Arithmil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARYTMIL (ARYTMIL)

Composition:

Active substance: amiodarone hydrochloride;

One tablet contains 200 mg of amiodarone hydrochloride (calculated as 100% dry substance);

Excipients: maize starch, microcrystalline cellulose, calcium stearate, povidone, lactose monohydrate.

Pharmaceutical form. Tablets.

Main physico-chemical characteristics: round-shaped tablets, white or almost white, with flat surface, bevelled edges and a score line.

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

Pharmacological Properties

Pharmacodynamics

Class III antiarrhythmic agent. The antiarrhythmic effect is due to prolongation of phase III of the action potential, primarily by blocking potassium channels in cardiomyocyte membranes, as well as calcium channels, slowing of conduction through the AV node, and reduction of sinus node automaticity. It also slightly blocks open and inactivated sodium channels and slows the rapid inward sodium current. The drug non-competitively blocks alpha- and beta-adrenergic receptors, predominantly in the myocardium, which contributes to slowing of sinoatrial, atrial, and AV conduction, without affecting intraventricular conduction. Amiodarone increases the refractory period and reduces myocardial excitability. It slows conduction and prolongs the refractory period in accessory atrioventricular pathways. The antianginal effect of amiodarone is due to reduced myocardial oxygen consumption resulting from decreased heart rate and reduced systemic vascular resistance. Amiodarone does not produce a significant negative inotropic effect.

Pharmacokinetics

Amiodarone has a large volume of distribution. During the first days of administration, the drug accumulates in nearly all tissues, particularly in adipose tissue, liver, spleen, and lungs. Elimination from the body begins after several days. Steady-state concentration is achieved within 1 to several months, depending on individual patient characteristics. Amiodarone is excreted via bile and feces. Renal excretion is minimal. The elimination half-life ranges from 20 to 100 days. After discontinuation of amiodarone therapy, the drug continues to be eliminated from the body over several months. Amiodarone contains iodine; therefore, during hepatic metabolism, iodine is cleaved off and excreted in urine as iodide salts. The majority of amiodarone and its metabolites are eliminated through the intestine over more than 30 days. After discontinuation of the drug, its pharmacological effect persists for several days or even weeks.

Clinical characteristics.

Indications.

Prevention of recurrences:

• Ventricular tachycardia that is life-threatening: treatment should 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 (see section "Pharmacodynamics").

Contraindications.

• Hypersensitivity to iodine and/or amiodarone, or to any other component of the drug;
• Sinus bradycardia (< 50–55 beats/min), sinoatrial block, sick sinus syndrome in the absence of a pacemaker (risk of sinus arrest);
• Severe conduction disturbances (second- or third-degree AV block, bifascicular or trifascicular block) in the absence of a pacemaker;
• Thyroid dysfunction (hypothyroidism, hyperthyroidism). Thyroid function should be evaluated in all patients before initiating treatment;
• Concomitant use with drugs that may cause polymorphic ventricular tachycardia of the type "torsade de pointes":
  • Class IA antiarrhythmic agents (quinidine, hydroquinidine, disopyramide);
  • Class III antiarrhythmic agents (sotalol, dofetilide, ibutilide);
  • Other drugs such as arsenic compounds, bepridil, cisapride, difemanel, dolasetron (intravenous), domperidone, dronedarone, prucalopride, erythromycin (intravenous), mesoridazine, moxifloxacin, levofloxacin, mequitazine, citalopram, escitalopram, spiramycin (intravenous), vinpocetine (intravenous), toremifene, and certain neuroleptics (see section "Interaction with other medicinal products and other forms of interaction" for details);
  • Telaprevir;
  • Cobicistat.

Interaction with other medicinal products and other forms of interaction.

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

Antiarrhythmic agents. Myocardial depression increases when multiple antiarrhythmic agents are used concomitantly. Most antiarrhythmic agents suppress cardiac automaticity, conduction, and myocardial contractility. Concurrent use of antiarrhythmic agents from different classes may achieve a favorable therapeutic effect, but such treatment usually requires careful clinical monitoring and ECG control. Concomitant use of antiarrhythmic agents capable of inducing "torsade de pointes" ventricular tachycardia (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 adverse cardiac effects.

