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

Composition:

Active substance: amiodarone;

1 tablet contains amiodarone hydrochloride 200 mg;

Excipients: colloidal anhydrous silicon dioxide; sodium starch glycolate (intragranular); lactose monohydrate; povidone K-30; sodium starch glycolate (extragranular); magnesium stearate; purified water.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex, uncoated tablets of white to almost white color, with imprints “8” and “4” separated by a break line on one side and “A” on the other side.

Pharmacotherapeutic group

Class III antiarrhythmic agents. ATC code C01B D01.

Pharmacological Properties

Pharmacodynamics

Antiarrhythmic properties. Prolongation of phase 3 of the myocardial action potential, primarily due to inhibition of potassium channels (class III according to Vaughan Williams classification). 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 refractory period and decreased excitability of myocardium 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 reduction in heart rate.

Increased 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 6553 patients who had recently suffered myocardial infarction (78%) or chronic heart failure (22%) was conducted.

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

This meta-analysis demonstrated that amiodarone significantly reduced total mortality by 13% (95% CI: 0.78–0.99; p = 0.030) and mortality due to arrhythmias 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 percentage of patients who discontinued the drug was higher in the amiodarone group (41%) than in the placebo group (27%).

Hypothyroidism developed in 7% of patients receiving amiodarone, compared with 1% in the placebo group. Hyperthyroidism was diagnosed in 1.4% of patients in the amiodarone group compared with 0.5% in the placebo group.

Interstitial pneumonitis occurred in 1.6% of patients in the amiodarone group compared with 0.5% in the placebo group.

Pediatric population. No controlled clinical trials have been conducted in children. Published data on the safety of amiodarone use have been evaluated in 1118 children with various types of arrhythmias.

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

Loading dose: 10–20 mg/kg/day for 7–10 days (i.e., 500 mg/m²/day calculated per body surface area);
Maintenance dose: the minimum effective dose should be used; depending 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.

After oral administration, bioavailability of amiodarone ranges from 30% to 80% (on average, 50%), depending on individual patient characteristics. After a single dose, maximum plasma concentration is reached within 3–7 hours. Therapeutic effect typically manifests within one week of treatment (ranging from several days to two weeks).

The elimination half-life of amiodarone is prolonged and characterized by considerable inter-individual variability (from 20 to 100 days). During the initial days of treatment, the drug accumulates in most body tissues, particularly in adipose tissue. Elimination begins after several days, and the input/output ratio reaches equilibrium within one or several months, depending on the patient.

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

A portion of iodine is released from the compound and excreted in urine as iodide; with a daily amiodarone dose of 200 mg, iodine 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. Residual drug activity may persist for a period of 10 days to 1 month.

Amiodarone is primarily metabolized by cytochrome CYP3A4 and also 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 a 1.1% increase in creatinine concentration (OCT2 substrate).

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

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

Preclinical data. Results from a 2-year carcinogenicity study in animals showed that amiodarone caused an increased incidence of follicular thyroid tumors (adenomas and/or carcinomas) in both sexes at clinically relevant exposures. Since mutagenicity study results were negative, the development of these tumors is likely explained by an epigenetic rather than genotoxic mechanism. Animal studies did not show development of any carcinomas, but dose-dependent follicular thyroid hyperplasia was observed. These effects on the thyroid gland in animals may have been due to the influence of amiodarone on synthesis and/or release of thyroid hormones. These findings have low relevance for human use.

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

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 disturbances, except in patients with an implanted cardiac pacemaker.

Hyperthyroidism, due to the potential for exacerbation during amiodarone therapy.

Known hypersensitivity to iodine, amiodarone, or any excipient of the medicinal product.

Second and third trimesters of pregnancy.

Breastfeeding period.

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

Interaction with other medicinal products and other forms of interaction

Antiarrhythmic drugs

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

Concomitant use of antiarrhythmic drugs from different classes may be beneficial but usually requires careful clinical and ECG monitoring. Concomitant use of antiarrhythmic drugs that may induce torsades de pointes (such as amiodarone, disopyramide, quinidine derivatives, sotalol) is contraindicated.

Concomitant use of antiarrhythmic drugs of the same class is not recommended, except in exceptional cases, as such treatment increases the risk of cardiac adverse effects.

