INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMIODARONE (Amiodarone)

Composition:

Active substance: amiodarone hydrochloride;

1 tablet contains amiodarone hydrochloride (calculated as 100% substance) 200 mg;

Excipients: maize starch, lactose monohydrate, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, flat cylindrical tablets with bevelled edges and a score line.

Pharmacotherapeutic group. Class III antiarrhythmic agents. Amiodarone.

ATC code C01B D01.

Pharmacological properties.

Pharmacodynamics.

Antiarrhythmic properties. Prolongation of phase 3 of the myocardial action potential, primarily due to inhibition of potassium channels (class III according to Vaughan-Williams classification).

Slowing of heart rate due to suppression of sinoatrial node automaticity. This effect is not blocked by atropine.

Non-competitive α- and β-antiadrenergic action.

Slowed sinoatrial, atrial, and nodal conduction, which becomes more pronounced with increased heart rate.

No changes in intraventricular conduction.

Increased refractory period and decreased myocardial excitability at the atrial, nodal, and ventricular levels.

Slowed conduction and prolonged refractory periods in accessory atrioventricular conduction pathways.

Other properties. Reduced oxygen consumption due to moderate reduction in peripheral vascular resistance and decreased heart rate.

Increased coronary blood flow due to direct action on myocardial vascular smooth muscle and maintenance of cardiac output despite reduced arterial pressure and peripheral vascular resistance, in the absence of negative inotropic effects.

A meta-analysis of data from 13 prospective, randomized, controlled trials involving 6553 patients who had recently suffered myocardial infarction (78%) or chronic heart failure (22%) was performed.

The mean duration of patient follow-up ranged from 0.4 to 2.5 years. The average daily maintenance dose of the drug varied between 200 and 400 mg.

This meta-analysis demonstrated that amiodarone significantly reduced total mortality by 13% (95% CI: 0.78–0.99; p = 0.030) and arrhythmia-related mortality by 29% (95% CI: 0.59–0.85; p = 0.0003).

However, these results should be interpreted with caution due to heterogeneity among the various studies (differences primarily related to the populations included, duration of follow-up, methodology used, and study outcomes).

The proportion of patients who discontinued treatment was higher in the amiodarone group (41%) compared to the placebo group (27%).

Hypothyroidism developed in 7% of patients receiving amiodarone, compared to 1% in the placebo group. Hyperthyroidism was diagnosed in 1.4% of patients in the amiodarone group compared to 0.5% in the placebo group.

Interstitial pneumonitis occurred in 1.6% of patients in the amiodarone group compared to 0.5% in the placebo group.

Pediatric population. No controlled clinical trials have been conducted in children. According to literature data, the safety of amiodarone use has been evaluated in 1118 children with various types of arrhythmias.

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

Loading dose: 10–20 mg/kg/day for 7–10 days (i.e., 500 mg/m²/day adjusted to body surface area);
Maintenance dose: the minimum effective dose should be used; based on individual response, it may range from 5 to 10 mg/kg/day (i.e., 250 mg/m²/day adjusted to body surface area).

Pharmacokinetics.

Amiodarone is a compound characterized by slow distribution and high tissue affinity.

Its oral bioavailability varies between 30% and 80% (on average, 50%) depending on individual patient characteristics. After a single dose, maximum plasma concentrations are reached within 3–7 hours.

Therapeutic activity typically manifests within one week of treatment (ranging from several days to two weeks).

The elimination half-life of amiodarone is prolonged and characterized by considerable inter-individual variability (ranging from 20 to 100 days). During the initial days of treatment, the drug accumulates in most body tissues, particularly in adipose tissue. Elimination begins after several days, and the input/output balance of the drug reaches equilibrium over one or several months, depending on the patient.

These characteristics justify the use of loading doses to rapidly achieve tissue concentrations required for therapeutic activity.

A portion of the iodine is cleaved from the compound and excreted in urine as iodide; with a daily amiodarone dose of 200 mg, iodine excretion amounts to 6 mg/24 hours. The remainder of the compound, and thus the majority of iodine, is excreted in feces following hepatic metabolism.

Since only a small amount of the drug is eliminated via urine, standard doses may be used in patients with renal impairment.

