Amiodarone tablets 200 mg

Instructions for use of Amiodarone tablets 200 mg

Proprietary name: Amiodarone

International nonproprietary name: amiodarone

Dosage form: tablets

Composition

1 tablet contains the active substance: Amiodarone hydrochloride 200 mg.

Excipients: potato starch - 81.6 mg; povidone - 8.6 mg;  colloidal silicon dioxide (aerosil) – 0.8 mg;  croscarmellose sodium - 6.0 mg;  magnesium stearate - 3.0 mg.

Description

Round, flat-cylindrical tablets from white to white with a creamy tint, with a bevel and a score line.

Pharmacotherapeutic group: antiarrhythmic agent

ATC code: C01BD01

Pharmacological properties

Pharmacodynamics

A class III antiarrhythmic drug (repolarization inhibitor). It also has antianginal, coronary dilating, alpha- and beta-adrenergic blocking, thyrotropic, and hypotensive effects.

The antiarrhythmic action is due to its effect on the electrophysiological processes of the myocardium; it prolongs the action potential of cardiomyocytes; increases the effective refractory period of the atria, ventricles, atrioventricular (AV) node, bundle of His and Purkinje fibers, and accessory conduction pathways.

By blocking "fast" sodium channels, it produces effects characteristic of class I antiarrhythmics. It inhibits the slow (diastolic) depolarization of the sinus node cell membrane, causing bradycardia and reduced AV conduction.

The antianginal effect is due to coronary vasodilating and antiadrenergic action, reducing myocardial oxygen demand. It has an inhibitory effect on the alpha- and beta-adrenergic receptors of the cardiovascular system (without complete blockade). Reduces sensitivity to hyperstimulation of the sympathetic nervous system, coronary vascular resistance; increases coronary blood flow; reduces heart rate; increases the energy reserves of the myocardium (by increasing the content of creatine sulfate, adenosine, and glycogen).

Its structure is similar to thyroid hormones. The iodine content is about 37% of its molecular weight. It affects the metabolism of thyroid hormones, inhibits the conversion of T4 to T3 (blockade of thyroxine-5-deiodinase) and blocks the uptake of these hormones by cardiocytes and hepatocytes, which leads to a weakening of the stimulating effect of thyroid hormones on the myocardium (T3 deficiency can lead to its overproduction and thyrotoxicosis). The onset of action (even when using "loading" doses) is from 2-3 days to 2-3 months, the duration of action varies from several weeks to months (detected in plasma for up to 9 months after discontinuation).

Pharmacokinetics

Absorption is slow and variable - 30-50%, bioavailability - 30-50%. Maximum plasma concentration (Cmax) is noted after  4-7 hours. The therapeutic plasma concentration range is 1-2.5 mg/l (but the clinical picture must also be considered when determining the dose). Volume of distribution - 60 L, indicating intensive distribution into tissues. It is highly lipophilic, found in high concentrations in adipose tissue and well-perfused organs (concentration in adipose tissue, liver, kidneys, myocardium is higher than in plasma - 300, 200, 50, and 34 times, respectively). The pharmacokinetic features of amiodarone necessitate the use of high loading doses. Penetrates the blood-brain barrier (BBB) and placenta (10-50%), secreted into breast milk (25% of the dose received by the mother). Plasma protein binding - 95% (62% with albumin, 33.5% with beta-lipoproteins).

Metabolized in the liver. It is an inhibitor of the CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP3A7 isoenzymes in the liver.  The main metabolite, desethylamiodarone, is pharmacologically active and may enhance the antiarrhythmic effect of the parent compound. Also possibly via deiodination (approximately 9 mg of elemental iodine is released from a 300 mg dose). During prolonged treatment, iodine concentrations can reach 60-80% of amiodarone concentrations.

Given the ability to accumulate and the associated high variability of pharmacokinetic parameters, data on the half-life (T1/2) are conflicting. Elimination of amiodarone after oral administration occurs in 2 phases: initial period - 4-21 hours, in the second phase T1/2 - 25-110 days. After prolonged oral administration, the average T1/2 is 40 days (this is important for dose selection, as it may take at least 1 month to stabilize a new plasma concentration, while complete elimination may take more than 4 months). Elimination of amiodarone begins after several days, and equilibrium between intake and elimination (steady state) is reached after one to several months, depending on individual patient characteristics. Excreted in bile (85-95%), less than 1% of the orally administered dose is excreted by the kidneys (so no dose adjustment is needed in renal impairment). Amiodarone and its metabolites are not dialyzable.

Indications for use

• Treatment and prevention of heart rhythm disorders associated with Wolff-Parkinson-White syndrome (WPW), paroxysms of atrial fibrillation and flutter; atrial and ventricular extrasystole; parasystole, ventricular arrhythmias in patients with Chagas myocarditis;
• Prevention of recurrent ventricular and atrial fibrillation;
• Treatment of ventricular tachycardia;
• Treatment of supraventricular tachycardia  to restore sinus rhythm in atrial fibrillation and flutter;
• Ventricular and supraventricular extrasystole;
• During the rehabilitation period after myocardial infarction, if there is a history of previously noted episodes of arrhythmia.