Concomitant use of amiodarone with medicinal products having negative inotropic effects, promoting bradycardia and/or slowing atrioventricular conduction, requires careful clinical monitoring and ECG control.

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

Medicinal products that may induce "torsade de pointes" ventricular tachycardia include, in particular, class IA and III antiarrhythmics and certain neuroleptics. For dolasetron, erythromycin, spiramycin, and vinpocetine, this interaction occurs only with intravenous formulations.

Concomitant use of two medicinal products, each capable of inducing "torsade de pointes" ventricular tachycardia, is generally contraindicated.

However, this does not apply to some of these agents considered absolutely necessary and only not recommended for concomitant use with other agents that may induce "torsade de pointes" ventricular tachycardia: methadone, certain antiparasitic agents (halofantrine, lumefantrine, pentamidine), and neuroleptics.

Medicinal products that slow heart rate. Many medicinal products may cause bradycardia. This includes, in particular, class IA antiarrhythmics, beta-blockers, certain class III antiarrhythmics, certain calcium channel blockers, digitalis glycosides, pilocarpine, and anticholinesterase agents.

Effect of amiodarone on other medicinal products. Amiodarone and/or its metabolite desethylamiodarone inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6, and P-glycoprotein, and may increase the effects of their substrates. Due to the long elimination half-life of amiodarone, the potential for interaction exists not only during concomitant therapy with other medicinal products but also with drugs administered for several months after discontinuation of amiodarone.

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

Contraindicated combinations (see section "Contraindications").

Medicinal products that may cause QT interval prolongation or increase the risk of polymorphic paroxysmal ventricular tachycardia of the type "torsade de pointes" (except antiparasitic agents, neuroleptics, and methadone; see subsection "Not recommended combinations"):

• Class IA antiarrhythmics (quinidine, hydroquinidine, procainamide, disopyramide);
• Class III antiarrhythmics (dofetilide, ibutilide, sotalol, bretylium, dronedarone);
• Lithium and tricyclic antidepressants, e.g., doxepin, maprotiline, amitriptyline; certain selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram;
• Certain antihistamines, e.g., loratadine, terfenadine, astemizole, mesoridazine, mequitazine;
• Certain antimalarial agents such as quinine, mefloquine, chloroquine;
• Other medicinal products such as: arsenic compounds, bepridil, cisapride, difemanel, dolasetron IV, domperidone, erythromycin IV, sparfloxacin, levofloxacin, vinpocetine IV, moxifloxacin, prucalopride, spiramycin IV, toremifene.

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

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

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

Sofosbuvir. Concomitant use of amiodarone and sofosbuvir in combination with another direct-acting antiviral agent for HCV (hepatitis C virus) (e.g., daclatasvir, simeprevir, or ledipasvir) may lead to severe symptomatic or even fatal bradycardia, the mechanism of which is unknown. If such a combination cannot be avoided, careful monitoring of the patient's condition and ECG parameters is required, especially during the first few weeks of combination therapy.

Substrates of CYP3A4.

Amiodarone is a CYP3A4 inhibitor and may increase 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, cyclosporine blood concentrations should be monitored, renal function assessed, and cyclosporine dosage adjusted.
• Injectable diltiazem, injectable verapamil. Possible potentiation of negative chronotropic effects and slowed conduction, with risk of pronounced bradycardia, AV block, and increased risk of ventricular arrhythmias, especially "torsade de pointes." If use of this combination cannot be avoided, careful pre-treatment monitoring of QT interval, clinical observation, and continuous ECG monitoring during treatment are required.
• Fingolimod. Potentiation of bradycardia-induced effects, potentially fatal. This is particularly relevant in combination with beta-blockers, which inhibit adrenergic compensatory mechanisms. Careful clinical observation and continuous ECG monitoring for 24 hours after the first dose are required.

Antiparasitic agents, namely halofantrine, lumefantrine, pentamidine, which may induce paroxysmal ventricular tachycardia of the type "torsade de pointes." Increased risk of ventricular arrhythmias, especially "torsade de pointes." Where possible, amiodarone or one of these agents should be discontinued. If this combination cannot be avoided, QT interval should be assessed before initiation and ECG monitored during treatment.

