid hormones on the myocardium;
restoration of cardiac activity in cardiac arrest caused by ventricular fibrillation resistant to defibrillation.

When the drug is administered intravenously, its activity reaches a maximum after 15 minutes and disappears approximately 4 hours after administration.

Pharmacokinetics

Suction

After intravenous administration of amiodarone, its concentration in the blood decreases rapidly due to the drug entering the tissues. In the absence of repeated injections, amiodarone is gradually eliminated. When it is resumed intravenously or when the drug is prescribed orally, amiodarone accumulates in the tissues.

Distribution

Protein binding is 95% (62% with albumin, 33.5% with beta-lipoproteins). Amiodarone has a large Vd and can accumulate in almost all tissues, especially in adipose tissue and in addition to it in the liver, lungs, spleen and cornea.

Metabolism

Amiodarone is metabolized in the liver via isoenzymes CYP3A4 and CYP2C8. Its main metabolite, desethylamiodarone, is pharmacologically active and can enhance the antiarrhythmic effect of the main compound. Amiodarone and its active metabolite desethylamiodarone in vitro have the ability to inhibit the isoenzymes CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, CYP2B6 and CYP2C8. Amiodarone and desethylamiodarone have also demonstrated the ability to inhibit certain transporters, such as P-gp and organic cation transporter (POK2). In vivo, interactions of amiodarone with substrates of the isoenzymes CYP3A4, CYP2C9, CYP2D6 and P-gp were observed.

Removal

It is mainly excreted with bile and feces through the intestines. Amiodarone elimination is very slow. Amiodarone and its metabolites are detected in blood plasma for 9 months after cessation of treatment.

Amiodarone and its metabolites are not dialyzable.

Indications

Relief of attacks of paroxysmal tachycardia:

relief of attacks of ventricular paroxysmal tachycardia;
relief of attacks of supraventricular paroxysmal tachycardia with a high frequency of ventricular contractions, especially against the background of Wolff-Parkinson-White syndrome;
relief of paroxysmal and stable forms of atrial fibrillation (atrial fibrillation) and atrial flutter.

Cardiac resuscitation for cardiac arrest caused by ventricular fibrillation resistant to defibrillation.

Contraindications

hypersensitivity to amiodarone or excipients of the drug;
SSS (sinus bradycardia, sinoatrial block) in the absence of an artificial pacemaker (pacemaker) (danger of “stopping” the sinus node);
AV blockade of II and III degrees in the absence of a permanent artificial pacemaker (pacemaker);
disturbances of intraventricular conduction (two- and three-fascicle blockades) in the absence of a permanent artificial pacemaker (pacemaker). In case of such conduction disturbances, the use of the drug Cordarone intravenously is possible only in specialized departments under the cover of a temporary pacemaker (pacemaker);
hypokalemia, hypomagnesemia;
severe arterial hypotension, collapse, cardiogenic shock;
thyroid dysfunction (hypothyroidism, hyperthyroidism);
congenital or acquired prolongation of the QT interval;
combination with drugs that can prolong the QT interval and cause the development of paroxysmal tachycardias, including torsades de pointes: class I A antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, procainamide); class III antiarrhythmic drugs (dofetilide, ibutilide, bretylium tosylate); ; other (non-antiarrhythmic) drugs such as bepridil; vincamine; some neuroleptics phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulpiride, tiapride, veralipride), butyrophenones (droperidol, haloperidol), sertindole, pimozide; cisapride; tricyclic antidepressants; antibiotics of the macrolide group (in particular erythromycin with intravenous administration, spiramycin); azoles; antimalarial drugs (quinine, chloroquine, mefloquine, halofantrine); pentamidine for parenteral administration; difemanil methyl sulfate; mizolastine; astemizole, terfenadine; fluoroquinolones;
pregnancy;
breastfeeding period;
age under 18 years (efficacy and safety have not been established).

Intravenous jet administration is contraindicated in the case of arterial hypotension, severe respiratory failure, cardiomyopathy or heart failure (these conditions may be aggravated).

All of the above contraindications do not apply to the use of Cordarone during cardiac resuscitation for cardiac arrest caused by ventricular fibrillation resistant to defibrillation.

Carefully

For arterial hypotension, decompensated or severe (III-IV functional classes according to the NYHA classification) heart failure, severe respiratory failure, liver failure, bronchial asthma, in elderly patients (high risk of developing severe bradycardia), with AV blockade of the first degree.

Dosage

Cordarone for intravenous administration is intended for use in cases where rapid achievement of an antiarrhythmic effect is required, or if it is impossible to administer the drug orally.

With the exception of emergency clinical situations, the drug should be used only in a hospital in an intensive care unit under constant monitoring of ECG and blood pressure.

When administered intravenously, Cordarone should not be mixed with other drugs. Other drugs should not be administered into the same infusion line as Cordarone. Use only in diluted form. To dilute the drug Cordarone, you should use only a 5% dextrose (glucose) solution. Due to the characteristics of the dosage form of the drug, it is not recommended to use concentrations of the infusion solution less than those obtained by diluting 2 ampoules in 500 ml of 5% dextrose (glucose).

To avoid injection site reactions, amiodarone should be administered through a central venous catheter, except in cases of cardiac resuscitation for defibrillation-resistant ventricular fibrillation, when, in the absence of central venous access, peripheral veins (the largest peripheral vein with maximum blood flow) can be used to administer the drug ).

Severe cardiac arrhythmias, in cases where it is impossible to take the drug orally (except in cases of cardiac resuscitation for cardiac arrest caused by ventricular fibrillation resistant to defibrillation)

Intravenous drip administration through a central venous catheter

Typically the loading dose is 5 mg/kg body weight in 250 ml of 5% dextrose (glucose) solution, administered using an electronic pump whenever possible over 20-120 minutes. Intravenous drip administration can be repeated 2-3 times within 24 hours. The rate of drug administration is adjusted depending on the clinical effect. The therapeutic effect appears within the first minutes of administration and gradually decreases after stopping the infusion, therefore, if it is necessary to continue treatment with the injection drug Cordarone, it is recommended to switch to continuous intravenous drip administration of the drug.

Maintenance doses: 10-20 mg/kg/24 hours (usually 600-800 mg, but can be increased to 1200 mg over 24 hours) in 250 ml of 5% dextrose (glucose) solution for several days. From the first day of infusion, a gradual transition to taking the drug Cordarone should begin orally (3 tablets of 200 mg/day). The dose can be increased to 4 or even 5 tablets. 200 mg/day.

Intravenous jet administration should be carried out only in emergency cases when other types of treatment are ineffective and only in the intensive care unit under constant monitoring of ECG and blood pressure.

The dose is 5 mg/kg body weight. Except in cases of cardiac resuscitation for defibrillation-resistant ventricular fibrillation, intravenous bolus administration of amiodarone should be administered over at least 3 minutes. Repeated administration of amiodarone should not be carried out earlier than 15 minutes after the first injection, even if the contents of only one ampoule were administered during the first injection (the possibility of irreversible collapse).

If there is a need for continued administration of amiodarone, it should be administered as an infusion.

Cardiac resuscitation for cardiac arrest caused by ventricular fibrillation resistant to defibrillation

Intravenous jet administration

The first dose is 300 mg (or 5 mg/kg of the drug Cordarone) after dilution in 20 ml of a 5% dextrose (glucose) solution and is administered intravenously.

If fibrillation does not stop, then additional intravenous jet administration of the drug Cordarone at a dose of 150 mg (or 2.5 mg/kg) is possible.

Side effects

Determination of the frequency of adverse reactions: very often (≥10%); often (≥1%,<10); нечасто (≥0.1%, <1%); редко (≥0.01%, <0.1%); очень редко, включая отдельные сообщения (<0.01%); частота неизвестна (по имеющимся данным частоту определить нельзя).

From the cardiovascular system: often - bradycardia (usually a moderate decrease in heart rate), a decrease in blood pressure, usually moderate and transient (cases of severe arterial hypotension or collapse were observed with an overdose or too rapid administration of the drug); very rarely - arrhythmogenic effect (/there are reports of the occurrence of new arrhythmias, including ventricular tachycardia "pirouette", or aggravation of existing ones, in some cases - with subsequent cardiac arrest/, however, with amiodarone it is less pronounced than with most antiarrhythmics drugs. These effects are observed mainly in cases of use of the drug Cordarone in combination with drugs that prolong the period of repolarization of the ventricles of the heart / QT interval / or with disturbances in the content of electrolytes in the blood. Based on the available data, it is impossible to determine whether the occurrence of these rhythm disturbances is caused by the action of the drug Cordarone, the severity of cardiac pathology or is a consequence of treatment failure), severe bradycardia or, in exceptional cases, sinus node arrest, requiring discontinuation of treatment with amiodarone, especially in patients with sinus node dysfunction and/or elderly patients), flushing of the facial skin; unknown frequency - ventricular tachycardia of the "pirouette" type.

From the endocrine system: frequency unknown - hyperthyroidism.

From the respiratory system: very rarely - cough, shortness of breath, interstitial pneumonitis, bronchospasm and/or apnea (in patients with severe respiratory failure, especially in patients with bronchial asthma), acute respiratory distress syndrome (sometimes fatal).

