Cordarone

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

Composition:

Active substance: amiodarone;

1 tablet contains amiodarone hydrochloride 200 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: round tablets, white to slightly cream-colored, with a dividing line and engraved symbol of a heart and "200" on one side.

Pharmacotherapeutic group. Class III antiarrhythmic agents. 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).

Reduction in heart rate due to suppression of sinus node automaticity. This effect is not blocked by atropine.

Non-competitive alpha- and beta-antiadrenergic activity.

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

No changes in intraventricular conduction.

Prolongation of the refractory period and reduction in myocardial excitability at the atrial, nodal, and ventricular levels.

Slowing of conduction and prolongation of refractory periods in accessory atrioventricular conduction pathways.

Other properties. Reduction in oxygen consumption due to moderate decrease in peripheral vascular resistance and heart rate.

Increase in 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 average 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 included patient populations, duration of follow-up, methodology used, and study outcomes).

The percentage of patients who discontinued the drug 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 trials involving 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 interindividual 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 balance between drug input and elimination is achieved 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 activity.

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, along with the majority of iodine, is excreted in feces following hepatic transport.

Since only a negligible 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. It should be noted that 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 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 (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 a 2-year carcinogenicity study in animals showed that amiodarone caused an increase in 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 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 amiodarone's impact on synthesis and/or release of thyroid hormones. These findings have low relevance for human use of the drug.

Clinical characteristics.

Indications.

Prevention of recurrences:

• Ventricular tachycardia that is life-threatening: treatment should be initiated in hospital conditions with continuous patient monitoring;
• Symptomatic ventricular tachycardia (documented) leading to disability;
• Supraventricular tachycardia (documented) requiring treatment, and in cases where 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 (see section "Pharmacodynamics").

Contraindications.

Sinus bradycardia, sinoatrial block, except in cases with implanted cardiac pacemaker.

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

Severe atrioventricular conduction disturbances, except in cases with implanted cardiac pacemaker.

Hyperthyroidism, due to possible exacerbation during amiodarone administration.

Known hypersensitivity to iodine, amiodarone, or to any excipient.

Second and third trimesters of pregnancy.

Lactation period.

Combination with drugs capable of inducing paroxysmal ventricular tachycardia of the «torsades de pointes» type (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, intravenous dolasetron, domperidone, dronedarone, intravenous erythromycin, levofloxacin, mequitazine, mizolastine, moxifloxacin, prucalopride, intravenous spiramycin, toremifene, intravenous vinpocetine (see section "Interaction with other medicinal products and other forms of interaction");
• Telaprevir;
• Cobicistat.

Interaction with other medicinal products and other forms of interaction.

Antiarrhythmic agents.

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

Concomitant use of antiarrhythmic agents belonging to different classes may 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, 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 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. Predisposing factors include hypokalemia (see subsection "Medicinal products that reduce potassium levels"), bradycardia (see subsection "Medicinal products that slow heart rate"), or congenital or acquired pre-existing 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 vinpocetine, such interaction occurs only with intravenous formulations.

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 promoting «torsades de pointes».

Medicinal products that slow heart rate.

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

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 thus increase its exposure.

Inhibitors of CYP3A4 (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 such as: arsenic compounds, bepridil, cisapride, citalopram, escitalopram, difemanil, intravenous dolasetron, domperidone, dronedarone, intravenous erythromycin, levofloxacin, mequitazine, mizolastine, intravenous vinpocetine, moxifloxacin, prucalopride, intravenous spiramycin, 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 (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 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 an inhibitor of CYP3A4 and increases plasma concentrations of CYP3A4 substrates, potentially increasing their toxicity.

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

During amiodarone treatment, quantitative determination of cyclosporine blood concentrations, monitoring of renal function, and cyclosporine dose adjustment should be performed.

Injectable diltiazem. Risk of bradycardia and atrioventricular block.

If use of this combination cannot be avoided, careful clinical observation and continuous ECG monitoring should be performed.

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

Injectable verapamil. Risk of bradycardia and atrioventricular block.

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

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 agents should be discontinued. If use of this combination cannot be avoided, it is extremely important to perform prior assessment of QT interval and ECG monitoring.

Neuroleptics that may induce «torsades de pointes» (amisulpride, chlorpromazine, tiaramide, droperidol, flupentixol, flufenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulthiapride, 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 (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 an inhibitor of P-glycoprotein. Increased blood concentrations of P-glycoprotein substrates are expected when used concomitantly.