After discontinuation of the drug, elimination continues for several months. Residual drug activity may persist for a period ranging from 10 days to 1 month.

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

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

Pediatric population. No controlled clinical trials have been conducted in children. Available limited data do not indicate differences in pharmacokinetic parameters between adults and children.

Preclinical data. Results from two-year carcinogenicity studies in animals are known to show that amiodarone causes an increased incidence of follicular thyroid tumors (adenomas and/or carcinomas) in both sexes of animals at clinically relevant exposures.

Since mutagenicity study results were negative, the development of these tumors is more likely explained by an epigenetic rather than genotoxic mechanism.

Animal study results do not indicate the development of any carcinomas, but dose-dependent follicular hyperplasia of the thyroid gland was observed. These effects on the thyroid gland in animals may have been due to the influence of amiodarone on the synthesis and/or release of thyroid hormones. These findings have low relevance for the use of the drug in humans.

Clinical characteristics.

Indications.

Prevention of recurrences:

Ventricular tachycardia that is life-threatening: treatment must be initiated in a hospital setting with continuous patient monitoring;
Symptomatic ventricular tachycardia (documented), leading to disability;
Supraventricular tachycardia (documented), requiring treatment, when other drugs are ineffective or contraindicated;
Ventricular fibrillation.

Treatment of supraventricular tachycardia: slowing or reducing atrial fibrillation or flutter.

Ischemic heart disease and/or left ventricular dysfunction.

Contraindications.

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

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

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

Hyperthyroidism, due to the potential for exacerbation during amiodarone administration.

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

Second and third trimesters of pregnancy.

Lactation period.

Combination with drugs capable of inducing torsade de pointes ventricular 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, diphenylhydantoin, dolasetron (intravenous), domperidone, dronedarone, erythromycin (intravenous), levofloxacin, mequitazine, mizolastine, vinpocetine (intravenous), moxifloxacin, prucalopride, spiramycin (intravenous), toremifene (see section "Interaction with other medicinal products and other types of interactions");
telaprevir;
cobicistat.

Interaction with other medicinal products and other types of interactions.

Antiarrhythmic drugs. Many antiarrhythmic drugs suppress cardiac automaticity, conduction, and myocardial contractility.

Concomitant use of antiarrhythmic agents from different classes may achieve a favorable therapeutic effect, but such treatment is usually very delicate and requires careful clinical and ECG monitoring. Concomitant use of antiarrhythmic agents capable of inducing torsades de pointes (e.g., amiodarone, disopyramide, quinidine derivatives, sotalol) is contraindicated.

Concomitant use of antiarrhythmic agents from 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 exerting negative inotropic effects promotes bradycardia and/or slows atrioventricular conduction, thus requiring careful clinical and ECG monitoring.

Medicinal products that may induce torsades de pointes. This serious arrhythmia may be induced by certain medicinal products, regardless of whether they belong to antiarrhythmic drugs or not. Predisposing factors include hypokalemia (see subsection "Drugs that reduce potassium levels"), bradycardia (see subsection "Drugs that slow heart rate"), or pre-existing congenital or acquired QT interval prolongation.

Medicinal products that may induce torsades de pointes include, in particular, Class Ia and III antiarrhythmic agents and certain neuroleptics. For dolasetron, erythromycin, spiramycin, and vinpocetine, such interaction occurs only when intravenous formulations are used.

Concomitant use of two medicinal products, each capable of inducing torsades de pointes, is generally contraindicated.

However, methadone, antiparasitic agents (halofantrine, lumefantrine, pentamidine), and neuroleptics, when their use is considered absolutely necessary, are not contraindicated but are not recommended for concomitant use with other agents that promote torsades de pointes.

Drugs that slow heart rate. Many medicinal products may cause bradycardia, including Class Ia antiarrhythmic agents, β-blockers, certain Class III antiarrhythmic agents, certain calcium channel blockers, digitalis preparations, pilocarpine, and cholinesterase inhibitors.

Effects of amiodarone on other medicinal products.

Amiodarone and/or its metabolite, desethylamiodarone, inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6, and P-glycoprotein and may increase exposure to their substrates. Due to the long duration of amiodarone's effect, such interactions may occur for several months after discontinuation of amiodarone treatment.

