Amiodaronum

General characteristics. Structure:

Active ingredient: 200 mg of Amiodaronum of a hydrochloride in 1 tablet.

Excipients: potato starch, cellulose microcrystallic, lactose (sugar milk), maltodextrin, sodium of a kroskarmelloz (primelloz), povidone (polyvinylpirrolidone low-molecular), magnesium stearate.

Medicine, possessing, preferential, antiarrhytmic action. It is applied to treatment and the prevention of disturbances of a heart rhythm, prevention of attacks of stenocardia.

Pharmacological properties:

Pharmacodynamics. Antiarrhytmic drug III of a class (repolarization inhibitor). Has also anti-anginal, koronarodilatiruyushchy, alpha and beta and adrenoceptor blocking effects.

Antiarrhytmic action is caused by influence on electrophysiologic processes of a myocardium; extends the action potential of cardiomyocytes, increasing the effective refractory period of auricles, ventricles, an atrioventricular (AV) node, ventriculonector and Purkinye's fibers, additional ways of carrying out excitement.

Blocking "bystry" natrium channels, renders the effects characteristic of antiaritmik of the I class. Slows down slow (diastolic) depolarization of a membrane of cells of a sinus node, causing bradycardia, AV carrying out (effect of antiaritmik of the IV class) oppresses.

The anti-anginal effect is caused by coronarodilator and anti-adrenergic action, reduction of need of a myocardium for oxygen. Exerts the braking impact on alpha and beta adrenoceptors of cardiovascular system (without their total block). Reduces sensitivity to hyper stimulation of a sympathetic nervous system, resistance of coronary vessels; increases a coronary blood stream; urezhat the heart rate (HR); raises power reserves of a myocardium (due to increase in maintenance of a kreatinsulfat, adenosine and a glycogen).

On the structure it is similar to thyroid hormones. Content of iodine makes about 37% of its molecular weight. Influences exchange of thyroid hormones, suppresses transformation of T3 into T4 (blockade of a thyroxine-5-deiodinase) and blocks capture of these hormones cardiocytes and hepatocytes that leads to weakening of the stimulating influence of thyroid hormones on a myocardium.

The beginning of action (even when using "load" doses) – from 2-3 days to 2-3 months, varies duration of action from several weeks to one months (is defined in a blood plasma for 9 months after the termination of its reception).

Pharmacokinetics. Absorption slow and variable, bioavailability – 35-65%. The maximum concentration (Cmax) in a blood plasma is noted in 3-7 h.

Range of therapeutic plasma concentration – 1-2,5 mg/l (but when determining a dose it must be kept in mind also a clinical picture). Time of achievement of stationary concentration (steady state) (TCss) – from one to several months (depending on specific features).

Distribution volume – 60 l that demonstrates intensive distribution in fabric.

Has high fat solubility, in high concentration is in fatty tissue and bodies with good blood supply (concentration in fatty tissue, a liver, kidneys, a myocardium above, than in plasma – respectively, in 300, 200, 50 and 34 times).

Features of pharmacokinetics of Amiodaronum cause need of use of drug for high load doses. Gets through a blood-brain barrier and a placenta (10-50%), cosecretes with breast milk (25% of the dose received by mother).

Communication with proteins of a blood plasma – 95% (62% – with albumine, 33,5% – with beta lipoproteins).

It is metabolized in a liver. The main metabolite – дезэтиламиодарон – pharmacological is active and can strengthen antiarrhytmic effect of the main connection. Perhaps, also by deiodinating (at a dose of 300 mg about 9 mg of elementary iodine are allocated). At long treatment of concentration of iodine can reach 60-80% of concentration of Amiodaronum. Is inhibitor of isoenzymes CYP2C9, CYP2D6 and CYP3A4, CYP3A5, CYP3A7 in a liver.

Considering ability to cumulation and the big variability of pharmacokinetic parameters connected with it, data on an elimination half-life (T1/2) are contradictory.

