Cardiodaron-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARDIODARON-ZDOROV'YA (CARDIODARON-ZDOROVYE)

Composition:

Active substance: amiodarone;

1 ml of solution contains amiodarone hydrochloride 50 mg;

Excipients: polysorbate-80, benzyl alcohol, concentrated hydrochloric acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: clear solution ranging in color from yellowish to greenish-yellow.

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 in 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 slowing of potassium current through potassium channels, with no changes in the function of sodium or calcium channels.

Slows heart rate by reducing sinus node automaticity. This effect is not blocked by atropine.

Non-competitively blocks both 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 prolongs the refractory period in accessory atrioventricular pathways.

Absence of negative inotropic effect.

Cardiopulmonary resuscitation in cardiac arrest due to ventricular fibrillation resistant to electrical defibrillation. 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 had 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 bolus of amiodarone 300 mg diluted in 20 mL of 5% glucose solution (246 patients), while the other group received placebo (258 patients). Amiodarone significantly increased the likelihood of successful resuscitation and hospital admission: among 197 patients (39%) alive at hospital admission, 44% were in the amiodarone group compared to 34% in the placebo group (p = 0.03).

After adjusting for other prognostic factors, the adjusted odds ratio for survival to hospital admission in the amiodarone group versus placebo was 1.6 (95% confidence interval: 1.1–2.4; p = 0.02). The amiodarone group had a higher incidence of arterial 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, and repeat defibrillation, or with recurrence of ventricular fibrillation after initially successful defibrillation, were randomized to receive either amiodarone (5 mg/kg body weight, diluted in 30 mL of 5% glucose solution) and matching lidocaine placebo, or lidocaine (1.5 mg/kg at a concentration of 10 mg/mL) and matching amiodarone placebo containing the same vehicle (polysorbate 80).

Amiodarone significantly improved the likelihood of successful resuscitation and hospital admission in the 347 patients enrolled: 22.8% in the amiodarone group (41 out of 180 patients) versus 12% in the lidocaine group (20 out of 167 patients), p = 0.009. After adjusting for other prognostic factors, the adjusted odds ratio for survival to hospital admission in the amiodarone group versus lidocaine group was 2.49 (95% confidence interval: 1.28–4.85; p = 0.007). No differences were observed between the two treatment groups in the number of patients requiring therapy for bradycardia with atropine or for low blood pressure with dopamine, or in the number of patients receiving additional lidocaine (beyond study-assigned treatment). The number of patients who developed asystole after defibrillation and study drug administration was statistically significantly higher in the lidocaine group (28.9%) than in the amiodarone group (18.4%), p = 0.04.

Pediatric population. Controlled clinical trials of amiodarone involving children have not been conducted. However, according to published data, the safety of amiodarone use has been evaluated in 1118 pediatric patients with various types of arrhythmias.

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

• 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 amiodarone therapy may be initiated simultaneously at the standard loading dose, starting on the first day of infusion.

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

Amiodarone is primarily metabolized by cytochrome CYP3A4 and also by cytochrome CYP2C8. Amiodarone and its metabolite, desethylamiodarone, are potential inhibitors in vitro of cytochrome CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, CYP2C8, and CYP2B6. Amiodarone and desethylamiodarone may also inhibit transport proteins such as P-glycoprotein 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-glycoprotein.

Pediatric population. Controlled clinical trials of amiodarone involving children have not been conducted.

Published limited data do not indicate differences in pharmacokinetic parameters between adults and children.

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

Since mutagenicity test results were negative, the development of these tumors has been proposed to be explained by an epigenetic rather than genotoxic mechanism.

Studies in mice did not reveal the development of carcinomas, but dose-dependent follicular hyperplasia of the thyroid gland was observed. These effects on the thyroid gland in rats and mice may have been due to amiodarone’s influence on the synthesis and/or release of thyroid hormones. These findings are considered to have limited relevance for human use of the drug.

Clinical Characteristics.

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

Intravenous amiodarone is indicated for the treatment of severe rhythm disturbances 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.

Intravenous amiodarone 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 pacemaker has been implanted.

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

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

Hyperthyroidism – since exacerbation of the disease may occur during amiodarone therapy.

Vascular insufficiency (vascular collapse).

Severe arterial hypotension.

