AMIODARONE-DARNITSA

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMIODARONE-DARNITSA

Composition:

Active substance: amiodarone;

1 tablet contains amiodarone hydrochloride 200 mg;

Excipients: lactose monohydrate, potato starch, povidone, microcrystalline cellulose, crospovidone, magnesium stearate.

Dosage form. Tablets.

Main physicochemical properties: tablets of white or white with slightly creamy shade, flat cylindrical shape, with bevel and score line.

Pharmacotherapeutic group. Antiarrhythmic agents, class III.

ATC code C01B D01.

Pharmacological properties.

Pharmacodynamics.

Class III antiarrhythmic agent. Exhibits antiarrhythmic and antianginal effects.

Antiarrhythmic properties:

• Prolongation of phase 3 of the cardiac myocyte action potential, primarily due to reduction of potassium ion current (class III according to Vaughan Williams classification);
• Slowing of heart rate due to suppression of sinoatrial node automaticity. This effect is not blocked by atropine;
• Non-competitive α- and β-antiadrenergic activity;
• Slowed sinoatrial, atrial, and nodal impulse conduction in myocardium, with greater effect at faster heart rates;
• No changes in intraventricular conduction;
• Increased refractory period and reduced myocardial excitability at atrial, nodal, and ventricular levels;
• Slowed conduction and prolonged refractory periods in accessory atrioventricular conducting pathways.

Other properties:

• Reduced oxygen consumption due to moderate decrease in peripheral vascular resistance and reduced heart rate;
• Increased coronary blood flow due to direct action on myocardial vascular smooth muscle and maintained cardiac output despite reduced arterial pressure and peripheral vascular resistance, in the absence of negative inotropic effects.

Pharmacokinetics.

Amiodarone is a drug with slow elimination and high tissue affinity.

Bioavailability after oral administration varies between 30% and 80% in different patients (average 50%). After a single dose, maximum plasma concentration is reached within 3–7 hours. Therapeutic effect is achieved on average within 1 week after initiation of treatment (ranging from several days to two weeks).

The elimination half-life of amiodarone is prolonged and shows considerable 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 steady-state equilibrium between intake and elimination is reached over several months, with individual variations.

These characteristics explain the necessity of using a loading dose to rapidly achieve adequate tissue accumulation of the drug, required for therapeutic effect.

Part of the iodine is released from the drug and excreted in urine as iodide; 6 mg of iodine per day corresponds to a daily amiodarone dose of 200 mg. The remainder of the drug, i.e. the majority of the iodine, is excreted in feces following hepatic metabolism.

Minimal renal excretion of the drug allows administration of usual doses in patients with impaired renal function.

After discontinuation of treatment, elimination from the body continues for several months. It should be noted that after stopping the drug, its effects persist for 10 days to 1 month.

Clinical characteristics.

Indications.

Prevention of recurrence:

• life-threatening ventricular tachycardia: AMIODARONE-DARNYTSIA should be administered only in hospital conditions under supervision;
• documented symptomatic and disabling ventricular tachycardia;
• documented supraventricular tachycardia, when treatment with the drug is indicated in patients with disease resistant to other therapies or with contraindications to other treatment methods for ventricular fibrillation.

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

Amiodarone may be used in patients with ischemic heart disease and/or left ventricular cardiac dysfunction (see section "Pharmacodynamics").

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 node arrest).

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

Thyroid gland dysfunction (hyperthyroidism) – possible exacerbation during amiodarone administration.

Hypersensitivity to iodine, amiodarone or to any of the excipients.

Pregnancy.

Breastfeeding period.

Combination with medicinal products that may induce torsades de pointes ventricular tachycardia (except antiparasitic agents, neuroleptics, and methadone):

• class Ia antiarrhythmic agents (quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmic agents (sotalol, dofetilide, ibutilide);
• other medicinal products such as arsenic compounds, bepridil, cisapride, citalopram, escitalopram, 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 medicinal products.

Many antiarrhythmic medicinal products suppress cardiac automaticity, conduction, and myocardial contractility.

