Amiodaronum

General characteristics. Structure:

Active agent - Amiodaronum a hydrochloride of 200 mg.

Excipients: potato starch, cellulose microcrystallic, magnesium stearate, кросповидон (Kollidon CL-M), silicon dioxide colloid, gipromelloz (gidroksipropilmetiltsellyuloz).

Pharmacological properties:

Pharmacokinetics. Absorption slow and variable - 30-50%, bioavailability - 30-50%. The maximum concentration in a blood plasma (Cmax) is noted in 4-7 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 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. 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 oral administration is carried out in 2 phases: an initial stage - 4-21 h, 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 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.

Pharmacodynamics. Amiodaronum Acre - antiarrhytmic drug III of a class (repolarization inhibitor). Possesses also anti-anginal, koronarodilatiruyushchy, alpha and beta and adrenoceptor blocking, thyritropic and hypotensive 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, 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 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 about 37% of its molecular weight. Influences exchange of thyroid hormones, inhibits 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 (deficit of T3 can bring to its hyperproduction and a thyrotoxicosis). 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).

Indications to use:

- treatment and the prevention of the disturbances of a heart rhythm connected with a WPW-syndrome (WPW), paroxysms of blinking and an atrial flutter; atrial and ventricular premature ventricular contraction; a parasystole, ventricular arrhythmias at patients with Shagas's myocarditis;

- prevention of repeated fibrillation of ventricles and auricles;

- treatment of ventricular tachycardia;

- treatment of supraventricular tachycardia for the purpose of recovery of a sinoatrial rate during the blinking and an atrial flutter;

- during rehabilitation after a myocardial infarction if in the anamnesis there are instructions on earlier noted arrhythmia episodes.

Route of administration and doses:

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

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

The sating dose makes 600 mg/days (3 tablets), divided into 2-3 receptions. Course of treatment of 8-15 days. If necessary the dose of the drug Amiodaronum Acre can be raised to 800-1200 mg/days (4-6 tablets), for the short period and under control of an ECG. After achievement of signs of saturation pass to a maintenance therapy.

Maintenance dose. At the supporting treatment the smallest effective dose depending on individual reaction of the patient is applied and usually makes from 200-400 mg/days (1-2 tablets) in 1-2 receptions. In cases when it is possible every 5 days administration of drug do a two-day break.

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 an initiation of treatment, and also every 3 month it is necessary to carry out an ECG control, at the same time it is necessary to consider that at elderly patients more expressed bradycardia is noted, it is also necessary to conduct X-ray inspection of lungs, to estimate function of a thyroid gland (content of hormones), a liver (enzymes). Frequency and weight of side effects depend on a drug dose therefore it is necessary to apply minimum effective maintenance doses.

At use of drug of Amiodaroni changes on an ECG are possible: lengthening of an interval of QT with possible emergence of a tooth of U. At emergence of an atrioventricular block of II and III degrees, sinuatrial blockade, and also blockade of legs of a ventriculonector treatment by the drug Amiodaronum should be stopped immediately.

The progressing asthma and unproductive cough can be signs of damage of lungs. It is recommended to conduct X-ray inspection of a thorax and pulmonary functional trials (each 6 months and in case of development of clinical signs of a disease of lungs).

Before therapy it is necessary to determine the content of electrolytes of a blood plasma. During treatment carry regularly out by the drug Amiodaronum control of activity of enzymes of a liver. During treatment carry periodically out the analysis of an ECG (width of the QRS complex and duration of an interval of QT), 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).

In the course of treatment it is necessary to conduct an ophthalmologic research (identification of considerable deposits on a cornea and a vision disorder cancellations of Amiodaronum demand). At cancellation a recurrence of disturbances of a rhythm is possible.

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 dysfunction of a thyroid gland of a fruit).

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

Drug contains iodine therefore can exert impacts on results of tests of accumulation of a radioiodine in a thyroid gland. Therefore before an initiation of treatment, during its carrying out and for several months after the end of treatment it is necessary to conduct researches of function of a thyroid gland. Before carrying out surgical interventions, and also the oxygenotherapy needs to warn the doctor about drug Amiodaronum use as exceptional cases of development acute respiratory a distress syndrome at adults in the postoperative period were celebrated.

In order to avoid development of a photosensitization patients should avoid stay in the sun or to use effective measures of protection.

It is necessary to be careful at use of drug during the general anesthesia, the risk of development of bradycardia, the expressed lowering of arterial pressure, disturbances of conductivity and reduction of a stroke output of heart is possible.

During treatment by the drug 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.

It is contraindicated to use in II and the III trimester of pregnancy as during this period the thyroid gland of the newborn begins to accumulate 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.