Contraindications

• Hypersensitivity to iodine, to amiodarone or to other components of the drug
• Sinus bradycardia and sinoatrial block
• Sick sinus syndrome (in the absence of a pacemaker)
• Atrioventricular block II – III degree, bifascicular, trifascicular block (in the absence of a pacemaker)
• Congenital or acquired prolongation of the QT interval
• Hypomagnesemia
• Thyroid dysfunction (hypo- and hyperthyroidism)
• Pregnancy and lactation (breastfeeding)
• Concomitant use with drugs that can cause polymorphic ventricular tachyarrhythmia of the "torsade de pointes" type
• Hypokalemia
• Interstitial lung diseases
• Taking monoamine oxidase (MAO) inhibitors
• Age under 18 years (efficacy and safety not established)

With caution

Caution should be exercised when using the drug in patients with hepatic insufficiency, bronchial asthma, chronic heart failure (NYHA class III and IV), AV block I degree and elderly patients (high risk of severe bradycardia).

Pregnancy and lactation

Contraindicated for use in the I, II, and III trimesters of pregnancy, since during this period the newborn's thyroid gland begins to accumulate iodine, and the use of amiodarone during this period can provoke the development of hypothyroidism due to   increased iodine concentration.

Amiodarone is excreted in breast milk in significant amounts, so the drug is contraindicated during lactation.

Dosage and administration

The tablets are taken orally whole during or after meals with plenty of fluid.

The dosage regimen is established individually and adjusted by a physician.

Adults

Loading dose

In hospital: initial dose, divided into several doses, is from 600 -800 mg (up to a maximum of 1200 mg) per day until a total dose of 10 g is reached (usually within 5-8 days).
Outpatient: initial dose, divided into several doses, is from 600 to 800 mg per day until a total dose of 10 g is reached (usually within 10-14 days).

If necessary, the dose of amiodarone can be increased to 800-1200 mg/day for a short period  and under ECG monitoring. After signs of saturation are achieved, switch to maintenance therapy.

Maintenance dose. 

For maintenance therapy, the lowest effective dose is used, depending on the individual patient's response, and is usually from 100-400 mg/day (1/2 - 4 tablets) in 1-2 doses. Due to the long half-life  the drug can be taken every other day or a break in taking the drug can be made for 2 days a week.

Average therapeutic single dose: 200 mg.

Average therapeutic daily dose: 400 mg.

Maximum single dose: 400 mg.

Maximum daily dose: 1200 mg.

Adverse reactions

The frequency of adverse reactions was defined as follows: very common (≥ 10%), common (≥1%, ˂10); uncommon (≥0.1%, < 1%); rare (≥0.01%, < 0.1%) and very rare, including isolated reports (˂0.01%), frequency not known (cannot be estimated from available data).

Cardiovascular system:

Common

• Moderate bradycardia, the severity of which is dose-dependent.
• Decreased blood pressure (usually moderate or transient).

Uncommon

• Conduction disturbances (sinoatrial block, atrioventricular block of varying degrees).
• Proarrhythmic effect (there are reports of the occurrence of new arrhythmias, or worsening of existing ones, in some cases followed by cardiac arrest).

Digestive system:

Very common

• Nausea, vomiting, dulling or loss of taste, metallic taste in the mouth, feeling of heaviness in the epigastrium, especially at the beginning of treatment, which disappear after dose reduction.
• Increased activity of "hepatic" transaminases in blood serum, usually moderate (1.5-3 times the upper limit of normal) and decreasing with dose reduction or even spontaneously.

Common

• Acute liver injury with increased "hepatic" transaminases and/or jaundice, including the development of liver failure, sometimes fatal.

Respiratory system:

Common

• Interstitial or alveolar pneumonitis and obliterative bronchiolitis with pneumonia (sometimes fatal), pleurisy.
• Severe shortness of breath or dry cough, with or without general deterioration (increased fatigue, weight loss, fever).

Sensory organs:

Very common

• Microdeposits in the corneal epithelium, consisting of complex lipids, including lipofuscin, disappearing after drug withdrawal.

Very rare

• Optic neuritis/optic neuropathy.

Metabolism:

Common

• Hypothyroidism with its classic manifestations: weight gain, chilliness, apathy, reduced activity, drowsiness, bradycardia excessive compared to the expected effect of amiodarone.
• Hyperthyroidism.

Skin:

Very common

• Photosensitivity.

Common

• Grayish or bluish skin pigmentation (in case of prolonged use of the drug in high daily doses).

Central nervous system:

Common

• Tremor or other extrapyramidal symptoms.
• Sleep disorders, including nightmares.

Overdose

If toxicity appears in the form of a proarrhythmic effect, the drug should be discontinued.

Symptoms: decreased blood pressure, sinus bradycardia, arrhythmias, atrioventricular block, cardiac arrest, episodes of ventricular tachycardia, torsade de pointes tachycardia, impaired liver function.

