Rotarhythmil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RОTARITMIL (ROTARITMIL)

Composition:

Active substance: amiodarone;

1 tablet contains 200 mg of amiodarone hydrochloride;

Excipients: corn starch; lactose monohydrate; povidone (K 90); magnesium stearate; colloidal anhydrous silicon dioxide; pregelatinized starch.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, round tablets with a score line.

Pharmacotherapeutic group.

Class III antiarrhythmic agents. ATC code C01B D01.

Pharmacological Properties

Pharmacodynamics

The active substance of the medicinal product, amiodarone, belongs to the main representatives of class III antiarrhythmic agents (class of repolarization inhibitors according to Vaughan-Williams classification).

Antiarrhythmic Properties of Amiodarone

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

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

Non-competitive alpha- and beta-adrenergic blocking 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 of myocardial excitability at the atrial, nodal, and ventricular levels.

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

Other Properties of Amiodarone

Reduction in oxygen consumption due to moderate decrease in peripheral vascular resistance and reduction in 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, and in the absence of negative inotropic effects.

A meta-analysis of data from 13 prospective, randomized, controlled trials involving 6,553 patients recently suffering from myocardial infarction (78%) or chronic heart failure (22%) has been conducted.

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

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

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

The proportion of patients who discontinued 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 has been evaluated in 1,118 children with various types of arrhythmias.

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

• Loading dose: 10–20 mg/kg/day for 7–10 days (i.e., 500 mg/m²/day calculated per body surface area);
• Maintenance dose: minimal effective dose; based on individual response, it may range from 5 to 10 mg/kg/day (i.e., 250 mg/m²/day calculated per 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 is typically observed within one week of amiodarone administration (ranging from several days to two weeks).

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

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

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

After discontinuation of the drug, elimination continues for several months. 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 the 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 2 (OCT2). Results from one study indicate an increase in creatinine concentration by 1.1% (an OCT2 substrate).

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

Pediatric Population

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

Preclinical Data

Results from a 2-year carcinogenicity study in animals showed that amiodarone causes an increased incidence of follicular thyroid tumors (adenomas and/or carcinomas) in both sexes of animals at clinically relevant exposures.

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

Animal 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 the influence of amiodarone on the synthesis and/or release of thyroid hormones. These findings have low relevance for the use of the drug in humans.

Clinical Characteristics.

Indications.

Prevention of recurrences:

• Ventricular tachycardia that is life-threatening (treatment 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 therapies have proven ineffective or are 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.

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

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

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

Severe atrioventricular conduction disorders, except in patients with an implanted cardiac pacemaker.

Hyperthyroidism.

Concomitant use with drugs capable of inducing paroxysmal ventricular tachycardia of the torsades de pointes type (except antiparasitic agents, neuroleptics, and methadone):

Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide);

Class III antiarrhythmics (sotalol, dofetilide, ibutilide);

other medicinal products such as arsenic compounds, bepridil, cisapride, citalopram, escitalopram, difemalane, dolasetron IV, domperidone, dronedarone, erythromycin IV, levofloxacin, mephenytoin, mizolastine, vinca alkaloids IV, moxifloxacin, prucalopride, spiramycin IV, toremifene, vinca alkaloids IV (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with telaprevir, cobicistat.

Second and third trimesters of pregnancy.

Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Antiarrhythmics.

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

Concomitant use of antiarrhythmics from different classes may be beneficial, but such treatment usually requires careful clinical and ECG monitoring. Concomitant use of antiarrhythmics capable of inducing paroxysmal ventricular tachycardia of the torsades de pointes type (such as amiodarone, disopyramide, quinidine derivatives, sotalol, and others) is contraindicated.

Concomitant use of antiarrhythmics within 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.

Agents that may induce torsades de pointes-type paroxysmal ventricular tachycardia.

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

Medicinal products that may induce torsades de pointes include, in particular, class Ia and III antiarrhythmics and certain neuroleptics. For dolasetron, erythromycin, spiramycin, and vinca alkaloids, 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 medicinal products that promote torsades de pointes.

Agents that slow heart rate.

Many medicinal products may cause bradycardia, including class Ia antiarrhythmics, beta-blockers, certain class III antiarrhythmics, certain 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 persist for several months after discontinuation of amiodarone therapy.

Effects of other medicinal products on amiodarone.

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

CYP3A4 inhibitors (e.g., grapefruit juice and certain medicinal products) are generally not used during amiodarone therapy.

Contraindicated combinations (see section "Contraindications").

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

• Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (dofetilide, ibutilide, sotalol);
• other medicinal products (arsenic compounds, bepridil, cisapride, citalopram, escitalopram, difemalane, dolasetron IV, domperidone, dronedarone, erythromycin IV, levofloxacin, mephenytoin, mizolastine, vinca alkaloids IV, moxifloxacin, prucalopride, spiramycin IV, 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. Close monitoring is recommended when these medicinal products are used concomitantly (see section "Special precautions for use").

