Cardiodarone - instructions for use, dose, side effects, contraindications

Antiarrhythmic drug of the III class (inhibitor of repolarization). It also has antianginal, coronarodilating, alpha and beta-adrenergic blocking effects. Antiarrhythmic effect is due to the effect on the electrophysiological processes of the myocardium; prolongs the action potential of cardiomyocytes, increasing the effective refractory period of the atria, ventricles, atrioventricular (AV) node, a bundle of His and Purkinje fibers, additional ways of conducting excitation.

By blocking the "fast" sodium channels, it has effects characteristic of class I antiarrhythmics. It inhibits the slow (diastolic) depolarization of the membrane of the cells of the sinus node, causing bradycardia, depresses AV conduction (effect of antiarrhythmics IV class).

The antianginal effect is due to coronary dilatory and antiadrenergic action, a decrease in myocardial oxygen demand. Has a retarding effect on alpha and beta-adrenergic receptors of the cardiovascular system (without complete blockade).Reduces sensitivity to hyperstimulation of the sympathetic nervous system, resistance of coronary vessels; increases coronary blood flow; decreases the heart rate (heart rate); increases the energy reserves of the myocardium (by increasing the content of creatine sulfate, adenosine and glycogen).

It is similar in its structure to thyroid hormones. The iodine content is about 37% of its molecular weight. Influences the metabolism of thyroid hormones, thyroxine suppresses the transformation (T4) to triiodothyronine (T3) (blockade of 5-thyroxine deiodinase) and blocks the capture of these hormones cardiocytes and hepatocytes, which leads to a weakening of the stimulating effect of thyroid hormones on the myocardium.

The onset of action (even with the use of "loading" doses) - from 2-3 days to 2-3 months, the duration of action varies from several weeks to months (determined in blood plasma for 9 months after discontinuation of its administration).

Pharmacokinetics:

Absorption is slow and variable, bioavailability is 35-65 %. The maximum concentration (Cmah) in the blood plasma is observed after 3-7 hours.

The range of therapeutic plasma concentration is 1-2.5 mg / l (but when determining the dose, one should also bear in mind the clinical picture). Time to reach equilibrium concentration in blood plasma (TCss) - from one to several months (depending on individual characteristics).

The volume of distribution is 60 liters, which indicates an intensive distribution in the tissue. It has high fat solubility, is in high concentrations in adipose tissue and organs with good blood supply (concentration in adipose tissue, liver, kidneys, myocardium is higher than in plasma - respectively, 300, 200, 50 and 34 times).

The pharmacokinetics of amiodarone cause the use of the drug in high loading doses. Penetrates through the blood-brain barrier and placenta (10-50%), is secreted with breast milk (25 % dose received by the mother). Communication with blood plasma proteins - 95% (62% - with albumin, 33,5% - with beta-lipoproteins).

Metabolised in the liver. The main metabolite, desethylamiodarone, is pharmacologically active and can enhance the antiarrhythmic effect of the basic compound. Perhaps also by deiodination (at a dose of 300 mg, about 9 mg of elemental iodine is released). With prolonged treatment, iodine concentrations can reach 60-80 % concentrations of amiodarone. Is an inhibitor of isoenzymes CYP2C9, CYP2D6 and CYP3A4, CYP3A5, CYP3A7 in the liver.

Given the capacity for cumulation and the large variability of pharmacokinetic parameters associated with this, the data on the half-life (T1 / 2) are inconsistent. Removal of amiodarone after ingestion is carried out in 2 phases: the initial period is 4-21 hours, in the second phase of T1 / 2 - 25-110 days. After long oral administration, the mean T1 / 2 is 40 days (this is important in choosing a dose, since it may take at least 1 month to stabilize the new plasma concentration, while complete elimination may last longer 4 months).

It is excreted with bile (85-95%), the kidneys are excreted less than 1% of the dose taken internally (therefore, if there is impaired renal function, there is no need to change the dose). Amiodarone and its metabolites are not dialyzed.

Indications:

Prevention of recurrences of paroxysmal rhythm disturbances: life threatening ventricular arrhythmias (including ventricular tachycardia, ventricular fibrillation); supraventricular arrhythmias (including with organic heart diseases, as well as ineffectiveness or impossibility of using other antiarrhythmic therapy); documented seizuresrecurrent persistent supraventricular paroxysmal tachycardia in patients with Wolff-Parkinson-White syndrome; atrial fibrillation (atrial fibrillation) and atrial flutter.

