Thiodarone®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIODARON® (THIODARON)

Composition:

Active substances: 1 tablet contains amiodarone hydrochloride, recalculated to 100% substance – 200 mg; morpholine salt of thiotropic acid, recalculated to 100% substance – 100 mg, equivalent to 66.5 mg of thiotropic acid.

Excipients: microcrystalline cellulose, sodium croscarmellose, potato starch, talc, polysorbate 80 (tween-80), calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets of white or white with yellowish tint color, flat cylindrical shape, with bevel and score line.

Pharmacotherapeutic group. Combined cardiovascular agents. ATC code C01EX.

Pharmacological Properties

Pharmacodynamics

This is a combination drug, whose properties are determined by its components – amiodarone hydrochloride and the morpholine salt of thiatic acid. Amiodarone hydrochloride primarily affects the heart and blood vessels. It exerts antiarrhythmic and antianginal effects due to its ability to block ion channels (mainly potassium, and to a lesser extent calcium and sodium) in the membranes of cardiomyocytes, as well as to inhibit mediator excitation processes at alpha- and beta-adrenergic receptors. Amiodarone hydrochloride produces a negative chronotropic effect. Sympatholytic activity and blockade of potassium and calcium channels reduce myocardial oxygen demand and lead to a negative dromotropic effect: slowing conduction and prolonging the refractory period in the sinoatrial and AV nodes. In addition, it possesses vasodilatory properties, enabling it to reduce resistance in coronary vessels.

The second component – the morpholine salt of thiatic acid – exerts effects primarily through its influence on biochemical processes in the heart and blood vessels, and has anti-ischemic, membrane-stabilizing, antioxidant, and immunomodulatory properties. It enhances compensatory activation of anaerobic glycolysis, activates oxidation processes in the Krebs cycle, thereby preserving intracellular ATP stores. The drug also activates the antioxidant system, inhibits lipid peroxidation in ischemic areas of the myocardium, reduces cardiac muscle sensitivity to catecholamines, prevents progressive suppression of contractile function of cardiomyocytes, stabilizes and reduces the area and volume of necrotic zones, and activates the fibrinolytic system.

Pharmacokinetics

Determined by the pharmacological properties of both components. Amiodarone hydrochloride is slowly absorbed from the gastrointestinal tract.

Bioavailability ranges from 30% to 80%. After a single dose, maximum plasma concentration is reached within 3–7 hours. Therapeutic activity generally becomes evident within one week of starting treatment (ranging from several days to 2 weeks). During the first days of administration, it accumulates in virtually all tissues, particularly in adipose tissue, liver, spleen, and lungs. Amiodarone hydrochloride is excreted via bile and feces. Renal excretion is minimal; therefore, standard doses can be used in patients with renal insufficiency. The elimination half-life is prolonged and shows considerable inter-individual variability (ranging from 20 to 100 days).

The morpholine salt of thiatic acid is rapidly absorbed after oral administration, with an absolute bioavailability of 53%. Maximum plasma concentration (Cmax) is achieved within 1.6 hours after a single 200 mg dose. The elimination half-life (t½) is approximately 8 hours.

Clinical characteristics.

Indications.

Prevention of recurrences:

• life-threatening ventricular tachycardia: treatment should be initiated in hospital conditions 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.

Contraindications.

Amiodarone.

Sinus bradycardia, sinoatrial block in the absence of a cardiac pacemaker.

Sick sinus syndrome in the absence of a cardiac pacemaker (risk of sinus arrest).

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

Hyperthyroidism, due to possible exacerbation during amiodarone therapy.

Known hypersensitivity to iodine, amiodarone, or any of the excipients.

Second and third trimesters of pregnancy.

Breastfeeding period.

Combination 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, difemanil, dolasetron IV, domperidone, dronedarone, erythromycin IV, levofloxacin, mequitazine, mizolastine, vinpocetine IV, moxifloxacin, prucalopride, spiramycin IV, toremifene (see section "Interaction with other medicinal products and other forms of interaction");

− telaprevir;

− cobicistat.

Morpholino salt of thiadiazole acid.

• Hypersensitivity to thiadiazole acid and other components of the drug;
• acute renal failure.

Interaction with other medicinal products and other forms of interaction.

Amiodarone.

Antiarrhythmic drugs.