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 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 should be performed, but not exceeding 150 mg/day.

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

Substrates of CYP2C9. Amiodarone increases plasma 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, especially neurological signs (due to inhibited hepatic metabolism of phenytoin). Clinical monitoring, monitoring of phenytoin plasma concentrations, and, if necessary, phenytoin dose adjustment should be performed.

Substrates of CYP2D6:

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

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

Other medicinal products metabolized via 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, quantitative determination of plasma lidocaine concentrations. If necessary – lidocaine dose adjustment during and after amiodarone treatment.

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.

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

Beta-blockers used for heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Impaired myocardial automaticity and conduction with risk of excessive bradycardia. Increased risk of ventricular arrhythmias, especially «torsades de pointes». Regular 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 when these agents are used concomitantly with amiodarone.

Medicinal products that reduce potassium levels: potassium-depleting diuretics (alone or in combination), stimulant laxatives, intravenous amphotericin B, systemic glucocorticoids, tetracosactide.

Increased risk of ventricular arrhythmias, especially «torsades de pointes» (hypokalemia being a predisposing factor). Hypokalemia must be corrected before administration of the medicinal product, 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 should be performed during and after treatment with the enzyme inhibitor.

Voriconazole. Increased risk of ventricular arrhythmias, especially «torsades de pointes», since reduced metabolism of amiodarone may occur. Clinical observation and ECG monitoring should be performed, and, if necessary, amiodarone dose adjustment should be performed.

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 should be performed before initiating treatment with the drug.

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

Amiodarone induces ECG changes. These changes include QT interval prolongation due to prolonged repolarization, possibly with appearance of a U wave. These are signs of the drug's therapeutic effect, not its toxicity.

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

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

Such proarrhythmic effects may occur particularly in the presence of factors predisposing to QT interval prolongation, including certain drug combinations 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 drugs in patients with similar degrees of QT interval prolongation.

Thyroid dysfunction. This medicinal product contains iodine, thereby affecting the results of certain thyroid function tests (radioactive iodine uptake, protein-bound iodine levels). However, thyroid function parameters T3, T4, and high-sensitivity TSH assay remain interpretable.

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

Pulmonary effects. The onset of dyspnea or non-productive cough, either isolated or associated with deterioration in general condition, should be considered as 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 peripheral sensory-motor or mixed neuropathy and myopathy (see section "Adive 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 "Adverse reactions").

Severe skin reactions. Life-threatening or even fatal skin reactions such as Stevens–Johnson syndrome or toxic epidermal necrolysis may occur. In case of signs or symptoms indicating these conditions (e.g., progressive skin rash with blistering or mucosal lesions), amiodarone treatment should be discontinued 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 the treatment of hepatitis C, such as daclatasvir, simeprevir, or ledipasvir.

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

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

If concomitant use of amiodarone with these drugs is necessary, patients are recommended to undergo cardiac monitoring in a hospital setting for the first 48 hours of concomitant use, 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 have 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 antiviral agents (DAAs).

All patients currently taking or who have recently taken amiodarone in combination with sofosbuvir-containing medications should be warned 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 (see section "Interaction with other medicinal products and other forms of interaction") with the following drugs:

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

should be considered only 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, flufenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulthiapride, 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, especially hypokalemia: It is important to consider any condition in which the patient may be at risk of hypokalemia, as hypokalemia may provoke proarrhythmic effects. Hypokalemia should be corrected before initiating amiodarone therapy.

The adverse effects listed below are most commonly associated with excessive intake of the drug; they can be avoided or minimized by careful adherence to the minimum maintenance dose.

During treatment with the 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 possible 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 treatment, as well as each time the dose is adjusted.

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

Adverse effects of chronic amiodarone therapy may exacerbate hemodynamic risks associated with general or local anesthesia. These effects include, in particular, bradycardia, arterial hypotension, reduced cardiac output, and disturbances in cardiac conduction.

Additionally, some 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 the possibility of prescribing 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, so malformation effects in humans are not expected. To date, substances causing developmental abnormalities in humans have been found to be teratogenic in animals in well-conducted studies in 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 week 14, no effect on the embryonic thyroid gland is expected if the drug was used before this time.

