INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KORDARONÒ (CORDARONEÒ)

Composition:

Active substance: amiodarone;

1 ml of solution contains 50 mg of amiodarone hydrochloride;

Excipients: benzyl alcohol, polysorbate 80, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, pale yellow liquid, practically free from suspended particles.

Pharmacotherapeutic group. Cardiological preparations. Antiarrhythmic agents of class III. Amiodarone. ATC code C01B D01.

Pharmacological properties.

Pharmacodynamics.

Antiarrhythmic properties. Prolongation of the third phase of the action potential of cardiomyocytes without affecting its amplitude or rate of rise (Class III according to the Vaughan Williams classification). Isolated prolongation of the third phase of the action potential occurs due to inhibition of potassium current through potassium channels, with no changes in sodium or calcium channel function.

Slows heart rate by reducing the automaticity of the sinoatrial node. This effect is not blocked by atropine.

Non-competitively blocks alpha- and beta-adrenergic receptors.

Slows sinoatrial, atrial, and nodal conduction, with more pronounced effects at higher heart rates.

Does not affect ventricular conduction.

Prolongs the refractory period and reduces myocardial excitability at the atrial, nodal, and ventricular levels.

Slows conduction and prolonges the refractory period in accessory atrioventricular pathways.

Absence of negative inotropic effect.

Cardiopulmonary resuscitation in cardiac arrest associated with ventricular fibrillation resistant to electrical cardioversion. The safety and efficacy of intravenous amiodarone in patients who experienced out-of-hospital cardiac arrest due to ventricular fibrillation resistant to electrical therapy were evaluated in two double-blind studies: the ARREST trial, in which amiodarone was compared with placebo, and the ALIVE trial, in which amiodarone was compared with lidocaine.

The primary endpoint in both studies was the number of patients surviving to hospital admission.

In the ARREST trial, 504 patients who experienced out-of-hospital cardiac arrest due to ventricular fibrillation or pulseless ventricular tachycardia, resistant to three or more defibrillation attempts and epinephrine administration, were randomized into two groups. In one group, patients received a rapid intravenous infusion of amiodarone 300 mg diluted in 20 mL of 5% glucose solution (246 patients); in the other group, placebo was administered (258 patients). Amiodarone significantly increased the likelihood of successful resuscitation and hospital admission: among 197 patients (39%) alive at hospital admission, 44% were from the amiodarone group compared to 34% in the placebo group (p=0.03).

After adjustment for other prognostic factors, the adjusted odds ratio for survival to hospital admission in the amiodarone group compared to placebo was 1.6 (95% confidence interval: 1.1–2.4; p=0.02). The amiodarone group showed higher incidences of hypotension (59% vs. 48%, p=0.04) and bradycardia (41% vs. 25%, p=0.004) compared to the placebo group.

In the ALIVE trial, 347 patients with ventricular fibrillation resistant to three or more defibrillation attempts, epinephrine administration, and one additional defibrillation, or with recurrent ventricular fibrillation after initial successful defibrillation, were randomized to receive either amiodarone (5 mg/kg ideal body weight, diluted in 30 mL of 5% glucose solution) and matching placebo simulating lidocaine, or lidocaine (1.5 mg/kg at a concentration of 10 mg/mL) and matching placebo simulating amiodarone containing the same solvent (polysorbate 80).

Amiodarone significantly increased the likelihood of successful resuscitation and hospital admission in the 347 patients included in the study: 22.8% in the amiodarone group (41 out of 180 patients) compared to 12% in the lidocaine group (20 out of 167 patients), p=0.009. After adjustment for other prognostic factors affecting survival, the adjusted odds ratio for survival to hospital admission in the amiodarone group compared to the lidocaine group was 2.49 (95% confidence interval: 1.28–4.85; p=0.007). No differences were observed between the two treatment groups regarding the number of patients requiring therapeutic interventions for bradycardia (with atropine) or low blood pressure (with dopamine), or regarding the number of patients receiving lidocaine (in addition to study treatment). The number of patients developing asystole after defibrillation and study drug administration was statistically significantly higher in the lidocaine group (28.9%) compared to the amiodarone group (18.4%), p=0.04.

Pediatric population

No controlled clinical trials of the drug have been conducted in children. According to published data, the safety of amiodarone has been studied in 1118 pediatric patients with various types of arrhythmias.

In clinical studies involving children, the following dosing regimens were used:

Loading dose: 5 mg/kg body weight administered over 20 minutes to 2 hours;
Maintenance dose: 10–15 mg/kg/day for several hours to several days.

If necessary, oral therapy with the standard loading dose may be initiated simultaneously starting on the first day of infusion.

Pharmacokinetics.

The concentration of intravenously administered amiodarone in the blood decreases rapidly due to tissue saturation and receptor binding. Peak activity is reached within 15 minutes and declines over 4 hours.

