ARITHMIL CARDIO

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT A R I T M I L C A R D I O (ARITMIL KARDIO)

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 physicochemical properties: white or off-white tablets, flat cylindrical in shape, with a score line and chamfer.

Pharmacotherapeutic group.

Class III antiarrhythmic agents. ATC code C01B D01.

Pharmacological Properties

Pharmacodynamics

Antiarrhythmic properties.

Prolongation of the cardiac myocyte action potential duration (phase III) 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 antiadrenergic action on both alpha and beta receptors.

Slowing of sinoatrial, atrial, and nodal conduction in the myocardium, with greater effect observed at faster heart rates.

No changes in intraventricular conduction.

Increased refractory period and decreased myocardial excitability at the atrial, nodal, and ventricular levels.

Slowed conduction and prolonged refractory periods in accessory atrioventricular conducting pathways.

Other properties.

Reduced oxygen consumption due to moderate decrease in peripheral vascular resistance and reduced heart rate.

Increased coronary blood flow due to direct action on myocardial vascular smooth muscle and maintained cardiac output despite reduced arterial pressure and peripheral vascular resistance, and in the absence of negative inotropic effects.

There is evidence that the drug statistically significantly reduces overall mortality and mortality due to rhythm-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 distribution and high tissue affinity.

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

Therapeutic activity typically appears within one week of starting treatment (ranging from several days to two weeks).

The elimination half-life of amiodarone is prolonged and characterized by significant 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 balance between drug intake and elimination is achieved 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.

Amiodarone releases a certain amount of iodine, which is excreted in the urine as iodide; with a daily dose of 200 mg amiodarone, iodine excretion amounts to 6 mg/day. The remainder of the compound, and thus the majority of the iodine, is excreted in feces following hepatic metabolism.

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

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:

• Life-threatening ventricular tachycardia: treatment must be initiated in a hospital setting with continuous patient monitoring;
• Symptomatic ventricular tachycardia (documentarily confirmed) leading to disability;
• Supraventricular tachycardia (documentarily confirmed) requiring treatment, in cases where other drugs are ineffective or contraindicated;
• Ventricular fibrillation.

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

Ischemic heart disease and/or left ventricular dysfunction.

Contraindications.

Sinus bradycardia, sinoatrial block in the absence of an endocardial cardiac pacemaker (artificial pacemaker).

Sick sinus syndrome in the absence of an endocardial cardiac pacemaker (risk of sinus node arrest).

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

Known hypersensitivity to iodine, amiodarone, or excipients.

Combinations with medicinal products capable of inducing paroxysmal ventricular tachycardia "torsades de pointes":

• Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide),
• Class III antiarrhythmics (sotalol, dofetilide, ibutilide),
• Other medicinal products (arsenic compounds, bepridil, cisapride, difemanil, intravenous dolasetron, intravenous erythromycin, mizolastine, intravenous vinca mine, moxifloxacin, intravenous spiramycin, toremifene, certain neuroleptics) (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Antiarrhythmic drugs

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

Concomitant use of antiarrhythmic agents belonging to different classes may achieve a favorable therapeutic effect, but treatment with such combinations usually requires a careful approach and thorough clinical and ECG monitoring. Concomitant use of antiarrhythmic agents that may induce torsades de pointes (such as amiodarone, disopyramide, quinidine derivatives, sotalol, etc.) is contraindicated.

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

Concomitant use with medicinal products that have negative inotropic effects, slow heart rate, and/or slow atrioventricular conduction requires a careful approach and thorough 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 "Medicinal products that reduce potassium levels"), bradycardia (see subsection "Medicinal products that slow heart rate"), or congenital or acquired QT interval prolongation.

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

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

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

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

Medicinal products that slow heart rate

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

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 (sotalol, dofetilide, ibutilide);
• Other medicinal products such as: arsenic compounds, bepridil, cisapride, difemanil, intravenous dolasetron, intravenous erythromycin, mizolastine, intravenous vinca mine, moxifloxacin, intravenous spiramycin, toremifene.

Increased risk of ventricular arrhythmias, especially torsades de pointes.

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

Cyclosporine. Possible increase in cyclosporine serum concentrations due to impaired hepatic metabolism, with risk of nephrotoxic effects. Serum cyclosporine concentrations should be monitored quantitatively, renal function monitored, and cyclosporine dose adjusted during amiodarone treatment.

Fluoroquinolones. Fluoroquinolone use should be avoided during amiodarone treatment.