Effects of other medicinal products on amiodarone.

Inhibitors of CYP3A4 and CYP2C8 may potentially inhibit amiodarone metabolism and thereby increase its exposure.

CYP3A4 inhibitors (e.g., grapefruit juice and certain medicinal products) should generally not be used during amiodarone treatment.

Contraindicated combinations (see section "Contraindications"). Medicinal products that may induce torsades de pointes (except antiparasitic agents, neuroleptics, and methadone; see subsection "Not recommended combinations"):

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

Increased risk of ventricular arrhythmias, especially torsades de pointes.

Telaprevir. Disorders of cardiomyocyte automaticity and conduction with risk of excessive bradycardia.

Cobicistat. Risk of increased frequency of amiodarone-induced adverse effects due to reduced metabolism.

Not recommended combinations.

Sofosbuvir. Concomitant use of amiodarone with medicinal products containing sofosbuvir may cause severe symptomatic bradycardia. Should be used only if 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 a CYP3A4 inhibitor and increases plasma concentrations of CYP3A4 substrates, potentially increasing their toxicity.

Cyclosporine. Increased serum cyclosporine concentrations due to reduced hepatic metabolism, with risk of nephrotoxic effects.

During amiodarone treatment, cyclosporine blood concentrations should be quantitatively determined, renal function monitored, and cyclosporine dose adjusted.

Diltiazem for injection. Risk of bradycardia and atrioventricular block.

If use of this combination cannot be avoided, careful clinical observation and continuous ECG monitoring are extremely important.

Fingolimod. Potentiation of bradycardia-induced effects, possibly with fatal outcome. This is particularly relevant for β-blockers that inhibit adrenergic compensatory mechanisms. After administration of the first dose, clinical observation and continuous ECG monitoring should be performed for 24 hours.

Verapamil for injection. Risk of bradycardia and atrioventricular block.

If use of this combination cannot be avoided, careful clinical observation and continuous ECG monitoring are extremely important.

Antiparasitic agents that may induce torsades de pointes (halofantrine, lumefantrine, pentamidine). Increased risk of ventricular arrhythmias, especially torsades de pointes. If possible, one of the two drugs should be discontinued. If use of this combination cannot be avoided, QT interval should be assessed prior to treatment and ECG monitoring performed.

Neuroleptics that may induce torsades de pointes ( amisulpride, chlorpromazine, tiaramide, droperidol, flupentixol, flufenazine, haloperidol, levomepromazine, pimozide, pipampersone, pipotiazine, sertindole, sulpiride, sulthiame, tiapride, zuclopenthixol). Increased risk of ventricular arrhythmias, especially torsades de pointes.

Methadone. Increased risk of ventricular arrhythmias, especially torsades de pointes.

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

Stimulant laxatives. Increased risk of ventricular arrhythmias, especially torsades de pointes ventricular tachycardia (hypokalemia being a triggering factor). Before administration, any hypokalemia should be corrected, and ECG monitoring, clinical observation, and electrolyte level monitoring should be performed.

Fidaxomicin. Increased plasma concentrations of fidaxomicin.

Combinations requiring precautions during use.

Substrates of P-glycoprotein. Amiodarone is a P-glycoprotein inhibitor. When used concomitantly with P-glycoprotein substrates, increased blood concentrations of these substrates are expected.

Digitalis preparations. Suppression of automaticity (excessive bradycardia) and impaired atrioventricular conduction.

When digoxin is used, increased digoxin blood levels occur due to reduced digoxin clearance, requiring ECG and clinical status monitoring. If necessary, digoxin blood levels should be monitored and digoxin dose adjusted.

Dabigatran. Increased plasma concentrations of dabigatran with increased risk of hemorrhagic events. If dabigatran is used after surgical intervention, clinical monitoring and dose adjustment of dabigatran, if necessary, but not exceeding 150 mg/day, should be performed.

Since amiodarone has a long elimination half-life, interactions may occur for several months after discontinuation of amiodarone treatment.

