INSTRUCTIONS for medical use of the medicinal product Amiokordin® (Amiokordin®)

Composition:

Active substance: amiodarone hydrochloride;

1 tablet contains amiodarone hydrochloride 200 mg;

Excipients: lactose monohydrate, corn starch, povidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex tablets of white to slightly cream color, with a score line on one side.

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

Pharmacological properties.

Pharmacodynamics.

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

It slows heart rate by suppressing the sinoatrial node automaticity. This effect is not blocked by atropine.

Exerts non-competitive alpha- and beta-antagonistic activity.

Slows sinoatrial, atrial, and nodal conduction, most pronounced during increased heart rate.

Does not alter intraventricular conduction.

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

Slows conduction and prolongs refractory periods in accessory atrioventricular conduction pathways.

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

Increases coronary blood flow by direct action on myocardial vascular smooth muscle and maintains cardiac output despite reduced arterial pressure and peripheral vascular resistance, without negative inotropic effects.

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

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

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

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

The proportion of patients requiring drug discontinuation 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 versus 0.5% in the placebo group.

Interstitial lung disease developed 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 scientific publications, the safety of amiodarone use has been evaluated in 1118 children with various types of arrhythmias.

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

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 was administered—depending on individual response, it ranged 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 depending on individual patient characteristics from 30% to 80% (on average, 50%). After a single dose, maximum plasma concentrations are reached within 3–7 hours.

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

The elimination half-life of amiodarone is prolonged and characterized by substantial inter-individual variability (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 ratio reaches equilibrium within one or several months, depending on the patient.

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

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

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

After discontinuation of amiodarone, elimination continues for several months. Residual drug activity may persist 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 transporter 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 safety data.

Results from a 2-year carcinogenicity study in animals showed that amiodarone causes 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 is more likely explained by an epigenetic rather than genotoxic mechanism.

Animal studies did not show evidence of 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 amiodarone’s influence on the synthesis and/or release of thyroid hormones. These findings have limited relevance for human use of the drug.

Clinical characteristics.

Indications.

Prevention of recurrences:

Life-threatening ventricular tachycardia: treatment should be initiated in a hospital setting under continuous patient monitoring;
Symptomatic ventricular tachycardia (documented), leading to loss of work capacity;
Supraventricular tachycardia (documented) requiring treatment, when other drugs are ineffective or contraindicated;
Ventricular fibrillation.

Treatment of supraventricular tachycardia:

Slowing or reduction of atrial fibrillation or flutter.

Ischemic heart disease and/or left ventricular dysfunction.

Contraindications.

Sinus bradycardia, sinoatrial heart block in the absence of an endocardial cardiac pacemaker (artificial pacemaker).

Sick sinus syndrome in the absence of an endocardial cardiac pacemaker (risk of sinus arrest).

High-degree atrioventricular conduction disturbances in the absence of an endocardial cardiac pacemaker.

Hyperthyroidism due to possible exacerbation during amiodarone administration.

Known hypersensitivity to iodine, amiodarone, or any component of the drug.

Pregnancy.

Breastfeeding period.

Combination with drugs capable of inducing paroxysmal ventricular tachycardia of the type "torsades de pointes" (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, difemanil, dolasetron (intravenous), domperidone, dronedarone, erythromycin (intravenous), levofloxacin, mequitazine, mizolastine, vinca alkaloids (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 agents.

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

Concomitant use of antiarrhythmic agents belonging to different classes may be beneficial, but such treatment usually requires careful clinical and ECG monitoring. Concomitant use of antiarrhythmic agents capable of inducing "torsades de pointes" (such as amiodarone, disopyramide, quinidine derivatives, sotalol, etc.) 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 exerting negative inotropic effects promotes bradycardia and/or slows atrioventricular conduction, thus requiring careful clinical and ECG monitoring.

Medicinal products that may induce development of "torsades de pointes".

This serious arrhythmia may be induced by certain medicinal products, regardless of whether they belong to antiarrhythmic agents or not. Additional risk factors include hypokalemia (see subsection "Medicinal products that reduce potassium levels" below), bradycardia (see subsection "Medicinal products that slow heart rate" below), 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 some neuroleptics. For dolasetron, erythromycin, spiramycin, and vinca alkaloids, such interaction occurs only when intravenous formulations are used.

Concomitant use of two medicinal products, each promoting the occurrence of "torsades de pointes", is generally contraindicated.

However, methadone, antiparasitic agents (halofantrine, lumefantrine, pentamidine), and neuroleptics, whose use is considered essential, are not contraindicated but are not recommended for concomitant use with other agents promoting the occurrence of "torsades de pointes".

Medicinal products that slow heart rate.