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

Injectable verapamil. Risk of bradycardia and atrioventricular block. If use of this combination cannot be avoided, careful clinical monitoring and ECG monitoring of cardiac function 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 or both agents should be discontinued. If use of this combination cannot be avoided, pre-assessment of QT interval and ECG monitoring of cardiac function are essential.

Neuroleptics that may induce torsades de pointes (amisulpride, chlorpromazine, thioridazine, droperidol, fluphenazine, haloperidol, levomepromazine, pimozide, pipampalone, 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.

Combinations requiring precautions during use

Oral anticoagulants. Enhanced anticoagulant effect and increased risk of hemorrhagic complications. More frequent monitoring of international normalized ratio (INR) is required. Possible adjustment of oral anticoagulant dose during amiodarone treatment and for 8 days after discontinuation of the drug.

Beta-blockers, except sotalol (contraindicated combination) and esmolol (combination requiring precautions during use). Impaired automaticity and conduction (suppression of compensatory sympathetic mechanisms). ECG and clinical monitoring should be performed.

Beta-blockers used for heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Impaired myocardial automaticity and conduction with risk of excessive heart rate slowing. Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical ECG monitoring should be performed.

Dabigatran. Increased plasma concentrations of dabigatran with increased risk of hemorrhagic events. Clinical monitoring should be performed and dabigatran dose adjusted if necessary, but not exceeding 150 mg/day.

Digitalis preparations. Suppressed automaticity (excessive heart rate slowing) and impaired atrioventricular conduction. When digoxin is used, increased digoxin blood levels are observed due to reduced digoxin clearance. ECG and clinical monitoring, quantitative determination of digoxin blood levels, and, if necessary, digoxin dose adjustment are required.

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

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

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

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

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 is a predisposing factor). Hypokalemia must be corrected before drug administration, and ECG monitoring, electrolyte level monitoring, and clinical monitoring should be performed.

Lidocaine. Risk of increased plasma lidocaine concentrations with possible neurological and cardiac adverse effects due to amiodarone-induced inhibition of hepatic metabolism. Clinical and ECG monitoring should be performed, and, if necessary, quantitative determination of plasma lidocaine concentrations. Lidocaine dose adjustment may be required during and after amiodarone treatment.

Orlistat. Risk of reduced plasma concentrations of amiodarone and its active metabolite. Clinical monitoring is required. ECG monitoring may also be necessary.

Phenytoin. Increased plasma phenytoin concentrations with signs of overdose, especially neurological signs (due to inhibited hepatic metabolism of phenytoin). Clinical monitoring and quantitative determination of plasma phenytoin concentrations are required. Dose adjustment may be necessary.

Simvastatin. Increased risk of concentration-dependent adverse effects such as rhabdomyolysis (due to inhibited hepatic metabolism of simvastatin). Simvastatin dose should not exceed 20 mg/day, or another statin should be used.

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

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

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

Medicinal products metabolized by cytochrome P450 3A4

When such medicinal products are used concomitantly with amiodarone, an inhibitor of CYP3A4, this may lead to increased plasma levels and increased toxicity:

• Cyclosporine: combination with amiodarone may increase cyclosporine plasma levels. Dose adjustment is required.
• Fentanyl: combination with amiodarone may enhance the pharmacological effect of fentanyl and increase the risk of its toxicity.
• Statins: concomitant use of amiodarone with statins metabolized by CYP3A4, such as simvastatin, atorvastatin, and lovastatin, increases the risk of muscle toxicity. When used concomitantly with amiodarone, statins not metabolized by CYP3A4 are recommended.
• Other medicinal products metabolized by CYP3A4: lidocaine, tacrolimus, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine.

Combinations requiring special attention

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

Special precautions for use.

Effects on the heart

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

In elderly patients, the drug may enhance the slowing of heart rate.

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

Although amiodarone may prolong the QT interval, its ability to provoke torsades de pointes ventricular tachycardia is weak.

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

Cases, sometimes fatal, of new-onset arrhythmia or worsening of pre-existing treated arrhythmia have been reported (see section "Side effects").

The arrhythmogenic effect of amiodarone is weak or even lower than that of most antiarrhythmic agents and usually occurs in the context of certain drug combinations (see section "Interaction with medicinal products and other forms of interaction") or in the presence of electrolyte disturbances, particularly hypokalemia. It is important to consider conditions associated with hypokalemia, which should be corrected before initiating amiodarone therapy.

Thyroid gland disorders

This medicinal product contains iodine and therefore affects the results of certain thyroid function tests (radioactive iodine uptake, protein-bound iodine). However, assessment of other thyroid function parameters (T3, T4, thyroid-stimulating hormone) remains possible.