Contraindications:

Hypersensitivity to iodine, amiodarone or to other components of the drug;
syndrome of weakness of the sinus node (sinus bradycardia and sinoatrial blockade, in the absence of an artificial pacemaker (risk of stopping the sinus node);
atrioventricular blockade of P-III degree, two- and three-beam blockades (in the absence of an artificial pacemaker);
hypokalemia, hypomagnesemia;
hypothyroidism, hyperthyroidism;
interstitial lung diseases;
congenital or acquired lengthening of the QT interval;
pregnancy and lactation;
simultaneous administration with drugs that can prolong the QT interval and cause the development of paroxysmal tachycardias, including a torsade de pointe polymorphic ventricular tachycardia;
antiarrhythmic drugs IA class (quinidine, disopyramide, procainamide), antiarrhythmic drugs of the third class (dofetilide, ibutilide, brethil tosylate); sotalol;
other (not anti-arrhythmic) drugs, such as, beprideal; wincamine; some neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulpiride, tiapride, verialpyride), butyrophenones (droperidol, haloperidol), sertindole, pimozide; cisapride; tricyclic antidepressants; macrolide antibiotics (in particular erythromycin with intravenous administration, spiramycin); azoles; antimalarial drugs (quinine, chloroquine, mefloquine, halofantrine); pentamidine with parenteral administration; diphenamyl methyl sulfate; misolastine; astemizole, terfenadine; fluoroquinolones.

- simultaneous administration of monoamine oxidase inhibitors (MAO);

- age under 18 years (effectiveness and safety not established);

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Carefully:

Use with caution in chronic heart failure (III-IV functional class by classification NYHA), AV blockade I degree, liver failure, bronchial asthma, in elderly patients (high risk of severe bradycardia).

Pregnancy and lactation:

Contraindicated in pregnancy, because during this period the thyroid gland of the newborn begins to accumulate iodine, and the use of amiodarone during this period can provoke the development of hypothyroidism due to an increase in iodine concentration. Amiodarone is excreted in breast milk in a significant amount, so the drug is contraindicated for use during lactation. If it is necessary to prescribe the drug during this period, breastfeeding should be stopped.

Dosing and Administration:

Tablets are taken orally, before eating, with plenty of water. The drug should be taken only as prescribed by the doctor!

Load ("saturating") dose

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

Ambulatory: the initial dose divided into several doses is 600-800 mg / day until a total dose of 10 g is reached (usually within 10-14 days).

Supportive dose. With maintenance treatment, the lowest effective dose is applied depending on the individual reaction of the patient and is usually from 100-400 mg / day (1-2 tablets) in 1-2 divided doses.

Due to the long half-life of the drug, you can take the drug every other day or take a break in taking the drug - 2 days a week.

The average therapeutic single dose is 200 mg.

The average therapeutic daily dose is 400 mg.

The maximum single dose is 400 mg.

The maximum daily dose is 1200 mg.

Side effects:

Frequency: very often (10% or more), often (1% or more, less than 10%), infrequently (0.1% or more, less than 1%), rarely (0.01% or more, less than 0.1%) , very rarely (less than 0.01%, including individual cases), the frequency is unknown (according to the available data, the frequency can not be determined).

From the cardiovascular system: often - mild bradycardia (dose-dependent); rarely - sinoatrial and AV blockade of various degrees, proaritmogenic action (the emergence of new or aggravation of existing arrhythmias, including with cardiac arrest); very rarely - severe bradycardia, stopping the sinus node (in patients with sinus node dysfunction and elderly patients); frequency unknown - progression of chronic heart failure (with prolonged use).

From the digestive system: very often - nausea, vomiting, decreased appetite, dullness or loss of taste, a feeling of heaviness in the epigastrium,isolated increased activity of "liver" transaminases (1.5-3 times higher than normal); often - acute toxic hepatitis with increased activity of "liver" transaminases and / or jaundice, including the development of hepatic insufficiency, incl. fatal; very rarely - chronic liver failure (pseudo-alcoholic hepatitis, cirrhosis), incl. fatal.

From the respiratory system: often - interstitial or alveolar pneumonitis, obliterating bronchiolitis with pneumonia, incl. with a lethal outcome, pleurisy, pulmonary fibrosis; very rarely - bronchospasm in patients with severe respiratory failure (especially in patients with bronchial asthma), acute respiratory syndrome, incl. with lethal outcome; frequency unknown - pulmonary hemorrhage.

From the sense organ: very often - microdeposition in the epithelium of the cornea, consisting of complex lipids, including lipofuscin (complaints of the appearance of a halo or fuzziness of contours of objects in bright light); very rarely - optic neuritis / visual neuropathy.

From the side of metabolism: often - hypothyroidism, hyperthyroidism; very rarely - the syndrome of impaired secretion of antidiuretic hormone.