Substrates of CYP2C9. Amiodarone increases concentrations of substances that are CYP2C9 substrates, such as vitamin K antagonists or phenytoin, due to inhibition of cytochrome P450 2C9 enzymes.

Vitamin K antagonists. Enhanced effects of vitamin K antagonists and increased risk of bleeding. Monitoring of international normalized ratio (INR) should be performed more frequently. The dose of vitamin K antagonist should be adjusted during amiodarone treatment and for 8 days after completion of treatment.

Phenytoin (by extrapolation – also fosphenytoin). Increased plasma concentrations of phenytoin with signs of overdose, particularly neurological signs (due to inhibited hepatic metabolism of phenytoin). Clinical monitoring, monitoring of phenytoin plasma concentrations, and, if necessary, dose adjustment of phenytoin should be performed.

Substrates of CYP2D6:

Flecainide. Amiodarone increases plasma levels of flecainide by inhibiting cytochrome CYP2D6. Therefore, flecainide dose adjustment should be performed.

Substrates of CYP3A4: amiodarone is a CYP3A4 inhibitor and increases plasma concentrations of substrates of this cytochrome, thereby increasing the toxic effects of these substrates.

Statins (simvastatin, atorvastatin, lovastatin): concomitant use of amiodarone and statins metabolized by CYP3A4, such as simvastatin, atorvastatin, and lovastatin, increases the risk of muscle toxicity (e.g., rhabdomyolysis). When used concomitantly with amiodarone, statins not metabolized by CYP3A4 are recommended.

Other medicinal products metabolized by CYP3A4 (lidocaine, sirolimus, tacrolimus, sildenafil, midazolam, dihydroergotamine, ergotamine, colchicine, triazolam). Amiodarone is a CYP3A4 inhibitor and increases plasma concentrations of these molecules, leading to potential increased toxicity.

Lidocaine. Risk of increased plasma concentrations of lidocaine, which may lead to neurological and cardiac adverse effects due to inhibition of hepatic metabolism by amiodarone. Clinical and ECG monitoring should be performed, and, if necessary, quantitative determination of plasma concentrations of lidocaine. Dose adjustment of lidocaine may be required during amiodarone treatment and after its discontinuation.

Tacrolimus. Increased blood concentrations of tacrolimus due to inhibition of its metabolism by amiodarone. Quantitative determination of tacrolimus blood concentrations, monitoring of kidney function, and dose adjustment of tacrolimus should be performed when used concomitantly with amiodarone and after its discontinuation.

β-blockers, except sotalol (contraindicated combination) and esmolol (combination requiring precautions during use). Impairment of automaticity and conduction (inhibition of compensatory sympathetic mechanisms). ECG and clinical monitoring are recommended.

β-blockers used for heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Impairment of automaticity and myocardial conduction with risk of excessive bradycardia. Increased risk of ventricular arrhythmias, especially torsades de pointes. Regular clinical and ECG monitoring is recommended.

Esmolol. Impairment of contractility, automaticity, and conduction (inhibition of compensatory sympathetic mechanisms). Regular clinical and ECG monitoring are recommended.

Diltiazem for oral use. Risk of bradycardia or atrioventricular block, especially in elderly patients. Regular clinical and ECG monitoring are recommended.

Verapamil for oral use. Risk of bradycardia and atrioventricular block, especially in elderly patients. Regular clinical and ECG monitoring are recommended.

Some macrolides (azithromycin, clarithromycin, roxithromycin). Increased risk of ventricular arrhythmias, especially torsades de pointes. Regular clinical and ECG monitoring are recommended when these drugs are used concomitantly.

Drugs that reduce potassium levels: potassium-depleting diuretics (alone or in combination), stimulant laxatives, amphotericin B (intravenous), glucocorticoids (systemic use), tetracosactide. Increased risk of ventricular arrhythmias, especially torsades de pointes (hypokalemia being a predisposing factor). Hypokalemia must be corrected before drug administration, and ECG monitoring, electrolyte level monitoring, and clinical monitoring should be performed.

Drugs that slow heart rate. Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical and ECG monitoring are recommended.

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

Tamsulosin. Risk of increased adverse effects caused by tamsulosin due to inhibition of its hepatic metabolism. Clinical monitoring should be performed and, if necessary, tamsulosin dose adjusted during treatment with the enzyme inhibitor and after discontinuation of its use.