Removal of Amiodaronum after intake is carried out in 2 phases: an initial stage – 4-21 h, in the second phase T1/2 – 25-110 days. After long intake average T1/2 – 40 days (it is important at the choice of a dose as, perhaps, at least, 1 month is necessary for stabilization of new plasma concentration while full removal can last more than 4 months).

It is removed with bile (85-95%), kidneys remove less than 1% of the dose accepted inside (therefore at an impaired renal function there is no need for change of a dosage). Amiodaronum and its metabolites are not exposed to dialysis.

Indications to use:

· Prevention of a recurrence of paroxysmal disturbances of a rhythm: life-threatening ventricular arrhythmias (including ventricular tachycardia, fibrillation of ventricles);

· supraventricular arrhythmias (including at organic heart diseases, and also at inefficiency or impossibility of use of other antiarrhytmic therapy);

· attacks of a recurrent steady supraventricular Bouveret's disease at patients with a WPW-syndrome;

· ciliary arrhythmia (fibrillation of auricles) and atrial flutter.

Route of administration and doses:

Pill is taken inside, in time or after meal, washing down with enough water.

The load ("sating") dose. In a hospital: the initial dose (divided into several receptions) makes 600-800 mg/days (to the maximum dose of 1 200 mg) before achievement of a total dose of 10 g (usually within 5-8 days).

On an outpatient basis: the initial dose divided into several receptions makes 600-800 mg/days before achievement of a total dose of 10 g (usually within 10-14 days).

Maintenance dose. At the supporting treatment the smallest effective dose depending on individual reaction of the patient is applied and usually makes from 100-400 mg/days (1-2 tablets) in 1-2 receptions.

Owing to a long elimination half-life drug can be accepted every other day or to do a break in administration of drug – 2 days a week.

Average therapeutic single dose – 200 mg.

Average therapeutic daily dose – 400 mg.

The maximum single dose – 400 mg.

The maximum daily dose – 1 200 mg.

Features of use:

Pregnancy and period of a lactation: It is contraindicated to use during pregnancy as during this period the thyroid gland of the newborn begins to kumulirovat iodine, and use of Amiodaronum during this period can provoke development of a hypothyroidism because of increase in concentration of iodine.

Amiodaronum is allocated with breast milk in a significant amount therefore drug is contraindicated to use in the period of a lactation. In need of purpose of drug during this period breastfeeding needs to be stopped.

Before therapy the ECG is recommended to conduct a research, to estimate function of a thyroid gland (concentration of hormones), and concentration of potassium ions in a blood plasma.

The hypopotassemia has to be corrected prior to treatment.

During therapy it is regularly necessary to control ECG indicators (each 3 months) both activity of "hepatic" transaminases and other indicators of function of a liver, and also function of a thyroid gland (including and within several months after drug withdrawal), X-ray inspection of lungs (each 6 months) and functional pulmonary trials.

At emergence in the course of treatment of an asthma and dry cough with or without deterioration in the general state (increased fatigue, fervescence) carrying out X-ray inspection of a thorax regarding possible development of an intersticial pneumonitis is necessary. In case of its development drug is cancelled. At early cancellation (with or without treatment by glucocorticosteroids) these phenomena are, as a rule, reversible. Clinical manifestations usually disappear in 3-4 weeks, recovery of a X-ray pattern and function of lungs happens more slowly (several months).

At introduction of Amiodaronum against the background of artificial ventilation of the lungs (including when carrying out surgical interventions) exceptional cases of development acute respiratory a distress syndrome, including with a lethal outcome were celebrated (probability of interaction with high doses of oxygen) therefore it is recommended to exercise strict control of a condition of such patients.

Before carrying out surgical intervention it is necessary to inform the anesthesiologist of administration of drug of Amiodaron® (risk of strengthening of hemodynamic effect of the general and local anesthetics).

At patients it is long receiving treatment concerning disturbances of a heart rhythm it was reported about cases of increase in frequency of fibrillation of ventricles and/or increases in a threshold of operation of a pacemaker or the implanted defibrillator that can reduce their efficiency. Therefore before the beginning and during treatment by the drug Amiodaron® it is necessary to check correctness of their functioning regularly.