Many medicinal products may cause bradycardia, including: class Ia antiarrhythmic agents, beta-blockers, certain class III antiarrhythmic agents, certain calcium channel blockers, digitalis glycosides, pilocarpine, and anticholinesterase agents.

Effects of amiodarone on other medicinal products.

Amiodarone and 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 persist for several months after discontinuation of amiodarone therapy.

Effects of other medicinal products on amiodarone.

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

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

Contraindicated combinations (see section "Contraindications").

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

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, difemanil, intravenous (i.v.) dolasetron, domperidone, dronedarone, i.v. erythromycin, levofloxacin, mequitazine, mizolastine, i.v. vinca alkaloids, moxifloxacin, prucalopride, i.v. spiramycin, toremifene.

Concomitant use of the above-mentioned drugs with amiodarone increases the risk of ventricular arrhythmias, especially "torsades de pointes".

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

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

Not recommended combinations (see section "Special precautions for use").

Sofosbuvir. Concomitant use of amiodarone with medicinal products containing sofosbuvir may cause severe symptomatic bradycardia. Should be prescribed only if there are no alternative treatment options. In such a case, careful monitoring is recommended (see section "Special precautions for use").

Substrates of CYP3A4. Amiodarone is an inhibitor of CYP3A4 and increases plasma concentrations of CYP3A4 substrates, potentially increasing the toxicity of these substrates.

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

During amiodarone therapy, cyclosporine blood concentration monitoring, renal function monitoring, and cyclosporine dose adjustment are required.

Intravenous diltiazem. Risk of bradycardia and atrioventricular block.

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

Fingolimod. Potentiation of bradycardic effects, potentially with fatal outcome. This is especially relevant for beta-blockers, which inhibit adrenergic compensatory mechanisms. After administration of the first dose, clinical observation and ECG monitoring for 24 hours are required.

Intravenous verapamil. Risk of bradycardia and atrioventricular block.

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

Antiparasitic agents that may induce "torsades de pointes" (halofantrine, lumefantrine, pentamidine). Increased risk of ventricular arrhythmias, especially "torsades de pointes". Discontinuation of one of the drugs is desirable. If use of this combination cannot be avoided, QT interval should be assessed beforehand and ECG monitoring performed.

Neuroleptics that may induce "torsades de pointes" ( amisulpride, chlorpromazine, tiapride, droperidol, flupentixol, flufenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sultopride, thiethylperazine, 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 ventricular tachycardia "torsades de pointes" (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.

P-glycoprotein substrates. Amiodarone is an inhibitor of P-glycoprotein. Concomitant use with P-glycoprotein substrates is expected to increase their blood concentrations.

Digitalis glycosides. Suppression of automaticity (excessive bradycardia) and disturbances in atrioventricular conduction.

When digoxin is used, increased digoxin blood levels occur due to reduced digoxin clearance, requiring ECG and clinical status monitoring. Monitoring of digoxin blood levels and dose adjustment may be necessary.

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

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

Substrates of CYP2C9. Amiodarone increases plasma concentrations of substances that are substrates of CYP2C9, 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. More careful monitoring of the international normalized ratio (INR) is required. The dose of vitamin K antagonist should be adjusted during amiodarone therapy and for 8 days after its discontinuation.

Phenytoin (may also apply to fosphenytoin). Increased plasma concentrations of phenytoin with signs of overdose, especially neurological symptoms (due to inhibition of hepatic phenytoin metabolism). Clinical monitoring, plasma phenytoin concentration monitoring, and dose adjustment if necessary are required.

Substrates of CYP2D6: flecainide. Amiodarone increases plasma concentrations of flecainide by inhibiting cytochrome CYP2D6. Therefore, flecainide dose adjustment is necessary.

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

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

Other medicinal products metabolized by CYP3A4 (lidocaine, sirolimus, tacrolimus, sildenafil, midazolam, dihydroergotamine, ergotamine, colchicine, triazolam). Amiodarone is an inhibitor of CYP3A4 and increases plasma concentrations of these molecules, potentially increasing their 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, plasma lidocaine concentration determination. Dose adjustment of lidocaine may be required during and after amiodarone therapy.

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

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

Beta-blockers used for heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Disturbances in myocardial automaticity and conduction with risk of excessive bradycardia. Increased risk of ventricular arrhythmias, especially "torsades de pointes". Clinical and ECG monitoring are recommended.

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

Oral diltiazem. Risk of bradycardia or atrioventricular block, especially in elderly patients. ECG and clinical monitoring are recommended.

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

Certain macrolides (azithromycin, clarithromycin, roxithromycin). Increased risk of ventricular arrhythmias, especially "torsades de pointes". ECG and clinical monitoring are recommended during concomitant use of these drugs with amiodarone.