Voriconazole. Increased risk of ventricular arrhythmias, especially torsades de pointes ventricular tachycardia, due to possible reduced metabolism of amiodarone. Clinical observation and ECG monitoring should be performed, and, if necessary, amiodarone dose adjusted.

Combinations requiring special attention.

Pilocarpine. Risk of excessive bradycardia (additive effects of drugs that slow heart rate).

Special precautions for use.

Cardiac effects. An ECG and serum potassium levels should be assessed prior to initiating treatment with the drug.

In elderly patients, the drug may enhance the reduction in heart rate.

Amiodarone induces ECG changes. These changes include QT interval prolongation due to prolonged repolarization, possibly with appearance of the U wave. These findings reflect the drug's therapeutic action, not toxicity.

Development of second- or third-degree AV block, sinoatrial block, or bifascicular block during treatment requires discontinuation of the drug. First-degree AV block requires intensified patient monitoring.

Cases of new arrhythmias or exacerbation of existing, treated arrhythmias, sometimes fatal, have been reported (see section "Adverse reactions").

This proarrhythmic effect may occur particularly in the presence of factors predisposing to QT interval prolongation, such as concomitant use of certain drugs and hypokalemia (see sections "Adverse reactions" and "Interaction with other medicinal products and other forms of interactions"). The risk of drug-induced torsades de pointes tachycardia with amiodarone is considered lower compared to other antiarrhythmic agents in patients with similar degrees of QT interval prolongation.

Thyroid dysfunction. This medicinal product contains iodine, thereby affecting results of certain thyroid function tests (radioactive iodine uptake, protein-bound iodine). However, thyroid function parameters such as T3, T4, and highly sensitive TSH assays remain interpretable.

Amiodarone may cause thyroid dysfunction, especially in patients with a history of thyroid disorders. Quantitative measurement of thyroid-stimulating hormone (TSH) is recommended for all patients before starting treatment, then regularly during therapy and for several months after discontinuation, as well as in case of clinical suspicion of thyroid dysfunction (see section "Adverse reactions").

Pulmonary effects. The onset of dyspnea or dry cough, either isolated or associated with deterioration in general condition, should be considered a possible sign of pulmonary toxicity of the drug, for example, interstitial pneumonitis, and requires radiological examination of the patient (see section "Adverse reactions").

Hepatic effects. Regular monitoring of liver function is recommended at the beginning of treatment and periodically during amiodarone therapy (see section "Adverse reactions").

Neuromuscular disorders. Amiodarone may cause sensory, motor, or mixed peripheral neuropathy and myopathy (see section "Adverse reactions").

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

Severe skin reactions. Life-threatening or even fatal skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis may occur. If signs or symptoms indicating these conditions appear (e.g., progressive skin rash with blistering or mucosal lesions), amiodarone treatment should be discontinued immediately.

Severe bradycardia and conduction disorders. Cases of severe, potentially life-threatening bradycardia and conduction disturbances have been observed in patients receiving amiodarone in combination with sofosbuvir and other direct-acting antiviral agents (DAAs) for hepatitis C treatment, such as daclatasvir, simeprevir, or ledipasvir.

Bradycardia usually occurred within several hours to several days, but cases with delayed onset, mostly within 2 weeks after initiation of hepatitis C antiviral therapy, have been reported.

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

If co-administration of amiodarone with these drugs is necessary, patients are recommended to undergo in-hospital cardiac monitoring for the first 48 hours of concomitant 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, either alone or in combination with other direct-acting antivirals.

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

Drug interaction-related disorders. Combinations (see section "Interaction with other medicinal products and other forms of interactions") with the following drugs:

β-blockers, except sotalol (combination contraindicated) and esmolol (combination requiring precautions);
verapamil and diltiazem

should only be considered for prevention of life-threatening ventricular arrhythmias. Concomitant use of amiodarone is not recommended with the following medicinal products:

cyclosporine, diltiazem (for injection), or verapamil (for injection), certain antiparasitic agents (halofantrine, lumefantrine, and pentamidine), certain neuroleptics (amisulpride, chlorpromazine, tiapride, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sultopride, tiapride, zuclopenthixol), fluoroquinolones (except levofloxacin and moxifloxacin), stimulant laxatives, methadone, or fingolimod (see section "Interaction with other medicinal products and other forms of interactions").