Owing to lengthening of the period of repolarization of ventricles of heart, pharmacological action of Amiodaronum causes certain changes on an ECG: lengthening of an interval of QT, QTS (korrigirovanny), is possible emergence U waves. Admissible lengthening of an interval of QT – no more than 450 ms or no more than at 25% of initial size. These changes are not manifestation of toxic effect of drug, however, demand control for dose adjustment and assessment of possible proaritmogenny action.

At development of AV of blockade of the II-III degree, sinuatrial blockade or dvukhpuchkovy intra ventricular blockade, treatment has to be stopped. At emergence of AV of blockade of the I degree it is necessary to double the watch of the patient.

At emergence of a vision disorder (an illegibility of visual perception, decrease in visual acuity) it is necessary to conduct ophthalmologic examination, including an eyeground research. At development of neuropathy or optic neuritis, treatment is stopped (risk of development of a blindness).

Use at pregnancy and in the period of a lactation perhaps only at life-threatening disturbances of a rhythm at inefficiency of other antiarrhytmic therapy (causes a hypothyroidism, a craw, bradycardia and a delay of intellectual development in newborns).

Safety and efficiency of use for children are not established, they can have a beginning, and effect duration less, than at adults.

Drug contains iodine therefore can exert impact on results of tests of accumulation of a radioiodine in a thyroid gland.

During treatment it is necessary to abstain from driving of the car and occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Frequency: very often (10% and more), it is frequent (1% and more; less than 10%), infrequently (0,1% and more; less than 1%), are rare (0,01% and more; less than 0,1%), are very rare (less than 0,01%, including separate cases), frequency is unknown (according to the available data frequency cannot be determined).

From cardiovascular system: often – moderate bradycardia (dozozavisimy); infrequently sinuatrial and AV blockade of various degrees, proaritmogenny action (emergence new or aggravation of the available arrhythmias, including with a cardiac standstill); very seldom – the expressed bradycardia, a stop of a sinus node (at patients with dysfunction of a sinus node and elderly patients); frequency is unknown – progressing of chronic heart failure (at prolonged use).

From the alimentary system: very often – nausea, vomiting, a loss of appetite, obtusion or loss of flavoring feelings, heavy feeling in epigastriums, the isolated increase in activity of "hepatic" transaminases (norms are 1,5-3 times higher); often – acute toxic hepatitis with increase in activity of "hepatic" transaminases and/or jaundice, including development of a liver failure, including fatal; very seldom – a chronic liver failure (pseudo-alcoholic hepatitis, cirrhosis), including fatal.

From respiratory system: often – the intersticial or alveolar pneumonitis obliterating a bronchiolitis with pneumonia including with a lethal outcome, pleurisy, pulmonary fibrosis; very seldom – a bronchospasm at patients with heavy respiratory insufficiency (especially at patients with bronchial asthma), an acute respiratory syndrome, including with a lethal outcome; frequency is unknown – pulmonary bleeding.

From sense bodys: very often – the microdeposits in a cornea epithelium consisting of difficult lipids including lipofuscin (complaints to emergence of a color aura or an illegibility of contours of objects at bright lighting); very seldom – neuritis of a visual nerve / visual neuropathy.

From a metabolism: often – a hypothyroidism, a hyperthyroidism; very seldom – a syndrome of disturbance of secretion of antidiuretic hormone.

From integuments: very often – a photosensitization; often – a grayish or bluish xanthopathy (at prolonged use; disappears after the termination of administration of drug); very seldom – an erythema (at simultaneous radiation therapy), skin rash, exfoliative dermatitis (connection with administration of drug is not established), an alopecia.

From the central nervous system: often – a tremor and other extrapyramidal symptoms, sleep disorders, including "dreadful" dreams; seldom – peripheral neuropathy (sensomotor, motor, mixed) and/or a myopathy; very seldom – a cerebellar ataxy, benign intracranial hypertensia (a brain pseudoneoplasm), a headache.