Medicinal products 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 an additional risk factor). Hypokalemia should be corrected before drug administration, and ECG monitoring, electrolyte level monitoring, and clinical monitoring should be performed.

Medicinal products 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 and, if necessary, ECG monitoring are recommended.

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

Voriconazole. Increased risk of ventricular arrhythmias, especially ventricular tachycardia "torsades de pointes", as metabolism of amiodarone may be reduced. 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 slowing heart rate).

Special precautions for use.

Effects on the heart. An ECG should be performed before starting treatment with this medicinal product.

In elderly patients, amiodarone may enhance the slowing of heart rate.

Amiodarone causes ECG changes, including QT interval prolongation due to prolonged repolarization, possibly with appearance of the U wave. These changes reflect the therapeutic effect of the drug and not its toxicity.

Development of second- or third-degree atrioventricular (AV) block, sinoatrial block, or bifascicular block during treatment requires discontinuation of amiodarone. In case of first-degree AV block, enhanced monitoring of the patient is necessary.

Instances of new-onset arrhythmia or worsening of pre-existing arrhythmia being treated have been reported (see section "Adverse reactions").

This proarrhythmic effect is more likely to occur in the presence of factors predisposing to QT interval prolongation, such as concomitant use of certain medicinal products and hypokalemia (see sections "Adverse reactions" and "Interaction with other medicinal products and other forms of interaction"). 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 gland disorders. This medicinal product contains iodine and therefore affects certain thyroid function parameters (radioactive iodine uptake, protein-bound iodine levels). However, thyroid function tests such as T3, T4, and highly sensitive TSH assay remain interpretable.

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

Lung disorders. The onset of dyspnea or non-productive cough, particularly associated with deterioration in general condition, may be a sign of pulmonary toxicity of the drug, such as interstitial pneumonitis, and requires radiological examination of the patient (see section "Adverse reactions").

Liver disorders. Regular monitoring of liver function is recommended at the beginning of amiodarone therapy and periodically throughout treatment (see section "Adverse reactions").

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

Ocular disorders. In case of blurred vision or decreased visual acuity, a complete ophthalmological examination including ophthalmoscopy should be performed immediately. Development of optic neuropathy or optic neuritis due to amiodarone requires discontinuation of treatment, as these disorders may progress to blindness (see section "Adverse 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 stopped immediately.

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 and other direct-acting antiviral agents (DAAs) for hepatitis C treatment, such as daclatasvir, simeprevir, or ledipasvir.

Bradycardia usually occurred within hours to days, but symptoms have been reported even later, mostly within 2 weeks after initiation of hepatitis C antiviral therapy.

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

If concomitant use of amiodarone with these medicinal products is absolutely necessary, cardiac monitoring in a hospital setting is recommended during the first 48 hours of co-administration, 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 applied to patients who discontinued amiodarone within the past several months and are about to start sofosbuvir, either alone or in combination with other direct-acting antiviral agents (DAAs).

All patients taking or who have recently taken amiodarone in combination with sofosbuvir-containing medicinal products should be informed about symptoms of bradycardia and conduction disturbances and advised to seek immediate medical attention if such symptoms occur.

Disorders related to interactions with other medicinal products. Combinations with the following agents:

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

should only be considered for prevention of life-threatening ventricular arrhythmias (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Electrolyte disturbances, particularly hypokalemia: Any situation associated with risk of hypokalemia in a patient should be carefully considered, as hypokalemia may provoke proarrhythmic effects. Hypokalemia should be corrected before initiating amiodarone therapy.

The adverse effects listed below are most often associated with excessive dosing; they can be avoided or minimized by strictly adhering to the lowest effective maintenance dose.

During treatment with this medicinal product, patients are advised to avoid sun exposure or to take appropriate protective measures.

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 starting amiodarone and several times after initiation of therapy, as well as each time the dose is adjusted.

Anaesthesia. The anaesthesiologist should be informed prior to surgery that the patient is taking amiodarone.

Potential hemodynamic disturbances associated with general or local anaesthesia may be exacerbated by the adverse effects of chronic amiodarone therapy. These effects include 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. Retrospective studies have associated amiodarone use prior to heart transplantation 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 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 amiodarone, and therefore malformations in humans are not expected. Currently, substances causing developmental malformations in humans have been found to be teratogenic in two animal species under properly controlled studies.

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 week 14 of gestation, no effect on the embryonic thyroid gland is expected if the drug is used before this time.

Excessive iodine intake from this medicinal product after this period may lead to fetal hypothyroidism or even clinical features of fetal hypothyroidism (goiter development).

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

Lactation period. Amiodarone and its metabolites, along with iodine, are excreted in breast milk in higher concentrations than in maternal plasma. Due to 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 vision should be considered.

Dosage and Administration.