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

Considering the effect of amiodarone on the fetal thyroid gland, this 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 visual organs should be considered.

Dosage and Administration.

Initial treatment. The usual recommended dose is 200 mg (1 tablet) three times daily for 8–10 days. In some cases, higher doses (4–5 tablets daily) may be required, 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 half a tablet daily (1 tablet every 2 days) to 2 tablets daily.

Children. The safety and efficacy of amiodarone in pediatric patients have not been established; therefore, the use of this medication in children is not recommended. Available data are provided 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.

Side effects

Side 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: Corneal microdeposits, occurring in almost all adult patients, usually located within the area beneath the pupil, which do not require discontinuation of amiodarone. In exceptional cases, these deposits are associated with colored halos in bright light or blurred vision.

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

Very rare: Optic neuropathy (optic neuritis), with blurred vision and visual deterioration, and, on fundus examination, optic disc swelling, potentially progressing to mild or more severe reduction in visual acuity. The causal relationship of this adverse effect with amiodarone use has not been definitively 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: Skin discoloration with a bluish or bluish-gray hue, occurring after prolonged use of high daily doses of the drug and slowly resolving after discontinuation (over 10–24 months).

Very rare: Erythema occurring during radiotherapy. Skin rashes, usually nonspecific. Exfoliative dermatitis, although the causal relationship of this adverse effect 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 disorders.

Endocrine system disorders.

Adverse effects related to the thyroid gland.

Very common: Except when clinical signs of thyroid dysfunction are present, changes in thyroid hormone levels in blood ("unrelated to drug intake")—elevated T4 levels, normal or slightly reduced T3 levels—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 discontinuation of 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 unexplained weight loss, inadequate efficacy of antianginal and/or antiarrhythmic drugs); elderly patients may exhibit 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 for clinical normalization within 3–4 weeks. Since severe cases of this adverse effect can be fatal, appropriate therapy must be initiated promptly.

If the underlying cause 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 lasting several months after amiodarone discontinuation have been reported.

Other endocrine disorders.

Very rare cases of SIADH (syndrome of inappropriate antidiuretic hormone secretion), particularly when amiodarone is used concomitantly with drugs 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 sclerotic-type pneumonia, sometimes with fatal outcomes, have been reported. The onset of dyspnea on exertion or dry cough, either isolated or associated with worsening general condition (increased fatigue, weight loss, and mild fever), warrants 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 documented, usually associated with interstitial pneumopathy.

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

Frequency not known (cannot be estimated from available data): Cases of pulmonary hemorrhage have been reported, which in some cases may present 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 appear 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. In case of isolated headache, diagnostic evaluation 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 reported:

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

Common: Acute liver injury with elevated transaminase levels in serum 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. Because clinical and laboratory signs are not clearly defined (variable hepatomegaly, transaminase levels elevated 1.5–5 times above normal), regular monitoring of liver function is indicated. In case of elevated transaminase levels—even moderate—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 of such changes have been documented.

Cardiac disorders.

Common: Bradycardia, usually moderate and dose-dependent.

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

Very rare: Marked bradycardia and, in exceptional cases, sinus node arrest, reported in a few cases (in patients with sinus node dysfunction, elderly patients). Development or worsening of pre-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), which usually occur at the beginning of treatment and resolve after dose reduction.

Frequency not known: Pancreatitis/acute pancreatitis, dry mouth, constipation.

Mammary gland and reproductive system disorders.

Very rare: Epididymitis. The causal relationship of this adverse effect with the use of 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 impairment with elevated serum creatinine levels.

Blood and lymphatic system disorders.

Very rare: Hemolytic anemia, 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 have been documented, primarily bone marrow granuloma.

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

Shelf life. 3 years.

Storage conditions.

Keep out of reach and sight of children. Store in the original packaging at a temperature not exceeding 30 °C.

Packaging.

No. 30 (10x3): 10 tablets in a blister, 3 blisters in a cardboard box.

No. 30 (15x2): 15 tablets in a blister, 2 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

1. Opella Helcsa Hungary Kft., Hungary
2. SANOFI WINTHROP INDUSTRIE, France

Manufacturer's address and place of business.

1. 2112 Veresed, Levaí u. 5, Hungary.
2. 1, rue de la Vierge, AMBARET ET LAGRAVE 33565 - CARBON BLANC Cedex, France.