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

Concomitant use of antiarrhythmic agents belonging to different classes may be beneficial, but such treatment usually requires careful clinical and ECG monitoring. Concomitant use of antiarrhythmic drugs capable of inducing "torsades de pointes" (such as amiodarone, disopyramide, quinidine derivatives, sotalol, etc.) 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 exerting negative inotropic effects promotes bradycardia and/or slows 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 drugs, regardless of whether they belong to antiarrhythmics 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 III antiarrhythmics and certain neuroleptics. For dolasetron, erythromycin, spiramycin, and vinpocetine, 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 their use is considered absolutely necessary, are not contraindicated but are not recommended for concomitant use with other agents that promote "torsades de pointes".

Drugs 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. Considering 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) should generally not be used during 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 antiarrhythmics (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (dofetilide, ibutilide, sotalol);
• other medicinal products such as: arsenic compounds, bepridil, cisapride, citalopram, escitalopram, difemanil, dolasetron IV, domperidone, dronedarone, erythromycin IV, levofloxacin, mequitazine, mizolastine, vinpocetine 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").

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

Due to amiodarone content during treatment with Tiordaron, quantitative determination of cyclosporine blood concentrations, monitoring of renal function, and cyclosporine dose adjustment should be performed.

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

Diltiazem for injection. Risk of bradycardia and atrioventricular block.

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

Verapamil for injection. Risk of bradycardia and atrioventricular block.

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

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, prior assessment of QT interval and ECG monitoring are essential.

Neuroleptics that may induce "torsades de pointes" (amisulpride, chlorpromazine, tiaramide, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulthiapride, tiapride, zuclopenthixol). Increased risk of ventricular arrhythmias, especially "torsades de pointes".

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

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.

CYP3A4 substrates. Amiodarone is a CYP3A4 inhibitor and increases plasma concentrations of CYP3A4 substrates, leading to potential increase in toxicity of these substrates.

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 monitoring and continuous ECG monitoring should be performed for 24 hours.

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

Fidaxomicin. Increased plasma concentrations of fidaxomicin.

Combinations requiring precautions during use.

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, especially "torsades de pointes". Regular clinical and ECG monitoring are recommended.

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

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

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

Digitalis preparations. Suppression of automaticity (excessive bradycardia) and impairment of 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 blood levels should be monitored and digoxin dose adjusted.

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

Certain macrolides (azithromycin, clarithromycin, roxithromycin). Increased risk of ventricular arrhythmias, especially "torsades de pointes".

ECG and clinical monitoring are recommended when these drugs are used concomitantly with amiodarone.

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

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

Drugs 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 should 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, which may lead to neurological and cardiac adverse effects due to inhibition of hepatic metabolism by amiodarone. Clinical and ECG monitoring should be performed, and if necessary, quantitative determination of plasma lidocaine concentrations. Dose adjustment of lidocaine may be required during and after amiodarone therapy.

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

Phenytoin (by extrapolation, also fosphenytoin). Increased plasma concentrations of phenytoin with signs of overdose, especially neurological signs (due to inhibition of hepatic phenytoin metabolism). Clinical monitoring, monitoring of phenytoin plasma concentrations, and dose adjustment of phenytoin if necessary should be performed.

Tacrolimus. Increased blood concentrations of tacrolimus due to inhibition of its metabolism by amiodarone. Quantitative determination of tacrolimus blood concentrations, monitoring of renal function, and dose adjustment of tacrolimus should be performed during concomitant use with amiodarone and after its discontinuation.

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

CYP2D6 substrates:

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

CYP3A4 substrates: amiodarone is a CYP3A4 inhibitor and increases plasma concentrations of substrates of this cytochrome, resulting in increased toxicity of these substrates.

− 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, midazolam, triazolam, dihydroergotamine, ergotamine, colchicine. Amiodarone is a CYP3A4 inhibitor and increases plasma concentrations of these molecules, leading to potential increase in their toxicity.

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

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

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

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

Combinations requiring special attention.

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

Special precautions for use.

Cardiac effects. An ECG should be performed before initiating treatment with the drug.

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

Amiodarone induces ECG changes. These changes include QT interval prolongation due to prolonged repolarization, with possible appearance of the U wave. These are signs of the drug's therapeutic effect, not of 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 arrhythmia or worsening of pre-existing arrhythmia being treated have been reported (see section "Adverse reactions").