From the digestive system: very rarely - nausea.

From the liver and biliary tract: very rarely - an isolated increase in the activity of hepatic transaminases in the blood serum (usually moderate, exceeding normal values by 1.5-3 times, decreases with dose reduction or even spontaneously), acute liver damage (within 24 hours after administration of amiodarone) with an increase in transaminases and/ or jaundice, including the development of liver failure, sometimes fatal.

For the skin and subcutaneous tissues: very rarely - feeling of heat, increased sweating; frequency unknown - urticaria.

From the nervous system: very rarely - benign intracranial hypertension (pseudotumor cerebri), headache.

From the immune system: very rarely - anaphylactic shock; unknown - angioedema (Quincke's edema).

From the musculoskeletal system: frequency unknown - pain in the lumbar and lumbosacral spine.

Local reactions: often - reactions at the injection site, such as pain, erythema, swelling, necrosis, extravasation, infiltration, inflammation, induration, thrombophlebitis, phlebitis, cellulitis, infection, pigmentation.

Overdose

There is no information on overdose of IV amiodarone. There is some information regarding acute overdose of amiodarone taken orally in tablet form. Several cases of sinus bradycardia, cardiac arrest, attacks of ventricular tachycardia, paroxysmal ventricular tachycardia of the “pirouette” type, circulatory and liver function disorders, and a pronounced decrease in blood pressure have been described.

Treatment should be symptomatic (for bradycardia - the use of beta-adrenergic agonists or the installation of a pacemaker, for ventricular tachycardia of the "pirouette" type - intravenous administration of magnesium salts, reducing cardiac pacing). Neither amiodarone nor its metabolites are removed during hemodialysis. There is no specific antidote.

Drug interactions

Drugs that can cause torsade de pointes (TdP) or prolong the QT interval

Drugs that can cause torsade de pointes (TdP)

Combination therapy with drugs that can cause ventricular tachycardia of the "pirouette" type is contraindicated, because. the risk of developing potentially fatal torsade de pointes (TdP) increases.

antiarrhythmic drugs: class I A (quinidine, hydroquinidine, disopyramide, procainamide), sotalol, bepridil;
other (non-antiarrhythmic) drugs such as; vincamine; some neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulpride, tiapride, veralipride), butyrophenones (droperidol, haloperidol), sertindole, pimozide; tricyclic antidepressants; cisapride; macrolide antibiotics (erythromycin with intravenous administration, spiramycin); azoles; antimalarial drugs (quinine, chloroquine, mefloquine, halofantrine, lumefantrine); pentamidine for parenteral administration; difemanil methyl sulfate; mizolastine; astemizole; terfenadine

Drugs that can prolong the QT interval

Co-administration of amiodarone with drugs that can prolong the QT interval should be based on a careful assessment for each patient of the ratio of expected benefit and potential risk (the possibility of an increased risk of developing torsade de pointes); when using such combinations, it is necessary to constantly monitor the ECG of patients (for detection of QT interval prolongation), potassium and magnesium content in the blood.

Fluoroquinolones, including moxifloxacin, should be avoided in patients taking amiodarone.

Drugs that reduce heart rate or cause automaticity or conduction disorders

Combination therapy with these drugs is not recommended.

Beta-blockers, slow calcium channel blockers that reduce heart rate (verapamil, diltiazem) can cause disturbances in automaticity (development of excessive bradycardia) and conduction.

Drugs that can cause hypokalemia

with laxatives that stimulate intestinal motility, which can cause hypokalemia, which increases the risk of developing ventricular tachycardia of the "priuet" type. When combined with amiodarone, laxatives from other groups should be used.

Combinations requiring caution when using

with diuretics that cause hypokalemia (in monotherapy or in combination with other drugs);
with systemic corticosteroids (glucocorticoids, mineralocorticoids), tetracosactide;
with amphotericin B (iv administration).

It is necessary to prevent the development of hypoglycemia, and if it occurs, restore the potassium content in the blood to normal levels, monitor the concentration of electrolytes in the blood and ECG (for possible prolongation of the QT interval), and in the event of ventricular tachycardia of the “pirouette” type, antiarrhythmic drugs should not be used (ventricular pacing should be started; intravenous administration of magnesium salts is possible).

Preparations for inhalation anesthesia

The possibility of developing the following severe complications in patients taking amiodarone while receiving anesthesia has been reported: bradycardia (resistant to atropine), arterial hypotension, conduction disturbances, decreased cardiac output.

There have been very rare cases of severe complications from the respiratory system, sometimes fatal (acute respiratory distress syndrome in adults), which developed immediately after surgery, the occurrence of which is associated with high oxygen concentrations.

Drugs that reduce heart rate (clonidine, guanfacine, cholinesterase inhibitors (donepezil, galantamine, rivastigmine, tacrine, ambenonium chloride, neostigmine bromide), pilocarpine

Risk of developing excessive bradycardia (cumulative effects).

Effect of amiodarone on other drugs

Amiodarone and/or its metabolite desethylamiodarone inhibit the isoenzymes CYP3A4, CYP2C9, CYP2D6 and P-glycoprotein and may increase the systemic exposure of drugs that are their substrates. Due to the long half-life of amiodarone, this interaction can be observed even several months after stopping its use.

Drugs that are P-gp substrates

Amiodarone is a P-gp inhibitor. It is expected that its combined use with drugs that are P-gp substrates will lead to increased systemic exposure of the latter.

Cardiac glycosides (digitalis preparations)

Possibility of disturbances in automaticity (severe bradycardia) and atrioventricular conduction. In addition, when combining digoxin with amiodarone, an increase in the concentration of digoxin in the blood plasma is possible (due to a decrease in its clearance). Therefore, when combining digoxin with amiodarone, it is necessary to determine the concentration of digoxin in the blood and monitor possible clinical and electrocardiographic manifestations of digitalis intoxication. Digoxin dosages may need to be reduced.

Dabigatran

Caution should be exercised when amiodarone is used concomitantly with dabigatran due to the risk of bleeding. The dose of dabigatran may need to be adjusted in accordance with the instructions in its instructions for use.

Medicines that are substrates of the CYP2C9 isoenzyme

Amiodarone increases the blood concentration of drugs that are substrates of the CYP2C9 isoenzyme, such as warfarin or phenytoin due to inhibition of cytochrome P450 2C9.

Warfarin

When warfarin is combined with amiodarone, the effects of the indirect anticoagulant may be enhanced, which increases the risk of bleeding. Prothrombin time (MHO) should be monitored more frequently and anticoagulant doses adjusted, both during treatment with amiodarone and after discontinuation of its use.

Phenytoin

When combining phenytoin with amiodarone, an overdose of phenytoin may develop, which can lead to the appearance of neurological symptoms; clinical monitoring is necessary and, at the first signs of overdose, a reduction in the dose of phenytoin; it is advisable to determine the concentration of phenytoin in the blood plasma.

Medicines that are substrates of the CYP2D6 isoenzyme

Flecainide

Amiodarone increases plasma concentrations of flecainide due to inhibition of the CYP2D6 isoenzyme. Therefore, dose adjustment of flecainide is required.

Medicines that are substrates of the CYP3A4 isoenzyme

When amiodarone, an inhibitor of the CYP3A4 isoenzyme, is combined with these drugs, their plasma concentrations may increase, which may lead to increased toxicity and/or increased pharmacodynamic effects and may require a reduction in their doses. Such drugs are listed below.

Cyclosporine

The combination of cyclosporine with amiodarone may increase plasma concentrations of cyclosporine; dose adjustment is necessary.

Fentanyl

Combination with amiodarone may increase the pharmacodynamic effects of fentanyl and increase the risk of developing its toxic effects.

HMG-CoA reductase inhibitors (statins) (simvastatin, atorvastatin and lovastatin)

Increased risk of statin muscle toxicity when used concomitantly with amiodarone. The use of statins that are not metabolized by the CYP3A4 isoenzyme is recommended.

Other drugs metabolized by the CYP3A4 isoenzyme: lidocaine(risk of developing sinus bradycardia and neurological symptoms), tacrolimus(risk of nephrotoxicity), sildenafil(risk of increased side effects), midazolam(risk of developing psychomotor effects), triazolam, dihydroergotamine, ergotamine, colchicine.

A drug that is a substrate of CYP2D6 and CYP3A4 isoenzymes - dextromethorphan

Amiodarone inhibits CYP2D6 and CYP3A4 and may theoretically increase plasma concentrations of dectromethorphan.

Clopidogrel

Clopidogrel, which is an inactive thienopyrimidine drug, is metabolized in the liver to form active metabolites. There is a possible interaction between clopidogrel and amiodarone, which may lead to a decrease in the effectiveness of clopidogrel.

Effect of other drugs on amiodarone

Inhibitors of CYP3A4 and CYP2C8 isoenzymes may have the potential to inhibit the metabolism of amiodarone and increase its concentration in the blood and, accordingly, its pharmacodynamic and side effects.