Amiodarone is primarily metabolized by cytochrome CYP3A4, as well as by CYP2C8. Amiodarone and its metabolite desethylamiodarone are potential in vitro inhibitors of cytochrome CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, CYP2C8, and CYP2B6. Amiodarone and desethylamiodarone may also inhibit transport proteins such as P-glycoprotein (P-GP) and organic cation transporter 2 (OCT2). One study showed a 1.1% increase in creatinine concentration (an OCT2 substrate).

In vivo data indicate interactions between amiodarone and substrates of CYP3A4, CYP2C9, CYP2D6, and P-GP.

Pediatric population

No controlled clinical trials of the drug have been conducted in children.

Available limited published data do not reveal differences in pharmacokinetic parameters between adults and children.

Preclinical safety data

In a 2-year carcinogenicity study in rats, amiodarone caused an increased incidence of follicular thyroid tumors (adenomas and/or carcinomas) in both sexes at clinically relevant exposures.

Since mutagenicity study results were negative, the development of these tumors has been proposed to occur via an epigenetic rather than genotoxic mechanism.

Mouse studies did not reveal any carcinomas; however, dose-dependent follicular hyperplasia of the thyroid gland was observed. These effects on the thyroid gland in rats and mice may have been caused by amiodarone’s influence on the synthesis and/or release of thyroid hormones. These findings have low relevance for human use of the drug.

Clinical characteristics.

Indications. Treatment with the medicinal product should be initiated and, as a rule, monitored only in a hospital setting or under the supervision of a specialist.

Cordarone® intravenous solution is indicated for the treatment of severe rhythm disorders when oral administration of the drug is not possible:

atrial arrhythmias with ventricular tachycardia;
tachyarrhythmias associated with Wolff-Parkinson-White syndrome;
documented symptomatic ventricular arrhythmias leading to loss of work capacity.

Tachyarrhythmias of all types, including supraventricular, nodal, and ventricular tachycardias; atrial flutter and atrial fibrillation; ventricular fibrillation; in cases where other medicinal products cannot be used.

Cardiopulmonary resuscitation in cases of ventricular fibrillation resistant to electrical defibrillation in patients with cardiac arrest.

Cordarone® for intravenous administration may be used when a rapid response to treatment is required or when oral administration of the drug is not possible.

Contraindications.

Known hypersensitivity to iodine, amiodarone, or any of the excipients of the medicinal product.

Sinus bradycardia, sinoatrial block, except in cases where a cardiac pacemaker has been implanted.

Sick sinus syndrome (risk of sinus arrest), except in cases where a cardiac pacemaker has been implanted.

Severe atrioventricular conduction disturbances, except in cases where a cardiac pacemaker has been implanted.

Hyperthyroidism, as treatment with amiodarone may exacerbate the condition.

Vascular insufficiency (vascular collapse).

Severe arterial hypotension.

Second and third trimesters of pregnancy.

Lactation period.

Concomitant use with medicinal products that may cause paroxysmal torsades de pointes tachycardia (except antiparasitic agents, neuroleptics, and methadone):

class Ia antiarrhythmic agents (quinidine, hydroquinidine, disopyramide);
class III antiarrhythmic agents (sotalol, dofetilide, ibutilide);
other medicinal products such as arsenic compounds, bepridil, cisapride, citalopram, escitalopram, difemanyl, intravenous dolasetron, domperidone, dronedarone, intravenous erythromycin, levofloxacin, mequitazine, mizolastine, moxifloxacin, prucalopride, intravenous spiramycin, toremifene, intravenous vinpocetine (see section "Interaction with other medicinal products and other forms of interaction");
telaprevir;
cobicistat.

These contraindications do not apply to the use of amiodarone for cardiopulmonary resuscitation in cardiac arrest caused by ventricular fibrillation resistant to external electrical impulse therapy.

Interaction with other medicinal products and other forms of interaction.

Antiarrhythmic agents. Many antiarrhythmic agents suppress cardiac automaticity, conduction, and myocardial contractility. Concomitant use of antiarrhythmic agents belonging to different classes may achieve a favorable therapeutic effect, but treatment with such combinations usually requires careful clinical monitoring and ECG control. Concomitant use of antiarrhythmic agents that may cause ventricular tachycardia of the torsade de pointes type (amiodarone, disopyramide, quinidine derivatives, sotalol, and others) is contraindicated.

Concomitant use of antiarrhythmic agents of the same class is not recommended, except in exceptional cases, as such treatment increases the risk of cardiac adverse effects.

Concomitant use of amiodarone with medicinal products that exert negative inotropic effects, promote bradycardia, and/or slow atrioventricular conduction requires careful clinical monitoring and ECG control.