Neuroleptics (amisulpride, chlorpromazine, tiapride, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulthiapride, tiapride, zuclopenthixol) capable of inducing "torsade de pointes." Increased risk of ventricular arrhythmias, especially "torsade de pointes."

Methadone. Increased risk of ventricular arrhythmias, especially "torsade de pointes." ECG and clinical monitoring are required.

Fluoroquinolones, except levofloxacin, sparfloxacin, and moxifloxacin (contraindicated combinations). Increased risk of ventricular arrhythmias, especially "torsade de pointes." If such a combination is unavoidable, careful pre-treatment monitoring of QT interval and continuous ECG monitoring are required.

Stimulant laxatives. Increased risk of ventricular arrhythmias, particularly "torsade de pointes" ventricular tachycardia (hypokalemia being a triggering factor); alternative laxatives should be used. Hypokalemia should be corrected before amiodarone administration, and ECG, clinical monitoring, and electrolyte levels should be monitored.

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 plasma concentrations of these substrates are expected.

• Cardiac glycosides (digitalis preparations), including digoxin. Possible disturbances in automaticity (excessive bradycardia) and AV conduction (synergistic effect).

Possible increase in digoxin plasma concentration (due to reduced clearance) and increased risk of digoxin toxicity. Clinical, laboratory (if possible, plasma digoxin level monitoring), and ECG monitoring are required for early detection of signs of glycoside intoxication; digoxin dose adjustment may be necessary.

• Dabigatran. Increased plasma concentration of dabigatran increases the risk of hemorrhagic events. Clinical monitoring is required, and if necessary, dabigatran dosage should be adjusted (not exceeding 150 mg/day) when used after surgical procedures.

Substrates of CYP2C9.

Amiodarone increases plasma concentrations of CYP2C9 substrates, e.g., oral anticoagulants (warfarin) and phenytoin, by inhibiting cytochrome P450 2C9.

• Oral anticoagulants (including warfarin). Enhanced anticoagulant effect with increased bleeding risk necessitates more frequent monitoring of prothrombin time/international normalized ratio (INR) and anticoagulant dose adjustment during amiodarone treatment and for at least 8 days after discontinuation.
• Phenytoin (by extrapolation, also fosphenytoin). Increased plasma phenytoin concentrations due to inhibited hepatic metabolism, with signs of overdose, particularly neurological symptoms. 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; flecainide dose adjustment is required. Careful patient monitoring is necessary to prevent adverse effects. Plasma flecainide level monitoring is strongly recommended under these conditions.

Substrates of CYP3A4.

Amiodarone is a CYP3A4 enzyme inhibitor and increases plasma concentrations of CYP3A4 substrates, potentially increasing their toxicity.

• Statins metabolized by CYP3A4 (including simvastatin, atorvastatin, lovastatin). Increased risk of muscle toxicity (e.g., rhabdomyolysis). When used concomitantly with amiodarone, statins not metabolized by CYP3A4 are recommended.

• Other drugs metabolized by CYP3A4: tacrolimus (risk of nephrotoxicity), sirolimus (increased sirolimus toxicity), sildenafil (risk of enhanced adverse effects), triazolam, midazolam (risk of psychomotor effects), dihydroergotamine, ergotamine, colchicine; dose adjustment is required.

• Lidocaine. Risk of increased plasma lidocaine concentrations, potentially leading to neurological and cardiac adverse effects due to amiodarone's inhibition of hepatic lidocaine metabolism. Clinical monitoring, ECG control, and possibly plasma lidocaine concentration monitoring are required. Lidocaine dose adjustment may be necessary during and after amiodarone treatment.

• Tacrolimus. Increased blood levels of tacrolimus due to inhibited metabolism by amiodarone. Tacrolimus blood concentrations should be monitored, renal function assessed, and tacrolimus dosage adjusted when used concomitantly with amiodarone and after its discontinuation.

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

Beta-blockers (bisoprolol, carvedilol, metoprolol, nebivolol) used for heart failure. Impairment of myocardial automaticity and conduction with risk of excessive bradycardia and increased risk of ventricular arrhythmias, especially "torsade de pointes." Regular clinical and ECG monitoring are recommended.