It is recommended to avoid CYP3A4 inhibitors (eg, grapefruit juice and certain drugs such as cimetidine and HIV protease inhibitors (including indinavir)) during amiodarone therapy. HIV protease inhibitors, when used concomitantly with amiodarone, may increase the concentration of amiodarone in the blood.

Inducers of the CYP3A4 isoenzyme

Rifampicin

Rifampicin is a potent inducer of the CYP3A4 isoenzyme; when used in combination with amiodarone, it can reduce plasma concentrations of amiodarone and desethylamiodarone.

Preparations of St. John's wort

St. John's wort is a potent inducer of the CYP3A4 isoenzyme. In this regard, it is theoretically possible to reduce the plasma concentration of amiodarone and reduce its effect (clinical data are not available).

special instructions

With the exception of emergency cases, intravenous administration of the drug Cordarone should be carried out only in the intensive care unit with constant monitoring of ECG (due to the possibility of developing bradycardia and arrhythmogenic effects) and blood pressure (due to the possibility of lowering blood pressure).

It should be remembered that even with slow intravenous jet administration of the drug Cordarone, the development of an excessive decrease in blood pressure and circulatory collapse is possible.

In order to avoid reactions at the injection site, the injectable form of the drug Cordarone is recommended to be administered through a central venous catheter. Only in the case of cardiac resuscitation for cardiac arrest caused by ventricular fibrillation resistant to defibrillation, in the absence of central venous access (no central venous catheter in place), the injectable form of the drug Cordarone can be administered into a large peripheral vein with maximum blood flow.

If it is necessary to continue treatment with Cordarone after cardiac resuscitation, Cordarone should be administered intravenously through a central venous catheter under constant monitoring of blood pressure and ECG.

Cordarone should not be mixed in the same syringe or dropper with other medications. Other drugs should not be administered into the same infusion line as Cordarone.

Although the occurrence of arrhythmias or worsening of existing arrhythmias, sometimes fatal, has been reported, the proarrhythmogenic effect of amiodarone is weak compared to most antiarrhythmic drugs and usually occurs in the context of factors that prolong the QT interval, such as interactions with other drugs and/or disorders of electrolytes in the blood. Despite the ability of amiodarone to prolong the QT interval, amiodarone has shown little activity in inducing torsade de pointes (TdP).

Due to the possibility of the development in very rare cases of interstitial pneumonitis after the IV administration of the drug Cordarone, if severe shortness of breath or dry cough appears after its IV administration, both accompanied and not accompanied by a deterioration in the general condition (increased fatigue, fever), it is required perform a chest x-ray and, if necessary, discontinue the drug, because interstitial pneumonitis can lead to the development of pulmonary fibrosis. However, these phenomena are mainly reversible with early withdrawal of amiodarone with or without the use of corticosteroids. Clinical manifestations usually disappear within 3-4 weeks. Recovery of the X-ray picture and lung function occurs more slowly (several months).

Following mechanical ventilation (eg, surgery) in patients treated with Cordarone, rare cases of adult acute respiratory distress syndrome, sometimes fatal, have been reported (possible interaction with high doses of oxygen). Therefore, it is recommended to strictly monitor the condition of such patients.

During the first 24 hours after starting to use the injection form of the drug Cordarone, severe acute liver damage may develop with the development of liver failure, sometimes with death. Careful monitoring of liver function tests (determining transaminase activity) is recommended before starting to take the drug Cordarone and regularly during treatment with the drug. Acute liver dysfunction (including hepatocellular failure or liver failure, sometimes fatal) and chronic liver damage may occur within the first 24 hours after IV administration of amiodarone. Therefore, treatment with amiodarone should be discontinued when transaminase activity increases to 3 times the ULN.

Before surgery, the anesthesiologist should be informed that the patient is receiving Cordarone. Treatment with Cordarone may increase the hemodynamic risk inherent in local or general anesthesia. This particularly applies to its bradycardic and hypotensive effects, decreased cardiac output and conduction disturbances.

Concomitant use with beta-blockers is not recommended; heart rate-reducing calcium channel blockers (verapamil and diltiazem); laxatives that stimulate intestinal motility, which can cause the development of hypokalemia.

Electrolyte disturbances, especially hypokalemia: It is important to consider situations that may be accompanied by hypokalemia as predisposing to proarrhythmic events. Hypokalemia should be corrected before using Cordarone.

Before starting treatment with Cordarone, it is recommended to record an ECG and determine the potassium content in the blood serum and, if possible, determine the serum concentrations of thyroid hormones (T3, T4 and TSH). Side effects of the drug are usually dose dependent; Therefore, care should be taken when determining the minimum effective maintenance dose to avoid or minimize the occurrence of adverse effects.

Amiodarone may cause thyroid dysfunction, especially in patients with a personal or family history of thyroid dysfunction. Therefore, if you switch to taking the drug Cordarone orally during treatment and several months after the end of treatment, careful clinical and laboratory monitoring should be carried out. If thyroid dysfunction is suspected, serum TSH concentrations should be determined (using an ultrasensitive TSH test).

The safety and effectiveness of amiodarone have not been studied in children. The ampoules of the injection drug Cordarone contain benzyl alcohol. Severe choking with fatal outcome has been reported in newborns after intravenous administration of solutions containing benzyl alcohol. Symptoms of the development of this complication are: acute development of suffocation, decreased blood pressure, bradycardia and cardiovascular collapse.

Amiodarone contains iodine and therefore can interfere with the absorption of radioactive iodine, which can distort the results of a radioisotope study of the thyroid gland, but its use does not affect the reliability of determining the content of T3, T4 and TSH in the blood plasma.

Impact on the ability to drive vehicles and operate machinery

Based on safety data, there is no evidence that amiodarone impairs the ability to drive or engage in other potentially hazardous activities. However, as a precautionary measure, it is advisable for patients with paroxysms of severe rhythm disturbances during treatment with Cordarone to refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Pregnancy and lactation

Pregnancy

Currently available clinical information is insufficient to determine the possibility or impossibility of developmental defects in the embryo when using amiodarone in the first trimester of pregnancy.

Since the fetal thyroid gland begins to bind iodine only from the 14th week of pregnancy (amenorrhea), amiodarone is not expected to affect it if it is used earlier. Excess iodine when using the drug after this period can lead to the appearance of laboratory symptoms of hypothyroidism in the newborn or even to the formation of a clinically significant goiter.

Due to the effect of the drug on the fetal thyroid gland, amiodarone is contraindicated during pregnancy, except in special cases when the expected benefit outweighs the risks (in case of life-threatening ventricular arrhythmias).

Breastfeeding period

Amiodarone is excreted into breast milk in significant quantities, so it is contraindicated during breastfeeding (therefore, during this period the drug should be discontinued or breastfeeding should be discontinued).

Use in childhood

Contraindication: children and adolescents under 18 years of age (efficacy and safety have not been established).

For impaired renal function

Insignificant excretion of the drug in the urine allows the drug to be prescribed in moderate doses for renal failure. Amiodarone and its metabolites are not dialyzable.

For liver dysfunction

Use with caution in case of liver failure.

Use in old age

WITH caution should be used in elderly patients (high risk of developing severe bradycardia).

Conditions for dispensing from pharmacies

The drug is available with a prescription.

Storage conditions and periods

The drug should be stored out of the reach of children at a temperature not exceeding 25°C. Shelf life - 2 years.

In this article you can read the instructions for use of the drug Amiodarone. Reviews of site visitors - consumers of this medicine, as well as the opinions of specialist doctors on the use of Amiodarone in their practice are presented. We kindly ask you to actively add your reviews about the drug: whether the medicine helped or did not help get rid of the disease, what complications and side effects were observed, perhaps not stated by the manufacturer in the annotation. Amiodarone analogues in the presence of existing structural analogues. Use for the treatment of arrhythmias and extrasystoles in adults, children, as well as during pregnancy and lactation. Composition and interaction of the drug with alcohol.

Amiodarone- antiarrhythmic drug of class 3, has an antianginal effect.

The antiarrhythmic effect is associated with the ability to increase the duration of the action potential of cardiomyocytes and the effective refractory period of the atria, ventricles of the heart, AV node, His bundle, and Purkinje fibers. This is accompanied by a decrease in the automaticity of the sinus node, a slowdown in AV conduction, and a decrease in the excitability of cardiomyocytes. It is believed that the mechanism for increasing the duration of the action potential is associated with blockade of potassium channels (the excretion of potassium ions from cardiomyocytes is reduced). By blocking inactivated “fast” sodium channels, it has effects characteristic of class 1 antiarrhythmic drugs. Inhibits the slow (diastolic) depolarization of the sinus node cell membrane, causing bradycardia, inhibits AV conduction (the effect of class 4 antiarrhythmics).

The antianginal effect is due to coronary dilatation and antiadrenergic effects, reducing myocardial oxygen demand. It has an inhibitory effect on alpha and beta adrenergic receptors of the cardiovascular system (without their complete blockade). Reduces sensitivity to hyperstimulation of the sympathetic nervous system, coronary vascular tone; increases coronary blood flow; reduces heart rate; increases the energy reserves of the myocardium (by increasing the content of creatine sulfate, adenosine and glycogen). Reduces peripheral vascular resistance and systemic blood pressure (with intravenous administration).