Concomitant use of antiarrhythmic agents belonging to different classes may achieve a favorable therapeutic effect, but treatment with such combinations is usually a very delicate process requiring careful clinical and ECG monitoring.

Concomitant use of antiarrhythmic agents that may induce torsades de pointes (such as amiodarone, disopyramide, quinidine derivatives, sotalol) 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 with medicinal products that have negative inotropic effects, slow heart rate and/or slow atrioventricular conduction is a delicate process requiring careful clinical and ECG monitoring.

Medicinal products that may induce torsades de pointes.

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

Medicinal products that may cause torsades de pointes include, in particular, class Ia and III antiarrhythmic agents and certain neuroleptics. For dolasetron, erythromycin, spiramycin, and vinca alkaloids, this interaction occurs only when intravenous formulations are used.

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

However, methadone and certain subgroups of medicinal products are exceptions to this rule:

• antiparasitic agents (halofantrine, lumefantrine, pentamidine) are also not recommended for concomitant use with other agents promoting torsades de pointes;
• neuroleptics that may induce torsades de pointes are also not recommended for concomitant use with other agents promoting torsades de pointes, but such combination is not contraindicated.

Medicinal products that slow heart rate.

Many medicinal products may cause bradycardia. This particularly applies to class Ia antiarrhythmic agents, β-blockers, certain class III antiarrhythmic agents, certain calcium channel blockers, digitalis agents, pilocarpine, and anticholinesterase medicinal products.

Effect of other medicinal products on amiodarone.

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

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. Since the effect of amiodarone is long-lasting, such interactions may occur for several months after discontinuation of 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"):

• 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, dolasetron intravenous, domperidone, dronedarone, erythromycin intravenous, levofloxacin, mequitazine, mizolastine, vinca alkaloids intravenous, moxifloxacin, prucalopride, spiramycin intravenous, toremifene.

Increased risk of ventricular arrhythmias, especially torsades de pointes.

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

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

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

Sofosbuvir. Bradycardia, including symptomatic or even fatal, may occur only in patients receiving dual combination therapy with daclatasvir/sofosbuvir or ledipasvir/sofosbuvir. If use of such combination cannot be avoided, careful clinical monitoring and ECG monitoring of cardiac function are required, especially during the first weeks of dual therapy.

Injectable diltiazem. Risk of bradycardia and atrioventricular block. If use of this combination cannot be avoided, careful clinical monitoring and ECG monitoring of cardiac function are required.

Fingolimod. Potentiation of bradycardia-induced effects, potentially fatal. This is particularly relevant for β-blockers that inhibit adrenergic compensatory mechanisms. After administration of the first dose, clinical monitoring and ECG monitoring of cardiac function are required for 24 hours.

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

Quantitative determination of serum cyclosporine concentrations, monitoring of renal function, and dose adjustment of cyclosporine during amiodarone therapy.

Verapamil and injectable diltiazem. Risk of bradycardia and atrioventricular block.

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

Antiparasitic medicinal products that may induce torsades de pointes (halofantrine, lumefantrine, pentamidine). Increased risk of ventricular arrhythmias, especially torsades de pointes.

If possible, one or both medicinal products 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, thioridazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulthiapride, tiapride, zuclopenthixol). Increased risk of ventricular arrhythmias, especially torsades de pointes.

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

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

Fidaxomicin. Increased plasma concentration of fidaxomicin.

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

Combinations requiring precautionary measures during use.

P-glycoprotein substrates. Amiodarone is a P-glycoprotein inhibitor. Concurrent use with P-glycoprotein substrates is expected to increase their blood concentrations.

Oral anticoagulants. Enhanced anticoagulant effect and increased risk of hemorrhagic complications.

More frequent monitoring of international normalized ratio (INR). Possible dose adjustment of the oral anticoagulant during amiodarone therapy and for 8 days after discontinuation of the drug.

