Cardiodaron-zdorovya

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARDIODARON-ZDOROV'YA (CARDIODARON-ZDOROVYE)

Composition:

Active substance: amiodarone;

One tablet contains 200 mg of amiodarone hydrochloride;

Excipients: lactose monohydrate, potato starch, microcrystalline cellulose, calcium stearate.

Pharmaceutical form. Tablets.

Main physical and chemical properties: white or almost white tablets, flat cylindrical shape, with a score line and bevelled edges.

Pharmacotherapeutic group. Antiarrhythmic agents, class III. ATC code C01BD01.

Pharmacological Properties

Pharmacodynamics

Antiarrhythmic properties:

• Prolongation of phase III of the cardiac myocyte action potential is primarily due to reduced potassium ion current (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 α- and β-antiadrenergic activity;
• Slowed conduction of impulses in the sinoatrial, atrial, and nodal myocardium, with a more pronounced effect at faster heart rates;
• No changes in intraventricular conduction;
• Increased refractory period and reduced myocardial excitability at atrial, nodal, and ventricular levels;
• Slowed conduction and prolonged refractory periods in accessory atrioventricular conducting pathways.

Other properties:

• Reduced oxygen consumption due to moderate decrease in peripheral vascular resistance and reduced heart rate;
• Increased coronary blood flow due to direct action on myocardial vascular smooth muscle and maintenance of cardiac output despite reduced arterial pressure and peripheral vascular resistance, without negative inotropic effects.

There is evidence that the drug significantly reduces overall mortality and mortality due to arrhythmia-related causes in patients with chronic heart failure and in patients who have recently suffered myocardial infarction.

Pharmacokinetics

Amiodarone is a compound characterized by slow transport and high tissue affinity.

Its oral bioavailability varies depending on individual patient characteristics from 30 to 80% (on average, 50%). After a single dose, maximum plasma concentration is reached within 3–7 hours.

Therapeutic activity manifests on average within one week of treatment (ranging from several days to two weeks).

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

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

Some iodine is released and excreted in urine as iodide; with amiodarone administration at a daily dose of 200 mg, iodine excretion amounts to 6 mg/day. The remainder of the compound, and consequently most of the iodine, is excreted in feces following hepatic metabolism.

Since only a negligible amount of the drug is eliminated in urine, patients with renal insufficiency can be given standard doses.

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.

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 controlling atrial fibrillation or flutter.

Ischemic heart disease and/or left ventricular dysfunction (see section "Pharmacodynamics").

Contraindications.

Sinus bradycardia, sinoatrial heart 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, as amiodarone may exacerbate the condition.

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

Second and third trimesters of pregnancy.

Breastfeeding period.

Combination with medicinal products capable of inducing torsades de pointes ventricular tachycardia (except antiparasitic agents, neuroleptics, and methadone), such as:

• Class Ia antiarrhythmic agents (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic agents (sotalol, dofetilide, ibutilide);
• other medicinal products such as arsenic compounds, bepridil, cisapride, citalopram, escitalopram, disopyramide, intravenous dolasetron, domperidone, dronedarone, intravenous erythromycin, levofloxacin, mequitazine, mizolastine, intravenous vinpocetine, moxifloxacin, prucalopride, intravenous spiramycin, toremifene (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 agents.

Many antiarrhythmic agents 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 agents capable of inducing torsades de pointes (such as amiodarone, disopyramide, quinidine derivatives, sotalol, and others) is contraindicated.

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

Concomitant use of amiodarone with medicinal products 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 medicinal products regardless of whether they belong to antiarrhythmic agents or not. Predisposing factors include hypokalemia (see subsection "Medicinal products that reduce potassium levels"), bradycardia (see subsection "Medicinal products that slow heart rate"), or pre-existing congenital or acquired QT interval prolongation.

Medicinal products that may induce torsades de pointes include, in particular, class Ia and III antiarrhythmic agents 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.

Medicinal products that slow heart rate.

Many medicinal products may cause bradycardia, including class Ia antiarrhythmic agents, beta-blockers, certain class III antiarrhythmic agents, certain calcium channel blockers, digitalis preparations, pilocarpine, and cholinesterase inhibitors.

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 treatment.

Effects of other medicinal products on amiodarone.