It is believed that amiodarone may increase the level of phospholipids in tissues.

Contains iodine. Affects the metabolism of thyroid hormones, inhibits the conversion of T3 to T4 (blockade of thyroxine-5-deiodinase) and blocks the uptake of these hormones by cardiocytes and hepatocytes, which leads to a weakening of the stimulating effect of thyroid hormones on the myocardium (T3 deficiency can lead to its overproduction and thyrotoxicosis) .

When taken orally, the onset of action ranges from 2-3 days to 2-3 months, the duration of action is also variable - from several weeks to several months.

After intravenous administration, the maximum effect is achieved within 1-30 minutes and lasts 1-3 hours.

Compound

Amiodarone hydrochloride + excipients.

Pharmacokinetics

After oral administration, it is slowly absorbed from the gastrointestinal tract, absorption is 20-55%. Penetrates the blood-brain barrier (BBB) and the placental barrier (10-50%), excreted in breast milk (25% of the dose received by the mother). Intensively metabolized in the liver to form the active metabolite desethylamiodarone, and also, apparently, by deiodination. With prolonged treatment, iodine concentrations can reach 60-80% of amiodarone concentrations. It is an inhibitor of the isoenzymes CYP2C9, CYP2D6 and CYP3A4, CYP3A5, CYP3A7 in the liver. It is excreted mainly in bile through the intestines; slight enterohepatic recirculation may occur. Amiodarone and desethylamiodarone are excreted in the urine in very small quantities. Amiodarone and its metabolites are not eliminated by dialysis.

Indications

life-threatening ventricular arrhythmias (including ventricular tachycardia);
prevention of ventricular fibrillation (including after cardioversion);
supraventricular arrhythmias (usually when other therapy is ineffective or impossible, especially associated with WPW syndrome), incl. paroxysm of atrial fibrillation and flutter;
atrial and ventricular extrasystole;
arrhythmias due to coronary insufficiency or chronic heart failure;
parasystole;
ventricular arrhythmias in patients with Chagas myocarditis;
angina pectoris.

Release forms

Tablets 200 mg.

Solution for intravenous administration 5% (injections in injection ampoules).

Instructions for use and dosage

When taken orally for adults, the initial single dose is 200 mg. For children, the dose is 2.5-10 mg per day. The treatment regimen and duration are determined individually.

For intravenous administration (stream or drip (in the form of a dropper)), a single dose is 5 mg/kg, a daily dose is up to 1.2 g (15 mg/kg).

Side effect

sinus bradycardia (refractory to m-anticholinergic drugs);
AV block;
progression of CHF;
ventricular arrhythmia of the "pirouette" type;
strengthening of existing arrhythmia or its occurrence;
decrease in blood pressure;
development of hypo- or hyperthyroidism;
cough;
dyspnea;
interstitial pneumonia or alveolitis;
pulmonary fibrosis;
pleurisy;
bronchospasm;
apnea (in patients with severe respiratory failure);
nausea, vomiting;
decreased appetite;
dullness or loss of taste;
feeling of heaviness in the epigastrium;
abdominal pain;
constipation, diarrhea;
flatulence;
toxic hepatitis;
cholestasis;
jaundice;
cirrhosis of the liver;
headache;
weakness;
dizziness;
depression;
feeling tired;
paresthesia;
auditory hallucinations;
peripheral neuropathy;
tremor;
memory and sleep disturbances;
optic neuritis;
intracranial hypertension;
uveitis;
deposition of lipofuscin in the corneal epithelium (if the deposits are significant and partially fill the pupil - complaints of luminous spots or a veil before the eyes in bright light);
retinal microdetachment;
thrombocytopenia;
hemolytic and aplastic anemia;
skin rash;
exfoliative dermatitis;
photosensitivity;
alopecia;
gray-blue coloration of the skin;
thrombophlebitis;
epididymitis;
myopathy;
decreased potency;
vasculitis;
increased sweating.

Contraindications

sinus bradycardia;
sick sinus syndrome (SSNS);
sinoatrial block;
2-3 degree AV block (without using a pacemaker);
cardiogenic shock;
hypokalemia;
collapse;
arterial hypotension;
hypothyroidism;
thyrotoxicosis;
interstitial lung diseases;
taking MAO inhibitors;
pregnancy;
lactation period;
hypersensitivity to amiodarone and iodine.

Use during pregnancy and breastfeeding

Contraindicated for use during pregnancy and lactation.

Amiodarone and desmethylamiodarone penetrate the placental barrier, their concentrations in the fetal blood are 10% and 25% of the concentration in the maternal blood, respectively.

Amiodarone and desmethylamiodarone are excreted in breast milk.

Use in children

Use with caution in people under 18 years of age (efficacy and safety of use have not been established).

Use in elderly patients

Use with caution in elderly patients (high risk of developing severe bradycardia).

special instructions

Should not be used in patients with severe respiratory failure.

Before starting the use of amiodarone, an X-ray examination of the lungs and thyroid function should be performed, and, if necessary, correction of electrolyte disturbances should be carried out.

With long-term treatment, regular monitoring of thyroid function, consultation with an ophthalmologist and x-ray examination of the lungs are necessary.

Parenterally can be used only in specialized hospital departments under constant monitoring of blood pressure, heart rate and ECG.

Patients receiving amiodarone should avoid direct exposure to sunlight.

When amiodarone is discontinued, relapses of cardiac arrhythmias are possible.

May affect test results for radioactive iodine accumulation in the thyroid gland.

Amiodarone should not be used simultaneously with quinidine, beta-blockers, calcium channel blockers, digoxin, coumarin, doxepin.

Drug interactions

Drug interactions between amiodarone and other drugs are possible even several months after the end of its use due to the long half-life.

With the simultaneous use of amiodarone and antiarrhythmic drugs of class 1 A (including disopyramide), the QT interval increases due to an additive effect on its value and the risk of developing ventricular tachycardia of the "pirouette" type increases.

When amiodarone is used concomitantly with laxatives that can cause hypokalemia, the risk of developing ventricular arrhythmia increases.

Drugs that cause hypokalemia, including diuretics, corticosteroids, amphotericin B (iv), tetracosactide, when used simultaneously with amiodarone, cause an increase in the QT interval and an increased risk of developing ventricular arrhythmias (including torsade de pointes).

With the simultaneous use of general anesthesia and oxygen therapy, there is a risk of developing bradycardia, arterial hypotension, conduction disturbances, and a decrease in stroke volume, which is apparently due to additive cardiodepressive and vasodilating effects.

When used simultaneously, tricyclic antidepressants, phenothiazines, astemizole, terfenadine cause an increase in the QT interval and an increased risk of developing ventricular arrhythmia, especially the pirouette type.

With the simultaneous use of warfarin, phenprocoumon, acenocoumarol, the anticoagulant effect is enhanced and the risk of bleeding increases.

With the simultaneous use of vincamine, sultopride, erythromycin (intravenously), pentamidine (intravenously, intramuscularly), the risk of developing ventricular arrhythmia of the “pirouette” type increases.

With simultaneous use, it is possible to increase the concentration of dextromethorphan in the blood plasma due to a decrease in the rate of its metabolism in the liver, which is caused by inhibition of the activity of the CYP2D6 isoenzyme of the cytochrome P450 system under the influence of amiodarone and a slowdown in the excretion of dextromethorphan from the body.

With the simultaneous use of digoxin, the concentration of digoxin in the blood plasma significantly increases due to a decrease in its clearance and, as a result, the risk of developing digitalis intoxication increases.

With the simultaneous use of diltiazem and verapamil, the negative inotropic effect, bradycardia, conduction disturbances, and AV block are enhanced.

A case of increased plasma concentrations of amiodarone during its simultaneous use with indinavir has been described. It is believed that ritonavir, nelfinavir, and saquinavir will have a similar effect.

With simultaneous use of cholestyramine, the concentration of amiodarone in the blood plasma decreases due to its binding to cholestyramine and reduced absorption from the gastrointestinal tract.

There are reports of an increase in the concentration of lidocaine in the blood plasma when used simultaneously with amiodarone and the development of seizures, apparently due to inhibition of the metabolism of lidocaine under the influence of amiodarone.

It is undesirable to combine Amiodarone with alcohol and ethanol-containing products.

It is believed that a synergistic effect on the sinus node is possible.

With simultaneous use of lithium carbonate, the development of hypothyroidism is possible.

With simultaneous use of procainamide, the QT interval increases due to an additive effect on its value and the risk of developing torsade de pointes (TdP). Increased plasma concentrations of procainamide and its metabolite N-acetylprocainamide and increased side effects.

With the simultaneous use of propranolol, metoprolol, sotalol, arterial hypotension, bradycardia, ventricular fibrillation, and asystole are possible.

With the simultaneous use of trazodone, a case of the development of pirouette-type arrhythmia has been described.

With simultaneous use of quinidine, the QT interval increases due to an additive effect on its value and the risk of developing torsade de pointes (TdP). An increase in the concentration of quinidine in the blood plasma and an increase in its side effects.