Medicinal products that may cause paroxysmal ventricular tachycardia of the torsade de pointes type. This serious type of arrhythmia may be caused by certain medicinal products regardless of whether they exhibit antiarrhythmic activity. Contributing factors include hypokalemia (see subsection "Agents that may cause hypokalemia"), as well as bradycardia (see subsection "Agents that slow heart rate") or congenital or acquired QT interval prolongation.

Medicinal products that may cause paroxysmal tachycardia of the torsade de pointes type include, in particular, class Ia, class III antiarrhythmic agents, and some neuroleptics. For dolasetron, erythromycin, spiramycin, and vinpocetine, this interaction occurs only with intravenous formulations.

Concomitant use of two medicinal products, each of which promotes the development of ventricular tachycardia of the torsade de pointes type, is generally contraindicated.

However, this does not apply to some of these agents considered absolutely essential; instead of being contraindicated, they are simply not recommended for use in combination with other agents promoting ventricular tachycardia of the torsade de pointes type. These include:

methadone;
antiparasitic agents (halofantrine, lumefantrine, pentamidine);
neuroleptics.

Agents that slow heart rate. Most medicinal products may cause bradycardia. This applies, in particular, to class Ia antiarrhythmic agents, beta-blockers, some class III antiarrhythmic agents, certain calcium channel blockers, digitalis preparations, pilocarpine, and anticholinesterase agents.

Effect of amiodarone on other medicinal products. Amiodarone and/or its metabolite desethylamiodarone inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6, and P-glycoprotein and may increase the effects of their substrates.

Due to the long elimination half-life of amiodarone, interactions may occur for several months after discontinuation of amiodarone.

Effect of other medicinal products on amiodarone. Inhibitors of CYP3A4 and CYP2C8 may inhibit amiodarone metabolism and increase its effects. During amiodarone treatment, it is recommended to avoid the use of CYP3A4 inhibitors (e.g., grapefruit juice and certain medicinal products).

Contraindicated combinations (see section "Contraindications"). Medicinal products that may cause paroxysmal ventricular tachycardia of the torsade de pointes type (except antiparasitic agents, neuroleptics, and methadone; see below "Combinations not recommended for use"):

class Ia antiarrhythmic agents (quinidine, hydroquinidine, disopyramide);
class III antiarrhythmic agents (dofetilide, ibutilide, sotalol);
other medicinal products such as arsenic compounds, bepridil, cisapride, citalopram, escitalopram, difemanyl, intravenous dolasetron, domperidone, dronedarone, intravenous erythromycin, levofloxacin, mequitazine, mizolastine, moxifloxacin, prucalopride, intravenous spiramycin, toremifene, intravenous vinpocetine.

High risk of developing ventricular arrhythmias, including paroxysmal ventricular tachycardia of the torsade de pointes type.

Telaprevir. Impairment of myocardial automaticity and conduction with risk of excessive bradycardia.

Cobicistat. Risk of increased adverse reactions caused by amiodarone due to slowed amiodarone metabolism.

Combinations not recommended for use (see section "Special precautions for use").

Sofosbuvir. Concomitant use of amiodarone with medicinal products containing sofosbuvir may cause severe symptomatic bradycardia. Should be used only when no alternative treatment options are available. Careful monitoring is recommended when these medicinal products are used concomitantly (see section "Special precautions for use").

Substrates of CYP3A4. Amiodarone is an inhibitor of the CYP3A4 enzyme and increases plasma concentrations of CYP3A4 substrates, which may enhance the toxic effects of these substrates.

Cyclosporine. Increased blood concentration of cyclosporine due to reduced hepatic metabolism, with risk of nephrotoxicity. Cyclosporine blood concentrations should be determined, renal function monitored, and doses adjusted during amiodarone treatment.

Intravenous formulation of diltiazem. Risk of developing bradycardia and atrioventricular block. If use of this combination cannot be avoided, careful clinical supervision and continuous ECG monitoring are mandatory.

Fingolimod. Potentiation of heart rate slowing effects with potentially fatal clinical consequences. This is particularly relevant for beta-blockers that suppress adrenergic compensatory mechanisms. Careful clinical supervision and continuous ECG monitoring for 24 hours after the first dose are required.

Intravenous formulation of verapamil. Risk of developing bradycardia and atrioventricular block. If use of this combination cannot be avoided, careful clinical supervision and continuous ECG monitoring are mandatory.

Antiparasitic agents that may cause paroxysmal ventricular tachycardia of the torsade de pointes type (halofantrine, lumefantrine, pentamidine). Increased risk of ventricular arrhythmia, particularly of the torsades de pointes type. If possible, one of these two agents should be discontinued. If use of this combination cannot be avoided, a prior assessment of QT interval duration should be performed before administration, and ECG parameters should be monitored during treatment.