Amiodarone may cause thyroid dysfunction, especially in patients with a history of thyroid disorders. Quantitative determination of TSH levels is recommended for 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 "Contraindications", "Side effects").

Lung disorders

The onset of dyspnea or dry cough, either isolated or associated with worsening general condition, should be considered as a possible sign of pulmonary toxicity of the drug, for example, development of interstitial pneumopathy, and requires radiological examination of the patient (see section "Side effects").

Careful monitoring of patients during mechanical ventilation is recommended.

Liver disorders

Liver function should be monitored regularly. The dose of amiodarone should be reduced or the drug discontinued if transaminase levels rise more than three times above normal values. Acute liver disorders (including severe hepatocellular insufficiency or liver failure, sometimes fatal) may occur during amiodarone treatment, and chronic liver disorders may also develop (variable hepatomegaly, elevation of transaminase levels in blood 1.5–5 times above normal) (see section "Side effects").

Neuro-muscular disorders

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

In isolated cases of headache, patients should be examined to determine the possible cause.

Eye disorders

In case of blurred vision or decreased visual acuity, a complete ophthalmological examination including fundoscopy 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 disorders and blindness (see section "Side effects").

Disorders related to interactions with other medicinal products

Combinations with beta-blockers, except for sotalol (combination contraindicated) and esmolol (combination requiring precautions), verapamil, and diltiazem may be used only for prevention of life-threatening ventricular arrhythmias (see section "Interaction with medicinal products and other forms of interaction").

The use of amiodarone in combination with cyclosporine, diltiazem (for injection), verapamil (for injection), certain antiparasitic agents (halofantrine, lumefantrine, pentamidine), certain neuroleptics ( amisulpride, chlorpromazine, thiethylperazine, droperidol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sertindole, sulpiride, sultopride, tiapride, zuclopenthixol), and methadone is not recommended (see section "Interaction with medicinal products and other forms of interaction").

Disorders related to excipients

This medicinal product contains lactose. Therefore, it is not recommended for use in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption (rare hereditary conditions).

Electrolyte disturbances, especially hypokalemia: Hypokalemia may promote the occurrence of proarrhythmic effects of the drug.

Hypokalemia must be corrected before initiating amiodarone therapy.

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

Patients should be advised to avoid sun exposure and to use sun protection products during treatment.

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

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

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

Long-term use of amiodarone increases the hemodynamic risk associated with general or local anesthesia and the risk of adverse effects, particularly bradycardia, arterial hypotension, reduced cardiac output, and disturbances in cardiac conduction. In addition, several cases of acute respiratory distress syndrome have been observed in patients receiving amiodarone in the early postoperative period. Therefore, careful monitoring of such patients during mechanical ventilation is recommended (see section "Side effects").

Use during pregnancy or breastfeeding.

Due to its effects on the fetal thyroid gland, amiodarone is contraindicated during pregnancy.

Amiodarone and its metabolites, along with iodine, are excreted in breast milk at concentrations higher than their plasma concentrations. Because of the risk of hypothyroidism in the newborn, 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.

Method of Administration and Dosage

Take orally by adults, during or after meals, without chewing, swallowing with a small amount of liquid.

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

In certain cases, higher doses (4–5 tablets daily) may be used at the beginning of treatment for a short period of time, with cardiac function monitored by ECG.

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

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

Overdose

Cases of acute amiodarone overdose are poorly documented. There have been reports of sinus bradycardia, ventricular arrhythmias, particularly torsades de pointes, and hepatic injury.

Treatment is symptomatic. Patient monitoring, especially of cardiac function, is recommended for a prolonged period of time.

Amiodarone and its metabolites are not removed by dialysis.

Adverse Reactions.

Ocular disorders: Corneal microdeposits, occurring in almost all adult individuals, usually within the area beneath the pupil, which do not require discontinuation of amiodarone. In rare cases, they are associated with colored halos in bright light or blurred vision. Corneal microdeposits represent complex lipid deposits and are always completely reversible after discontinuation of the drug. Optic neuropathy (optic neuritis), which may progress to complete blindness, with papilledema and may progress to more or less severe reduction in visual acuity. A causal relationship between this adverse effect and amiodarone use has not been established to date. However, if no other obvious causes for this adverse effect are identified, 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 discoloration with bluish or bluish-gray hue during prolonged use of high daily doses, which slowly resolves after discontinuation of the drug (within 10–24 months); erythema in irradiated areas; skin rashes, usually nonspecific; exfoliative dermatitis, although a causal relationship between its occurrence and drug intake has not been clearly established; alopecia; urticaria.