With simultaneous use, a case of increased side effects of clonazepam has been described, which is apparently due to its accumulation due to inhibition of oxidative metabolism in the liver under the influence of amiodarone.

With simultaneous use of cisapride, the QT interval significantly increases due to an additive effect, the risk of developing ventricular arrhythmia (including pirouette type).

With simultaneous use, the concentration of cyclosporine in the blood plasma increases, the risk of developing nephrotoxicity.

A case of pulmonary toxicity has been described with the simultaneous use of high-dose cyclophosphamide and amiodarone.

The concentration of amiodarone in the blood plasma increases due to a slowdown in its metabolism under the influence of cimetidine and other inhibitors of microsomal liver enzymes.

It is believed that due to the inhibition under the influence of amiodarone of liver enzymes, with the participation of which phenytoin is metabolized, it is possible to increase the concentration of the latter in the blood plasma and increase its side effects.

Due to the induction of microsomal liver enzymes under the influence of phenytoin, the rate of metabolism of amiodarone in the liver increases and its concentration in the blood plasma decreases.

Analogues of the drug Amiodarone

Dosage form

Solution for injection 50 mg/ml

Compound

One ampoule (3 ml solution) contains

active substance: amiodarone hydrochloride - 150 mg;

Excipients: sodium acetate trihydrate, glacial acetic acid, 1 M acetic acid solution, polysorbate 80, benzyl alcohol, water for injection.

Description

Transparent liquid with a yellowish or greenish tint.

Pharmacotherapeutic group

Drugs for the treatment of heart diseases. Class III antiarrhythmic drugs. Amiodarone.

ATX code C01BD01.

Pharmacological properties

Pharmacokinetics

The amount of parenterally administered amiodarone in the blood decreases very quickly due to tissue saturation with the drug and its reaching the binding sites; the effect reaches a maximum 15 minutes after administration and disappears after approximately 4 hours.

Pharmacodynamics

Antiarrhythmic properties of Amiodarone.

Extension of the 3rd phase of the action potential of cardiomyocytes without changing its height or rate of rise (class III according to the Vaughan Williams classification). Isolated prolongation of phase 3 of the action potential occurs due to a slowdown in potassium currents, without changing sodium or calcium currents.

Bradycardic effect due to decreased automatism of the sinus node. This effect is not eliminated by the administration of atropine.

Non-competitive inhibitory effect on alpha and beta adrenergic receptors, without their complete blockade.

Slowing of sinoatrial, atrial and atrioventricular conduction, which is more pronounced against the background of tachycardia.

Does not change intraventricular conduction.

Increases the refractory period and reduces myocardial excitability at the sinoatrial, atrial and atrioventricular levels.

Slows down conduction and lengthens the refractory period of additional atrioventricular pathways.

Does not have a negative inotropic effect.

Indications for use

Treatment of severe cardiac arrhythmias in cases where oral administration is not possible, namely:

Atrial rhythm disturbances with high ventricular rate

Tachycardia associated with Wolff-Parkinson-White syndrome

Approved symptomatic, life-threatening, disabling ventricular rhythm disturbances

Cardiopulmonary resuscitation for cardiac arrest caused by refractory ventricular fibrillation.

Directions for use and doses

Due to the peculiarities of the dosage form of the drug, a concentration of less than 2 ampoules per 500 ml cannot be used; only an isotonic glucose solution is used. Do not add other drugs to the infusion solution.

Amiodarone should be administered via a central vein, except during cardiopulmonary resuscitation during cardiac arrest, when peripheral veins may be used in the absence of central venous access (see Precautions).

Indicated for severe arrhythmias in which the use of oral drugs is not possible, with the exception of cardiopulmonary resuscitation for cardiac arrest caused by refractory ventricular fibrillation.

Central vein infusion

Initial dose: usually 5 mg/kg, in a glucose solution (if possible, using an infusion pump), over 20 minutes to 2 hours; infusion can be repeated 2-3 times within 24 hours. The short-term effect of the drug requires continued administration.

Maintenance treatment: 10-20 mg/kg per day (average 600-800 mg/day and up to 1200 mg/day) in 250 ml of glucose solution for several days. From the first day of infusion, a gradual transition to oral administration begins (3 tablets per day). The dose can be increased to 4 or even 5 tablets per day.

Peripheral venous infusion during cardiopulmonary resuscitation for cardiac arrest caused by ventricular fibrillation refractory to electrical defibrillation .

Given the route of administration and the situation in which this indication occurs, the use of a central venous catheter is recommended if available; otherwise, the drug can be injected into the largest peripheral vein.

The initial intravenous dose is 300 mg (or 5 mg/kg), after dilution in 20 ml of 5% glucose solution. It is introduced in a stream.

If fibrillation does not stop, an additional intravenous injection of 150 mg (or 2.5 mg/kg) is used.

Do not mix with other drugs in the same syringe!

Side effects

Frequency of occurrence of adverse reactions:

Very often - > 10%;

Uncommon - >1%,<10%;

Rarely - >0.1%,<1%;

Very rare>0.01%,<0,1%;

Frequency cannot be determined from available data -<0,01% и менее.

Often: bradycardia; infrequently - severe bradycardia; rarely - sinus node arrest; in some cases, especially in elderly patients, a proarrhythmogenic effect was noted, usually a moderate and passing drop in blood pressure.

Often: nausea.

Local reactions at the injection site: Inflammatory reactions (superficial phlebitis) are possible when injected directly into a peripheral vein, reactions at the injection site such as pain, erythema, swelling, necrosis, extravasation, infiltration, inflammation, phlebitis and cellulitis.

There have been reports of cases of liver dysfunction; these cases were diagnosed by elevated serum transaminase levels. The following was noted:

Very rarely: usually a moderate and isolated increase in transaminase levels (1.5-3 times higher than normal), disappearing after dose reduction and even spontaneously; acute hepatitis (several isolated cases) with increased levels of transaminases in the blood and/or jaundice, sometimes with death; treatment discontinuation is required; chronic hepatitis with long-term treatment (orally). The histological picture corresponds to pseudoalcoholic hepatitis. Since the clinical and laboratory picture of the disease is very heterogeneous (passing hepatomegaly, increased transaminase levels 1.5 - 5 times above normal), regular monitoring of liver function is required. Even with a moderate increase in the level of transaminases in the blood, observed after treatment lasting more than 6 months, chronic liver dysfunction should be suspected. Clinical abnormalities and laboratory abnormalities usually resolve after discontinuation of the drug. Several cases of irreversible progression have been noted.

Anaphylactic shock

Tides

Benign intracranial hypertension (pseudotumor of the brain).

Several cases of acute respiratory distress syndrome have been observed, mostly associated with interstitial pneumonitis, sometimes fatal and sometimes immediately after surgery (suggesting the possibility of interaction with high doses of oxygen during mechanical ventilation). The possibility of discontinuing amiodarone and the advisability of prescribing corticosteroids should be considered; bronchospasm and/or apnea in severe respiratory failure, especially in patients with bronchial asthma.

Sweating, hair loss.

Usually a mild and transient drop in blood pressure. Cases of severe hypotension or circulatory shock have been reported, especially after overdose or due to too rapid administration.

Contraindications

– sick sinus syndrome (unless the patient is using a pacemaker), sinus bradycardia, sinoatrial block, unless corrected by an artificial pacemaker

– atrioventricular block II and III degrees, intraventricular conduction disorders (blockade of two and three legs of the His bundle); in these cases, intravenous amiodarone can be used in specialized departments under the cover of an artificial pacemaker (pacemaker);

– cardiogenic shock, collapse

– severe arterial hypotension

– simultaneous use with drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type

– thyroid dysfunction (hypothyroidism, hyperthyroidism)

– hypokalemia

– pregnancy, lactation period

– hypersensitivity to iodine and/or amiodarone

– severe pulmonary dysfunction (interstitial lung disease)

– cardiomyopathy or decompensated heart failure (possible deterioration of the patient’s condition)

Due to the presence of benzyl alcohol, intravenous administration of amiodarone is contraindicated in newborns, infants and children under 3 years of age.

Drug interactions

Medicines that can cause torsades de pointes are primarily class Ia and class III antiarrhythmic drugs and some antipsychotics. Hypokalemia is a predisposing factor, as is bradycardia or congenital or acquired prolongation of the QT interval.

Combinations with

- drugs that can cause ventricular tachycardia of the “pirouette” type.

- antiarrhythmic drugs classIa (quinidine, hydroquinidine, isopyramide).

- class III antiarrhythmic drugs (dofetilide, ibutilide, sotalol).

- other drugs, such as bepridil, cisapride, difemanil, IV ritromycin, mizolastine, IV vincamine, moxifloxacin, IV spiramycin.

- sultopride

These contraindications do not apply to the use of amiodarone for cardiopulmonary resuscitation in cardiac arrest refractory to electrical defibrillation.

Cyclosporine

There may be an increase in the level of cyclosporine in plasma, associated with a decrease in the metabolism of the drug in the liver, with possible nephrotoxic manifestations.

Determination of the level of cyclosporine in the blood, checking renal function and reviewing the dosage during treatment with amiodarone and after discontinuation of the drug.

