medicalmeds.eu Medicines Antiarrhytmic means. Amiodaronum

Amiodaronum

Producer: CJSC Biokom Russia

Code of automatic telephone exchange: C01BD01

Release form: Firm dosage forms. Tablets.

Indications to use: Prevention of arrhythmia. Fibrillation of ventricles. Supraventricular arrhythmia. WPW-syndrome. Prevention of sudden coronary death.

General characteristics. Structure:

Active ingredient: hydrochloride Amiodaronum - 200 mg,

excipients: лудипресс (lactoses monohydrate, K30 povidone (коллидон 30), кросповидон (коллидон CL)) – 204,2 mg, potato starch – 8,4 mg, magnesium stearate – 4,2 mg, silicon dioxide colloid (aerosil) – 4,2 mg.

Pharmacological properties:

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

Antiarrhytmic action is caused by influence on electrophysiologic processes of a myocardium; extends the action potential of cardiomyocytes; increases the effective refractory period of auricles, ventricles, an atrioventricular (AV) node, Giss's bunch 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 and decrease in AV of conductivity.

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 heart rate; 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 near
37% of its molecular weight. Influences exchange of thyroid hormones, inhibits transformation _{of T4} into _TZ (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 (deficit _{of TZ} can lead to its hyperproduction and a thyrotoxicosis). The beginning of action (even when using "load" doses) - from
2-3 days up to 2-3 months, vary 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 - 30-50 %, bioavailability -
30-50 %. The maximum concentration in a blood plasma (Cmax) is noted in 4-7 hours. 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 equilibrium concentration in a blood plasma – from one to several months. 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 a blood 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 (GEB) 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, is inhibitor of isoenzymes CYP2C9, CYP2D6 and CYP3A4, CYP3A5, CYP3A7 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.

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 hour, in the second _{phase T1/2} - 25-110 days. After long oral administration 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 other antiarrhytmic therapy, connected with a WPW syndrome), blinking and an atrial flutter.

Prevention of sudden death owing to arrhythmia at patients from group of high risk: patients after recently postponed myocardial infarction with quantity of ventricular extrasystoles more than 10/h, clinical signs of chronic heart failure and fraction of emission of a left ventricle less than 40 %.

Route of administration and doses:

Pill is taken inside entirely before meal, washing down with enough liquid.

The mode of dosing is set individually and adjusted by the doctor.

The load ("sating") dose: in a hospital – the initial dose (divided into several receptions) makes 600-800 mg/days (3 tablets), 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. At the supporting treatment the minimal effective dose depending on individual reaction of the patient is applied and usually makes from 100 to 400 mg/days (1/2-2 tablets). 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.

Average therapeutic single dose - 200 mg.

Average therapeutic daily dose - 400 mg.

The maximum single dose - 400 mg.

The maximum daily dose - 1200 mg.

Features of use:

Before therapy it is recommended to conduct an ECG research, to estimate function of a thyroid gland (concentration of hormones), and content of potassium in a blood plasma. The hypopotassemia has to be corrected prior to treatment. During treatment it is regularly necessary to control an ECG (each 3 months) both activity of "hepatic" transaminases and other indicators of function of a liver, and also function of a thyroid gland (including within several months after its cancellation), 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 glucosteroids) 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 use 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 reception of Amiodaronum (risk of strengthening of hemodynamic effect of the general and local anesthetics).

At patients it is long receiving treatment concerning disturbances of a 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 Amiodaronum 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 of 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 an atrioventricular block of the II-III degree, sinuatrial blockade or dvukhpuchkovy intra ventricular blockade, treatment has to be stopped. At emergence of an atrioventricular block 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).

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

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

Influence on ability to driving of motor transport and to control of mechanisms.

During treatment by Amiodaronum 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 - a sinuatrial and atrioventricular block of various degrees, proaritmogenny action (emergence new or aggravation of the available arrhythmias, including with a cardiac standstill); very seldom - 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 (psevdoalkogolny 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 distress 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 - an optic neuritis, 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; frequency is unknown – a Quincke's disease, a small tortoiseshell.