Neuroleptics that may cause paroxysmal ventricular tachycardia of the torsade de pointes type: amisulpride, chlorpromazine, tiaramide, droperidol, flupentixol, fluphenazine, haloperidol, levopromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulpiride, tiapride, zuclopenthixol. Increased risk of ventricular arrhythmias, particularly of the torsade de pointes type.

Methadone. Increased risk of ventricular arrhythmias, particularly of the torsade de pointes type.

Fluoroquinolones, except levofloxacin and moxifloxacin (contraindicated combinations). Increased risk of ventricular arrhythmias, particularly of the torsade de pointes type.

Stimulant laxatives. Increased risk of ventricular arrhythmias, especially torsades de pointes (hypokalemia is a predisposing factor). Hypokalemia should be corrected before administration of the medicinal product, and ECG parameters, clinical status of the patient, and electrolyte levels should be monitored during treatment.

Fidaxomicin. Increased plasma concentrations of fidaxomicin.

Combinations requiring precautions during use.

Substrates of P-glycoprotein. Amiodarone is an inhibitor of P-glycoprotein. Increased blood concentrations of P-glycoprotein substrates are expected when used concomitantly.

Digitalis preparations. Suppression of automaticity (pronounced bradycardia) and impairment of atrioventricular conduction. When digoxin is used, its blood level increases due to reduced clearance. ECG monitoring, clinical observation, monitoring of digoxin blood levels, and, if necessary, adjustment of digoxin doses are required.

Dabigatran. Increased plasma concentration of dabigatran with increased risk of bleeding. When dabigatran is used in the postoperative period, clinical monitoring is required and, if necessary, dose adjustment of dabigatran, although the dose should not exceed 150 mg/day.

Substrates of CYP2C9. Amiodarone increases plasma concentrations of substances that are CYP2C9 substrates, such as vitamin K antagonists or phenytoin.

Vitamin K antagonists. Increased effect of vitamin K antagonist and increased risk of bleeding. International normalized ratio (INR) should be monitored more frequently. The dose of vitamin K antagonist should be adjusted during amiodarone treatment and for 8 days after its discontinuation.

Phenytoin (by extrapolation – also fosphenytoin). Increased plasma concentration of phenytoin with signs of overdose, particularly neurological (reduced hepatic metabolism of phenytoin). Clinical observation, monitoring of phenytoin plasma concentration, and possibly dose adjustment are required.

Flecainide (substrate of CYP2D6). Amiodarone increases plasma concentration of flecainide due to inhibition of cytochrome CYP2D6. Therefore, the dose of flecainide should be adjusted.

Substrates of CYP3A4. Amiodarone is an inhibitor of the CYP3A4 enzyme and increases plasma concentrations of substrates of this cytochrome, which may enhance the toxic effects of these substrates.

Statins (simvastatin, atorvastatin, and lovastatin). Concomitant use of amiodarone increases the risk of muscle toxicity manifestations (e.g., rhabdomyolysis), as statins may be metabolized by CYP3A4. If statins are necessary, statins not metabolized by CYP3A4 are recommended.

Other agents metabolized by CYP3A4 (lidocaine, sirolimus, tacrolimus, sildenafil, midazolam, dihydroergotamine, ergotamine, colchicine, triazolam). Amiodarone is an inhibitor of the CYP3A4 enzyme and increases plasma concentrations of these molecules, which may enhance their toxic effects.

Lidocaine. Risk of increased plasma concentration of lidocaine, which may cause neurological and cardiovascular adverse reactions due to amiodarone-induced inhibition of lidocaine metabolism in the liver. Clinical observation and ECG monitoring are required; if necessary, monitoring of lidocaine plasma concentration and dose adjustment of lidocaine during and after amiodarone treatment.

Tacrolimus. Increased blood concentration of tacrolimus due to inhibition of its metabolism by amiodarone. Determination of tacrolimus blood concentration, monitoring of renal function, and dose adjustment of tacrolimus are required during concomitant use with amiodarone and after its discontinuation.

Beta-blockers, except esmolol and sotalol. Impairment of automaticity and conduction (suppression of compensatory sympathetic mechanisms). ECG monitoring and clinical observation are required.

Beta-blockers used in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Impairment of myocardial automaticity and conduction with risk of developing pronounced bradycardia. Increased risk of developing ventricular arrhythmia, particularly of the torsade de pointes type. Regular ECG monitoring and clinical observation are required.

Esmolol. Impairment of contractility, automaticity, and conduction (suppression of compensatory sympathetic mechanisms). ECG and clinical monitoring are required.

Oral diltiazem. Risk of bradycardia or atrioventricular block, particularly in elderly patients. ECG monitoring and clinical observation are required.