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

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

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 antiarrhythmic agents (quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmic agents (sotalol, dofetilide, ibutilide);
• other medicinal products such as: arsenic compounds, bepridil, cisapride, citalopram, escitalopram, disopyramide, intravenous dolasetron, domperidone, dronedarone, intravenous erythromycin, levofloxacin, mequitazine, mizolastine, intravenous vinpocetine, moxifloxacin, prucalopride, intravenous spiramycin, 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 amiodarone-induced adverse effects due to reduced metabolism.

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

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

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

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

During amiodarone treatment, quantitative determination of cyclosporine blood concentration, monitoring of renal function, and cyclosporine dose adjustment are required.

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-related 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 for 24 hours are required.

Intravenous verapamil. Risk of bradycardia and atrioventricular block. If use of this combination cannot be avoided, 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, especially torsades de pointes. If possible, one of the two agents should be discontinued. If use of this combination cannot be avoided, prior assessment of QT interval and ECG monitoring are essential.

Neuroleptics capable of inducing torsades de pointes (amisulpride, chlorpromazine, thiethylperazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipothiazine, sertindole, sulpiride, sultopride, 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 ventricular tachycardia torsades de pointes (hypokalemia being a triggering factor). Before administration of the drug, 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 an inhibitor of P-glycoprotein. Concomitant use with P-glycoprotein substrates is expected to increase their blood concentration.

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 monitoring. If necessary, digoxin blood levels should be monitored and digoxin 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, if necessary, but not exceeding 150 mg/day, are required.

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

Substrates of CYP2C9. Amiodarone increases concentrations of substances that are substrates of CYP2C9, 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 treatment and for 8 days after its discontinuation.

Phenytoin (by extrapolation — also fosphenytoin). Increased plasma concentrations of phenytoin with signs of overdose, especially neurological signs (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 concentration of flecainide by inhibiting cytochrome CYP2D6. Therefore, flecainide dose adjustment should be performed.

Substrates of CYP3A4:

Amiodarone is an inhibitor of CYP3A4 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 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 an inhibitor of CYP3A4 and increases plasma concentrations of these molecules, potentially increasing their toxicity.

Lidocaine. Risk of increased plasma concentration 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, plasma lidocaine concentration determination and lidocaine dose adjustment during and after amiodarone treatment.

Tacrolimus. Increased blood concentration of tacrolimus due to inhibition of its metabolism by amiodarone. Quantitative determination of tacrolimus blood concentration, monitoring of renal function, and dose adjustment of tacrolimus during and after concomitant use with amiodarone are required.

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

Beta-blockers used for 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. Regular clinical and ECG monitoring are recommended.

Esmolol. Impaired 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, especially torsades de pointes. ECG and clinical monitoring are recommended during concomitant use of these agents.

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

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

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

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

Tamsulosin. Risk of enhanced adverse effects caused by tamsulosin due to inhibited hepatic metabolism. Clinical monitoring and, if necessary, tamsulosin dose adjustment during and after treatment with the enzyme inhibitor are required.

Voriconazole. Increased risk of ventricular arrhythmias, especially ventricular tachycardia 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 drugs slowing heart rate).

Special precautions for use.

Effects on the heart

An ECG and serum potassium levels should 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 induced changes include QT interval prolongation due to prolonged repolarization, possibly with appearance of the U wave. These changes reflect the drug's therapeutic effect rather than its toxicity.

Development of second- or third-degree atrioventricular block, sinoatrial block, or bifascicular block during treatment requires discontinuation of the drug. Development of first-degree atrioventricular 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 concomitant use of certain drugs 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 drugs in patients with similar degrees of QT interval prolongation.

Thyroid gland disorders

This medicinal product contains iodine and therefore may affect 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 highly sensitive TSH assays remain interpretable.

Amiodarone may cause thyroid dysfunction, especially in patients with a history of thyroid disorders. Quantitative measurement of TSH levels is recommended in all patients before starting treatment, and 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").

Lung disorders

The onset of dyspnea or non-productive cough, either alone 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").

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 and blindness (see section "Adverse reactions").

Severe bradycardia

Cases of severe, potentially life-threatening bradycardia and severe conduction disturbances have been reported in patients receiving amiodarone in combination with sofosbuvir, either alone or in combination with other direct-acting antiviral agents for the treatment of hepatitis C, 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 beginning of treatment with sofosbuvir, either 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, either alone or in combination with other direct-acting antiviral agents.