Diltiazem for injection

Verapamil for injection

Risk of bradycardia and atrioventricular block. If a combination is unavoidable, strict clinical and continuous ECG monitoring should be established.

If the combination is unavoidable, preliminary control of the QT interval and ECG monitoring is necessary.

Neuroleptics that can cause ventricular tachycardia of the “pirouette” type:

Some phenothiazine antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, tiapride, veralipride), butyrophenones (droperidol, haloperidol), other antipsychotics (pimozide).

The risk of ventricular rhythm disturbances (pirouette-type tachycardia) increases.

Methadone

The risk of ventricular rhythm disturbances (pirouette-type tachycardia) increases. Recommended: ECG and clinical observation.

Combinations requiring precautions when using Amiodarone with:

Oral anticoagulants:

Increased anticoagulation effect and risk of bleeding, due to increased concentrations of anticoagulants in plasma. The need for more frequent monitoring of the level of prothrombin in the blood and MHO (INR), as well as adaptation of doses of anticoagulants during treatment with amiodarone and after discontinuation of the drug.

Beta blockers, with the exception of sotalol (contraindicated combination) and esmolol (combination requiring caution when used)

Beta blockers prescribed for heart failure (bisoprolol, carvedilol, metoprolol)

Impaired contractility and conduction (synergistic effect) with the risk of developing severe bradycardia. Increased risk of ventricular arrhythmias, especially torsade de pointes.

Regular clinical and electrocardiographic monitoring is necessary.

Cardiac glycosides

Disorders of automaticity (excessive bradycardia) and atrioventricular conduction (synergism of action). When using digoxin, its concentration in plasma increases (due to decreased clearance of the alkaloid).

It is necessary to carry out clinical and ECG monitoring, as well as determination of plasma digoxin levels; It may be necessary to change the dose of digoxin.

Diltiazem for oral administration

Verapamil for oral administration

Risk of bradycardia and atrioventricular block, especially in the elderly. Clinical and ECG control.

Essex scraper

Violations of contractility, automatism and conduction (suppression of compensatory sympathetic mechanisms). Clinical and ECG monitoring.

Hypokalemic drugs: potassium-sparing diuretics (in monotherapy or combination), stimulant laxatives, amphotericin B (iv), glucocorticoids (systemic), tetracosactide.

The risk of ventricular rhythm disturbances increases, especially tachycardia of the “pirouette” type (hypokalemia is a predisposing factor). Clinical and ECG monitoring, laboratory tests.

Lidocaine

Risk of increased lidocaine plasma concentrations, with the possibility of neurological and cardiac side effects, due to amiodarone's decreased metabolism of lidocaine in the liver. Clinical and ECG monitoring, if necessary, dose adjustment of lidocaine during treatment with amiodarone and after its discontinuation.

Orlistat

Risk of decreased plasma concentrations of amiodarone and its active metabolite. Clinical and, if necessary, ECG monitoring,

Phenytoin (and, by extrapolation, fosphenytoin)

An increase in the level of phenytoin in plasma with symptoms of overdose, especially of a neurological nature (decreased metabolism of phenytoin in the liver). Clinical monitoring and determination of plasma phenytoin levels; if possible, reduce the dose of phenytoin.

Simvastatin

Increased risk of side effects (depending on dose) such as rhabdomyolysis (decreased metabolism of simvastatin in the liver). The dose of simvastatin should not exceed 20 mg per day.

If a therapeutic effect is not achieved at this dose, you should switch to another statin that does not interact with this type of interaction.

Tacrolimus

An increase in the level of tacrolimus in the blood due to inhibition of its metabolism by amiodarone. Measurement of tacrolimus blood levels, monitoring of kidney function and leveling of tacrolimus levels should be carried out.

Drugs that cause bradycardia:

Many drugs can cause bradycardia. This is especially true for class Ia antiarrhythmic drugs, beta blockers, some class III antiarrhythmic drugs, some calcium channel blockers, digitalis, pilocarpine and anticholinesterase agents.

Risk of excessive bradycardia (cumulative effect).

Combinations to Consider

Drugs that cause bradycardia: calcium channel blockers with bradycardic effect (verapamil), beta blockers (except sotalol), clonidine, guanfacine, digitalis alkaloids, mefloquine, cholinesterase inhibitors (donezepil, galantamine, rivastigmine, tacrine, ambemonium, pyridostigmine, neostigmine), pilocarpine.

Risk of excessive bradycardia (cumulative effects).

Incompatibilities

When PVC material or medical equipment plasticized with 2-diethylhexyl phthalate (DEHP) is used in the presence of amiodarone injection solution, DEHP may be released. To minimize exposure to DEHP, it is recommended that the solution be final diluted before infusion in DEHP-free equipment.

special instructions

Except in cases of emergency therapy, Amiodarone in the form of a solution for intravenous injection can only be used in a hospital and with constant monitoring (ECG, blood pressure).

WITH caution used for chronic heart failure, liver failure, bronchial asthma, and in old age.

Anesthesia

Before surgery, the anesthesiologist should be informed that the patient is receiving amiodarone.

Prolonged treatment with amiodarone may increase the hemodynamic risk inherent in local or general anesthesia (may cause bradycardia, hypotension, decreased cardiac output or conduction disturbances).

Combinations (see Drug Interactions and Other Forms of Interaction) with beta blockers other than sotalol (a contraindicated combination) and esmolol (a combination requiring special caution when used), verapamil and diltiazem should only be considered in the context of the prevention of life-threatening ventricular arrhythmias and in the case of cardiopulmonary resuscitation for cardiac arrest caused by refractory ventricular fibrillation.

Pregnancy and lactation

Animal tests have not revealed the teratogenic effects of Amiodarone. Therefore, malformations in humans should not be expected since malformation-causing drugs have been shown to exhibit teratogenic effects in animals in properly conducted experiments in two different animal species.

In clinical practice, the information currently available is insufficient to assess whether amiodarone causes malformations when used in the first trimester of pregnancy. Since the fetal thyroid gland begins to bind iodine only from the 14th week of pregnancy, the drug is not expected to affect it if used earlier. Excess iodine when using the drug after this period can lead to laboratory signs of hypothyroidism in the fetus or even clinical goiter.

The drug is contraindicated during pregnancy.

Amiodarone, its metabolite and iodine are excreted into breast milk in concentrations exceeding the level in maternal plasma. If the mother is being treated with this drug, breastfeeding is contraindicated due to the risk of developing hypothyroidism in the child.

Impact on the ability to drive vehicles and operate machinery

Release form and packaging

3 ml in glass ampoules with a capacity of 5 ml.

10 ampoules together with a knife for opening ampoules or an ampoule scarifier are placed in a cardboard box with a corrugated liner made of corrugated paper.

The box is covered with a label-parcel made from printing paper or offset paper or offset paper of improved quality.

The boxes, together with instructions for medical use in the state and Russian languages, are placed in group packaging.

The number of instructions for medical use in the state and Russian languages must correspond to the number of packages.

5 ampoules per blister pack made of polyvinyl chloride film. 2 blister packs of polyvinyl chloride film together with a knife for opening ampoules or an ampoule scarifier and instructions for medical use in the state and Russian languages are placed in a cardboard pack.

Manufacturer

Open Joint Stock Company "Borisov Medical Preparations Plant", Republic of Belarus, Minsk region, Borisov, st. Chapaeva, 64/27,

Release form: Liquid dosage forms. Injection.

General characteristics. Compound:

Active ingredient: 150 mg of amiodarone hydrochloride in 1 ml of solution.

Excipients: sodium acetate trihydrate, glacial acetic acid, polysorbate 80, benzyl alcohol, water for injection.

Class III antiarrhythmic drug. Has antiarrhythmic and antianginal effects.

Pharmacological properties:

Pharmacodynamics. Antiarrhythmic properties: prolongation of the 3rd phase of the action potential of cardiomyocytes without changing its height or rate of rise (Class III according to the Vaughan Williams classification). Isolated prolongation of phase 3 of the action potential occurs due to a slowdown in potassium currents, without changing sodium or calcium currents.

Bradycardic effect due to decreased automatism of the sinus node. This effect is not eliminated by the administration of atropine.

Non-competitive inhibitory effect on alpha and beta adrenergic receptors, without their complete blockade.

Slowing of sinoatrial, atrial and atrioventricular conduction, which is more pronounced against the background.

Does not change intraventricular conduction.

Increases the refractory period and reduces myocardial excitability at the sinoatrial, atrial and atrioventricular levels.

Slows down conduction and lengthens the refractory period of additional atrioventricular pathways.

Does not have a negative inotropic effect.

Pharmacokinetics. The amount of parenterally administered amiodarone in the blood decreases very quickly due to tissue saturation with the drug and its reaching the binding sites; the effect reaches a maximum 15 minutes after administration and disappears after approximately 4 hours.

Indications for use:

Treatment of severe cardiac arrhythmias in cases where oral administration is not possible, namely:

Atrial rhythm disturbances with high ventricular rates;

Tachycardia associated with Wolff-Parkinson-White syndrome;

Documented symptomatic, life-threatening, disabling ventricular rhythm disturbances;

Cardiopulmonary resuscitation for cardiac arrest caused by refractory ventricular fibrillation.