Oral verapamil. Risk of bradycardia or atrioventricular block, especially in elderly patients. ECG monitoring and clinical observation are required.

Certain macrolides (azithromycin, clarithromycin, roxithromycin). Increased risk of developing ventricular arrhythmia, particularly ventricular tachycardia of the torsade de pointes type. ECG monitoring and clinical observation are required during concomitant use of these agents.

Agents that may cause hypokalemia: diuretics (causing hypokalemia either alone or in combination with other agents), amphotericin B (for intravenous administration), glucocorticoids (for systemic use), tetracosactide. Increased risk of ventricular arrhythmia, particularly of the torsade de pointes type (hypokalemia is a predisposing factor). Hypokalemia should be corrected before administration of the medicinal product, and monitoring of ECG parameters, electrolyte levels, and clinical observation should be ensured during treatment.

Agents causing bradycardia. Increased risk of developing ventricular arrhythmia, particularly ventricular tachycardia of the torsade de pointes type. Clinical observation and ECG monitoring should be performed.

Orlistat. Risk of reduced plasma concentration of amiodarone and its active metabolites. Clinical observation is required and, if necessary, ECG monitoring.

Tamsulosin. Risk of increased adverse reactions caused by tamsulosin due to inhibition of its hepatic metabolism. Clinical monitoring and, if necessary, dose adjustment of tamsulosin are required during and after treatment with this enzyme inhibitor.

Voriconazole. Increased risk of developing ventricular arrhythmias, particularly torsades de pointes, as amiodarone metabolism may be reduced. Clinical monitoring and ECG monitoring are required, and, if necessary, amiodarone dose adjustment.

Combinations requiring special attention.

Pilocarpine. Risk of excessive bradycardia (additive effects of agents causing bradycardia).

Special precautions for use.

Warnings regarding method of administration.

Central venous infusion: severe rhythm disturbances when oral administration of the drug is impossible, except for cardiopulmonary resuscitation in ventricular fibrillation resistant to external electrical cardioversion in patients with cardiac arrest.

Amiodarone solution should be administered via central veins, as administration via peripheral veins may cause local reactions such as superficial phlebitis. Amiodarone solution must be administered only by infusion, since even very slow intravenous injection of the drug may exacerbate arterial hypotension, heart failure, or severe respiratory failure (see section "Adverse reactions").

Cardiopulmonary resuscitation in cardiac arrest due to ventricular fibrillation resistant to external electrical cardioversion.

Administration via peripheral veins is generally not recommended due to the risk of hemodynamic disturbances (severe arterial hypotension, circulatory failure). Central venous infusion should always be used when possible.
A central venous catheter is recommended, provided it is available and ready for use. Otherwise, the drug may be administered via peripheral veins—preferably the largest peripheral vein with maximum blood flow.
Do not mix with other drugs in the same syringe.
Continuous monitoring of blood pressure and ECG parameters in an intensive care unit should be ensured as soon as possible.
If amiodarone therapy needs to be continued, it should be administered via central venous infusion with continuous monitoring of blood pressure and ECG.

Interaction with other medicinal products

Concomitant use of amiodarone with the following medicinal products is not recommended: cyclosporine, diltiazem (injectable), verapamil (injectable), certain antiparasitic agents (halofantrine, lumefantrine, pentamidine), some neuroleptics ( amisulpride, chlorpromazine, thioridazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulpiride, tiapride, zuclopenthixol), fluoroquinolones (except levofloxacin and moxifloxacin), stimulant laxatives, methadone, or fingolimod (see section "Interaction with other medicinal products and other forms of interaction").

Cardiac disorders

Cases of new-onset or worsening of pre-existing arrhythmias have been reported (see section "Adverse reactions").
Proarrhythmic effects of amiodarone may occur, particularly in the presence of factors predisposing to QT interval prolongation, such as certain drug combinations and hypokalemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). The risk of treatment-induced ventricular arrhythmia torsades de pointes with amiodarone is lower compared to other antiarrhythmic drugs in patients with a similar degree of QT interval prolongation.

Severe skin reactions. Life-threatening or even fatal skin reactions such as Stevens−Johnson syndrome or toxic epidermal necrolysis may occur. If patients develop signs or symptoms suggestive of these conditions (e.g., progressive skin rash with blisters or mucosal involvement), amiodarone treatment must be discontinued immediately.

Ocular disorders

In case of decreased visual acuity or blurred vision, a complete ophthalmological examination including fundoscopy should be performed immediately. Amiodarone-induced optic neuropathy or optic neuritis requires discontinuation of amiodarone therapy, as continued treatment may lead to progression of visual disturbances up to blindness (see section "Adverse reactions").

Severe bradycardia and conduction disorders Severe, potentially life-threatening bradycardia and conduction disturbances have been observed in patients receiving amiodarone in combination with sofosbuvir.

