Amiodaronum

General characteristics. Structure:

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

Excipients: lactoses monohydrate, starch, povidone, calcium stearate.

Pharmacological properties:

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

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, a tone of coronary vessels; increases a coronary blood stream; urezhat heart rate; raises power reserves of a myocardium (due to increase in contents creatine of sulfate, adenosine and glycogen).

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

Blocking the inactivated "bystry" natrium channels, renders the effects characteristic of antiarrhytmic medicines I of a class.

Slows down slow (diastolic) depolarization of a membrane of cells of a sinus node, causing bradycardia, atrioventricular carrying out (effect of antiaritmik of the IV class) oppresses.

On the structure it is similar to thyroid hormones. Content of iodine makes about 37% its pier. masses. Influences exchange of thyroid hormones, suppresses transformation of T4 into T3 (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 plasma for 9 months after the termination of its reception).

Pharmacokinetics. Absorption slow and variable - 30-50%, bioavailability - 30-50%. The maximum concentration 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). 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 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, it is metabolized 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 the fermental CYP2C9, CYP2D6 and CYP3A4, CYP3A5, CYP3A7 system in a liver.

Considering ability to cumulation and the big variability of pharmacokinetic parameters connected with it, data on an elimination half-life are contradictory. Removal of Amiodaronum after oral administration is carried out in 2 phases: an initial stage - 4-21 h, in the second phase an elimination half-life - 25-110 days. After long oral administration an average elimination half-life - 40 days (it is important at the choice of a dose since, perhaps, it is necessary at least 1 month 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:

Therapy by Amiodaronum can be performed only in hospitals or is out-patient under observation of the cardiologist. Amiodaronum is shown only for treatment of the heavy arrhythmias which are not giving in to therapy by other medicines or when other medicines cannot be appointed.

The tachyarrhythmias connected with a WPW syndrome.

Blinking and atrial flutter if other medicines cannot be appointed.

Tachyarrhythmias of paroxysmal character, including atrial, atrioventricular and ventricular tachycardias, fibrillation of ventricles when other medicines cannot be appointed.

Route of administration and doses:

Inside, before meal, washing down with enough water.

The load ("sating") dose: in a hospital - the initial dose (divided into several receptions) - 600-800 mg/days, the maximum-1200 mg/days 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) 600-800 mg/days - before achievement of a total dose of 10 g (usually within 10-14 days).

Maintenance dose - 100-400 mg/days. It is necessary to use a minimal effective dose.

Owing to long T1/2 drug can be accepted every other day or to do a break in administration of drug - 2 days a week.

Features of use:

Before therapy it is necessary to conduct an ECG, X-ray inspection of lungs, to estimate function of a thyroid gland (concentration of hormones), a liver (activity of transaminases) and concentration of electrolytes (potassium) of plasma.

During treatment carry periodically out the analysis of transaminases (at increase by 3 times or doubling in case of initially increased their activity the dose is reduced, up to complete cessation of therapy) and an ECG (width of the QRS complex and duration of an interval of QT). Increase in an interval of QTc no more than 450 ms or no more than at 25% of initial size is admissible. These changes are not manifestation of toxic effect of drug, however demand control for dose adjustment and assessment of possible proaritmogenny action of Amiodaronum.

Annual X-ray inspection of lungs, 1 time in half a year – a research of function of external respiration, the maintenance of T3 and T4 is recommended. In the absence of clinical signs of dysfunction of a thyroid gland treatment should not be stopped. Emergence of an asthma or unproductive cough can be connected with toxic action of Amiodaronum on lungs. Disturbances from respiratory system are generally reversible at early cancellation of Amiodaronum. Clinical symptoms usually pass within 3-4 weeks, and then there is slower recovery of a X-ray pattern and function of lungs (several months). Therefore it is necessary to consider the possibility of revaluation of therapy by Amiodaronum and purposes of glucocorticosteroids.

For prevention of development of a photosensitization it is recommended to avoid stay in the sun or to use special sunblock creams.

At emergence of an illegibility of sight or decrease in visual acuity against the background of reception of Amiodaronum, it is recommended to conduct full ophthalmologic examination, including a fundoskopiya. Cases of a neuropathy and/or an optic neuritis require the solution of a question of expediency of use of Amiodaronum.