Disorders related to excipients. This medicinal product contains lactose and therefore is not recommended for use in patients with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption (rare hereditary conditions).

Electrolyte disturbances, particularly hypokalemia. Any condition predisposing a patient to hypokalemia should be carefully considered, as hypokalemia may provoke proarrhythmic effects. Hypokalemia should be corrected prior to initiating amiodarone therapy.

The undesirable effects listed below are most frequently associated with excessive drug intake; they can be avoided or minimized by careful adherence to the lowest effective maintenance dose.

During treatment with this drug, patients are advised to avoid sun exposure or to take protective measures against sunlight.

The safety and efficacy of amiodarone in children have not been evaluated in controlled clinical trials.

Due to the potential increase in defibrillation threshold and/or pacing threshold in patients with implanted cardiac defibrillators or pacemakers, this threshold should be checked before amiodarone treatment, several times after initiation of therapy, and each time the dose is adjusted.

Anesthesia. The anesthesiologist should be informed prior to surgery that the patient is taking amiodarone.

Chronic amiodarone therapy may potentiate the hemodynamic risks associated with general or local anesthesia. These effects include, in particular, bradycardia, arterial hypotension, reduced cardiac output, and conduction disturbances.

Additionally, cases of acute respiratory distress syndrome have been observed in the early postoperative period in patients receiving amiodarone. Therefore, careful monitoring during mechanical ventilation is recommended (see section "Adverse reactions").

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

PGD is a life-threatening complication after heart transplantation, manifesting within the first 24 hours post-transplantation as left ventricular, right ventricular, or biventricular dysfunction, for which 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 early as possible before transplantation in patients awaiting heart transplantation.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown any teratogenic effects, and therefore malformation effects in humans are not expected. Substances causing developmental abnormalities in humans have been found to be teratogenic in animals in well-conducted studies involving two species.

There are insufficient clinical data to assess potential teratogenic or fetotoxic effects of amiodarone when administered at therapeutic doses during the first trimester of pregnancy.

Since the fetal thyroid gland begins to bind iodine from the 14th week of gestation, no effect on the embryonic thyroid gland is expected if the drug was used before this time.

Excess iodine intake from this medicinal product during treatment may lead to fetal hypothyroidism or even clinical manifestations of fetal hypothyroidism (goiter development).

Due to the effect of amiodarone on the fetal thyroid gland, this drug is contraindicated from the second trimester of pregnancy.

Breastfeeding. Amiodarone and its metabolites, along with iodine, pass into breast milk in higher concentrations than in maternal plasma. Considering the risk of hypothyroidism in the infant, breastfeeding is contraindicated during amiodarone treatment.

Ability to affect reaction speed when driving or operating machinery.

The possibility of adverse reactions affecting the nervous system and visual organs should be considered.

Dosage and Administration.

Initiation of treatment. The usual recommended dose for adults is 200 mg three times daily for 8–10 days.

In some cases, higher initial doses (4–5 tablets daily) may be used at the beginning of treatment, but always for a short duration and under electrocardiographic monitoring.

Maintenance therapy. The minimum effective dose should be used. Depending on the patient's response to the drug, the maintenance dose for adults may range from half a tablet daily (one tablet every two days) to two tablets daily.

Children. The safety and efficacy of amiodarone in children have not been established; therefore, the use of the drug in pediatric patients is not recommended. Available data are presented in the section "Pharmacological Properties".

Overdose.

Cases of acute amiodarone overdose following oral administration are poorly documented. Several cases of sinus bradycardia, ventricular arrhythmias, particularly torsades de pointes, and hepatic injury have been reported. Treatment should be symptomatic. Due to the pharmacokinetic profile of this drug, prolonged monitoring of the patient, especially cardiac function, is recommended.

Amiodarone and its metabolites are not removed by dialysis.

Adverse Reactions

Adverse effects are classified by organ system 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).