β-blockers, except sotalol (contraindicated combination) and esmolol (combination requiring precautionary measures). Impaired automaticity and conduction (suppression of compensatory sympathetic mechanisms). ECG and clinical monitoring.

β-blockers used for treatment of heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Impaired myocardial automaticity and conduction with risk of excessive slowing of heart rate.

Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical and regular ECG monitoring.

Dabigatran. Increased plasma concentrations of dabigatran with increased risk of hemorrhagic events.

If dabigatran is administered after surgical intervention, clinical observation and dose adjustment of dabigatran if necessary, but not exceeding 150 mg/day, should be performed.

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

Digitalis preparations. Suppression of automaticity (excessive slowing of heart rate) and impaired atrioventricular conduction.

When digoxin is used, increased digoxin blood levels occur due to reduced digoxin clearance, requiring ECG monitoring of cardiac function, clinical observation, quantitative determination of digoxin blood levels, and appropriate dose adjustment of digoxin.

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

Certain macrolides (azithromycin, clarithromycin, roxithromycin). Increased risk of ventricular arrhythmias, especially torsades de pointes. ECG and clinical monitoring during concomitant use of these medicinal products.

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

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

Medicinal products that reduce potassium levels: potassium-depleting diuretics (alone or in combination), stimulant laxatives, amphotericin B (intravenous administration), glucocorticoids (systemic use), tetracosactide. Increased risk of ventricular arrhythmias, especially torsades de pointes (hypokalemia being a predisposing factor).

Hypokalemia must be corrected before drug administration, and ECG monitoring, electrolyte level monitoring, and clinical monitoring should be performed.

Lidocaine. Risk of increased plasma concentrations of lidocaine, with possible neurological and cardiac adverse effects, due to inhibition of hepatic metabolism of the drug by amiodarone. Clinical and ECG monitoring, and if necessary, quantitative determination of plasma lidocaine concentrations. Dose adjustment of lidocaine during and after amiodarone therapy if needed.

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

Phenytoin (by extrapolation – fosphenytoin). Increased plasma concentrations of phenytoin with signs of overdose, especially neurological signs (due to inhibition of hepatic metabolism of phenytoin). Clinical monitoring, quantitative determination of plasma phenytoin concentrations, and possible dose adjustment.

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 during concomitant use with amiodarone and after its discontinuation.

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

Voriconazole. Increased risk of ventricular arrhythmias, especially torsades de pointes ventricular tachycardia, due to possible reduced metabolism of amiodarone. Clinical observation and ECG monitoring of cardiac function are required, and dose adjustment of amiodarone if necessary.

Substrates of CYP2D6.

Flecainide. Amiodarone increases plasma concentrations of flecainide due to inhibition of cytochrome CYP2D6. Therefore, the dose of flecainide should be adjusted.

Medicinal products metabolized by cytochrome P450 3A4 (fentanyl, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine, statins, including atorvastatin, lovastatin). Administration with amiodarone, which is an inhibitor of this enzyme, increases plasma concentrations of these medicinal products and may consequently increase their toxicity.

Cyclosporine: combination with amiodarone may lead to increased plasma levels of cyclosporine. Dose adjustment is required.

Fentanyl: combination with amiodarone may enhance the pharmacological effect of fentanyl and increase the risk of its toxicity.

Substrates of CYP3A4.

Amiodarone is an inhibitor of CYP3A4 and increases plasma concentrations of substrates of this cytochrome, resulting in enhanced toxic effects of the indicated substrates.

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

Simvastatin. Increased risk of concentration-dependent adverse effects, such as rhabdomyolysis (due to inhibition of hepatic metabolism of simvastatin). Considering this type of interaction, the dose of simvastatin should not exceed 20 mg per day or another statin should be used.

Other medicinal products metabolized by CYP3A4: lidocaine, sirolimus, tacrolimus, sildenafil, fentanyl, midazolam, triazolam, dihydroergotamine, ergotamine, and colchicine.

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

Amiodarone is an inhibitor of CYP3A4 and increases plasma concentrations of these molecules, leading to increased toxicity.