At cancellation a recurrence of disturbances of a rhythm is possible.

Use at pregnancy and a lactation is possible only at life-threatening disturbances of a rhythm at inefficiency of other antiarrhytmic therapy (causes dysfunction of a thyroid gland of a fruit). Safety and efficiency of use for children are not defined.

After cancellation the pharmakodinamichesky effect remains within 10-30 days.

Contains iodine (in 200 mg – 75 mg of iodine) therefore can exert impact on results of tests of accumulation of a radioiodine in a thyroid gland.

When carrying out surgical interventions it is necessary to inform the anesthesiologist of administration of drug (a possibility of development acute respiratory a distress syndrome at adults directly after surgical intervention).

In case of simultaneous use of Amiodaronum and a simvastatin the dose of a simvastatin should not exceed 20 mg a day in connection with potential risk of development of a rabdomioliz in such patients. The patient also has to be informed on need of the immediate address to the doctor for a case emergence of any unexpected muscular pain, muscular weakness.

During treatment it is necessary to abstain from driving of motor transport 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 (dozozavisima); infrequently - SA 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 eligastriya, 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 ADG.

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

Others: very seldom - the vasculitis, elididimit, impotence (connection with administration of drug is not established), thrombocytopenia, hemolitic and aplastic anemia.

Interaction with other medicines:

Contraindicated combinations (risk of development of polymorphic ventricular tachycardia like "pirouette"): antiarrhytmic medicines 1 of a class A (quinidine, hydroquinidine, Disopyramidum, procaineamide), III class (дофетилид, ибутилид, bretylium tosylate), соталол; bepridit, Vincaminum, fenotiazina (Chlorpromazinum, циамемазин, levomepromazinum, thioridazine, трифлуоперазин, Fluphenazin), benzamides (амисульприд, сультоприд, Sulpiridum, тиаприд, вералиприд), phenyl propyl ketones (Droperidolum, a haloperidol), сертиндол, Pimozidum; tricyclic antidepressants, цизаприд, macroleads (erythromycin in/in, Spheromycinum), azoles, antimalarial medicines (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 laxative medicines stimulating an intestines peristaltics – risk of development of ventricular tachycardia like "pirouette" against the background of the hypopotassemia caused by laxative medicines.

The combinations demanding use with care:

- the diuretics causing a hypopotassemia, Amphotericinum In (in/in), 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-of an atsetilprokainamid);

- anticoagulants of indirect action (warfarin) – Amiodaronum increases concentration of warfarin (risk of development of bleedings) at the expense of CYP2C9 isoenzyme inhibition; 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);

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

- 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), decrease in the ABP, disturbance 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 the St. John's Wort which is made a hole (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 (including to iodine), a sick sinus syndrome, a sinus bradycardia, sinuatrial blockade, an atrioventricular block of the II-III Art. (without use of a pacemaker), cardiogenic shock, a hypopotassemia, a collapse, arterial hypotension, a hypothyroidism, a thyrotoxicosis, intersticial pulmonary diseases, reception of monoamine oxidase inhibitors.

Two - and trekhpuchkovy blockade (without use of a pacemaker), a hypomagnesiemia, a hypothyroidism, a hyperthyroidism, the inborn or acquired lengthening of an interval of Q-T, a concomitant use of the medicines extending an interval of Q-T and causing a Bouveret's disease (including polymorphic ventricular the pirouette type), pregnancy, the lactation period.

With care. Chronic heart failure (the III-IV FC on NYHA classification), AV blockade the I Art., a liver failure, bronchial asthma, advanced age (high risk of development of heavy bradycardia).

Overdose:

Symptoms: bradycardia, an atrioventricular block, a lowering of arterial pressure, a Bouveret's disease like "pirouette", aggravation of the available HSN, an abnormal liver function, a cardiac standstill.

Treatment: purpose of absorbent carbon, gastric lavage, purpose of Colestyraminum; at bradycardia - beta адреностимуляторов or installation of a pacemaker; at tachycardia like "pirouette" - in/in administration of salts of magnesium, cardiostimulation. The hemodialysis is inefficient.

Storage conditions:

To store the place protected from light and moisture, at a temperature not over 25 ºС. To store in the place, unavailable to children. A period of validity - 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

On 3 or 6 blister strip packagings on 10 tablets in a pack.