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

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

During amiodarone therapy, plasma cyclosporine levels should be quantitatively determined, renal function monitored, and cyclosporine dose adjusted.

Injectable diltiazem. Risk of bradycardia and atrioventricular block.

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

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, careful clinical observation and continuous ECG monitoring are required.

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

Neuroleptics that may induce torsades de pointes-type paroxysmal ventricular tachycardia (amisulpride, chlorpromazine, tiaramide, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipothiazine, 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). Prior to drug administration, any hypokalemia should be corrected, and ECG and clinical monitoring with electrolyte level control should be performed.

Fidaxomicin. Increased plasma concentration of fidaxomicin.

Combinations requiring precautions during use.

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

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

When digoxin is used, increased digoxin blood levels occur due to reduced digoxin clearance, requiring ECG and clinical status monitoring. If necessary, digoxin plasma levels should be monitored and 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 as needed are required, but not exceeding 150 mg/day.

Due to amiodarone's long half-life, interactions may occur for several months after discontinuation of amiodarone therapy.

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

Vitamin K antagonists. Enhanced effects of vitamin K antagonists and increased risk of bleeding. International normalized ratio (INR) monitoring should be performed more frequently. The dose of vitamin K antagonist should be adjusted during amiodarone therapy and for 8 days after its discontinuation.

Phenytoin (by extrapolation – also fosphenytoin). Increased plasma concentrations of phenytoin with signs of overdose, particularly neurological symptoms (due to inhibited hepatic metabolism of phenytoin). Clinical monitoring, plasma phenytoin concentration monitoring, 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 a CYP3A4 inhibitor and increases plasma concentrations of substrates of this cytochrome, thereby increasing their toxic effects.

• Statins (simvastatin, atorvastatin, lovastatin). Concomitant use of amiodarone with statins metabolized via CYP3A4, such as simvastatin, atorvastatin, and lovastatin, increases the risk of muscle toxicity (e.g., rhabdomyolysis). 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 a CYP3A4 inhibitor 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 amiodarone-induced inhibition of hepatic metabolism. Clinical and ECG monitoring should be performed, and, if necessary, quantitative determination of plasma lidocaine concentrations. Dose adjustment of lidocaine may be required during and after amiodarone therapy.

Tacrolimus. Increased plasma concentration of tacrolimus due to inhibition of its metabolism by amiodarone. Quantitative determination of tacrolimus plasma concentration, monitoring of renal function, and dose adjustment of tacrolimus should be performed during concomitant use 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). Clinical and ECG monitoring are recommended.

Beta-blockers used in 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. Clinical and ECG monitoring are recommended.

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

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

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

Certain macrolides (azithromycin, clarithromycin, roxithromycin). Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical and ECG monitoring are recommended during concomitant use of these agents.

Agents that reduce potassium levels: potassium-depleting diuretics (alone or in combination), stimulant laxatives, amphotericin B (IV), 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, electrolyte levels, and clinical monitoring should be performed.

Agents 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 adjusted during and after use of the enzyme inhibitor.

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

Combinations requiring special attention.

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

Special precautions for use.

Effects on the heart.

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

In elderly patients, amiodarone may enhance bradycardia.

Cases of new-onset arrhythmia or worsening of pre-existing arrhythmia have been reported (see section "Adverse reactions"). This proarrhythmic effect may occur particularly in the presence of factors predisposing to QT interval prolongation, such as concomitant use of certain 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 agents in patients with similar degrees of QT interval prolongation.

An ECG should be performed before initiating treatment.

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

Thyroid dysfunction.

Amiodarone may cause thyroid dysfunction, especially in patients with a history of thyroid disorders.

Quantitative measurement of thyroid-stimulating hormone (TSH) levels is recommended before starting treatment, then regularly during therapy and for several months after discontinuation of the drug, as well as in case of clinical suspicion of thyroid dysfunction (see section "Adverse reactions").

The drug contains iodine, which affects the results of certain thyroid function tests (e.g., radioactive iodine uptake, protein-bound iodine levels). However, thyroid function parameters such as T3, T4, and high-sensitivity TSH assays remain interpretable.

Pulmonary effects.

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

Hepatic effects.

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

Neuromuscular effects.

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

Ocular effects.

If visual blurring or decreased visual acuity occurs during treatment, a complete ophthalmological examination including ophthalmoscopy should be performed immediately. If amiodarone-induced optic neuropathy or optic neuritis develops, the drug should be discontinued, as continued treatment may lead to progression of visual disturbances up to blindness (see section "Adverse reactions").

Severe skin reactions.

Life-threatening or even fatal skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, may occur during amiodarone therapy. If symptoms suggestive of these conditions develop (e.g., progressive skin rash with blistering or mucosal involvement), the drug should be discontinued immediately.