Initial treatment. The usual recommended dose of the drug is 200 mg (1 tablet) three times daily for 8–10 days. In some cases, higher doses (4–5 tablets daily) may be required for individual patients, but always for a short duration and under electrocardiographic monitoring.

Maintenance treatment. The minimum effective dose should be used, which is individually determined for each patient and may range from ½ tablet daily (1 tablet every 2 days) to 2 tablets daily.

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

Overdose.

Information regarding amiodarone overdose is limited. There have been reports of several cases of sinus bradycardia, ventricular arrhythmias, particularly torsades de pointes, and hepatic injury. Due to the pharmacokinetic profile of this drug, prolonged monitoring of the patient, especially cardiac function, is recommended.

Treatment should be symptomatic. Amiodarone and its metabolites are not removed by dialysis.

Adverse Reactions

Adverse effects 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).

Eye disorders

Very common: Corneal microdeposits, occurring in nearly all adults, usually within the area under the pupil—do not require discontinuation of amiodarone. In exceptional cases associated with colored halos in bright light or blurred vision.

Corneal microdeposits are complex lipid deposits that completely resolve after discontinuation of the drug.

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

Skin and subcutaneous tissue disorders

Very common: Photosensitization. Exposure to sunlight (and ultraviolet radiation in general) should be avoided during treatment with the drug.

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

Very rare: Erythema following radiation therapy. Skin rashes, usually nonspecific. Exfoliative dermatitis, although a causal relationship between this adverse effect and 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

Adverse effects related to the thyroid gland

Very common: Alterations in thyroid hormone levels in blood (increased T4, normal or slightly decreased T3): do not require discontinuation of the drug, except in cases where clinical signs of thyroid dysfunction unrelated to drug intake are present.

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

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

Markedly decreased levels of high-sensitivity TSH confirm this diagnosis. In such cases, amiodarone must be discontinued immediately, which is usually sufficient for clinical normalization within 3–4 weeks. As severe cases of this adverse effect may be fatal, appropriate therapy should be initiated without delay.

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

Other endocrine disorders

Very rare cases of SIADH (syndrome of inappropriate antidiuretic hormone secretion), especially when amiodarone is used concomitantly with drugs that may induce hyponatremia. See also "Laboratory findings" below.

Respiratory, thoracic and mediastinal disorders

Common: Cases of diffuse interstitial or alveolar pneumonitis and obliterative bronchiolitis with sclerotic-type pneumonia, sometimes fatal, have been reported. The onset of dyspnea on exertion or dry cough, particularly together with worsening general condition (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, promotes gradual resolution of symptoms. Clinical signs usually resolve 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 failure, particularly in patients with bronchial asthma. Acute respiratory distress syndrome, occasionally fatal, sometimes occurring in the early postoperative period (suspected interaction with high-dose oxygen) (see section "Special precautions").

Frequency not known: Cases of pulmonary hemorrhage have been reported, sometimes manifesting as hemoptysis. These pulmonary adverse effects are often associated with amiodarone-induced pneumopathy.

Nervous system disorders

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

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

Very rare: Cerebellar ataxia. Benign intracranial hypertension, headache. If isolated headache occurs, examination is required to determine its possible cause.

Frequency not known: Parkinsonism syndrome, parosmia.

Hepatobiliary disorders

Cases of liver injury have been reported; these were diagnosed based on elevated serum transaminase levels. The following adverse effects have been observed:

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

Common: Acute liver injury with elevated serum transaminase levelswithout emphasis 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. As clinical and laboratory signs are poorly defined (variable hepatomegaly, serum transaminase levels 1.5–5 times above normal), liver function monitoring is indicated. Chronic liver injury should be suspected if transaminase levels are elevated—even mildly—after more than 6 months of drug intake. 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 degree).

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

Frequency not known: Paroxysmal ventricular tachycardia of the torsade de pointes type.

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—causal relationship with this medicinal product has not been clearly established to date.

Frequency not known: Decreased libido.

Vascular disorders

Very rare: Vasculitis.

Laboratory findings

Rare: Rare cases of hyponatremia may indicate the development of SIADH.

Very rare: Renal injury with elevated serum creatinine levels.

Blood and lymphatic system disorders

Very rare: Thrombocytopenia.

Frequency not known: Neutropenia, agranulocytosis.

Immune system disorders

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

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").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life: 5 years.

Storage conditions: Store at temperatures not exceeding 25 °C in the original packaging to protect from light. Keep out of reach of children.

Packaging: 10 tablets per blister; 3 or 6 blisters per cardboard box.

Prescription status: Prescription only.

Manufacturer:

KRKA, d.d., Novo mesto, Slovenia /
KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business:

Šmarješka cesta 6, 8501 Novo mesto, Slovenia /
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.