II and III trimesters of pregnancy.

Lactation period.

Concomitant use with medicinal products that may cause 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, difemanel, 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 types of interactions").

Telaprevir.

Cobicistat.

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

Interaction with other medicinal products and other types of interactions.

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 such treatment usually requires careful clinical monitoring and ECG control. Concomitant use of antiarrhythmic agents that may cause ventricular tachycardia of the type torsades de pointes (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 have 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 type torsades de pointes. This serious type of arrhythmia may be caused by certain medicinal products regardless of whether they exhibit antiarrhythmic effects. 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 pre-existing QT interval prolongation.

Medicinal products that may cause paroxysmal tachycardia of the type torsades de pointes include, in particular, class Ia and class III antiarrhythmic agents and some neuroleptics. For dolasetron, erythromycin, spiramycin, and vinpocetine, this interaction occurs only when their intravenous forms are used.

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

However, this does not apply to some of these agents considered absolutely necessary; instead of being contraindicated, they are simply not recommended for use in combination with other agents that promote the development of ventricular tachycardia of the type torsades de pointes. 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, some calcium channel blockers, digitalis preparations, pilocarpine, and cholinesterase inhibitors.

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 type torsades de pointes (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, difemanel, 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 type torsades de pointes.

Telaprevir. Disturbances in 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. Blood concentrations of cyclosporine should be measured, renal function monitored, and doses adjusted during amiodarone treatment.

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

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

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

Antiparasitic agents that may cause paroxysmal ventricular tachycardia of the type torsades de pointes (halofantrine, lumefantrine, pentamidine). Increased risk of ventricular arrhythmia, particularly of the type torsades de pointes. If possible, one of these two drugs should be discontinued. If 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 type torsades de pointes: amisulpride, chlorpromazine, tiaramide, droperidol, flupentixol, fluphenazine, haloperidol, levopromazine, pimozide, pipampersone, pipotiazine, sertindole, sulpiride, sulthiapride, tiapride, zuclopenthixol. Increased risk of ventricular arrhythmias, particularly of the type torsades de pointes.

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

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

Stimulant laxatives. Increased risk of ventricular arrhythmias, especially torsades de pointes (hypokalemia is a contributing factor). Hypokalemia should be corrected before administration of the medicinal product, and ECG monitoring, clinical monitoring, and electrolyte level control should be ensured during treatment.

Fidaxomicin. Increased plasma concentrations of fidaxomicin.

Combinations requiring precautions during use.

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

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

Dabigatran. Increased plasma concentration of dabigatran with increased risk of bleeding. Clinical monitoring is required when dabigatran is used in the postoperative period, and dose adjustment of dabigatran may be necessary, but the dose should not exceed 150 mg/day.

Substrates of CYP2C9. Amiodarone increases plasma concentrations of substances that are substrates of CYP2C9, 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 possible 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). When amiodarone is used concomitantly, the risk of muscle toxicity manifestations (e.g., rhabdomyolysis) increases, 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 inhibition of lidocaine metabolism in the liver by amiodarone. Clinical observation and ECG monitoring are required, and 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 during and after concomitant use with amiodarone are required.

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

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

Esmolol. Disturbances in contractility, automaticity, and conduction (inhibition of compensatory sympathetic mechanisms). Monitoring of ECG parameters 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.

Some macrolides (azithromycin, clarithromycin, roxithromycin). Increased risk of ventricular arrhythmia, particularly ventricular tachycardia of the type torsades de pointes. 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), intravenous amphotericin B, systemic glucocorticoids, tetracosactide. Increased risk of ventricular arrhythmia, particularly of the type torsades de pointes (hypokalemia is a contributing factor). Hypokalemia should be corrected before administration of the medicinal product, and ECG monitoring, electrolyte level monitoring, and clinical observation should be ensured during treatment.

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

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

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

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

Combinations requiring special attention.

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

Special precautions for use.

Warnings regarding the method of administration.