Such proarrhythmic effects may occur particularly in the presence of factors predisposing to QT interval prolongation, including certain drug combinations and hypokalemia (see sections "Adverse reactions" and "Interaction with other medicinal products and other forms of interaction"). The risk of drug-induced tachycardia "torsades de pointes" 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). Thyroid function parameters T3, T4, and high-sensitivity TSH analysis remain interpretable.

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

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

Hepatic 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").

Ocular disorders. In case of blurred vision or decreased visual acuity, a complete ophthalmological examination including ophthalmoscopy should be performed immediately. Development of amiodarone-induced optic neuropathy or optic neuritis requires discontinuation of the drug, as continued treatment may lead to progression of visual disturbances up to blindness (see "Adverse reactions").

Severe skin reactions. Life-threatening or even fatal skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis may occur. If signs or symptoms indicating these conditions appear (e.g., progressive skin rash with blistering or mucosal lesions), amiodarone treatment should be stopped immediately.

Severe bradycardia. Cases of severe, potentially life-threatening bradycardia and severe disturbances of cardiac conduction 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 medicinal products with amiodarone cannot be avoided, careful monitoring of patients should be performed at the beginning of treatment with sofosbuvir alone or in combination with other direct-acting antiviral agents. Patients with known high risk of bradyarrhythmia should be under appropriate continuous monitoring for at least 48 hours after initiation of sofosbuvir 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 medicinal products for hepatitis C treatment in combination with amiodarone, regardless of concomitant use of other drugs that reduce heart rate, should be informed about symptoms of bradycardia and severe disturbances of cardiac conduction and advised to seek immediate medical help if such symptoms occur.

Disorders related to interactions with other medicinal products. Combinations (see section "Interaction with 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, and pentamidine), certain neuroleptics ( amisulpride, chlorpromazine, 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, particularly hypokalemia: It is important to consider any situation in which the patient may develop hypokalemia, as hypokalemia may provoke proarrhythmic effects.

Hypokalemia must be corrected before starting amiodarone treatment.

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

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

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

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

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

Adverse effects of chronic amiodarone therapy may increase hemodynamic risk associated with general or local anesthesia. These effects include, in particular, bradycardia, arterial hypotension, reduced cardiac output, and disturbances of cardiac conduction. In addition, 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").

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown any teratogenic effects, so malformation effects in humans are not expected. To date, substances causing developmental 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 in 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.

Excess iodine intake from this medicinal product during treatment may lead to fetal hypothyroidism or even to the development of clinical signs of fetal hypothyroidism (goiter development).

Considering the effect of amiodarone on the fetal thyroid gland, this drug is contraindicated from the second trimester of pregnancy.

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

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration.

Thiodaron® should be administered orally in doses calculated as amiodarone hydrochloride.

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

Maintenance treatment. The minimum effective dose should be used, which is individual for each patient and 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 pediatric patients is not recommended.

Overdose.

Amiodarone.
Cases of acute amiodarone overdose following oral administration are poorly documented. A few 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, monitoring of the patient's condition, especially cardiac function, is recommended for a prolonged period. Amiodarone and its metabolites are not removed by dialysis.

Morpholine salt of thiazothionic acid.

In case of overdose, increased concentrations of sodium and potassium in urine may occur. The drug should be discontinued in such cases. Treatment is symptomatic.

Adverse Reactions

Adverse effects are classified by organ systems 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).

Amiodarone:

Disorders of the visual system.

Very common. Corneal microdeposits, found in almost all adults, usually located within the area beneath the pupil. These do not require discontinuation of amiodarone. In exceptional cases, they may be 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 worsening of visual acuity, and fundus examination revealing 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 administration has not been established to date. However, if no other obvious causes for this adverse effect are identified, discontinuation of amiodarone is recommended.

Disorders of the skin and subcutaneous tissue.

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 pigmentation, occurring during prolonged administration of high daily doses and slowly disappearing after discontinuation of the drug (within 10–24 months).

Very rare. Erythema following radiation therapy. Skin rashes, usually nonspecific. Exfoliative dermatitis, although the causal relationship of this adverse effect with drug administration 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).

Disorders of the endocrine system.

Adverse effects related to the thyroid gland.