Eye disorders

Very common: Microdeposits in the cornea, occurring in almost all adult patients, usually located within the area beneath the pupil. These deposits do not require discontinuation of amiodarone. In rare cases, they may be associated with colored halos in bright light or blurred vision.

Corneal microdeposits consist of complex lipid accumulations and are always completely reversible after discontinuation of the drug.

Very rare: Optic neuropathy (optic neuritis), with blurred vision and visual deterioration, and fundus examination revealing optic disc swelling, which may progress to mild or severe reduction in visual acuity. A causal relationship between this adverse effect and amiodarone use has not been definitively established. However, if no other obvious causes are identified, discontinuation of amiodarone is recommended.

Skin and subcutaneous tissue disorders

Very common: Photosensitivity. Exposure to sunlight (and ultraviolet radiation in general) should be avoided during treatment with this medication.

Common: Skin discoloration with bluish or bluish-gray pigmentation, occurring after prolonged use of high daily doses and resolving slowly after discontinuation of the drug (over 10–24 months).

Very rare: Radiation-induced erythema. Skin rashes, usually nonspecific. Exfoliative dermatitis, although a causal relationship with drug intake has not been clearly established to date. Alopecia.

Frequency not known: Eczema. Severe, sometimes fatal, skin reactions, including toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome. Bullous dermatitis. DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).

Endocrine system disorders

Very common: Except in cases with clinical signs of thyroid dysfunction, changes in thyroid hormone levels in blood (elevated T4, normal or slightly reduced T3) considered unrelated to drug intake do not require discontinuation of the drug.

Common: Hypothyroidism, characterized by typical symptoms: weight gain, cold intolerance, apathy, and somnolence. Markedly elevated TSH levels confirm this diagnosis. After stopping the drug, normal thyroid function gradually returns within 1 to 3 months. Discontinuation of the drug is not mandatory: if amiodarone use is necessary, treatment may continue in combination with thyroid hormone replacement therapy using levothyroxine. L-thyroxine doses may be adjusted based on TSH levels.

Hyperthyroidism is more difficult to diagnose: symptoms are less pronounced (slight weight loss, reduced efficacy of antianginal and/or antiarrhythmic drugs); elderly patients may present with psychiatric symptoms, even thyrotoxicosis.

Markedly decreased levels of highly sensitive TSH confirm this diagnosis. In such cases, amiodarone must be discontinued immediately, which is usually sufficient to achieve clinical normalization within 3–4 weeks. Since severe cases of this adverse effect may be fatal, appropriate therapy must be initiated promptly.

When the underlying problem is thyrotoxicosis (directly or via its impact on vulnerable myocardial equilibrium), the variable efficacy of synthetic antithyroid drugs necessitates the recommendation to administer high-dose corticosteroids (1 mg/kg) for a sufficiently prolonged period (3 months). Cases of hyperthyroidism have been reported several months after discontinuation of amiodarone.

Very rare cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH), particularly when the drug is used concomitantly with medications that may induce hyponatremia. See also "Laboratory findings".

Respiratory, thoracic and mediastinal disorders

Common: Cases of diffuse interstitial or alveolar pneumonitis and obliterative bronchiolitis with pneumonia, sometimes fatal, have been reported. The onset of dyspnea on exertion or dry cough, either isolated or associated with worsening general health (increased fatigue, weight loss, and mild fever), requires radiological examination and, if necessary, discontinuation of the drug, as these lung diseases may lead to pulmonary fibrosis.

Early discontinuation of amiodarone, with or without corticosteroid therapy, leads to gradual resolution of symptoms. Clinical signs usually disappear within 3–4 weeks; radiological improvement and lung function recovery occur more slowly (over several months).

Several cases of pleuritis have been reported, usually associated with interstitial pneumopathy.

Very rare: Bronchospasm in patients with acute respiratory insufficiency, especially in patients with bronchial asthma. Acute respiratory distress syndrome, occasionally fatal, sometimes occurring in the early postoperative period after surgery (possible interaction with high-dose oxygen suspected) (see section "Special precautions").

Frequency not known: Cases of pulmonary hemorrhage have been reported, which in some cases may manifest as hemoptysis. These pulmonary adverse effects are often associated with amiodarone-induced pneumopathy.