Others: very seldom – a vasculitis, an epididymite, impotence (connection with administration of drug is not established), thrombocytopenia, hemolitic or aplastic anemia.

Interaction with other medicines:

Amiodaronum interacts with a large number of medicines. Because of a big elimination half-life, the possibility of emergence of interactions exists not only with at the same time applied medicines, but also with medicines which will be applied after the therapy termination by Amiodaronum.

Contraindicated combinations (risk of development of polymorphic ventricular tachycardia like "pirouette"):

- antiarrhytmic means of IA of a class (quinidine, hydroquinidine, Disopyramidum, procaineamide), III class (дофетилид, ибутилид, bretylium tosylate); соталол;

- others (not antiarrhytmic means), such as bepridit, Vincaminum, some neuroleptics: fenotiazina (Chlorpromazinum, циамемазин, levomepromazinum, thioridazine, трифлуоперазин, Fluphenazin), benzamides (амисульприд, сультоприд, Sulpiridum, тиаприд, вералиприд), phenyl propyl ketones (Droperidolum, haloperidol), сертиндол, Pimozidum; tricyclic antidepressants; цизаприд; makrolidny antibiotics (erythromycin at intravenous administration, Spheromycinum); azoles; antimalarial means (quinine, chloroquine, мефлохин, галофантрин, лумефантрин); pentamidine (parenterally); difemanit methyl sulfate; мизоластин; астемизол; терфенадин; ftorkhinolona (including moxifloxacin).

Not recommended combinations:

- beta adrenoblockers, blockers of "slow" calcium channels (verapamil, diltiazem) – risk of disturbance of automatism (the expressed bradycardia) and conductivity;

- the purgatives stimulating an intestines peristaltics – risk of development of ventricular tachycardia like "pirouette" against the background of the hypopotassemia caused by purgatives; at a combination to Amiodaronum it is necessary to use purgatives of other groups.

The combinations demanding use with care:

- the diuretics causing a hypopotassemia, Amphotericinum In (intravenously), system glucocorticosteroids, тетракозактид – risk of development of ventricular disturbances of a rhythm, including ventricular tachycardia like "pirouette";

- procaineamide – risk of development of side effects of procaineamide (Amiodaronum increases plasma concentration of procaineamide and its metabolite of N-atsetilprokainamida);

- anticoagulants of indirect action (warfarin) – Amiodaronum increases concentration of warfarin (risk of development of bleedings) at the expense of CYP2C9 isoenzyme inhibition. Regular control of a prothrombin time and correction of doses of anticoagulant is necessary both during therapy by Amiodaronum, and after its cancellation.

- cardiac glycosides – automatism disturbance (the expressed bradycardia) and AV of conductivity (increase in concentration of digoxin);

- эсмолол – disturbance of contractility, automatism and conductivity (suppression of compensatory reactions of a sympathetic nervous system). Clinical and electrocardiographic (ECG) control is required.

- Phenytoinum, фосфенитоин – risk of development of neurologic disturbances (Amiodaronum increases concentration of Phenytoinum at the expense of CYP2C9 isoenzyme inhibition);

- флекаинид – Amiodaronum increases its concentration (at the expense of CYP2D6 isoenzyme inhibition);

- the medicines which are metabolized with participation of an isoenzyme of CYP3A4 (cyclosporine, fentanyl, lidocaine, такролимус, sildenafit, midazolam, to triazoles, dihydroergotamine, ergotamine, statines, including симвастатин) – Amiodaronum increases their concentration (risk of development of their toxicity and/or strengthening of pharmakodinamichesky effects);

- орлистат reduces concentration of Amiodaronum and its active metabolite in a blood plasma;

- a clonidine, гуанфацин, cholinesterase inhibitors (donepezil, Galantaminum, ривастигмин, такрин, an ambenoniya chloride, pyridostigmine, неостигмин), Pilocarpinum – risk of development of the expressed bradycardia (cumulative effect);