Bradycardia usually occurs within several hours to several days, although cases with delayed onset have been reported, mostly within 2 weeks after initiation of hepatitis C (HCV) antiviral therapy.

Patients receiving sofosbuvir-containing medications should take amiodarone only if other antiarrhythmic agents are contraindicated or not tolerated.

If concomitant use of amiodarone with these drugs is necessary, patients are recommended to undergo cardiac monitoring in a hospital setting for the first 48 hours of combined treatment, followed by outpatient monitoring or daily self-monitoring of heart rate for at least the first 2 weeks of treatment.

Due to the long elimination half-life of amiodarone, the cardiac monitoring described above should also be performed in patients who discontinued amiodarone within the past several months and are about to start treatment with sofosbuvir-containing medications.

All patients currently taking or who recently took amiodarone in combination with sofosbuvir-containing medications should be warned about symptoms of bradycardia and conduction disorders and advised to seek immediate medical attention if such symptoms occur.

Pulmonary effects. Several cases of interstitial pneumonitis have been reported with intravenous amiodarone. The onset of dyspnea or dry cough, alone or accompanied by deterioration in general condition, may indicate pulmonary toxicity such as interstitial pneumonitis and requires patient monitoring by radiological examination (see section "Adverse reactions"). Additionally, cases of acute respiratory distress syndrome have been observed in some patients treated with amiodarone immediately after surgical procedures; therefore, careful monitoring is recommended during mechanical ventilation.

Hepatic effects. Severe, sometimes fatal hepatocellular failure may develop within 24 hours after initiation of amiodarone solution. Liver function should be monitored regularly at the beginning and throughout the entire course of amiodarone treatment (see section "Adverse reactions").

Excipients. CordaroneÒ contains 60 mg of benzyl alcohol in a 3 ml vial. Benzyl alcohol may cause allergic reactions.

Intravenous administration of benzyl alcohol has led to serious adverse reactions and fatal outcomes in neonates ("gasping syndrome"). The minimal amount of benzyl alcohol that may cause toxicity is unknown. Younger children are at increased risk due to accumulation of benzyl alcohol.

Large amounts of benzyl alcohol should be used with caution and only when necessary, especially in patients with impaired liver or kidney function, pregnant women, and breastfeeding women, due to the risk of accumulation and toxicity (metabolic acidosis).

For effects during pregnancy and breastfeeding, see section "Use during pregnancy or breastfeeding".

Warnings. Electrolyte disturbances, especially hypokalemia: it is important to consider conditions associated with hypokalemia that may trigger proarrhythmic effects. Hypokalemia should be corrected before administering amiodarone.

Except in emergencies, intravenous amiodarone should be administered only in specialized intensive care units with continuous monitoring (ECG, blood pressure).

Anesthesia. The anesthesiologist must be informed about amiodarone therapy prior to surgery.

Long-term amiodarone treatment may increase the risk of hemodynamic adverse effects associated with general or local anesthesia, such as bradycardia, arterial hypotension, reduced cardiac output, and conduction disturbances.

Combinations (see section "Interaction with other medicinal products and other forms of interaction") with beta-blockers, except for sotalol (combination is contraindicated) and esmolol (combination requires caution), verapamil, and diltiazem should only be considered for prevention of life-threatening ventricular arrhythmias and for cardiopulmonary resuscitation in cardiac arrest due to ventricular fibrillation resistant to external electrical cardioversion.

Transplantation

In retrospective studies, amiodarone use in transplant recipients prior to heart transplantation has been associated with an increased risk of primary graft dysfunction (PGD).

PGD is a life-threatening complication after heart transplantation, characterized by left ventricular, right ventricular, or biventricular dysfunction within the first 24 hours after surgery, for which no secondary cause can be identified (see section "Special precautions for use"). Severe PGD may be irreversible.

Consideration should be given to earlier initiation of an alternative antiarrhythmic agent prior to transplantation in patients awaiting heart transplant.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown any teratogenic effects of the drug, and therefore developmental abnormalities in humans are not expected. Currently, substances known to cause developmental abnormalities in humans have demonstrated teratogenicity in two animal species in properly controlled studies.

From a clinical standpoint, there is currently insufficient data to assess the potential teratogenic effects of amiodarone during the first trimester of pregnancy.

Since the fetal thyroid gland begins to bind iodine from the 14th week of pregnancy, no negative effects on the fetal thyroid gland are expected if the drug is used before this time. Excessive iodine load from amiodarone use after this period may cause fetal hypothyroidism, which may be detected by laboratory tests or even clinically manifest as goiter.

Therefore, the use of this medicinal product is contraindicated from the second trimester of pregnancy.