Concomitant use of amiodarone with drugs having negative inotropic effects may promote bradycardia and/or slow atrioventricular conduction, thus 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 drugs or not. Predisposing factors include hypokalemia (see subsection "Drugs that reduce potassium levels"), bradycardia (see subsection "Drugs 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 class III antiarrhythmics and some neuroleptics. For dolasetron, erythromycin, spiramycin, and vinca alkaloids, such interaction occurs only when intravenous formulations are used.

Concomitant use of two medicinal products, each capable of inducing torsades de pointes, is generally contraindicated.

However, methadone, antiparasitic agents (halofantrine, lumefantrine, pentamidine), and neuroleptics, when considered absolutely necessary, are not contraindicated but are not recommended for concomitant use with other drugs that may induce torsades de pointes.

Drugs that slow heart rate

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

Effects of amiodarone on other medicinal products

Amiodarone and/or its metabolite desethylamiodarone inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6, and P-glycoprotein and may increase exposure to their substrates. Due to the long duration of amiodarone's effect, such interactions may occur for several months after discontinuation of amiodarone therapy.

Effects of other medicinal products on amiodarone

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

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

Contraindicated combinations (see section "Contraindications")

Medicinal products capable of inducing torsades de pointes (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 such as: arsenic compounds, bepridil, cisapride, citalopram, escitalopram, difeminal, intravenous dolasetron, domperidone, dronedarone, intravenous erythromycin, levofloxacin, mequitazine, mizolastine, intravenous vinca alkaloids, moxifloxacin, prucalopride, intravenous spiramycin, toremifene.

Increased risk of ventricular arrhythmias, particularly torsades de pointes. Telaprevir. Disorders of cardiomyocyte automaticity and conduction with risk of excessive bradycardia.

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

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

Sofosbuvir. Only in patients receiving dual combination therapy with daclatasvir/sofosbuvir or ledipasvir/sofosbuvir: bradycardia, possibly symptomatic or even fatal. If use of such combination cannot be avoided, careful clinical monitoring and ECG monitoring are required, especially during the first few weeks of dual therapy.

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

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

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

Intravenous 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.

Intravenous verapamil. Risk of bradycardia and atrioventricular block. If use of this combination cannot be avoided, extremely careful clinical observation and continuous ECG monitoring are essential.

Antiparasitic agents capable of inducing torsades de pointes (halofantrine, lumefantrine, pentamidine). Increased risk of ventricular arrhythmias, particularly torsades de pointes. If possible, one of the two drugs should be discontinued. If use of this combination cannot be avoided, prior assessment of QT interval and ECG monitoring are extremely important.

Neuroleptics capable of inducing torsades de pointes (amisulpride, chlorpromazine, tiaramide, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulthiapride, tiapride, zuclopentixol). Increased risk of ventricular arrhythmias, particularly torsades de pointes.

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

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

Stimulant laxatives. Increased risk of ventricular arrhythmias, particularly torsades de pointes ventricular tachycardia (hypokalemia being a triggering factor). Before administration, any hypokalemia should be corrected, and ECG monitoring, clinical observation, and 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 blood concentrations.

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

When digoxin is used, increased digoxin blood levels occur due to reduced digoxin clearance, requiring ECG and clinical monitoring. If necessary, digoxin blood levels should be monitored and digoxin dosage adjusted.

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

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

Substrates of CYP2C9. Amiodarone increases 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 control, and, if necessary, phenytoin dose adjustment should be performed.

Substrates of CYP2D6:

Flecainide. Amiodarone increases plasma flecainide concentration by inhibiting cytochrome CYP2D6. Therefore, flecainide dosage adjustment is required.

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 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.

Other medicinal products metabolized by CYP3A4 (lidocaine, sirolimus, tacrolimus, sildenafil, fentanyl, 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 lidocaine concentrations, which may lead to neurological and cardiac adverse reactions due to amiodarone-induced inhibition of hepatic metabolism. Clinical and ECG monitoring should be performed, and, if necessary, quantitative determination of plasma lidocaine concentrations. Lidocaine dosage should be adjusted during amiodarone therapy and after its discontinuation, if necessary.