Patients receiving these medicinal products for the treatment of hepatitis C in combination with amiodarone, regardless of concomitant use of other drugs that reduce heart rate, should be warned about symptoms of bradycardia and severe conduction disturbances and should be informed that they must seek emergency 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 sotalol (contraindicated combination) and esmolol (combination requiring precautionary measures),
• 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), verapamil (for injection), certain antiparasitic agents (halofantrine, lumefantrine, pentamidine), certain neuroleptics ( amisulpride, chlorpromazine, tiapride, cyamemazine, droperidol, flupentixol, flufenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sulthiame, 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, especially hypokalemia

Any condition associated with a risk of hypokalemia should be carefully considered, as hypokalemia may provoke proarrhythmic effects. Hypokalemia must be corrected before initiating amiodarone therapy.

The adverse effects listed below are most commonly associated with excessive intake of the drug; 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 initiating amiodarone and several times after starting treatment, as well as each time the dose is adjusted.

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

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

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").

Disorders related to excipients

The drug contains lactose; therefore, if the patient has known intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. No teratogenic effects have been observed in animals; therefore, malformation effects in humans are not expected. To date, substances causing developmental abnormalities in humans have 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 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 is used before this time. However, the excess iodine supplied to the body during treatment may lead to fetal hypothyroidism or even clinical manifestations of fetal hypothyroidism (goiter development). Considering the effect of amiodarone on the fetal thyroid gland, this drug is contraindicated during pregnancy, except when 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 considered.

Administration and Dosage

Initial treatment. The usual recommended dose for adults is 200 mg (1 tablet) three times daily for 8–10 days.

In certain cases, higher initial doses (4–5 tablets daily) may be used for a short period under ECG monitoring.

Maintenance treatment. The minimum effective dose should be used. Depending on the therapeutic response in individual patients, the maintenance dose for adults may range from ½ tablet daily (or 1 tablet every two days) to 2 tablets daily.

Children. Safety and efficacy of amiodarone in children have not been established; therefore, use of this medication in children is not recommended.

Overdose. Information regarding amiodarone overdose is limited. There have been reports of several cases of sinus bradycardia, ventricular arrhythmias, particularly "torsades de pointes," and hepatic injury. Treatment is symptomatic. Due to the pharmacokinetic profile of this drug, monitoring of the patient, especially cardiac function, is recommended for a prolonged period of time.

Amiodarone and its metabolites are not removed by dialysis.

Side effects.

The frequency of side effects indicated below corresponds to the following MedDRA classification: common (≥ 1%, < 10%), rare (≥ 0.01%, < 0.1%), very rare (< 0.01%), frequency not known (cannot be estimated from the available data).

Eye disorders:
Microdeposits in the cornea, observed in almost all adult individuals, usually within the area beneath the pupil, which do not require discontinuation of amiodarone. In exceptional cases, these 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. Optic neuropathy (optic neuritis), which may progress to complete blindness, and, according to fundus examination, optic disc edema, which may progress to more or less severe visual acuity reduction. A causal relationship between this adverse effect and amiodarone intake has not been established to date. However, if no other obvious causes for the development of this adverse effect are present, discontinuation of amiodarone is recommended.

Skin and subcutaneous tissue disorders:
Photosensitization; exposure to sunlight (and ultraviolet radiation in general) should be avoided during treatment with the drug. Skin pigmentation with a bluish or bluish-gray color during prolonged use of high daily doses of the drug, which slowly resolves after discontinuation (within 10–24 months). Erythema superimposed on radiation therapy; skin rashes, usually nonspecific; exfoliative dermatitis, although the association between its occurrence and drug intake has not been clearly established; alopecia.

Endocrine disorders:
Except in cases where clinical signs of thyroid dysfunction are present, changes in thyroid hormone levels in blood (increased T4 levels, normal or slightly decreased T3 levels) unrelated to drug intake do not require discontinuation of the drug.

Hypothyroidism causes typical symptoms: weight gain, cold intolerance, apathy, drowsiness. A significant increase in TSH levels confirms this diagnosis. After stopping treatment with 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 thyroid hormone replacement therapy using levothyroxine. Levothyroxine doses can be adjusted according to TSH levels.