Since benzyl alcohol crosses the placental barrier, large amounts should be used with caution and only when necessary due to the risk of accumulation and toxicity (metabolic acidosis).

Breastfeeding. Amiodarone and its metabolites, along with iodine, are excreted in breast milk at concentrations higher than their plasma concentrations in the mother. Due to the risk of hypothyroidism in the newborn, breastfeeding is contraindicated during amiodarone treatment.

Ability to affect reaction speed when driving or operating machinery. Not applicable.

Method of Administration and Dosage.

Due to the pharmaceutical form of the drug, concentrations equivalent to at least 2 ampoules per 500 mL must be used. CordaroneÒ may be administered only in 5% glucose isotonic solution.

Do not dilute the drug with isotonic sodium chloride solution, as precipitation may occur!

Do not mix with other drugs in the same infusion system.

CordaroneÒ for intravenous administration should be used only when appropriate equipment for monitoring cardiac function, defibrillation, and cardiac pacing is available.

CordaroneÒ for intravenous administration may be used prior to direct-current cardioversion.

Amiodarone should be administered via central venous access, except in cases of cardiopulmonary resuscitation for ventricular fibrillation resistant to electrical defibrillation in patients with cardiac arrest. In such circumstances, peripheral access may be used if central venous access cannot be established (see section "Special Precautions").

Severe arrhythmias, for which oral administration of the drug is not suitable, except for cases of cardiopulmonary resuscitation for ventricular fibrillation resistant to electrical defibrillation in patients with cardiac arrest:

Intravenous infusion via central venous access.

Loading dose: the standard recommended dose is 5 mg/kg body weight, administered by intravenous infusion over a period of 20 minutes to 2 hours, preferably using an infusion pump, and should be repeated 2 or 3 times within a 24-hour period.

The effect of this medicinal product is short-term, necessitating continued administration by infusion.

Maintenance dose: 10–20 mg/kg per day (on average 600–800 mg per day, up to 1.2 g per day) in 250 mL of glucose solution over several days.

Transition to oral therapy (3 tablets per day) should be initiated from the first day of infusion therapy. The dose may be increased to 4 or even 5 tablets per day.

Cardiopulmonary resuscitation for ventricular fibrillation resistant to electrical defibrillation in patients with cardiac arrest.

When using the drug in such situations, a central venous catheter is recommended (if available and ready for use); otherwise, the drug may be administered through peripheral veins, using the largest possible peripheral vein with maximum blood flow.

Initial dose is 300 mg (or 5 mg/kg body weight), diluted in 20 mL of 5% glucose solution and administered by rapid injection.
If ventricular fibrillation persists, an additional 150 mg (or 2.5 mg/kg body weight) of the drug may be administered intravenously.
Do not add any other agents to the syringe.

Children. Safety and efficacy of amiodarone in children have not been established. For currently available information, see sections "Pharmacodynamics" and "Pharmacokinetics." Since amiodarone ampoules for injection contain benzyl alcohol, the drug should be used with particular caution in neonates and children under 3 years of age (see section "Special Precautions").

Overdose.

There is no information regarding amiodarone overdose following intravenous administration.

Information on amiodarone overdose following oral administration is limited. A few cases of sinus bradycardia, ventricular arrhythmias, including paroxysmal torsade de pointes tachycardia, and liver injury have been reported.

Treatment should be symptomatic. Due to the pharmacokinetic properties of the drug, prolonged monitoring of the patient and cardiac function control are recommended. Amiodarone and its metabolites are not dialyzable.

Adverse Reactions

Adverse reactions are classified by system organ classes and frequency of occurrence according to the following criteria: very common (≥ 10%); common (≥ 1%, < 10%); uncommon (≥ 0.1%, < 1%); rare (≥ 0.01%, < 0.1%); very rare (< 0.01%), frequency not known (cannot be estimated from available data).

Cardiac disorders

Common: bradycardia.

Very rare: severe bradycardia has been reported in individual cases, and in even more exceptional cases, sinoatrial arrest, particularly in elderly patients. Proarrhythmic effect.

Frequency not known: paroxysmal ventricular tachycardia of the torsade de pointes type (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Gastrointestinal disorders

Very common: nausea.

Frequency not known: pancreatitis/acute pancreatitis.

General disorders and administration site conditions

Common: inflammatory reactions may occur, particularly phlebitis of superficial veins, when administered directly into a peripheral vein; reactions at the injection site, including pain, erythema, swelling, necrosis, extravasation, infiltration formation, inflammation, phlebitis and phlegmon.