Tacrolimus. Increased blood concentration of tacrolimus due to amiodarone-induced inhibition of its metabolism. Quantitative determination of tacrolimus blood concentration, renal function monitoring, 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). Impairment of automaticity and conduction (inhibition of compensatory sympathetic mechanisms). ECG and clinical monitoring are recommended.

Beta-blockers used for heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Impairment of myocardial automaticity and conduction with risk of excessive bradycardia. Increased risk of ventricular arrhythmias, particularly torsades de pointes. Regular clinical and ECG monitoring is recommended.

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

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

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

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

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

Increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalemia being a predisposing factor). Hypokalemia should be corrected before drug administration, and ECG, electrolyte levels, and clinical monitoring should be performed.

Drugs that slow heart rate. Increased risk of ventricular arrhythmias, particularly torsades de pointes. Clinical and ECG monitoring are recommended.

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

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 dosage adjusted during therapy with the enzyme inhibitor and after its discontinuation.

Voriconazole. Increased risk of ventricular arrhythmias, particularly torsades de pointes ventricular tachycardia, due to possible reduced metabolism of amiodarone. Clinical observation and ECG monitoring are required, and amiodarone dosage should be adjusted if necessary.

Combinations requiring special attention

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

Special precautions for use

Effects on the heart. An ECG and serum potassium levels must be assessed before initiating treatment with the drug.

In elderly patients, the drug may enhance the reduction in heart rate.

Amiodarone induces ECG changes. These changes include 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.

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

Cases of new-onset arrhythmias or worsening of pre-existing arrhythmias being treated have been reported (see section "Adverse reactions"). This proarrhythmic effect may occur particularly in the presence of factors predisposing to QT interval prolongation, including concomitant use of certain drugs and hypokalemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). The risk of drug-induced torsades de pointes tachycardia with amiodarone is considered lower compared to other antiarrhythmic drugs in patients with similar degrees of QT interval prolongation.

Thyroid gland disorders. This medicinal product contains iodine and therefore affects the results of certain thyroid function tests (radioactive iodine uptake, protein-bound iodine levels). However, thyroid function parameters such as T3, T4, and high-sensitivity TSH assays remain interpretable. Amiodarone may cause thyroid dysfunction, particularly in patients with a history of thyroid disorders. Quantitative measurement of TSH levels is recommended for all patients 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").

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

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

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

Eye disorders. In case of blurred vision or decreased visual acuity, a complete ophthalmological examination, including ophthalmoscopy, should be performed immediately. Development of optic neuropathy or optic neuritis due to amiodarone requires discontinuation of the drug, 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. If signs or symptoms indicating these conditions appear (e.g., progressive skin rash with blistering or mucosal lesions), amiodarone treatment should be discontinued immediately.

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

If concomitant use of these drugs with amiodarone cannot be avoided, careful monitoring of patients is required at the start of treatment with sofosbuvir alone or in combination with other direct-acting antiviral agents. Patients with known high risk of bradyarrhythmias should be continuously monitored for at least 48 hours after initiation of sofosbuvir treatment.

Due to the long 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 medicinal products for hepatitis C treatment in combination with amiodarone, regardless of concomitant use of other drugs that reduce heart rate, should be warned about symptoms of bradycardia and severe cardiac conduction disturbances and should be instructed to seek immediate medical help if such symptoms occur.

Disorders related to interactions with other medicinal products. Combinations (see section "Interaction with other medicinal products and other forms of interaction") with the following drugs:

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

should only be considered for prevention of life-threatening ventricular arrhythmias. Concomitant use of amiodarone is not recommended with the following medicinal products: cyclosporine, diltiazem (for injection), or verapamil (for injection), certain antiparasitic agents (halofantrine, lumefantrine, pentamidine), certain neuroleptics ( amisulpride, chlorpromazine, thioridazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulpiride, tiapride, zuclopenthixol), fluoroquinolones (except levofloxacin and moxifloxacin), stimulant laxatives, methadone, or fingolimod (see section "Interaction with other medicinal products and other forms of interaction").

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

Electrolyte disturbances, particularly hypokalemia: It is important to consider any condition in which the patient may be at risk of developing hypokalemia, as hypokalemia may provoke proarrhythmic effects. Hypokalemia should be corrected before initiating amiodarone treatment.

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 the drug, patients are advised to avoid sun exposure or to take protective measures against sunlight.