Esmolol. Impairment of automaticity, conduction, and myocardial contractility due to inhibition of sympathetic compensatory mechanisms. Clinical and ECG monitoring of the patient are required.

Oral diltiazem (CYP3A4 inhibitor) and verapamil (CYP3A4 substrate). Risk of bradycardia or AV block, especially in elderly patients. ECG monitoring and clinical observation are required.

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

Medicinal products that may cause hypokalemia:

• Diuretics, alone or in combination;
• Systemic glucocorticoids and mineralocorticoids, tetracosactide;
• Amphotericin B (intravenous).

Increased risk of "torsade de pointes" paroxysmal tachycardia (hypokalemia being a predisposing factor). Hypokalemia should be corrected before drug administration, and ECG, blood electrolyte levels, and clinical status should be monitored.

Medicinal products causing bradycardia. Increased risk of ventricular arrhythmias, especially "torsade de pointes." Clinical and ECG monitoring are recommended.

Orlistat. Possible reduction in plasma concentrations of amiodarone and its active metabolite. Clinical monitoring and, if necessary, ECG monitoring are recommended.

Tamsulosin. Risk of enhanced adverse effects due to tamsulosin caused by inhibited hepatic metabolism. Clinical monitoring and, if necessary, tamsulosin dose adjustment are recommended during and after amiodarone treatment.

Voriconazole. Increased risk of ventricular arrhythmias, especially "torsade de pointes" ventricular tachycardia, due to increased amiodarone blood levels resulting from reduced metabolism. Clinical monitoring, ECG monitoring, and, if needed, amiodarone dose adjustment are required.

Grapefruit juice inhibits cytochrome P450 3A4, potentially increasing amiodarone plasma concentration. Consumption should be avoided during amiodarone treatment.

Combinations requiring special attention.

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

Special precautions for use.

Amiodarone therapy must be initiated and supervised only by a physician experienced in the management of cardiac arrhythmias.

Cardiac effects.

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

In elderly patients, a more pronounced reduction in heart rate may occur.

Amiodarone therapy may cause ECG changes, including QT interval prolongation (due to repolarization prolongation), appearance of the U wave, and T wave deformation. These changes are signs of the drug's therapeutic effect and not manifestations of toxicity.

If second- or third-degree AV block, sinoatrial block, or bifascicular block develops, treatment with the drug must be discontinued. Development of first-degree AV block requires intensified patient monitoring.

Cases of new-onset or exacerbation of pre-existing arrhythmias, sometimes with fatal outcomes, have been reported during amiodarone therapy.

Such proarrhythmic effects may occur, particularly in the presence of factors predisposing to QT interval prolongation, such as certain drug combinations and/or hypokalemia (see sections "Adverse reactions" and "Interaction with other medicinal products and other forms of interactions").

Amiodarone has a low proarrhythmic potential. The risk of inducing torsade de pointes ventricular tachycardia during amiodarone therapy is considered lower compared to other antiarrhythmic drugs in patients with a similar degree of QT interval prolongation.

Amiodarone may increase defibrillation threshold and/or pacing threshold in patients with implanted cardioverter-defibrillators or pacemakers, potentially compromising device efficacy. Regular threshold monitoring is recommended to ensure proper device function both before and several times after initiation of amiodarone therapy, as well as with any dosage adjustment.

Electrolyte disturbances, particularly hypokalemia.

Any condition associated with hypokalemia should be carefully considered, as hypokalemia may trigger proarrhythmic effects. Hypokalemia and other electrolyte imbalances must be corrected prior to initiating amiodarone therapy. Continuous monitoring of ECG, serum electrolytes, and the patient's clinical status is required throughout treatment.

Severe bradycardia.

Cases of severe, symptomatic, potentially life-threatening bradycardia and severe conduction disturbances have been observed when amiodarone is used concomitantly with sofosbuvir and another direct-acting antiviral agent for hepatitis C treatment (e.g., daclatasvir, simeprevir, or ledipasvir); the mechanism is unknown. Therefore, co-administration of these drugs with amiodarone is not recommended.