- Cimetidinum, grapefruit juice slow down metabolism of Amiodaronum and increase its plasma concentration;

- medicines for an inhalation anesthesia – risk of development of bradycardia (resistant to administration of atropine), lowerings of arterial pressure, disturbances of conductivity, decrease in cordial emission, acute respiratory a distress syndrome, including fatal which development is connected with high concentration of oxygen;

- the radioiodine – Amiodaronum (contains iodine in the structure) can break absorption of a radioiodine that can distort results of a radio isotope research of a thyroid gland;

- rifampicin and drugs of a St. John's Wort (powerful inductors of an isoenzyme CYP3A4) reduce concentration of Amiodaronum in plasma;

- HIV protease inhibitors (CYP3A4 isoenzyme inhibitors) can increase plasma concentration of Amiodaronum;

- klopidogret – possibly decrease in its plasma concentration;

- dextromethorphan (substrate of isoenzymes of CYP3A4 and CYP2D6) – increase in its concentration is possible (Amiodaronum inhibits CYP2D6 isoenzyme.

Contraindications:

- Hypersensitivity to iodine, Amiodaronum or to other components of drug;

- a sick sinus syndrome (a sinus bradycardia and sinuatrial blockade, in the absence of an artificial pacemaker (risk of a stop of a sinus node);

- AV blockade of the II-III degree, two - and trekhpuchkovy blockade (in the absence of an artificial pacemaker);

- hypopotassemia, hypomagnesiemia;

- hypothyroidism, hyperthyroidism;

- intersticial pulmonary diseases;

- the inborn or acquired lengthening of an interval of QT;

- pregnancy and period of a lactation;

- a concomitant use with drugs which can extend an interval of QT and cause development of Bouveret's diseases, including polymorphic ventricular tachycardia like "pirouette" (torsade de pointe):

- antiarrhytmic means of IA of a class (quinidine, Disopyramidum, procaineamide), antiarrhytmic means of the III class (дофетилид, ибутилид, bretylium tosylate); соталол;

- other (not antiarrhytmic) means, such as, bepridit; Vincaminum; some neuroleptics: fenotiazina (Chlorpromazinum, циамемазин, levomepromazinum, thioridazine, трифлуоперазин, Fluphenazin), benzamides (амисульприд, сультоприд, Sulpiridum, тиаприд, вералиприд), phenyl propyl ketones (Droperidolum, haloperidol), сертиндол, Pimozidum; цизаприд; tricyclic antidepressants; makrolidny antibiotics (in particular erythromycin at intravenous administration, Spheromycinum); azoles; antimalarial means (quinine, chloroquine, мефлохин, галофантрин); pentamidine at parenteral administration; difemanit methyl sulfate; мизоластин; астемизол, терфенадин; ftorkhinolona.

- concomitant use of inhibitors of a monoaminooxidase (MAO);

- age up to 18 years (efficiency and safety are not established);

- lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption.

With care: to apply at chronic heart failure (the III-IV functional class on NYHA classification), AV to blockade of the I degree, a liver failure, bronchial asthma, at patients of advanced age (high risk of development of the expressed bradycardia).

Overdose:

Symptoms: a sinus bradycardia, an atrioventricular block, ventricular tachycardia, a Bouveret's disease like "pirouette", aggravation of the available chronic heart failure, an abnormal liver function, a cardiac standstill.

Treatment: a gastric lavage and reception of absorbent carbon if drug is accepted recently; symptomatic therapy (at bradycardia – beta адреностимуляторы or installation of a pacemaker; at tachycardia like "pirouette" - in/in administration of salts of magnesium or cardiostimulation). There is no specific antidote, the hemodialysis is inefficient.

Storage conditions:

Period of validity - 3 years. Not to use after the period of validity specified on packaging. List B. In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets of 200 mg. On 10, 15, 20 or 30 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1, 2 or 3 blister strip packagings with the application instruction in a pack from a cardboard.