Treatment: gastric lavage and administration of activated charcoal, if the drug was taken recently. In other cases, symptomatic therapy is carried out. There is no specific antidote; hemodialysis is not effective; amiodarone and its metabolites are not removed by dialysis. In case of bradycardia, atropine, beta1-adrenergic stimulants may be prescribed; in severe cases, cardiac pacing. For torsade de pointes - intravenous administration of Mg2+ salts, cardiac pacing.

Drug interactions

Contraindicated combinations:

• With antiarrhythmic drugs, neuroleptics,  MAO inhibitors, parenteral pentamidine, as the risk of torsade de pointes ventricular tachycardia increases.

Not recommended combinations:

• With beta-blockers, some "slow" calcium channel blockers (verapamil, diltiazem), because disturbances in automaticity (bradycardia) and conduction may develop;
• With laxatives that can cause hypokalemia, as the risk of torsade de pointes ventricular tachycardia increases.

Combinations requiring caution:

• With drugs causing hypokalemia (diuretics, systemic glucocorticosteroids, tetracosactide, intravenous amphotericin B), as torsade de pointes ventricular tachycardia may develop;
• With oral anticoagulants, as the risk of bleeding increases (it is necessary to monitor prothrombin levels and adjust the dose of anticoagulants);
• With cardiac glycosides, as disturbances in automaticity (manifested by bradycardia) and disturbances in atrioventricular conduction may be observed. In addition, the plasma concentration of digoxin may increase due to a decrease in its clearance (it is necessary to monitor the plasma concentration of digoxin, ECG monitoring);
• With phenytoin, cyclosporine, their plasma concentrations may increase (the plasma concentration of phenytoin or cyclosporine should be monitored);
• Grapefruit juice may increase the side effects of amiodarone by increasing the amount of this medicine in your body.

Special instructions

Before starting Amiodarone, it is recommended to perform an ECG and determine the blood potassium level. Hypokalemia must be corrected before starting amiodarone. Since Amiodarone can cause hypothyroidism and hyperthyroidism, clinical and laboratory (TSH) examination of the thyroid gland should be performed before taking the drug.

Patients should be warned to avoid direct sunlight during treatment or take protective measures (e.g., use sunscreen, wear appropriate clothing).

The frequency and severity of adverse reactions are dose-dependent, so the minimum effective maintenance doses of Amiodarone should be used to minimize the possibility of their occurrence.

During treatment, ECG (QRS width and QT interval duration) should be monitored every 3 months, taking into account that elderly patients have more pronounced bradycardia.

When using amiodarone, ECG changes are possible: prolongation of the QT interval with possible appearance of a U wave. If atrioventricular block II and III degree, sinoatrial block, or bundle branch block appears, treatment with Amiodarone should be stopped immediately.

During treatment with Amiodarone, transaminase activity (if the transaminase level increases by 3 times or by 2 times in case of initially elevated activity, the dose of Amiodarone is reduced until therapy is completely discontinued) and other liver function indicators should be regularly monitored.

The drug contains iodine, so it can affect the results of radioactive iodine uptake tests by the thyroid gland. Therefore, before starting treatment, during its course, and for several months after the end of treatment, thyroid function tests should be performed.

During treatment with amiodarone and for several months after its discontinuation, thyroid function (hormone levels) should be regularly assessed. If hyperthyroidism is detected, amiodarone should be discontinued.

Progressive shortness of breath and non-productive cough may be signs of lung damage. Regardless of the presence or absence of pulmonary symptoms during treatment with amiodarone, it is recommended to perform a chest X-ray and pulmonary function tests every 6 months.

Before surgical interventions, as well as oxygen therapy, the doctor must be warned about the use of Amiodarone, as rare cases of acute respiratory distress syndrome in adults in the postoperative period have been reported. Caution should be exercised when using the drug during general anesthesia; there is a risk of bradycardia, pronounced decrease in blood pressure, conduction disturbances and decreased cardiac output.

During treatment, an ophthalmological examination should be performed (detection of significant corneal deposits and visual impairment require discontinuation of Amiodarone).

When discontinuing the drug, relapses of rhythm disturbances are possible.

After discontinuation, the pharmacodynamic effect persists for 10-30 days.

Pharmaceutical form

Tablets 200 mg.

10 tablets in a blister pack made of polyvinyl chloride film and printed lacquered aluminum foil.

1, 2, or 3 blister packs together with the instructions for use are placed in a cardboard carton.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 25 °C.

Keep out of reach of children.

Shelf life

2 years. Do not use after the expiration date printed on the packaging.

Prescription status

By prescription.

Name and address of the legal entity in whose name the registration certificate is issued / organization accepting claims:

JSC "AVVA RUS", Russia, 121614, Moscow, Krylatskie Kholmy st., 30, building 9. Tel/Fax: +7 (495) 956-75-54. avva.com.ru

Address of the production site:

JSC "AVVA RUS", Russia, 610044, Kirov region, Kirov, Luganskaya st., 53a. Tel.: +7 (8332) 25-12-29; +7 (495) 956-75-54.