Important! Get to know the treatment

Directions for use and dosage:

Indicated for severe arrhythmias in which the use of oral drugs is not possible, with the exception of cardiopulmonary resuscitation for cardiac arrest caused by refractory ventricular fibrillation.

Infusion into the central vein. Initial dose: usually 5 mg/kg, in a glucose solution (if possible, using an infusion pump), over 20 minutes to 2 hours; infusion can be repeated 2-3 times within 24 hours. The short-term effect of the drug requires continued administration.

Peripheral vein infusion during cardiopulmonary resuscitation for cardiac arrest caused by ventricular fibrillation refractory to electrical defibrillation.

The initial intravenous dose is 300 mg (or 5 mg/kg), after dilution in 20 ml of 5% glucose solution. It is introduced in a stream.

If fibrillation does not stop, an additional intravenous injection of 150 mg (or 2.5 mg/kg) is used.

Do not mix with other drugs in the same syringe!

Features of application:

Electrolyte disturbances, especially hypokalemia: It is important to consider situations that may be accompanied by hypokalemia as predisposing to proarrhythmic events. must be adjusted before starting amiodarone

Except in cases of emergency therapy, Amiodarone in the form of a solution for intravenous injection can only be used in a hospital and with constant monitoring (ECG, blood pressure).

Use with caution for bronchial asthma and in old age.

Anesthesia. Before surgery, the anesthesiologist should be informed that the patient is receiving amiodarone.

Long-term treatment with amiodarone may increase local or systemic hemodynamic risk (may cause bradycardia, hypotension, decreased cardiac output or conduction disturbances).

Pregnancy and breastfeeding. Animal tests have not revealed the teratogenic effects of Amiodarone. Therefore, malformations in humans should not be expected since malformation-causing drugs have been shown to exhibit teratogenic effects in animals in properly conducted experiments in two different animal species.

The drug is contraindicated starting from the second trimester of pregnancy. Amiodarone, its metabolite and iodine are excreted into breast milk in concentrations exceeding the level in maternal plasma. If the mother is being treated with this drug, breastfeeding is contraindicated due to the risk of developing hypothyroidism in the child.

Influence on the ability to drive vehicles and operate machinery. Currently, there is no evidence that amiodarone affects the ability to drive vehicles and operate machinery.

Side effects:

Frequency of occurrence of adverse reactions:

Very often - > 10%;

Uncommon - >1%,<10%;

Rarely - >0.1%,<1%;

Very rare>0.01%,<0,1%;

Frequency cannot be determined from available data -<0,01% и менее.

From the cardiovascular system: very often: ; infrequently - severe bradycardia; rarely - sinus node arrest; proarrhythmogenic effects were noted in some cases, especially in elderly patients.

From the digestive system: often: .

Local reactions at the injection site: very common: inflammatory reactions (superficial) are possible when injected directly into a peripheral vein, reactions at the injection site such as pain, erythema, edema, extravasation, infiltration, inflammation, phlebitis, etc.

From the liver: there are reports of cases of liver dysfunction; these cases were diagnosed by elevated serum transaminase levels. The following was noted:

Very rare: usually a moderate and isolated increase in transaminase levels (1.5-3 times higher than normal), disappearing after dose reduction and even spontaneously; (several isolated cases) with increased levels of transaminases in the blood and/or jaundice, sometimes with death; treatment discontinuation is required; for long-term treatment (orally). The histological picture corresponds to pseudoalcoholic hepatitis. Since the clinical and laboratory picture of the disease is very heterogeneous (passing, an increase in transaminase levels 1.5 - 5 times above normal), regular monitoring of liver function is required. Even with a moderate increase in the level of transaminases in the blood, observed after treatment lasting more than 6 months, chronic disease should be suspected. Clinical abnormalities and laboratory abnormalities usually resolve after discontinuation of the drug. Several cases of irreversible progression have been noted.

From the immune system: very rarely: .

From the nervous system: very rarely: benign (pseudotumor of the brain).

From the respiratory system: very rarely, several cases of acute pneumonia have been observed, mainly associated with interstitial pneumonitis, sometimes with a fatal outcome and sometimes immediately after surgery (possibility of interaction with high doses of oxygen during mechanical ventilation is assumed). The possibility of discontinuing amiodarone and the advisability of prescribing corticosteroids should be considered; and/or apnea in severe respiratory failure, especially in patients with bronchial asthma.

Skin and subcutaneous tissue disorders: very rarely, sweating, hair loss.

From the vascular system: very often - usually a moderate and transient drop in blood pressure. Cases of severe hypotension or circulatory shock have been reported, especially after overdose or due to too rapid administration.

Very rare: hot flashes.

Interaction with other drugs:

Combinations with:

Drugs that can cause ventricular tachycardia of the “pirouette” type.

Class Ia antiarrhythmic drugs (quinidine, hydroquinidine, isopyramide).

Class III antiarrhythmic drugs (dofetilide, ibutilide, sotalol).

Other drugs, such as bepridil, cisapride, difemanil, IV ritromycin, mizolastine, IV vincamine, moxifloxacin, IV spiramycin.

Sultopride.

These contraindications do not apply to the use of amiodarone for cardiopulmonary resuscitation in cardiac arrest refractory to electrical defibrillation.

Cyclosporine. There may be an increase in the level of cyclosporine in plasma, associated with a decrease in the metabolism of the drug in the liver, with possible nephrotoxic manifestations. Determination of the level of cyclosporine in the blood, checking renal function and reviewing the dosage during treatment with amiodarone and after discontinuation of the drug.

Diltiazem for injection. Risk of bradycardia and atrioventricular block. If a combination is unavoidable, strict clinical and continuous ECG monitoring should be established.

Neuroleptics that can cause torsades de pointes: some phenothiazine antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, tiapride, veraliprid), butyrophenones (droperidol, haloperidol), other antipsychotics (pimozide).

The risk of ventricular rhythm disturbances (pirouette-type tachycardia) increases.

Methadone. The risk of ventricular rhythm disturbances (pirouette-type tachycardia) increases. Recommended: ECG and clinical observation.

Combinations requiring precautions when using Amiodarone with:

Oral anticoagulants: increased anticoagulant effect and risk of bleeding due to increased plasma concentrations of anticoagulants. The need for more frequent monitoring of the level of prothrombin in the blood and MHO (INR), as well as adaptation of doses of anticoagulants during treatment with amiodarone and after discontinuation of the drug.

Beta blockers, with the exception of sotalol (contraindicated combination) and esmolol (combination requiring caution when used)

Violations of contractility, automatism and conduction (suppression of compensatory sympathetic mechanisms). Clinical and ECG monitoring.

Beta blockers prescribed for heart failure (bisoprolol, carvedilol, metoprolol). Impaired contractility and conduction (synergistic effect) with the risk of developing severe bradycardia. Increased risk of ventricular arrhythmias, especially torsade de pointes.

Regular clinical and electrocardiographic monitoring is necessary.

Cardiac glycosides. Disorders of automaticity (excessive bradycardia) and atrioventricular conduction (synergism of action). When using digoxin, its concentration in plasma increases (due to decreased clearance of the alkaloid).

It is necessary to carry out clinical and ECG monitoring, as well as determination of plasma digoxin levels); It may be necessary to change the dose of digoxin.

Diltiazem for oral administration. Risk of bradycardia and atrioventricular block, especially in the elderly. Clinical and ECG control.

Verapamil for oral administration. Risk of bradycardia and atrioventricular block, especially in the elderly. Clinical and ECG control.

Essex scraper. Violations of contractility, automatism and conduction (suppression of compensatory sympathetic mechanisms). Clinical and ECG monitoring.

Hypokalemic drugs: potassium-sparing diuretics (in monotherapy or combination), stimulant laxatives, amphotericin B (iv), glucocorticoids (systemic), tetracosactide.

The risk of ventricular rhythm disturbances increases, especially tachycardia of the “pirouette” type (hypokalemia is a predisposing factor). Clinical and ECG monitoring, laboratory tests.

Lidocaine. Risk of increased lidocaine plasma concentrations, with the possibility of neurological and cardiac side effects, due to amiodarone's decreased metabolism of lidocaine in the liver. Clinical and ECG monitoring, if necessary, dose adjustment of lidocaine during treatment with amiodarone and after its discontinuation.

Orlistat. Risk of decreased plasma concentrations of amiodarone and its active metabolite. Clinical and, if necessary, ECG monitoring,

Phenytoin (and, by extrapolation, fosphenytoin). An increase in the level of phenytoin in plasma with symptoms of overdose, especially of a neurological nature (decreased metabolism of phenytoin in the liver). Clinical monitoring and determination of plasma phenytoin levels; if possible, reduce the dose of phenytoin.

Simvastatin. Increased risk of side effects (depending on dose) such as rhabdomyolysis (decreased metabolism of simvastatin in the liver). The dose of simvastatin should not exceed 20 mg per day.

If a therapeutic effect is not achieved at this dose, you should switch to another statin that does not interact with this type of interaction.