Central nervous system disorders

Common: Tremor or other extrapyramidal symptoms. Sleep disturbances, including night terrors. Peripheral sensory-motor or mixed peripheral neuropathy.

Uncommon: Myopathy. Sensory, motor, or mixed peripheral neuropathy and myopathy may develop several months after initiation of treatment, but sometimes after several years. These adverse effects are usually reversible after discontinuation of the drug. However, recovery may be incomplete, very slow, and observed only several months after stopping the medication.

Very rare: Cerebellar ataxia. Benign intracranial hypertension, headache. In case of isolated headache, investigation should be performed to determine its possible cause.

Frequency not known: Parkinsonism syndrome, parosmia.

Hepatobiliary disorders

Cases of liver injury have been reported. These cases were diagnosed based on elevated serum transaminase levels. The following adverse effects have been reported.

Very common: Usually mild and isolated elevation of transaminase levels (1.5 to 3 times above normal), resolving after dose reduction or even spontaneously.

Common: Acute liver injury with elevated transaminase levels in blood and/or jaundice, including liver failure, sometimes fatal, requiring discontinuation of the drug.

Very rare: Chronic liver injury requiring prolonged treatment. Histological changes correspond to pseudo-alcoholic hepatitis or liver cirrhosis. Since clinical and laboratory signs are not clearly defined (variable hepatomegaly, elevated transaminase levels 1.5 to 5 times above normal), regular monitoring of liver function is indicated. In case of elevated transaminase levels, even mild, occurring after more than 6 months of drug intake, chronic liver injury should be suspected. These clinical and biological changes usually resolve after discontinuation of the drug. Several reversible cases have been reported.

Cardiac disorders

Common: Bradycardia, usually moderate and dose-dependent.

Uncommon: Myocardial conduction disturbances (sinoatrial block, AV block of varying degrees).

Very rare: Severe bradycardia and, in exceptional cases, sinus node failure, reported in a few cases (in patients with sinus node dysfunction, elderly patients). Development or worsening of existing arrhythmia, sometimes accompanied by cardiac arrest.

Frequency not known: Paroxysmal ventricular tachycardia torsade de pointes.

Gastrointestinal disorders

Very common: Mild gastrointestinal disturbances (nausea, vomiting, dysgeusia), usually occurring at the beginning of treatment and resolving after dose reduction.

Frequency not known: Pancreatitis/acute pancreatitis. Dry mouth. Constipation.

Reproductive system and breast disorders

Very rare: Epididymitis. A causal relationship between this adverse effect and drug intake has not been clearly established to date.

Frequency not known: Decreased libido.

Vascular disorders

Very rare: Vasculitis.

Laboratory findings

Rare cases of hyponatremia may indicate the development of SIADH.

Very rare: Renal impairment with moderate increase in serum creatinine levels.

Blood and lymphatic system disorders

Very rare: Hemolytic and aplastic anemia, thrombocytopenia.

Frequency not known: Neutropenia, agranulocytosis.

Immune system disorders

Frequency not known: Cases of angioedema and/or urticaria have been reported. Anaphylactic shock/anaphylactoid reaction, including shock.

General disorders

Frequency not known: Cases of granuloma, mainly bone marrow granuloma, have been reported.

Metabolism and nutrition disorders

Frequency not known: Decreased appetite.

Psychiatric disorders

Common: Decreased libido.

Frequency not known: Confusion, delirium, hallucinations.

Musculoskeletal and connective tissue disorders

Frequency not known: Lupus erythematosus.

Injury, poisoning and procedural complications

Frequency not known: Primary graft dysfunction after heart transplantation, potentially fatal (see section "Special precautions").

Shelf life: 2 years.

Storage conditions: Store out of reach of children at a temperature not exceeding 25 °C.

Packaging: 10 tablets in a blister; 3 blisters per carton.

Prescription status: Prescription only.

Manufacturer: Private Joint-Stock Company "Lekhim-Kharkiv". PJSC "Tekhnolog".

Manufacturer's address and location of business activity:

36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.

8 Stara Prorizna Street, Uman, Cherkasy Oblast, 20300, Ukraine.