From the skin: very often - photosensitivity; often - grayish or bluish skin pigmentation (with prolonged use, disappears after discontinuation of the drug); very rarely - erythema (with simultaneous radiotherapy), skin rash, exfoliative dermatitis (there is no connection with taking the drug), alopecia.

From the central nervous system: often - tremor and other extrapyramidal symptoms, sleep disorders, incl. "nightmarish" dreams; rarely - peripheral neuropathy (sensory, motor, mixed) and / or myopathy; very rarely - cerebellar ataxia, benign intracranial hypertension (pseudotumour of the brain), headache.

Other: very rarely - vasculitis, epididymitis, impotence (there is no connection with taking the drug), thrombocytopenia, hemolytic or aplastic anemia.

Overdose:

Symptoms: sinus bradycardia, atrioventricular block, ventricular tachycardia, paroxysmal tachycardia of the pirouette type, aggravation of existing chronic heart failure, impaired liver function, cardiac arrest.

Treatment: gastric lavage and intake of activated charcoal,if the drug is taken recently; symptomatic therapy (with bradycardia - beta-adrenostimulyatorov or staging pacemaker, with tachycardia such as "pirouette" - intravenous magnesium salts or pacing). There is no specific antidote, hemodialysis is ineffective.

Interaction:

Amiodarone interacts with a large number of drugs. Because of the long half-life, the possibility of the emergence of interactions exists not only with concomitantly used drugs, but also with drugs that will be used after discontinuing amiodarone therapy.

Contraindicated combinations (risk of developing polymorphic ventricular tachycardia type "pirouette"):

- antiarrhythmic agents IA class (quinidine, hydroquinidine, disopyramide, procainamide), Class III (dofetilide, ibutilide, brethil tosylate); sotalol;

- others (not anti-arrhythmic drugs), such as beprideal, wincamine, some neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulpiride, tiapride, verialpyride), butyrophenones (droperidol, haloperidol), sertindole, pimozide; tricyclic antidepressants; cisapride; macrolide antibiotics (erythromycin with intravenous administration, spiramycin); azoles; antimalarial drugs (quinine, chloroquine, mefloquine, halofantrine, lumefantrine); pentamidine (parenterally); diphenamyl methyl sulfate; misolastine; astemizole; terfenadine; fluoroquinolones (incl. moxifloxacin).

Not recommended combinations:

- beta-adrenoblockers, blockers of "slow" calcium channels (verapamil, diltiazem) - the risk of violation of automatism (pronounced bradycardia) and conduction;

- laxatives, stimulating peristalsis of the intestine - risk of developing a ventricular tachycardia such as "pirouette" against a background of hypokalemia caused by laxatives; When combined with amiodarone, laxatives of other groups should be used.

Combinations requiring use with caution:

- diuretics that cause hypokalemia, amphotericin B (intravenously), systemic glucocorticosteroids, tetracosactide - risk of developing ventricular rhythm disturbances, incl. ventricular tachycardia of the "pirouette" type;

- procainamide - the risk of side effects of procainamide (amiodarone increases the plasma concentration of procainamide and its metabolite N- acetylprocainamide);

- anticoagulants of indirect action (warfarin) - amiodarone increases the concentration of warfarin (risk of bleeding) due to inhibition of the isoenzyme CYP2C9. Regular monitoring of prothrombin time (MNO) and correction of anticoagulant doses are necessary both during and after amiodarone therapy;

- cardiac glycosides - a violation of automatism (pronounced bradycardia) and AV conductivity (increase in digoxin concentration);

- esmolol - violation of contractility, automatism and conduction (suppression of compensatory reactions of the sympathetic nervous system). Clinical and ECG monitoring is required;

- phenytoin, phosphenytoin - the risk of developing neurological disorders (amiodarone increases the concentration of phenytoin by inhibiting the isoenzyme CYP2C9);

- flecainide - amiodarone increases its concentration (due to inhibition of the isoenzyme CYP2D6);

- drugs metabolized with the participation of isoenzyme CYP3A4 (ciclosporin, fentanyl, lidocaine, tacrolimus, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine, statins, incl. simvastatin) - amiodarone increases their concentration (the risk of their toxicity and / or increased pharmacodynamic effects);

- orlistat reduces the concentration of amiodarone and its active metabolite in the blood plasma;

- clonidine, guanfacine, acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine, tacrine, ambenonium chloride, pyridostigmine, neostigmine), pilocarpine - risk of development of severe bradycardia (cumulative effect);

- cimetidine, grapefruit juice slows the metabolism of amiodarone and increases its plasma concentration;