If concomitant use cannot be avoided, close clinical monitoring is required from the start of sofosbuvir in combination with another direct-acting antiviral agent. Patients at high risk of bradyarrhythmias should be continuously monitored in a specialized hospital setting for at least 48 hours after initiating concomitant therapy with sofosbuvir.

Due to the long elimination half-life of amiodarone, appropriate monitoring should also be performed in patients who have discontinued amiodarone within the previous several months before starting sofosbuvir, either alone or in combination with another direct-acting antiviral agent.

Patients receiving these hepatitis C treatments together with amiodarone, regardless of concomitant use of other heart rate-lowering drugs, should be warned about symptoms of bradycardia and severe conduction disturbances and instructed to seek immediate medical attention if such symptoms occur.

Endocrine effects.

Amiodarone contains iodine (approximately 75 mg of iodine in 200 mg of the drug) and may therefore interfere with radioactive iodine uptake tests and protein-bound iodine levels. However, interpretation of thyroid function tests (fT3, fT4, and TSH levels) remains possible.

Amiodarone use may induce hyperthyroidism or hypothyroidism, particularly in patients with a history of thyroid dysfunction (including familial), and in elderly patients. A thorough clinical and laboratory assessment (including TSH) of thyroid function should be performed in all patients before starting treatment, regularly during treatment (every 6 months), and for several months after discontinuation of amiodarone, as well as whenever clinical suspicion of thyroid dysfunction arises (see section "Adverse reactions").

Pulmonary effects.

The onset of dyspnea and/or non-productive cough, either isolated or associated with worsening general condition, should be considered a possible sign of drug-induced pulmonary toxicity (e.g., interstitial pneumonitis) and requires radiological evaluation (see section "Adverse reactions").

Hepatobiliary effects.

Liver function, particularly transaminase activity, should be monitored at the beginning and regularly during amiodarone therapy to detect early signs of hepatic injury (see section "Adverse reactions").

Neurological effects.

Long-term amiodarone therapy may cause peripheral sensory, motor, or mixed neuropathy and/or myopathy (see section "Adverse reactions").

Ophthalmological effects.

Any decrease in visual acuity or blurring of vision requires immediate comprehensive ophthalmological examination, including fundoscopy. Amiodarone-induced optic neuropathy and/or optic neuritis necessitate discontinuation of amiodarone, as continued treatment carries a risk of progression to complete blindness (see section "Adverse reactions").

Dermatological effects.

Patients should be advised to avoid direct sunlight and UV radiation and to use sun-protective measures during therapy, as the skin may become highly photosensitive.

This photosensitivity may persist for several months after discontinuation of the drug.

Severe bullous skin reactions.

There have been reports of life-threatening or even fatal skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). If symptoms or signs suggestive of SJS/TEN (e.g., progressive skin rash often with blistering and/or mucosal involvement) or any other signs of hypersensitivity occur, amiodarone therapy must be discontinued immediately.

Drug interactions (see detailed information in section "Interaction with other medicinal products and other forms of interactions").

Combination of amiodarone with beta-blockers (except sotalol, which is contraindicated, and esmolol, which requires caution), verapamil, and diltiazem should be considered only for the prevention of life-threatening ventricular arrhythmias.

Amiodarone is not recommended for use with cyclosporine, intravenous diltiazem, intravenous verapamil, certain antiparasitic agents (halofantrine, lumefantrine, pentamidine), certain neuroleptics (amisulpride, chlorpromazine, tiacemazine, droperidol, flupentixol, flufenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulpiride, tiapride, zuclopenthixol), fluoroquinolones (except levofloxacin and moxifloxacin, which are contraindicated), stimulant laxatives, methadone, and fingolimod (see section "Interaction with other medicinal products and other forms of interactions").

To prevent adverse effects, concomitant therapy must be carefully prescribed, taking into account clinically significant interactions with amiodarone.

Anesthesia.

The anesthesiologist must be informed prior to surgery that the patient is receiving or has received amiodarone.

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

Cases of acute respiratory distress syndrome (ARDS), sometimes fatal, have been reported during amiodarone therapy, typically in the immediate postoperative period. Close monitoring is recommended during mechanical ventilation (see section "Adverse reactions").