Hyperthyroidism is more difficult to recognize, as 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 highly sensitive TSH levels confirms this diagnosis. In such cases, amiodarone must be discontinued, 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 immediately.

If the underlying problem is thyrotoxicosis (directly or via its impact 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.

Very rare cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH), particularly when the drug is used concomitantly with medications that may induce hyponatremia.

Respiratory, thoracic and mediastinal disorders:
Diffuse interstitial or alveolar pneumonitis and obliterative bronchiolitis with sclerotic-type pneumonia, sometimes with fatal outcomes. The onset of dyspnea on exertion or dry cough, either alone or associated with worsening general health (increased fatigue, weight loss, and mild fever), requires radiological examination and, if necessary, discontinuation of the drug, as these lung conditions may lead to pulmonary fibrosis. Early discontinuation of amiodarone, with or without corticosteroid therapy, leads to gradual resolution of symptoms, which usually disappear within 3–4 weeks. Radiological improvement and lung function recovery occur more slowly (over several months). Pleuritis, usually associated with interstitial pneumopathy; bronchospasm in patients with acute respiratory failure, especially in patients with bronchial asthma; acute respiratory distress syndrome (ARDS), in some cases fatal, sometimes occurring early after surgical intervention (possible interaction with high oxygen doses was suspected) (see section "Special precautions"). Pulmonary hemorrhages, which may occasionally manifest as hemoptysis. These pulmonary adverse effects are often associated with amiodarone-induced pneumopathy.

Nervous system disorders:
Tremor or other extrapyramidal symptoms; sleep disturbances, including nightmares; peripheral sensory-motor or mixed peripheral neuropathy; myopathy. Peripheral sensory, motor, or mixed neuropathy and myopathy may develop several months after starting treatment, but sometimes occur after several years. These adverse effects are usually reversible after discontinuation of treatment, but recovery may be incomplete, very slow, and observed only several months after stopping the drug. Cerebellar ataxia; benign intracranial hypertension; headache. When headache occurs, examination should be performed to determine its possible cause.

Psychiatric disorders:
Common: decreased libido; frequency not known: hallucinations.

Hepatobiliary disorders:
Cases of liver injury have been reported; these were diagnosed based on elevated serum transaminase levels. Reported adverse effects include: usually mild and isolated increases in transaminase levels (1.5–3 times above normal), which resolve after dose reduction or even spontaneously; acute liver injury with increased transaminase levels in blood and/or jaundice, including liver failure, sometimes fatal, requiring discontinuation of the drug; 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, transaminase levels elevated 1.5–5 times above normal), regular monitoring of liver function is indicated. If transaminase levels increase—even moderately—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 reported.

Cardiac disorders:
Bradycardia, usually moderate and dose-dependent; myocardial conduction disturbances (sinoatrial block, atrioventricular block of varying degrees); marked bradycardia and, in exceptional cases, sinus node failure; development or worsening of existing arrhythmia, sometimes accompanied by cardiac arrest; paroxysmal ventricular tachycardia "torsade de pointes".

Gastrointestinal disorders:
Mild digestive disturbances (nausea, vomiting, dysgeusia), which usually occur at the beginning of treatment and resolve after dose reduction; pancreatitis/acute pancreatitis.

Breast and reproductive system disorders:
Epididymitis (the causal relationship between this adverse effect and drug intake has not been clearly established to date).

Vascular disorders:
Vasculitis.

Blood and lymphatic system disorders:
Thrombocytopenia; frequency not known: neutropenia, agranulocytosis.

Immune system disorders:
Angioedema and/or urticaria.

General disorders:
Cases of granuloma have been reported, mainly bone marrow granuloma.

Investigations:
Rare cases of hyponatremia may indicate the development of SIADH. Renal impairment with mild increase in creatinine levels.

Shelf life. 4 years.

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

Packaging. Tablets No. 30 (10×3) in blisters in a box.

Prescription status. Prescription only.

Manufacturer.
Limited Liability Company "Pharmaceutical Company "Zdorovya".
Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and location of business activity.
Ukraine, 61013, Kharkiv region, Kharkiv, Shevchenka Street, 22.
(Limited Liability Company "Pharmaceutical Company "Zdorovya")

Ukraine, 08301, Kyiv region, Boryspil, Shevchenka Street, 100.
(Limited Liability Company "FARMEKS GROUP")