During amiodarone therapy, it is recommended to avoid use of CYP3A4 inhibitors (e.g., grapefruit juice and certain medicinal products).

Medicinal products that slow heart rate. Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical and ECG monitoring.

Substrates of CYP2C9: amiodarone increases concentrations of substances that are substrates of CYP2C9, such as warfarin or phenytoin, due to inhibition of cytochrome P450 2C9 enzymes.

Combinations requiring special attention.

Pilocarpine: risk of excessive slowing of heart rate (additive effects of medicinal products that slow heart rate).

Special precautions for use.

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

The frequency and severity of adverse effects are dose-dependent; therefore, the lowest effective maintenance dose should be used.

Cardiac effects.

An ECG and serum potassium levels should be assessed before initiating treatment.

In elderly patients, amiodarone may enhance the reduction in heart rate. Caution is advised in elderly patients due to the risk of bradycardia. Amiodarone induces ECG changes, including QT interval prolongation due to prolonged repolarization, possibly with appearance of a U wave. These changes reflect the drug’s therapeutic effect and not its toxicity.

Treatment must be discontinued if sinoatrial block, second- or third-degree atrioventricular (AV) block, or bifascicular block of the His bundle occurs.

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

Cases of new-onset arrhythmia or exacerbation of pre-existing arrhythmia have been reported during treatment (see section "Adverse reactions").

The risk of drug-induced torsades de pointes tachycardia with amiodarone is low or even lower than with most other antiarrhythmic agents in patients with similar degrees of QT prolongation, and typically occurs in the context of concomitant use of certain drug combinations (see section "Interaction with medicinal products and other forms of interaction") or in the presence of electrolyte imbalances (e.g., hypokalemia).

Primary graft dysfunction after heart transplantation

Retrospective studies have shown an association between amiodarone use by recipients prior to heart transplantation and an increased risk of primary graft dysfunction (PGD). PGD is a life-threatening complication occurring within the first 24 hours after transplantation, characterized by left ventricular, right ventricular, or biventricular dysfunction, in the absence of identifiable secondary causes (see section "Adverse reactions"). Severe PGD may be irreversible.

Patients on the waiting list for heart transplantation should be considered for alternative antiarrhythmic therapy as early as possible before transplantation.

Thyroid dysfunction.

This medicinal product contains iodine, which may interfere with certain thyroid function tests (e.g., radioactive iodine uptake, protein-bound iodine). However, thyroid function parameters (T3, T4, TSH) can still be measured.

Amiodarone may cause thyroid dysfunction, particularly in patients with a history of thyroid disorders. Quantitative TSH measurement is recommended in all patients before starting treatment, regularly during therapy, for several months after discontinuation, and whenever clinical suspicion of thyroid dysfunction arises (see section "Adverse reactions").

Lung disorders.

The onset of dyspnea or dry cough, either isolated or associated with deterioration in general condition, should be considered a possible sign of pulmonary toxicity, such as interstitial pneumonitis, and requires radiological evaluation (see section "Adverse reactions").

Liver disorders.

Regular monitoring of liver function is recommended at the beginning of treatment and periodically throughout amiodarone therapy (see section "Adverse reactions"). Amiodarone dose should be reduced or discontinued if transaminase levels increase by more than three times the upper normal limit.

Acute hepatic disorders (including severe hepatocellular insufficiency or liver failure, sometimes fatal) and chronic liver disorders may occur during amiodarone treatment.

Nerve and muscle disorders.

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

Eye disorders.

Blurred vision or decreased visual acuity requires immediate comprehensive ophthalmological examination, including fundoscopy. Development of amiodarone-induced optic neuropathy or optic neuritis necessitates immediate discontinuation of the drug, as continued treatment may lead to progression of visual disturbances up to blindness (see section "Adverse reactions").

Severe bradycardia.