Infusion via central veins: severe arrhythmias 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 through 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). Infusion via central veins should always be used whenever possible.
• A central venous catheter is recommended, provided it is available and ready for use. Otherwise, the drug may be administered via peripheral veins—into the largest peripheral vein with maximum blood flow.
• Do not mix with other drugs in the same syringe.
• Prompt monitoring of the patient in an intensive care unit with continuous monitoring of arterial pressure and ECG parameters should be ensured.
• If amiodarone therapy needs to be continued, it should be administered by infusion via central veins 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) or verapamil (injectable), certain antiparasitic agents (halofantrine, lumefantrine, and pentamidine), some neuroleptics ( amisulpride, chlorpromazine, tiapride, droperidol, flupentixol, flufenazine, 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 existing arrhythmias have been observed (see section "Adverse reactions").
• Proarrhythmic effects of amiodarone may occur, particularly in the presence of factors predisposing to QT interval prolongation, such as concomitant use of 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 the risk with 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 impaired visual clarity, a complete ophthalmologic examination including fundoscopy should be performed immediately. Optic neuropathy or optic neuritis induced by amiodarone 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 disturbances. Cases of severe, potentially life-threatening bradycardia and conduction disturbances have been observed in patients receiving amiodarone in combination with sofosbuvir.

Bradycardia usually occurred within several hours or days, but in some cases symptoms appeared later, mostly within 2 weeks after initiation of hepatitis C antiviral therapy.

Amiodarone may be used in patients receiving sofosbuvir-containing medications only if there is intolerance or contraindication to other antiarrhythmic agents.

If concomitant use of amiodarone with these drugs is necessary, patients should be recommended to undergo cardiac monitoring in a hospital setting during the first 48 hours of concomitant therapy. Subsequently, outpatient monitoring or daily self-monitoring of heart rate should be performed 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.

Patients taking or who recently took amiodarone in combination with sofosbuvir-containing medications should be warned about symptoms of bradycardia and conduction disturbances and advised to seek immediate medical help if such symptoms occur.

Pulmonary effects. Several cases of interstitial pneumonitis have been observed with intravenous amiodarone. The onset of dyspnea or dry cough, either alone or accompanied by deterioration in general condition, may indicate pulmonary toxicity, such as interstitial pneumonitis, and requires patient monitoring by radiological imaging (see section "Adverse reactions"). Additionally, cases of acute respiratory distress syndrome have been observed in some patients treated with amiodarone immediately after surgery; 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. Regular monitoring of liver function is recommended at the beginning and throughout the entire course of amiodarone therapy (see section "Adverse reactions").

Excipients. The medicinal product contains 60 mg of benzyl alcohol in a 3 ml ampoule. 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 toxic effects is unknown. Younger children are at increased risk of such effects due to accumulation of benzyl alcohol.

Large amounts of benzyl alcohol should be used cautiously and only when urgently needed, 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 information on effects during pregnancy and breastfeeding, see section "Use during pregnancy or breastfeeding."

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

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

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

Long-term amiodarone therapy 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 contraindicated) and esmolol (caution required), verapamil, and diltiazem should be considered only for prevention of life-threatening ventricular arrhythmias and for cardiopulmonary resuscitation in cardiac arrest due to ventricular fibrillation resistant to external electrical cardioversion.

Transplantation. Retrospective studies have associated amiodarone use in heart transplant recipients prior to transplantation 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 when no secondary cause can be identified (see section "Special precautions for use"). Severe PGD may be irreversible.

Consideration should be given to initiating an alternative antiarrhythmic agent as soon as possible in patients awaiting heart transplantation.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown any teratogenic effects of amiodarone; therefore, there is no basis to expect developmental malformations in humans. All known substances causing malformations in humans have demonstrated teratogenicity in adequately controlled studies in at least two animal species.

Currently, there is insufficient clinical data to assess the potential teratogenic effect of amiodarone when used 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 during pregnancy from the second trimester onward.

Since benzyl alcohol crosses the placental barrier, large amounts should be used cautiously and only when urgently needed 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 exceeding those in maternal plasma. Due to the risk of hypothyroidism in the newborn, breastfeeding is contraindicated during amiodarone therapy.

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

Administration and Dosage

Due to the specific characteristics of the drug formulation, concentrations equivalent to at least 2 ampoules per 500 mL should be used. The drug must be administered only in 5% glucose isotonic solution.

Do not dilute the drug with 0.9% sodium chloride solution, as precipitation may occur!

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

Intravenous amiodarone should be used only when appropriate equipment for cardiac monitoring, defibrillation, and cardiac pacing is available.

Intravenous amiodarone may be administered prior to direct-current cardioversion.