Primary graft dysfunction after heart transplantation.

Retrospective studies have linked preoperative amiodarone use in heart transplant recipients to an increased risk of primary graft dysfunction (PGD). PGD is a life-threatening complication of heart transplantation occurring within the first 24 hours after surgery, characterized by left ventricular, right ventricular, or biventricular dysfunction without any other identifiable secondary cause (see section "Adverse reactions"). Severe PGD may be irreversible. For patients awaiting heart transplantation, consideration should be given to using an alternative antiarrhythmic agent as early as possible before transplantation.

Excipients.

Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine due to its lactose content.

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

Adverse effects (see section "Adverse reactions") are most frequently associated with excessive dosing. Because these reactions may be delayed, patients undergoing long-term therapy should be closely monitored. Since adverse effects are dose-dependent, they can be avoided or minimized by using the lowest effective maintenance dose.

Use during pregnancy or breastfeeding.

Animal studies have not shown any teratogenic effects of amiodarone, and thus malformations in humans are not expected. However, adequate clinical data on potential teratogenic or fetotoxic effects of amiodarone in humans during the first trimester of pregnancy are lacking.

Since the fetal thyroid begins to bind iodine from week 14, no effect on the embryonic thyroid is expected if amiodarone is used before this time. Excessive iodine load after this period may cause fetal hypothyroidism, detectable by laboratory tests and possibly manifesting clinically as goiter. Due to amiodarone's effects on the fetal thyroid, the drug is contraindicated during pregnancy except when the benefit outweighs the risks.

Amiodarone and its metabolites, as well as iodine, are excreted in breast milk at concentrations exceeding those in maternal plasma. Because of the risk of hypothyroidism in the infant, breastfeeding is contraindicated during amiodarone therapy.

Ability to influence reaction speed when driving or operating machinery.

The drug may impair reaction speed when driving or operating machinery, particularly in patients with amiodarone-induced visual or neurological disturbances.

Method of administration and dosage.

Adults.

Loading dose.

Treatment should usually begin with 200 mg (1 tablet) three times daily for 8–10 days, followed by reducing the dose to 200 mg twice daily during the next week.

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

Maintenance dose.

The minimum effective dose should be used according to the patient's response to the drug. After the loading period, the dose may be reduced to ½ tablet (100 mg) daily or 1 tablet (200 mg) every 2 days. Occasionally, a patient may require a higher maintenance dose (up to 2 tablets daily). The maintenance dose should be regularly reviewed.

Excessively high doses during maintenance therapy may cause adverse effects, which are believed to be associated with high tissue levels of amiodarone and its metabolites.

The tablet form of the drug is used for stabilization and long-term treatment. The dosing regimen should be determined individually by a physician.

elderly patients.

As with all patients, it is very important to use the minimum effective doses. Elderly patients may exhibit increased sensitivity to the effects of Arilma even when standard doses are administered. Particular attention should be paid to monitoring thyroid function.

Children.

The safety and efficacy of amiodarone in children have not been established; therefore, its use in children is not recommended.

Overdose.

There is insufficient information regarding acute overdose with oral amiodarone. Several cases of sinus bradycardia, cardiac arrest, episodes of ventricular tachycardia, paroxysmal "torsade de pointes" tachycardia, circulatory failure, and hepatic injury have been reported.

Treatment: discontinue the drug and provide symptomatic therapy. Considering the pharmacokinetic profile of amiodarone, monitoring of the patient (especially cardiac function) for a prolonged period is recommended.

Amiodarone and its metabolites are not removed by dialysis.

Adverse Reactions

Blood and lymphatic system.

• Hemolytic anemia, aplastic anemia, thrombocytopenia;
• cases of bone marrow granulomas have been reported in patients receiving amiodarone. The clinical significance of this finding is unknown.
• Neutropenia, agranulocytosis.

Cardiovascular system.

• Bradycardia, usually moderate and dose-dependent;
• development or exacerbation of arrhythmias (including "torsade de pointes"), accompanied by angina attacks, sometimes leading to cardiac arrest; conduction disturbances (sinoatrial block, AV block of varying degrees) – mainly when used concomitantly with drugs that prolong ventricular repolarization or in the presence of electrolyte imbalances;
• in some cases – marked bradycardia, rarely sinus arrest requiring discontinuation of treatment, particularly in patients with sinus node dysfunction and/or elderly patients;
• vasculitis.