- medicines for inhalation anesthesia - the risk of developing bradycardia (resistant to atropine), reducing blood pressure, conduction disorders, reducing cardiac output, acute respiratory distress syndrome, incl. fatal, the development of which is associated with high concentrations of oxygen;

- radioactive iodine - amiodarone (contains in its composition iodine) can disrupt the absorption of radioactive iodine, which can distort the results of a radioisotope study of the thyroid gland;

- Rifampicin and preparations of St. John's wort (powerful isoenzyme inducers CYP3A4) reduce the concentration of amiodarone in plasma;

- HIV protease inhibitors (inhibitors of isoenzyme CYP3A4) can increase plasma concentrations of amiodarone;

- Clopidogrel - it is possible to reduce its plasma concentration;

- dextromethorphan (substrate of isoenzymes CYP3A4 and CYP2D6) - it is possible to increase its concentration (amiodarone inhibits isoenzyme CYP2D6).

Special instructions:

Before the beginning of therapy it is recommended to conduct an electrocardiogram, to evaluate the thyroid function (concentration of hormones), and the concentration of potassium ions in the blood plasma.

Hypokalemia should be adjusted before treatment begins.

During the therapy it is necessary to regularly monitor the ECG (every 3 months) and the activity of "liver" transaminases and other indicators of liver function, as well as the thyroid function (including within a few months after drug discontinuation), lung X-ray (every 6 months) and functional pulmonary tests.

If there is a shortness of breath and a dry cough during treatment, with or without worsening of the general condition (increased fatigue,an increase in body temperature) it is necessary to perform a chest X-ray study for possible development of interstitial pneumonitis. In case of its development the drug is canceled. With early cancellation (with or without treatment with glucocorticosteroids), these phenomena are usually reversible. Clinical manifestations usually disappear after 3-4 weeks, the restoration of the radiographic pattern and lung function takes place more slowly (several months).

With the use of amiodarone against the background of artificial ventilation (including during surgical interventions), rare cases of development of acute respiratory distress syndrome were noted, incl. with a fatal outcome (the probability of interaction with high doses of oxygen), therefore it is recommended to strictly monitor the condition of such patients.

Before conducting a surgical procedure, it is necessary to inform the anesthetist about taking Cardiodarone® (the risk of increasing the hemodynamic effect of general and local anesthetics).

Patients on long-term treatment for cardiac arrhythmias reported cases of increased incidence of ventricular fibrillationand / or an increase in the threshold of operation of a pacemaker or an implanted defibrillator, which may reduce their effectiveness. Therefore, before the beginning and during treatment with the drug Kardiodarone ® should regularly check the correctness of their functioning.

Due to the prolongation of the repose period of the ventricles of the heart, the pharmacological action of amiodarone causes certain changes in the ECG: lengthening of the interval QT, QTc (corrected), possibly the appearance U waves. Allowable lengthening interval QT - no more than 450 ms or no more than 25% of the initial value. These changes are not are a manifestation of the toxic effect of the drug, however, require monitoring for dose adjustment and evaluation of possible pro-arrhythmogenic action.

When developing AV blockade of MI degree, sinoatrial blockade or a two-beam intraventricular blockade, treatment should be discontinued. When AV blockade of the I degree, it is necessary to strengthen patient monitoring.

If there is a visual impairment (blurred vision, reduced visual acuity), an ophthalmological examination, including examination of the fundus, should be performed.With the development of neuropathy or optic neuritis, treatment is discontinued (risk of developing blindness).

Application in pregnancy and lactation is possible only with life-threatening rhythm disturbances with the ineffectiveness of other antiarrhythmic therapy (causes hypothyroidism, goitre, bradycardia and mental retardation in newborns).

Safety and effectiveness of use in children are not established, the onset and duration of the effect in them may be less than in adults.

The preparation contains iodine, so it can influence the results of tests of accumulation of radioactive iodine in the thyroid gland.

Effect on the ability to drive transp. cf. and fur:

During the treatment period, one should refrain from driving a car and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets 200 mg.

Packaging:

For 10 tablets in a planar cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

3 contour mesh packages together with instructions for use are placed in a pack of cardboard.

Storage conditions:

List B.Keep in dry the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:P N003269 / 01

Date of registration:09.09.2009 / 13.09.2017

Expiration Date:Unlimited

The owner of the registration certificate:VALENTA PHARM, PAO VALENTA PHARM, PAO Russia

Manufacturer: & nbsp

VALENTA PHARMACEUTICS, JSC Russia

Information update date: & nbsp10.12.2017

Illustrated instructions

Instructions

Cardiodarone® (Cardiodarone®)