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

Common. Hypothyroidism manifests with typical symptoms: weight gain, cold intolerance, apathy, somnolence. A significant increase in TSH levels 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 may be continued in combination with replacement thyroid hormone therapy using levothyroxine. L-thyroxine doses may be adjusted according to 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 levels of highly sensitive TSH confirms this diagnosis. In such cases, Thiadarone® as an amiodarone-containing drug must be discontinued, which is usually sufficient for clinical normalization within 3–4 weeks. Since severe cases of this adverse effect can be fatal, appropriate therapy must be initiated immediately.

If the underlying problem is thyrotoxicosis (directly or due to 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 long 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 the drug is used concomitantly with medications that may induce hyponatremia. See also "Laboratory findings."

Disorders of the respiratory system, thorax, and mediastinum.

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 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 resolution of symptoms. Clinical signs usually disappear within 3–4 weeks; radiological improvement and lung function recovery occur more slowly (over several months).

Several cases of pleuritis have been documented, usually associated with interstitial pneumopathy.

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

Frequency not known (cannot be estimated from available data). Cases of pulmonary hemorrhage have been reported, which in some cases may present as hemoptysis. These pulmonary adverse effects are often associated with amiodarone-induced pneumopathy.

Disorders of the nervous system.

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 stopping the drug.

Very rare. Cerebellar ataxia. Benign intracranial hypertension, headache. In case of isolated headache, examination is necessary to determine possible causes.

Frequency not known. Parkinsonism syndrome, parosmia.

Disorders of the liver and biliary system.

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

Very common. Usually 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 serum 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 pseudoalcoholic hepatitis or liver cirrhosis. Since clinical and laboratory signs are not clearly expressed (variable hepatomegaly, serum transaminase levels elevated 1.5–5 times above normal), regular monitoring of liver function is indicated. In case of elevated transaminase levels, even mild, occurring after more than 6 months of drug administration, chronic liver injury should be suspected. These clinical and biological changes usually resolve after discontinuation of the drug. Several reversible cases of such changes have been documented.

Cardiac disorders.

Common. Bradycardia, usually moderate and dose-dependent.

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

Very rare. Marked bradycardia and, in exceptional cases, sinus node 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.

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

Gastrointestinal disorders.

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

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

Disorders of the mammary glands and reproductive system.

Very rare. Epididymitis. The causal relationship with administration 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 the development of SIADH.

Very rare. Renal injury with elevated serum creatinine levels.

Blood and lymphatic system disorders.

Very rare. Thrombocytopenia.

Frequency not known. Neutropenia, agranulocytosis.

Immune system disorders.

Frequency not known. Cases of angioedema and/or urticaria have been documented.

General disorders.

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

Metabolism and nutrition disorders.

Frequency not known. Decreased appetite.

Psychiatric disorders.

Frequency not known. Confusion, delirium, hallucinations.

Common. Decreased libido.

Musculoskeletal and connective tissue disorders.

Frequency not known. Lupus erythematosus.

Morpholinium salt of thiazothionic acid:

The drug is generally well tolerated.

In patients with increased individual sensitivity, the following rare adverse effects may occur:

skin and subcutaneous tissue disorders: itching, skin hyperemia, rash, urticaria, angioedema.

When used in combination therapy, primarily in elderly patients, the following may occur:

immune system disorders: anaphylactic shock;

central and peripheral nervous system disorders: dizziness, tinnitus;

gastrointestinal disorders: dyspeptic symptoms, including dry mouth, nausea, vomiting; abdominal distension;

respiratory, thoracic and mediastinal disorders: dyspnea, suffocation;

general disorders: fever, general weakness.

During post-marketing surveillance, the following reactions were also observed, although their relationship to Thiadarone® administration has not been proven:

cardiovascular system disorders: arterial hypertension, tachycardia.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions during the post-marketing period is an important measure. This allows continued monitoring of the benefit-risk balance of the drug. Healthcare professionals are requested to report any suspected adverse reactions in accordance with legal requirements.

Shelf life. 2 years.

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

Packaging. Tablets, 10 in a blister, 3 or 6 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

1. JSC "Halychpharm";
2. JSC "Kyivmedpreparat".

Manufacturer's address and location of business activity.

1. JSC "Halychpharm", Ukraine, 79024, Lviv, Opryshkivska St., 6/8;
2. JSC "Kyivmedpreparat", Ukraine, 01032, Kyiv, Saksaganskogo St., 139.