Injury, poisoning and procedural complications.

• Primary graft dysfunction after heart transplantation with frequency "unknown" (see section "Special precautions for use").

Endocrine system (see section "Special precautions for use").

Adverse reactions related to the thyroid gland.

Apart from cases with clinical signs of thyroid dysfunction, isolated dissociation of thyroid hormones (increased fT4 levels, slightly decreased/normal fT3 levels in serum) in clinically euthyroid patients does not require discontinuation of treatment.

• Hypothyroidism. Hypothyroidism should be suspected if the following clinical signs, usually mild, occur: weight gain, cold intolerance, decreased activity, excessive bradycardia. Diagnosis is confirmed by increased serum high-sensitivity TSH levels. Euthyroid state usually returns within 1–3 months after amiodarone discontinuation. Discontinuation of the drug is not mandatory if amiodarone use is clinically justified. Treatment may continue in combination with L-thyroxine replacement therapy, with dosage adjusted according to TSH levels;
• hyperthyroidism, sometimes with fatal outcome. Diagnosis of hyperthyroidism is more difficult, as initial symptoms are less pronounced (slight unexplained weight loss, reduced efficacy of antianginal and/or antiarrhythmic therapy). Elderly patients may develop psychiatric symptoms, even thyrotoxicosis. Diagnosis is confirmed by a significant decrease in serum high-sensitivity TSH levels. In confirmed cases of hyperthyroidism, amiodarone therapy must be discontinued. Clinical recovery precedes normalization of thyroid function tests and usually begins 3–4 weeks after amiodarone withdrawal. Since severe cases presenting with clinical features of thyrotoxicosis are potentially fatal, they require immediate and appropriate treatment.

If the course of thyrotoxicosis is concerning (either by itself or due to its impact on vulnerable myocardial equilibrium), and considering the variable efficacy of synthetic antithyroid drugs, combination therapy with high-dose corticosteroids (e.g., 1 mg/kg prednisolone) for a prolonged period (3 months) is recommended. Cases of hyperthyroidism occurring several months after amiodarone discontinuation have been reported.

Other endocrine disorders.

• Syndrome of inappropriate antidiuretic hormone secretion (SIADH), particularly when the drug is used concomitantly with medications that may induce hyponatremia.

Eyes.

• Microdeposits in the corneal epithelium, usually located beneath the pupil, visible only upon slit-lamp examination, manifesting as colored halos in bright light or blurred vision. Corneal microdeposits consist of lipid complexes, resolve after drug discontinuation, and do not require treatment cessation;
• optic neuropathy/optic neuritis with optic disc swelling and blurred or decreased vision, which may progress to blindness. A causal relationship between this adverse effect and amiodarone use has not been definitively established. However, if no other obvious causes are identified, amiodarone should be discontinued (see section "Special precautions for use").

Gastrointestinal tract.

• Gastrointestinal disturbances (nausea, vomiting, dysgeusia), usually occurring during the loading phase and resolving with dose reduction;
• pancreatitis/acute pancreatitis, dry mouth, constipation.

Hepatobiliary system (see section "Special precautions for use").

Cases of liver injury (diagnosed by elevated serum transaminase levels).

• Isolated increase in serum transaminase activity at the beginning of treatment, usually mild (1.5–3 times above normal). Normalization of these parameters occurs with dose reduction or even spontaneously;
• acute liver injury with high serum transaminase levels and/or jaundice, including acute liver failure, requiring drug discontinuation; sometimes with fatal outcome;
• chronic liver injury (pseudoalcoholic hepatitis, cirrhosis, liver failure), requiring prolonged treatment; sometimes with fatal outcome.

Since clinical and laboratory signs are not clearly defined (variable hepatomegaly, serum transaminase levels elevated 1.5–5 times above normal), regular monitoring of liver function is indicated. Persistent moderate elevation of serum transaminases during treatment for more than 6 months and/or appearance of clinical signs (hepatomegaly) should raise suspicion of chronic liver injury. Clinical and laboratory abnormalities usually regress after drug discontinuation, although irreversible changes have been reported in isolated cases. Histological findings correspond to pseudoalcoholic hepatitis or liver cirrhosis.