Severe, potentially life-threatening bradycardia and severe conduction disturbances have been reported in patients receiving amiodarone in combination with sofosbuvir, alone or with other direct-acting antiviral agents for hepatitis C treatment (e.g., daclatasvir, simeprevir, ledipasvir). Therefore, concomitant use of these drugs with amiodarone is not recommended.

If concomitant use cannot be avoided, close monitoring is required at the initiation of sofosbuvir treatment (alone or in combination). Patients at high risk of bradyarrhythmias should be monitored for at least 48 hours after starting sofosbuvir.

Due to amiodarone’s long half-life, appropriate monitoring is also required in patients who have discontinued amiodarone within several months prior to starting sofosbuvir (alone or in combination with other direct-acting antivirals).

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

Interactions with other medicinal products.

Combinations with β-blockers (except sotalol, which is contraindicated, and esmolol, which requires precaution), verapamil, and diltiazem should be considered only for prevention of life-threatening ventricular arrhythmias (see section "Interaction with medicinal products and other forms of interaction").

Amiodarone is not recommended for concomitant use with cyclosporine, diltiazem (injection), verapamil (injection), certain antiparasitic agents (halofantrine, lumefantrine, pentamidine), certain neuroleptics (* amisulpride, chlorpromazine, thiethylperazine, droperidol, flupentixol*, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulthiapide, tiapride, zuclopenthixol), fluoroquinolones (except levofloxacin and moxifloxacin), stimulant laxatives, methadone, or fingolimod (see section "Interaction with medicinal products and other forms of interaction").

Electrolyte disturbances, particularly hypokalemia.

Hypokalemia may predispose to proarrhythmic effects of the drug.

Concomitant use of amiodarone with β-blockers, calcium channel blockers that reduce heart rate (verapamil, diltiazem), or stimulant laxatives that may cause hypokalemia is not recommended.

Hypokalemia must be corrected before initiating amiodarone therapy. Serum potassium levels should be monitored regularly.

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

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

Due to the potential increase in defibrillation and/or pacing thresholds in patients with implanted cardiac defibrillators or pacemakers, threshold testing is required before starting amiodarone treatment, several times after initiation, and each time the dose is adjusted.

Effects on skin and subcutaneous tissue.

Patients should be advised to avoid ultraviolet radiation during amiodarone treatment.

Severe bullous reactions.

Amiodarone should be used with caution in patients at high risk of serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Amiodarone must be discontinued immediately at the first sign of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Anaesthesia.

The anaesthesiologist must be informed prior to surgery that the patient is receiving amiodarone.

Long-term amiodarone treatment may increase the hemodynamic risks associated with general and local anaesthesia due to its side effects, including bradycardia, arterial hypotension, reduced cardiac output, and conduction disturbances. Additionally, several cases of acute respiratory distress syndrome have been reported in patients receiving amiodarone in the early postoperative period. Therefore, careful monitoring during mechanical ventilation is recommended (see section "Adverse reactions").

Effects related to excipients.

This medicinal product contains lactose. Therefore, it is contraindicated in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption (rare hereditary conditions).

Use during pregnancy or breastfeeding.

Pregnancy. No teratogenic effects were observed in animal studies, and therefore malformation effects in humans are not expected.

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.

As fetal thyroid gland begins to bind iodine from week 14, no effect on embryonic thyroid is expected if the drug is used before this time. However, excess iodine intake during treatment may lead to fetal hypothyroidism. Due to the effects of amiodarone on the fetal thyroid gland, this medicinal product is contraindicated during pregnancy.

Breastfeeding. Amiodarone and its metabolites, along with iodine, are excreted in breast milk at concentrations higher than in maternal plasma. Breastfeeding is contraindicated during amiodarone treatment due to the risk of hypothyroidism in the newborn.

Ability to influence reaction speed when driving or operating machinery.

Caution is advised when driving or operating machinery during treatment, due to possible adverse effects on vision or the nervous system, which may impair attention and psychomotor reaction speed.

Dosage and Administration

Administer orally to adults during or after meals, without chewing, with a small amount of liquid.

Initial treatment

The usual dosage regimen is 3 tablets daily for 8–10 days.