Hepatobiliary disorders

Hepatic injury has been reported, diagnosed by elevated serum transaminase levels. The following adverse effects have been reported:

Very rare:

usually mild and isolated elevation of transaminase levels (1.5–3 times above normal) at the beginning of treatment, which resolves after dose reduction or even spontaneously;
acute liver injury with marked elevation of serum transaminase levels and/or jaundice, including hepatic failure, sometimes fatal (see section "Special warnings and precautions for use"), requiring discontinuation of the drug;
chronic liver injury during long-term treatment (with oral administration). The histological picture corresponds to pseudo-alcoholic hepatitis. Since clinical and laboratory signs are not clearly expressed (variable hepatomegaly, serum transaminase levels elevated 1.5–5 times above normal), regular monitoring of liver function tests is indicated. Chronic liver injury should be suspected in case of elevated transaminase levels, even moderate, occurring after more than 6 months of treatment. Clinical abnormalities and laboratory deviations usually resolve after discontinuation of the drug, although in several reported cases these changes were irreversible.

Immune system disorders

Very rare: anaphylactic shock.

Frequency not known: angioedema and/or urticaria have been reported.

Endocrine disorders

Very common: thyroid disorders: in the absence of any clinical signs of thyroid dysfunction, certain "discordance" in thyroid hormone levels (elevated T4, normal or slightly decreased T3) does not require discontinuation of the drug.

Common: thyroid disorders:

hypothyroidism manifests with classical symptoms such as weight gain, increased cold sensitivity, apathy, and drowsiness. A clearly elevated TSH level confirms this diagnosis. Normal thyroid function usually recovers gradually within 1–3 months after discontinuation of treatment; discontinuation of the drug is not mandatory. If amiodarone use is clinically justified, treatment may continue in combination with thyroid hormone replacement therapy using L-thyroxine, with dose adjustment based on TSH levels.
hyperthyroidism is significantly more difficult to diagnose, as its symptoms are less pronounced (slight unexplained weight loss, reduced efficacy of antianginal and/or antiarrhythmic therapy). Elderly patients may develop psychiatric symptoms or manifestations resembling thyrotoxicosis. Diagnosis is confirmed by a marked decrease in highly sensitive TSH levels. In such cases, amiodarone must be discontinued; clinical recovery usually begins 3–4 weeks thereafter. Potentially life-threatening cases require immediate appropriate treatment.

If thyrotoxicosis is a concern (both as a condition itself and due to its impact on vulnerable myocardial equilibrium), given the variable efficacy of synthetic antithyroid drugs, treatment with corticosteroids (1 mg/kg) for a prolonged period (3 months) can be unambiguously recommended. Cases of hyperthyroidism occurring several months after amiodarone discontinuation have been reported.

Very rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Nervous system disorders

Very rare: benign intracranial hypertension (pseudotumor cerebri).

Respiratory, thoracic and mediastinal disorders

Very rare:

interstitial pneumonitis or fibrosis, sometimes fatal;
acute respiratory distress syndrome, usually associated with interstitial pneumonitis, occasionally fatal, sometimes occurring in the early postoperative period (possible interaction with high-dose oxygen was suspected). In case of this adverse reaction, discontinuation of amiodarone should be considered and the appropriateness of corticosteroid therapy evaluated (see section "Special warnings and precautions for use");
bronchospasm and/or apnea in cases of severe respiratory insufficiency, particularly in patients with bronchial asthma.

Skin and subcutaneous tissue disorders

Very rare: excessive sweating, alopecia.

Common: eczema.

Frequency not known:

severe, sometimes fatal, skin reactions such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome;
bullous dermatitis;
DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).

Eye disorders

Frequency not known: optic neuropathy/optic neuritis, which may progress to complete blindness.

Vascular disorders

Common: usually mild and transient decrease in arterial blood pressure. Cases of severe arterial hypotension or collapse have been reported, particularly in cases of overdose or very rapid administration.

Very rare: hot flushes.

Musculoskeletal and connective tissue disorders

Frequency not known: lumbar pain, back pain.

Blood and lymphatic system disorders

Frequency not known: neutropenia, agranulocytosis.

Psychiatric disorders

Common: decreased libido.

Frequency not known: delirium (including confusion), hallucinations.

Reproductive system and breast disorders

Frequency not known: decreased libido.

Injury, poisoning and procedural complications

Frequency not known: primary graft dysfunction after heart transplantation with potentially fatal outcome (see section "Special warnings and precautions for use").

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

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

Incompatibilities. Use only authorized solvents (see section "Directions for use and dosage").

Packaging. No. 6: 3 ml in a vial; 6 vials in polymer blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Sanofi Winthrop Industrie.
Sanofi S.r.l.

Manufacturer's address and location of operations.

1 rue de la Virgule Ambarès et Lagrave, 33565 CARBON BLANC Cedex, France.
Via Valsalva, 4, ANAGNI (FR), 03012, Italy.

Marketing Authorization Holder.

LLC "Sanofi-Aventis Ukraine", Ukraine.