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

Due to the possible increase in defibrillation threshold and/or pacing threshold in patients with implanted cardiac defibrillators or pacemakers, this threshold should be checked before starting amiodarone, several times after initiation of treatment, and each time the dose is adjusted.

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

Adverse effects of chronic amiodarone treatment may increase the haemodynamic risk associated with general or local anaesthesia. These effects include, in particular, bradycardia, arterial hypotension, reduced cardiac output, and disturbances in cardiac conduction.

In addition, some cases of acute respiratory distress syndrome have been observed in the early postoperative period in patients receiving amiodarone. Therefore, careful monitoring is recommended during mechanical ventilation (see section "Adverse reactions").

Primary graft dysfunction after heart transplantation

Retrospective studies have associated pre-transplant amiodarone use by the recipient with an increased risk of primary graft dysfunction (PGD). PGD is a life-threatening complication after heart transplantation, manifested as left, right, or biventricular dysfunction occurring within the first 24 hours after surgery and without an identified secondary cause (see section "Adverse reactions"). Severe PGD may be irreversible.

For patients on the waiting list for heart transplantation, consideration should be given to using an alternative antiarrhythmic agent as early as possible before transplantation.

Use during pregnancy or breastfeeding

Pregnancy. Animal studies have not shown any teratogenic effects, so malformation effects in humans are not expected. Currently, substances causing developmental defects in humans have been found to be teratogenic in animals in well-conducted studies in two species.

There are insufficient clinical data to assess possible teratogenic or fetotoxic effects of amiodarone when administered at therapeutic doses during the first trimester of pregnancy.

Since the fetal thyroid gland begins to bind iodine from week 14, no effect on the embryonic thyroid gland is expected if the drug was used before this time. However, excess iodine intake during treatment may lead to fetal hypothyroidism or even clinical manifestations of fetal hypothyroidism (goiter development).

Due to amiodarone's effect on the fetal thyroid gland, this drug is contraindicated during pregnancy, except in cases where the benefit of treatment outweighs the associated risk.

Lactation period. Amiodarone and its metabolites, along with iodine, are excreted in breast milk in higher concentrations than in maternal plasma. Due to the risk of hypothyroidism in the infant, breastfeeding is contraindicated during amiodarone treatment.

Ability to affect reaction speed when driving or operating machinery

The possibility of adverse reactions affecting the nervous system and vision should be taken into account.

Dosage and Administration

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

Maintenance treatment. The minimum effective dose should be used. Depending on the patient's response to the drug, 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 the drug in children is not recommended.

Overdose

Cases of acute amiodarone overdose following oral administration are poorly documented. Several cases of sinus bradycardia, ventricular arrhythmias, particularly torsades de pointes, and hepatic injury have been reported. Treatment should be symptomatic. Due to the pharmacokinetic profile of this drug, patients should be monitored, particularly cardiac function, for a prolonged period. Amiodarone and its metabolites are not removed by dialysis.

Adverse Reactions

Adverse reactions are classified by system organ class and frequency of occurrence:

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

Eye disorders

Very common: Corneal microdeposits in almost all adult patients, usually within the area under the pupil, which do not require discontinuation of amiodarone. In exceptional cases, they are associated with colored halos in dazzling 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), which may progress to complete blindness, and, based on fundus examination, papilledema of the optic nerve, which may progress to more or less severe reduction in visual acuity. The causal relationship of this adverse effect with amiodarone intake has not been established to date. 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 pigmentation with bluish or bluish-gray color, occurring during prolonged use of high daily doses of the drug and slowly disappearing after its discontinuation (within 10–24 months).

Very rare: Erythema occurring during radiation therapy. Skin rashes, usually nonspecific. Exfoliative dermatitis, although the causal relationship of this adverse effect with drug intake has not been clearly established to date. Alopecia.

Frequency not known: Eczema. Severe, sometimes fatal, skin reactions, including toxic epidermal necrolysis (Lyell’s syndrome) and Stevens–Johnson syndrome. Bullous dermatitis. DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).

Endocrine disorders

Endocrine system disorders

Adverse effects related to the thyroid gland.

Very common: Except when clinical signs of thyroid dysfunction are present, "unrelated to drug intake" changes in thyroid hormone levels in blood (increased T4 level, normal or slightly decreased T3 level) do not require discontinuation of the drug.