In certain cases, higher initial doses (4–5 tablets daily) may be used, but always for a short duration and with electrocardiogram monitoring.

Maintenance therapy

The minimum effective dose should be determined, which may vary depending on the patient, from 0.5 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, administration of this medicinal product to children is not recommended.

Overdose

Cases of amiodarone overdose are poorly documented. There have been reports of several cases of sinus bradycardia, ventricular arrhythmias, particularly torsades de pointes, and hepatic injury. Treatment should be symptomatic. Considering the pharmacokinetic profile of this medicinal product, patient monitoring—especially of cardiac function—is recommended for a prolonged period of time. AMIODARONE-DARNYTSIA and its metabolites are not eliminated by dialysis.

Adverse reactions

Adverse effects are classified by organ systems and frequency as follows: very common (> 10%); common (> 1%, < 10%); uncommon (> 0.1%, < 1%); rare (> 0.01%, < 0.1%); very rare (< 0.01%).

Eye disorders:
Very common – corneal microdeposits, occurring in almost all adult patients, usually within the area beneath the pupil. These deposits do not require discontinuation of amiodarone. In rare cases, they may be associated with colored halos in bright light or blurred vision. Corneal microdeposits represent complex lipid deposits and are fully reversible after discontinuation of the drug.
Very rare – optic neuropathy (optic neuritis) presenting with blurred vision and visual deterioration, and on fundus examination, with optic disc swelling, potentially progressing to moderate or severe visual acuity loss. A causal relationship between this adverse effect and amiodarone use has not yet been definitively established.

However, if no other obvious causes for this adverse effect are identified, discontinuation of amiodarone is recommended.

Respiratory, thoracic and mediastinal disorders:
Common – cases of interstitial or diffuse alveolar lung disease and obliterative bronchiolitis with organizing pneumonia (OBOP), sometimes fatal, have been reported. Development of dyspnea on exertion or dry cough, either isolated or associated with worsening general health (increased fatigue, weight loss, and mild fever), requires radiological evaluation and, if necessary, discontinuation of the drug, as these lung disorders may lead to pulmonary fibrosis.

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

There have been several reports of pleuritis, usually associated with interstitial pneumonopathy.
Very rare – bronchospasm, particularly in patients with bronchial asthma.

Acute respiratory distress syndrome (ARDS), occasionally with fatal outcome, has been reported, sometimes in the early postoperative period following surgery (a possible interaction with high-dose oxygen has been suspected) (see section "Special precautions").

Frequency not known (cannot be estimated from available data):
Cases of pulmonary hemorrhage, which in some instances may manifest as hemoptysis, and respiratory failure. These pulmonary adverse effects are often associated with amiodarone-induced pneumonopathy.

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.

Hepatobiliary disorders:
Cases of liver injury (diagnosed based on elevated serum transaminase levels).
Very common – usually mild and isolated elevation of transaminase levels (1.5–3 times above normal), which resolves after dose reduction or spontaneously.
Common – acute liver injury with elevated transaminase levels and/or jaundice, sometimes fatal, requiring discontinuation of the drug.
Very rare – chronic liver injury, liver cirrhosis requiring long-term treatment, and hepatic failure. Histological changes resemble those of pseudo-alcoholic hepatitis. As 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 recommended.

In cases of elevated transaminase levels—even mild elevations—occurring after more than 6 months of drug use, chronic liver injury should be suspected. These clinical and biological changes usually resolve after discontinuation of the drug. However, several irreversible cases have been reported.

Nervous system disorders:
Common – tremor or other extrapyramidal symptoms, sleep disturbances including nightmares, sensory, motor, or mixed peripheral neuropathy.
Rare – myopathy. Sensory, motor, or mixed peripheral neuropathy and myopathy may develop several months after initiation of treatment, but sometimes appear after several years. These adverse effects are usually reversible after discontinuation of the drug.

However, recovery may be incomplete and very slow, occurring only several months after stopping the drug.
Very rare – cerebellar ataxia, benign intracranial hypertension, headache. If isolated headaches occur, evaluation should be performed to determine their possible cause.