Immune system.

• Angioedema and/or urticaria;
• anaphylactic/anaphylactoid reactions, including anaphylactic shock.

Nervous system.

• Tremor or other extrapyramidal symptoms (which may require dose reduction or discontinuation), nightmares, sleep disturbances;
• peripheral sensory, motor, or mixed neuropathies and/or myopathies, which may develop several months after treatment initiation, sometimes years later, usually reversible after drug discontinuation. However, recovery may be incomplete, very slow, and occur only several months after discontinuation;
• cerebellar ataxia (improves with dose reduction or discontinuation), benign intracranial hypertension (pseudotumor cerebri), headache, vertigo. Isolated headache requires evaluation to determine its possible cause;
• parkinsonism syndrome, parosmia.

Psychiatric disorders.

• Decreased libido.
• Confusion/delirium, hallucinations.

Reproductive system.

• Epididymitis, orchitis (causal relationship with amiodarone use not clearly established), impotence.

Urinary system.

• Renal injury with moderate increase in creatinine levels.

Respiratory system.

• Signs of toxic effects on lung tissue (hypersensitivity pneumonitis, diffuse alveolar/interstitial pneumopathy or fibrosis, obliterative bronchiolitis with organizing pneumonia), sometimes with fatal outcome (see section "Special precautions for use"). Patients developing dyspnea (which may be severe and unexplained by current cardiac status) or non-productive cough, either isolated or associated with worsening general condition (increased fatigue, weight loss, fever), should undergo chest X-ray and pulmonary function tests. The need for amiodarone discontinuation and potential use of glucocorticosteroids should be considered in such cases. Such pneumopathies may lead to pulmonary fibrosis. Pleuritis associated with interstitial pneumonia may occur in individual cases.

Worsening of condition usually occurs gradually, but rapid progression is possible. Most cases occurred during long-term therapy, with only a few developing soon after treatment initiation.

Lung disorders are mainly reversible with early amiodarone discontinuation, both with and without corticosteroid use. Clinical symptoms usually resolve within 3–4 weeks, followed by slower recovery of radiological findings and lung function (over several months). Some patients' conditions may worsen despite drug discontinuation;

• severe respiratory complications (acute respiratory distress syndrome), sometimes in the early postoperative period, possibly related to interaction with high oxygen concentrations, sometimes with fatal outcome (see section "Special precautions for use");
• bronchospasm in patients with severe respiratory insufficiency, particularly in patients with bronchial asthma.

Cases of pulmonary hemorrhage (in some cases presenting as hemoptysis) and respiratory failure have been reported. These pulmonary adverse effects are often associated with amiodarone-induced pneumopathy.

Skin and subcutaneous tissue.

• Photosensitization (see section "Special precautions for use");
• eczema;
• grayish or bluish pigmentation of exposed skin areas, especially the face, during prolonged high-dose treatment; this pigmentation slowly resolves after treatment cessation (within 10–24 months);
• erythema during radiotherapy; usually nonspecific rashes; exfoliative dermatitis (causal relationship with drug use not clearly established); alopecia;
• severe, sometimes fatal, skin reactions such as toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, bullous dermatitis, DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).

Musculoskeletal and connective tissue disorders.

• Lupus-like syndrome.

Metabolic and nutritional disorders.

• Decreased appetite.

Laboratory investigations.

• Increased serum creatinine levels; hyponatremia (may indicate development of SIADH).

Adverse reactions of the drug are usually dose-dependent; therefore, the minimum effective maintenance dose should be carefully determined to prevent or minimize the risk of adverse effects.

Shelf life. 4 years.

Do not use the medication after the expiry date stated on the packaging!

Storage conditions.

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

Keep out of reach of children.

Packaging. 10 tablets per blister, 2, 3, or 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchahivsky Chemical and Pharmaceutical Plant".

Manufacturer's address and location of business activity.

17 Myru Street, Kyiv, 03134, Ukraine.