Endocrine system disorders: Changes in thyroid hormone levels in blood (increased T4 levels, normal or slightly decreased T3 levels) in the absence of clinical signs of thyroid dysfunction, which do not require discontinuation of the drug; hypothyroidism, characterized by typical symptoms: weight gain, cold intolerance, apathy, somnolence. Significant elevation of TSH levels confirms this diagnosis. Symptoms resolve within 1–3 months after discontinuation of the drug; discontinuation of the drug is not mandatory: if amiodarone use is clinically justified, treatment with this drug may continue in combination with thyroid hormone replacement therapy using levothyroxine. Levothyroxine doses may be adjusted according to TSH levels; hyperthyroidism is more difficult to diagnose, 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 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 without delay. If the underlying problem is thyrotoxicosis (either directly or via its impact on vulnerable myocardial equilibrium), the variable effectiveness of synthetic antithyroid drugs necessitates recommending high-dose corticosteroid therapy (1 mg/kg) for a sufficiently prolonged period (3 months). Cases of hyperthyroidism have been reported for several months after discontinuation of amiodarone.

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

Respiratory, thoracic and mediastinal disorders: Cases of interstitial or diffuse alveolar lung disease and obliterative bronchiolitis with organizing pneumonia (sometimes fatal), associated with dyspnea on exertion or dry cough, either isolated or combined with deterioration in general health (increased fatigue, weight loss, and mild fever), requiring radiological examination and, in some cases, discontinuation of the drug, as they may lead to pulmonary fibrosis. Early discontinuation of amiodarone, with or without corticosteroid therapy, promotes gradual resolution of symptoms. Clinical symptoms usually resolve 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; hemoptysis; acute respiratory distress syndrome, in isolated cases with fatal outcome, sometimes in the early postoperative period (possible interaction with high oxygen doses). Cases of pulmonary hemorrhage, which may present as hemoptysis, often associated with amiodarone-induced pneumopathy, have been reported.

Nervous system disorders: Tremor or other extrapyramidal symptoms; sleep disturbances, including nightmares; sensory, motor, or mixed peripheral neuropathy (usually reversible after discontinuation of the drug); myopathy. Sensory, motor, or mixed peripheral neuropathy and myopathy may develop several months after initiation of treatment, but sometimes appear after several years. These adverse effects are usually reversible after discontinuation of the drug. However, recovery may be incomplete, very slow, and observed only several months after discontinuation of the drug. Cerebellar ataxia; benign intracranial hypertension; headache. In case of isolated headaches, examination should be performed to determine their possible cause.

Hepatobiliary disorders: Hepatic injury – diagnosed based on elevated serum transaminase levels. Usually mild and isolated elevation of transaminase levels (1.5–3 times above normal); acute hepatic injury with elevated transaminase levels and/or jaundice, including hepatic failure, sometimes fatal, requiring discontinuation of the drug; chronic hepatic injury requiring prolonged liver treatment, with histological changes consistent with pseudo-alcoholic hepatitis (should be suspected in case of elevated transaminase levels, even mild, occurring after more than 6 months of drug use); cirrhosis of the liver. Since clinical and laboratory signs are not clearly expressed (variable hepatomegaly, elevated transaminase levels 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 use, development of chronic hepatic 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.

Cardiovascular disorders: Bradycardia, usually moderate and dose-dependent, myocardial conduction disturbances (sinoatrial block, atrioventricular block of varying degrees), marked bradycardia and sinus node arrest, reported in several cases (in the context of sinus node dysfunction, in elderly patients); occurrence or exacerbation of pre-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.

Breast and reproductive system disorders: Epididymitis – causal relationship between this adverse effect and drug intake has not been clearly established to date; impotence.

Vascular disorders: Vasculitis.

Investigations: Rare cases of hyponatremia – may indicate development of SIADH; renal impairment with moderate increase in creatinine levels.

Blood and lymphatic system disorders: Thrombocytopenia, hemolytic and aplastic anemias.

Immune system disorders: Angioneurotic edema.

Shelf life. 4 years from the date of manufacture of the bulk product.

Storage conditions.

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

Packaging.

No. 30 (10×3): 10 tablets in a blister, 3 blisters in a carton.

Prescription category. Prescription only.

Manufacturer.

LLC "FARMEKS GROUP".

Manufacturer's location and address of business activity.

100 Shevchenka St., Boryspil, Kyiv Oblast, 08301, Ukraine.