From a nervous system: often - a tremor and other 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.

Laboratory indicators: seldom - at prolonged use - thrombocytopenia, hemolitic and aplastic anemia.

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

Interaction with other medicines:

Contraindicated combinations:

- antiarrhytmic IA medicines of a class (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 (доксепин, amitriptyline), Maprotilinum, 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) as the risk of development of ventricular tachycardia like "pirouette" increases.

Not recommended combinations:

- with beta adrenoblockers, some blockers of "slow" calcium channels (verapamil, diltiazem), there is a risk of disturbance of automatism (the expressed bradycardia) and conductivity.

- with purgatives which can cause a hypopotassemia as the risk of development of ventricular tachycardia like "pirouette" increases.

Combinations at which it is necessary to show 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-atsetilprokainamida);

- anticoagulants of indirect action (warfarin) - Amiodaronum increases concentration of warfarin in a blood plasma (risk of development of bleedings) at the expense of CYP2C9 isoenzyme inhibition; cardiac glycosides - automatism disturbance (the expressed bradycardia) and atriventrikulyarny conductivity (increase in concentration of digoxin in a blood plasma);

- 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 in a blood plasma at the expense of CYP2C9 isoenzyme inhibition);

- флекаинид - Amiodaronum increases its concentration in a blood plasma (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, HMG-CoA reductase inhibitors) - Amiodaronum increases their concentration in a blood plasma (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;

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

- 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 the St. John's Wort which is made a hole (powerful inductors of an isoenzyme CYP3A4) reduce concentration of Amiodaronum in a blood plasma;

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

- klipodogret - possibly decrease in its concentration in a blood plasma;

- dextromethorphan (substrate of isoenzymes of CYP3A4 and CYP2D6) - increase in its concentration in a blood plasma is possible (Amiodaronum inhibits CYP2D6 isoenzyme);

- at simultaneous use with drugs of lithium development of a hypothyroidism is possible;

- at simultaneous use with Colestyraminum concentration of Amiodaronum in a blood plasma owing to its linkng with Colestyraminum and reduction of absorption from a GIT decreases;

- at simultaneous use with drug co-trimoxazole deterioration in intra-atrial conduction is possible.

Contraindications:

Hypersensitivity to drug components (including to iodine), a sick sinus syndrome (a sinus bradycardia, sinuatrial blockade), in the absence of an artificial pacemaker (risk of a stop of a sinus node), an atrioventricular block of the II-III degree and two - and trekhpuchkovy blockade (without use of a pacemaker), cardiogenic shock, a collapse, arterial hypotension, age up to 18 years, a lactose intolerance, deficit of lactase, glyukozo-galaktozny malabsorption, a refractory hypopotassemia, a hypomagnesiemia, a hypothyroidism, a hyperthyroidism, intersticial pulmonary diseases, the inborn or acquired lengthening of an interval of QT, a concomitant use of inhibitors of a monoaminooxidase, pregnancy, the lactation period.

Concomitant use of the medicine extending an interval of QT and causing a Bouveret's disease including polymorphic ventricular the pirouette type: antiarrhytmic IA medicines of a class (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 (доксепин, amitriptyline), Maprotilinum, 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).

Overdose:

In case of toxicity in the form of proaritmogenny effect drug is cancelled.

Symptoms: a sinus bradycardia, arrhythmias, 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 (1-2 hours from the reception moment). At tachycardia like "pirouette" - intravenous administration of salts of magnesium, cardiostimulation. In other cases carry out symptomatic therapy. There is no specific antidote, the hemodialysis is inefficient, Amiodaronum and its metabolites are not removed at dialysis. At development of bradycardia purpose of atropine, beta1-adrenostimulyator, in hard cases - cardiostimulation is possible.