Reactions associated with interaction with sofosbuvir (risk of severe bradycardia)

In patients receiving amiodarone in combination with sofosbuvir alone or in combination with other direct-acting antiviral agents for hepatitis C treatment (e.g., daclatasvir, simeprevir, or ledipasvir), cases of severe, potentially life-threatening bradycardia and serious cardiac conduction disturbances have been reported. Bradycardia typically occurred within hours to days, but cases with delayed onset, mostly within 2 weeks after initiation of hepatitis C virus (HCV) antiviral therapy, have also been observed.

Patients receiving medications containing sofosbuvir should only take amiodarone if they are intolerant to or contraindicated for other antiarrhythmic agents.

If concomitant use of amiodarone with these drugs is necessary, patients should undergo cardiac monitoring in a hospital setting for the first 48 hours of combined treatment, followed by outpatient monitoring or daily self-monitoring of heart rate for at least the first 2 weeks of treatment.

Due to the long elimination half-life of amiodarone, appropriate monitoring should also be performed in patients who have discontinued amiodarone within several months prior to starting treatment with sofosbuvir alone or in combination with other direct-acting antiviral agents.

Patients receiving these drugs for hepatitis C treatment in combination with amiodarone, regardless of concomitant use of other heart rate-lowering agents, should be warned about symptoms of bradycardia and serious cardiac conduction disturbances and instructed to seek immediate medical attention if such symptoms occur.

Reactions associated with interactions with other medicinal products.

Concomitant use of the drug should only be considered for the prevention of life-threatening ventricular arrhythmias with the following medicinal products:

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

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

Electrolyte disturbances.

It is important to consider any condition in which the patient may be at risk of hypokalemia, as hypokalemia may trigger proarrhythmic effects. Hypokalemia should be corrected before initiating treatment.

Use during anesthesia.

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

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

PGD is a life-threatening complication following heart transplantation, manifesting within the first 24 hours after 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.

Alternative antiarrhythmic therapy should be considered as early as possible before transplantation in patients awaiting heart transplantation.

Reactions related to excipients.

The drug contains lactose and therefore should not be used in patients with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption (rare hereditary conditions).

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

During treatment with this drug, patients are advised to avoid sun exposure or to take protective measures against sun exposure. 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 initiating amiodarone, several times after starting treatment, and each time the dose is adjusted.

Use during pregnancy or breastfeeding.

Pregnancy.

Animal studies with amiodarone have not shown any teratogenic effects, and thus malformations in humans are not expected. Substances causing developmental abnormalities in humans have consistently shown teratogenic effects in animals in well-conducted studies in two species.

There are insufficient clinical data to assess potential teratogenic or fetotoxic effects of amiodarone when used 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 amiodarone was used before this time.

Excessive iodine intake from amiodarone may lead to fetal hypothyroidism or even clinical manifestations of fetal hypothyroidism (goiter development).

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

Breastfeeding period.

Amiodarone and its metabolites, along with iodine, are excreted in breast milk in higher concentrations than in maternal plasma. Considering the risk of hypothyroidism in the infant, breastfeeding is contraindicated during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

During treatment with this drug, the possibility of adverse reactions affecting the nervous system and visual organs should be considered.

Method of Administration and Dosage.

The medication is intended for oral use.

The medication should be used only as prescribed by a physician.

Tablets should be taken orally before meals with a sufficient amount of water.

Adults.

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 used for initial treatment, but always for a short duration and under ECG monitoring.

Maintenance Therapy.

The medication should be administered at the lowest effective dose. Depending on the patient's response, the maintenance dose for adults may range from ½ tablet daily (1 tablet every 2 days) to 2 tablets daily.

Children.

The safety and efficacy of amiodarone in children have not been established; therefore, the use of this medication in this patient population is not recommended.

Overdose.

Symptoms.

Cases of acute amiodarone overdose following oral administration are poorly documented. A few cases of sinus bradycardia, ventricular arrhythmias, particularly of the torsades de pointes type, and hepatic injury have been reported.

Treatment.

In case of overdose, symptomatic therapy should be administered. Given the pharmacokinetic profile of this medication, prolonged monitoring of the patient’s condition, particularly cardiac function, is recommended.

Amiodarone and its metabolites are not removed by dialysis.

Side effects.

Adverse effects are classified by organ system and frequency of occurrence:

very common (> 10%); common (> 1%, < 10%); uncommon (> 0.1%, < 1%); rare (> 0.01%, < 0.1%); very rare (< 0.01%), unknown (frequency cannot be estimated from available data).

Eye disorders.

Very common – corneal microdeposits, occurring in almost all adult individuals, usually within the area beneath the pupil, which do not require discontinuation of amiodarone therapy. In exceptional cases, they are associated with colored halos in bright light or blurred vision.