Psychiatric disorders:
Common – decreased libido.
Frequency not known – hallucinations.

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, particularly in elderly patients with pre-existing sinus node dysfunction), development or worsening of arrhythmias associated with angina attacks. Paroxysmal ventricular tachycardia torsade de pointes.
Very rare – vasculitis.

Blood and lymphatic system disorders:
Very rare – thrombocytopenia, aplastic anemia, hemolytic anemia. Granulomas of the bone marrow have been reported in patients receiving amiodarone. The clinical significance of this finding is unknown.
Frequency not known – neutropenia and agranulocytosis.

Immune system disorders:
Frequency not known (cannot be estimated from available data) – cases of angioedema, allergic reactions including skin rashes.

Skin and subcutaneous tissue disorders:
Very common – photosensitivity. Exposure to sunlight (and ultraviolet radiation in general) should be avoided during amiodarone treatment.
Common – skin discoloration with bluish or bluish-gray pigmentation, occurring after prolonged use of high daily doses and slowly resolving after discontinuation of the drug (within 10–24 months).
Very rare – erythema in irradiated areas, nonspecific skin rashes, exfoliative dermatitis (causal relationship with drug use has not been definitively established), alopecia.
Frequency not known – severe, sometimes fatal, skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Reproductive system and breast disorders:
Very rare – epididymitis, impotence. A causal relationship between these adverse effects and amiodarone use has not been definitively established.

Injury, poisoning and procedural complications:
Frequency not known – primary graft dysfunction after heart transplantation (see section "Special precautions").

Laboratory findings:
Rare – rare cases of hyponatremia may indicate syndrome of inappropriate antidiuretic hormone secretion (SIADH), particularly when AMIODARONE-DARNYTSIA is used concomitantly with drugs that may induce hyponatremia.
Very rare – renal impairment with mild increase in creatinine levels.

Endocrine disorders:
Very common – apart from cases with clinical signs of thyroid dysfunction, "drug-unrelated" changes in thyroid hormone levels in blood (elevated T4, normal or slightly reduced T3) do not require discontinuation of the drug.
Common – hypothyroidism, presenting with typical symptoms: weight gain, cold intolerance, apathy, somnolence. Markedly elevated TSH levels confirm the diagnosis. Euthyroidism is usually restored within 1–3 months after stopping the drug. Discontinuation of amiodarone is not mandatory: if amiodarone use is clinically justified, treatment may continue in combination with thyroid hormone replacement therapy using levothyroxine. Levothyroxine doses may be adjusted based on TSH levels.
Hyperthyroidism is more difficult to diagnose: symptoms are less pronounced (unexplained mild weight loss, inadequate response to antianginal and/or antiarrhythmic drugs); in elderly patients, psychiatric symptoms or even thyrotoxicosis may occur.
Markedly reduced levels of highly sensitive TSH confirm the diagnosis. In such cases, amiodarone must be discontinued immediately, which is usually sufficient to achieve clinical normalization within 3–4 weeks. As severe cases of this adverse effect may be fatal, appropriate therapy must be initiated promptly.

If thyrotoxicosis is the cause of complications (directly or via its impact on vulnerable myocardial balance), the variable efficacy of synthetic antithyroid drugs necessitates the recommendation to administer high-dose corticosteroids (1 mg/kg) for a sufficiently long duration (3 months).

Cases of hyperthyroidism have been reported up to several months after discontinuation of amiodarone.

Other endocrine disorders
Very rare cases of SIADH (syndrome of inappropriate antidiuretic hormone secretion), particularly when AMIODARONE-DARNYTSIA is used concomitantly with drugs that may induce hyponatremia (also see section "Laboratory findings").

Shelf life.
3 years.

Storage conditions.
Store in original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.

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

Prescription status.
Prescription only.

Manufacturer.
JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and place of business.
13, Boryspilska Street, Kyiv, 02093, Ukraine.