Amiodarone should be administered via a 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 for use").

Severe arrhythmias where oral administration of the drug is not feasible, except during 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. This dose should be repeated 2 or 3 times within a 24-hour period.

The effect of this medicinal product is short-lived, 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 begin on 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 this situation, a central venous catheter is recommended (if available and ready for use); otherwise, the drug may be administered via 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 intravenous dose of 150 mg (or 2.5 mg/kg body weight) may be administered.
• Do not add any other agents to the syringe.

Children. The safety and efficacy of amiodarone in children have not been established. Available data are presented in the sections "Pharmacodynamics" and "Pharmacokinetics".

Since the injection solution contains benzyl alcohol, the medicinal product should be used with particular caution in neonates and children under 3 years of age (see section "Special precautions for use").

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 torsades de pointes tachycardia, and hepatic injury have been reported.

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

Adverse Reactions

Adverse reactions are classified by organ systems and frequency of occurrence: 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, usually moderate and dose-dependent.

Uncommon: myocardial conduction disturbances (sinus node block, atrioventricular block of varying degrees).

Very rare: marked bradycardia has been reported in individual cases, and in more exceptional cases — sinus arrest, particularly in elderly patients. Proarrhythmic effect.

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

Gastrointestinal disorders.

Very common: mild gastrointestinal disturbances (nausea, vomiting, dysgeusia), which usually occur at the beginning of treatment and resolve after dose reduction.

Common: constipation.

Uncommon: dry mouth.

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, inflammation, phlebitis, and phlegmon.

Hepatobiliary disorders.

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

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 significant elevation of serum transaminase levels and/or jaundice, including hepatic failure, sometimes fatal (see section "Special precautions for use"), requiring discontinuation of the drug;
• chronic liver injury during long-term treatment (with oral administration). Histological findings are consistent with 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 parameters is recommended. In case of elevated transaminase levels, even mild, occurring after more than 6 months of treatment, chronic liver injury should be suspected. Clinical abnormalities and laboratory deviations from normal usually resolve after discontinuation of the drug, although in several reported cases these changes were irreversible.

Immune system disorders.

Frequency not known: cases of angioneurotic edema and/or urticaria have been reported; anaphylactic shock / anaphylactoid reactions, including shock.

Endocrine disorders.

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

Common: thyroid dysfunction:

• hypothyroidism manifests with classical symptoms such as weight gain, increased cold sensitivity, apathy, and somnolence. Markedly elevated TSH levels confirm 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 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 after discontinuation. Potentially life-threatening cases require immediate initiation of appropriate treatment.

If thyrotoxicosis is a concern (both in itself and due to its impact on vulnerable myocardial balance), 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 discontinuation of amiodarone have been reported.

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

Nervous system disorders.

Common: extrapyramidal tremor, which usually regresses after dose reduction or discontinuation of the drug, nightmares, sleep disturbances.

Uncommon: peripheral sensorimotor neuropathy and/or myopathy, usually reversible after discontinuation of the drug.

Very rare: cerebellar ataxia, which usually regresses after dose reduction or discontinuation of the drug, benign intracranial hypertension (pseudotumor cerebri), headache, dizziness.

Frequency not known: parkinsonism syndrome, parosmia.

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). If this adverse reaction occurs, discontinuation of amiodarone should be considered and the appropriateness of corticosteroid therapy should be evaluated (see section "Special 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/neuritis, which may progress to complete blindness.

Vascular disorders.

Common: usually mild and transient decrease in blood pressure. Cases of severe 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: back pain, lumbar pain.

Blood and lymphatic system disorders.

Very rare: hemolytic anemia, aplastic anemia, thrombocytopenia.

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.

Metabolism and nutrition disorders.

Frequency not known: decreased appetite.

Injury, poisoning and procedural complications.

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

Reporting suspected adverse reactions. Reporting suspected adverse reactions after drug approval is an important procedure. It allows continuous monitoring of the benefit-risk ratio for the medicinal product. Healthcare professionals are requested to report all suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Incompatibility. Use only authorized solvents (see section "Instructions for use and dosage").

Packaging. 3 ml in vials, pack of 10 in a box; packs of 5, 5x2 in blisters in a box.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Manufacturer's address and location of business activity. 22 Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.