Corneal microdeposits represent 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, according to fundus examination, with optic disc swelling, which may progress to more or less severe reduction in visual acuity. The causal relationship of this adverse effect with amiodarone intake has not yet been established. However, if no other obvious causes for this adverse effect are present, 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 bluish or bluish-gray hue, occurring during prolonged administration of high daily doses of the drug and slowly resolving after discontinuation of the drug (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 yet been clearly established. Alopecia.

Unknown – eczema. Severe, sometimes fatal skin reactions such as toxic epidermal necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome. Bullous dermatitis. DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).

Endocrine system disorders.

Adverse effects related to the thyroid gland.

Very common – apart from cases where 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, drowsiness. Markedly elevated TSH levels confirm this diagnosis. Normal thyroid function gradually returns within 1 to 3 months after discontinuation of amiodarone. Discontinuation of the drug is not mandatory: if amiodarone therapy is necessary, treatment may be continued 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 (slight unexplained weight loss, inadequate efficacy of antianginal and/or antiarrhythmic drugs); in elderly patients, psychiatric symptoms may occur, even thyrotoxicosis.

Markedly decreased levels of high-sensitivity TSH confirm this diagnosis. In such cases, drug discontinuation is mandatory, which is usually sufficient to achieve clinical normalization within 3–4 weeks. Since severe cases of this adverse effect may be fatal, appropriate therapy must be initiated immediately.

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

Other endocrine disorders.

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

Respiratory, thoracic and mediastinal disorders.

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

Early discontinuation of amiodarone, with or without corticosteroid therapy, 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 development have been documented, usually associated with interstitial pneumopathy.

Very rare – bronchospasm in patients with acute respiratory failure, especially in patients with bronchial asthma. Acute respiratory distress syndrome, occasionally fatal, sometimes occurring early after surgical intervention (possible interaction with high-dose oxygen was suspected) (see section "Special precautions").

Unknown – cases of pulmonary hemorrhage have been reported, which in some cases may manifest as hemoptysis. These pulmonary adverse effects are often associated with amiodarone-induced pneumopathy.

Nervous system disorders.

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

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

Very rare – cerebellar ataxia. Benign intracranial hypertension, headache. If headache occurs, examination should be performed to determine its possible cause.

Unknown – parkinsonism syndrome, parosmia.

Hepatobiliary disorders.

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

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

Common – acute liver injury with elevated plasma transaminase levels and/or jaundice, including liver failure, sometimes fatal, requiring discontinuation of the drug.

Very rare – chronic liver injury requiring prolonged treatment. Histological changes correspond to pseudo-alcoholic hepatitis or liver cirrhosis. Since clinical and laboratory signs are not clearly defined (variable hepatomegaly, plasma transaminase levels elevated 1.5–5 times above normal), regular monitoring of liver function is indicated. In case of elevated plasma transaminase levels, even mild, occurring after more than 6 months of drug intake, chronic liver injury should be suspected. These clinical and biological changes usually resolve after discontinuation of the drug. Several irreversible 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 failure, reported in a few cases (in patients with sinus node dysfunction, elderly patients). Development or worsening of existing arrhythmia, sometimes accompanied by cardiac arrest.

Unknown – paroxysmal torsade de pointes-type ventricular tachycardia (see section "Special precautions", "Interaction with other medicinal products and other forms of interaction").

Gastrointestinal disorders.

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

Unknown – pancreatitis/acute pancreatitis, dry mouth, constipation.

Breast and reproductive system disorders.

Very rare – epididymitis. The causal relationship of this adverse effect with amiodarone intake has not yet been clearly established.

Vascular disorders.

Very rare – vasculitis.

Laboratory findings.

Rare – rare cases of hyponatremia may indicate development of SIADH.

Very rare – renal impairment with moderate increase in creatinine levels.

Blood and lymphatic system disorders.

Very rare – thrombocytopenia, hemolytic anemia, aplastic anemia.

Unknown – neutropenia, agranulocytosis.

Immune system disorders.

Unknown – angioedema and/or urticaria. Anaphylactic/anaphylactoid reaction, and even shock.

General disorders.

Unknown – granulomas, mainly bone marrow granulomas.

Metabolism and nutrition disorders.

Unknown – decreased appetite.

Psychiatric disorders.

Common – decreased libido.

Unknown – confusion, delirium, hallucinations.

Musculoskeletal and connective tissue disorders.

Unknown – lupus erythematosus.

Injury, poisoning and procedural complications.

Unknown – primary graft dysfunction after heart transplantation, potentially fatal (see section "Special precautions").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is very important. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in a place inaccessible to children.

Packaging.

10 tablets per blister. 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Rivopharm SA.

Manufacturer’s location and address of place of business.

Centro Insema, 6928 Manno, Switzerland.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.