Tacrolimus. An increase in the level of tacrolimus in the blood due to inhibition of its metabolism by amiodarone. Measurement of tacrolimus blood levels, monitoring of kidney function and leveling of tacrolimus levels should be carried out.

Drugs that cause bradycardia: Many drugs can cause bradycardia. This is especially true for class Ia antiarrhythmic drugs, beta blockers, some class III antiarrhythmic drugs, some calcium channel blockers, digitalis, pilocarpine and anticholinesterase agents. Risk of excessive bradycardia (cumulative effect).

Combinations to consider. Drugs that cause bradycardia: calcium channel blockers with bradycardic effect (verapamil), beta blockers (except sotalol), clonidine, guanfacine, digitalis alkaloids, mefloquine, cholinesterase inhibitors (donezepil, galantamine, rivastigmine, tacrine, ambemonium, pyridostigmine, neostigmine), pilocarpine. Risk of excessive bradycardia (cumulative effects).

Incompatibilities. When PVC material or medical equipment plasticized with 2-diethylhexyl phthalate (DEHP) is used in the presence of amiodarone injection solution, DEHP may be released. To minimize exposure to DEHP, it is recommended that the solution be final diluted before infusion in DEHP-free equipment.

Contraindications:

SSS, sinus bradycardia, sinoatrial block, except in cases of correction with an artificial pacemaker;

Atrioventricular block II and III degrees, intraventricular conduction disorders (blockade of two and three branches of the His bundle); in these cases, intravenous amiodarone can be used in specialized departments under the cover of an artificial pacemaker (pacemaker);

Simultaneous use with drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type;

Hypokalemia;

Pregnancy;

Breast-feeding;

Hypersensitivity to iodine and/or amiodarone;

Severe pulmonary dysfunction (interstitial lung disease);

Or decompensated heart failure (the patient's condition may worsen).

Due to the presence of benzyl alcohol, intravenous administration of amiodarone is contraindicated in newborns, infants and children under 3 years of age.

Overdose:

Symptoms: sinus bradycardia, paroxysmal ventricular tachycardia, ventricular tachycardia of the “pirouette” type, circulatory disorders, liver dysfunction, decreased blood pressure.

Treatment: symptomatic therapy is carried out (for bradycardia - beta-adrenergic stimulants or installation of a pacemaker, for tachycardia of the “pirouette” type - intravenous administration of magnesium salts, reducing pacemaker). Amiodarone and its metabolites are not removed by hemodialysis and peritoneal dialysis.

Storage conditions:

In a place protected from light, at a temperature of 15 to 25 ºС. Keep out of the reach of children. Shelf life - 2 years. Do not use after expiration date.

Vacation conditions:

On prescription

Package:

In ampoules of 3 ml in packaging No. 5x1, No. 5x2, No. 10.

The description is valid on 24.01.2015

Latin name: Amiodaron
ATX code: C01BD01
Active substance: Amiodarone
Manufacturer: Balkanpharma-Dupnitza (Bulgaria), North Star, Organics, Biokom CJSC, AVVA-RUS, Obolenskoye FP (Russia)

Compound

One tablet of Amiodarone contains 200 mg amiodarone hydrochloride and excipients such as lactose, corn starch, alginic acid, low molecular weight povidone and magnesium stearate.

Release form

Amiodarone is available in tablets in blisters of 10 pieces or in a light-protective glass jar of 30 pieces. The drug is packaged in cardboard packs that can hold 30 or 60 tablets.

Solution for intravenous administration (prescription in Latin): Rp.: Sol. 300 mg Amiodaroni diluitur Dextrosum 5% - 20 ml.

pharmachologic effect

It has antiarrhythmic, coronary vasodilating and antianginal effects.

Pharmacodynamics and pharmacokinetics

Amiodarone - an active substance that can facilitate the work of the heart without significantly changing cardiac output and contractility of the heart muscle myocardium . At the same time, the drug increases coronary blood flow by reducing resistance in the arteries of the heart, and also reduces heart rate and blood pressure due to peripheral vasodilating effect . This significantly reduces the level of oxygen consumption by the myocardium and at the same time increases the energy reserves of the myocardium by increasing the content creatine phosphate And glycogen .

Indications for use of Amiodarone

Used for treatment as well as prevention paroxysmal rhythm disturbances :

ventricular that are life-threatening, as well as in patients with Chagas myocarditis ;
ventricular ;
prevention ventricular fibrillation , among other things - after the events cardioversion ;
paroxysm of flicker ;
atrial flutter ;
atrial extrasystole or ventricular ;
arrhythmias appearing in the background chronic cardiac or coronary insufficiency ;
parasystole ;

Indications for the use of Amiodarone are also supraventricular arrhythmias in cases of ineffectiveness or impossibility of using other therapy, which is usually associated with WPW syndrome.

Contraindications

sinus bradycardia ;
weak sinus syndrome ;
sinoatrial or 2nd and 3rd degrees (without using pacemaker );
cardiogenic shock ;
collapse ;
hypokalemia ;
arterial hypotension ;
(insufficient secretion of thyroid hormones);
interstitial lung diseases ;
reception MAO inhibitors ;
period and ;
hypersensitivity to the components of Amiodarone or to;
should be used with caution in children and adolescents under 18 years of age.

Side effects

The use of Amiodarone tablets can cause the following side effects in relation to certain organs and systems:

The cardiovascular system: sinus bradycardia (refractory to m-anticholinergics ), AV block , vasculitis , with long-term use - progression of CHF , ventricular arrhythmia like " pirouette ", strengthening the existing arrhythmias or its occurrence, with parenteral use - decrease in blood pressure .
Endocrine system: developing hypo - or hyperthyroidism .
Respiratory system: Long-term use may lead to cough , interstitial pneumonia or and also pulmonary fibrosis , pleurisy. With parenteral use it is possible bronchospasm , especially in people with severe forms of respiratory failure.
Digestive system: most often occurs nausea , vomit , or , heaviness in epigastrium , decreases, taste sensations become dull, less often - increased activity liver transaminases , in case of long-term use - toxic hepatitis , cholestasis , icteric staining of the integument , and .
Central and peripheral nervous system: possible, asthenia , auditory In case of long-term use - peripheral neuropathy , extrapyramidal manifestations, memory, sleep disturbances, ataxia , neuritis optic nerve . When administered parenterally, it may develop intracranial hypertension .
Sense organs: uveitis (inflammation of the choroid of the eye of various localization), deposits glycolipoprotein — lipofuscin V cornea , which can manifest itself in bright light in the form of disturbances: complaints of luminous points or the so-called “veil before the eyes”, in addition, it is possible retinal microdetachment .
Blood-forming organs: thrombocytopenia , hemolytic or aplastic anemia .
Skin: rash , defeat in the form exfoliative , photosensitivity , manifestations in the form of gray-blue discoloration of the skin rarely occurred.
Others: epididymitis and decline, myopathy , with parenteral use it is also possible increased sweating .

The use of the drug in elderly patients significantly increases the risk of developing severe forms bradycardia .

Amiodarone tablets, instructions for use (Method and dosage)

Amiodarone tablets should be taken orally, before meals, with the required amount of water for swallowing. Instructions for use of Amiodarone require an individual dosage regimen, which must be established and adjusted by the attending physician.

Standard dosage regimen:

The loading (in other words, saturating) initial dose for inpatient treatment, which is divided into several doses, is 600–800 mg per day, with the maximum allowable daily dose being up to 1200 mg. It must be taken into account that the total dose should be 10 g, usually it is achieved in 5–8 days.
For outpatient treatment, an initial dose of 600–800 mg per day is prescribed, which is divided into several doses, also reaching a total dose of no more than 10 g, but in 10–14 days.
To continue the course of treatment with Amiodarone, it is enough to take 100–400 mg per day. Attention! The minimum effective maintenance dose is used.
To avoid accumulation of the drug, it is necessary to take tablets either every other day or with a break of 2 days, once a week.
The average single dose with a therapeutic effect is 200 mg.
The average daily dose is 400 mg.
The maximum permissible dose is no more than 400 mg at a time, no more than 1200 mg at a time.
For children, the dose is usually in the range of 2.5-10 mg per day.

Overdose

A single significant dose may cause:

decline ;
bradycardia or ;
disruption of the normal functioning of the liver;
atrioventricular block .

Prescribed as treatment gastric lavage , symptomatic measures, during development bradycardia — , β1-adrenergic agonists , in extreme cases - cardiac stimulation .

Specific does not exist, turns out to be ineffective.

Interaction

When this drug is used simultaneously with the following drugs, various reactions may occur:

Antiarrhythmic drugs class 1A and Disopyramide , Procainamide , Quinidine increase the cardiac QT interval and increase the risk of developing torsade de pointes (TdP).
Laxatives that cause hypokalemia , and diuretics , corticosteroids, incl. i.v., Tetracosactide , in combination with Amiodarone, increase the risk of developing ventricular arrhythmia.
General means anesthesia , oxygen therapy - the risk of developing bradycardia, cardiac conduction disorders, arterial hypotension, and a decrease in cardiac output.
Tricyclic antidepressants, phenothiazines , Astemizole And