Common: Hypothyroidism manifests with typical symptoms: weight gain, cold intolerance, apathy, somnolence. A significant increase in TSH level confirms this diagnosis. After discontinuation of the drug, normal thyroid function gradually returns within 1 to 3 months. Discontinuation of the drug is not mandatory: if amiodarone use is necessary, treatment with this drug may continue in combination with replacement thyroid hormone therapy using levothyroxine. L-thyroxine doses may be adjusted depending 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.

A significant decrease in high-sensitivity TSH level confirms this diagnosis. In such cases, amiodarone must be discontinued immediately, which is usually sufficient for clinical normalization within 3–4 weeks. Since severe cases of this adverse effect may be fatal, appropriate therapy must be initiated promptly. If the problem is caused by thyrotoxicosis (directly or through its effect on vulnerable myocardial balance), 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 amiodarone discontinuation 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 with fatal outcome, have been reported. The onset of dyspnea during physical exertion or dry cough, either isolated or associated with worsening general condition (increased fatigue, weight loss, and slight 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 disappearance of symptoms. Clinical signs usually resolve within 3–4 weeks; radiological improvement and lung function recovery occur more slowly (over several months).

Several cases of pleuritis 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, in individual cases with fatal outcome, sometimes in the early period after surgery (possible interaction with high oxygen doses was suspected) (see section "Special precautions").

Frequency not known (cannot be estimated from available data): Pulmonary hemorrhage has 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 treatment. However, recovery may be incomplete, very slow, and observed only several months after discontinuation of the drug.

Very rare: Cerebellar ataxia. Benign intracranial hypertension, headache. When headache occurs, examination should be performed to determine its possible cause.

Frequency not known: Parkinsonism syndrome, parosmia.

Hepatobiliary disorders

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

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

Common: Acute liver injury with elevated transaminase levels in blood 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 expressed (variable hepatomegaly, elevated transaminase levels in blood 1.5–5 times above normal), regular monitoring of liver function is indicated. If transaminase levels in blood increase, even mildly, after more than 6 months of drug intake, chronic liver injury should be suspected. These clinical and biological changes usually resolve after discontinuation of the drug. Several reversible cases of such changes have been documented.

Cardiac disorders

Common: Bradycardia, usually moderate and dose-dependent.

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

Very rare: Marked bradycardia and, in exceptional cases, sinus node arrest, reported in a few cases (on the background of sinus node dysfunction, in elderly patients). Development or worsening of existing arrhythmia, sometimes accompanied by cardiac arrest.

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

Gastrointestinal disorders

Very common: Mild digestive disturbances (nausea, vomiting, dysgeusia), which usually occur at the beginning of treatment and resolve after dose reduction.

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

Breast and reproductive system disorders

Very rare: Epididymitis. The causal relationship of this adverse effect with intake of this medicinal product has not been clearly established to date.

Frequency not known: Loss of libido.

Vascular disorders

Very rare: Vasculitis.

Laboratory findings

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

Very rare: Renal injury with moderate increase in creatinine levels.

Blood and lymphatic system disorders

Very rare: Thrombocytopenia, hemolytic anemia, aplastic anemia.

Frequency not known: Neutropenia, agranulocytosis.

Immune system disorders

Frequency not known (cannot be estimated from available data): Cases of angioedema (Quincke's edema) and/or urticaria have been documented. Anaphylactic shock/anaphylactoid reaction, including shock.

General disorders

Frequency not known: Cases of granuloma, mainly bone marrow granuloma, have been documented.

Metabolic and nutritional disorders

Frequency not known: Decreased appetite.

Psychiatric disorders

Common: Decreased libido.

Frequency not known: Confusion, delirium, hallucinations.

Musculoskeletal and connective tissue disorders

Frequency not known: Lupus erythematosus.

Injury, poisoning and procedural complications

Frequency not known: Primary graft dysfunction after heart transplantation, potentially fatal (see section "Special precautions").

Reporting suspected adverse reactions

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

Shelf life: 3 years.

Storage conditions

Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging

10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription status: Prescription only.

Manufacturer

Aurobindo Pharma Limited – Unit VII / Aurobindo Pharma Limited – Unit VII.

Manufacturer's location and address of its business operations

Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India / Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos., 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India.

Amiostedi