Side effects:

Very often (≥ 10):

- nausea;

- vomiting;

- taste disturbance;

- lock;

- meteorism;

- diarrhea;

- pain in epigastric area;

- adjournment of lipofuscin in a cornea epithelium (often subjective complaints at the same time are absent, but if deposits considerable and partially fill a pupil, complaints to emergence of color auras or an illegibility of contours are possible);

- uveitis;

- photosensitization (dermahemia).

Often (> 1/100, <1/10):

- a sinus bradycardia (refractory to cholinolytics);

- at prolonged use - toxic hepatitis, a cholestasia, a liver failure, cough, an asthma, an alveolar and/or intersticial pneumonitis, pneumonia, a pneumosclerosis, pleurisy, an apnoea;

- increase in the T4 level at the normal or slightly expressed decrease in T3 (in the absence of clinical signs of dysfunction of a thyroid gland treatment should not be stopped). At prolonged use development of a hypothyroidism or hyperthyroidism is possible (it is necessary to cancel drug);

- the lead-blue or bluish xanthopathy (at long use), after the treatment termination pigmentation slowly disappears within 10-14 days;

- tremor;

- extrapyramidal frustration;

- sleep disorder.

Not really often (> 1/1 000, <1/100):

- sinuatrial blockade;

- AV blockade;

- "inflows" of blood to face skin;

- aritmogenny action.

Seldom (> 1/10 000, <1/1 000):

- at prolonged use peripheral neuropathy, a myopathy (symptoms are reversible after drug withdrawal).

Very seldom (<1/10 000):

- cirrhosis;

- a bronchospasm (especially at patients with heavy respiratory insufficiency or bronchial asthma);

- an acute respiratory distress syndrome, sometimes with a lethal outcome and sometimes directly after surgical interventions (the possibility of interaction with high doses of oxygen is supposed);

- retina microamotio;

- optic neuritis;

- development of a syndrome of inadequate secretion of antidiuretic hormone;

- skin rash, including exfoliative dermatitis;

- alopecia;

- headache;

- general weakness;

- dizziness;

- depression;

- feeling of fatigue;

- paresthesias;

- auditory hallucinations;

- memory disturbance;

- cerebellar ataxy;

- benign intracranial hypertensia (brain pseudoneoplasm);

- Quincke's disease;

- increase in activity of "hepatic" transaminases;

- at prolonged use – thrombocytopenia, hemolitic and aplastic anemia;

- epididymite;

- decrease in a libido;

- disturbance of a potentiality;

- vasculitis;

- damage of kidneys with increase in level of creatinine.

Frequency is unknown:

- at prolonged use - progressing of symptoms of chronic heart failure, tachycardia like "pirouette", weighting of a course of the existing arrhythmia or its emergence;

- pulmonary bleeding.

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.

Not recommended combinations:

- with galofantriny, pentamidine, astemizoly, terfenadiny, lume-fantriny, tricyclic antidepressants as lengthening of an interval of QT is possible that increases risk of development of ventricular disturbances of a rhythm, in particular tachycardias like "pirouette";

- with beta adrenoblockers, some blockers of "slow" calcium channels (verapamil, diltiazem) as automatism disturbances (bradycardia) and conductivity can develop;

- with purgatives which can cause a hypopotassemia as the risk of development of ventricular tachycardia like "pirouette" (torsade de pointe) increases;

- from ftorkhinolona (in particular moksifloksatsiny) – lengthening of an interval of QT is possible.

Combinations at which it is necessary to show care:

- with the drugs causing a hypopotassemia (diuretics, system glucocorticosteroids, тетракозактид, pentamidine, Amphotericinum In (intravenously), as possibly development of ventricular tachycardia like "pirouette" (torsade de pointe);

- with anticoagulants for intake as the risk of development of bleedings increases (it is necessary to control the level of a prothrombin and to adjust a dose of anticoagulants);

- with cardiac glycosides as automatism disturbances can be observed (are shown by bradycardia) and disturbances of atrioventricular conductivity. Besides, increase in concentration of digoxin in a blood plasma due to decrease in its clearance is possible (it is necessary to control concentration of digoxin in a blood plasma, an ECG – control);

- with Phenytoinum, cyclosporine increase in their concentration in a blood plasma is possible (it is necessary to control concentration of Phenytoinum or cyclosporine in a blood plasma);

- Colestyraminum reduces absorption, an elimination half-life and concentration of Amiodaronum;

- Cimetidinum slows down metabolism of Amiodaronum that can cause increase in concentration of Amiodaronum in a blood plasma;

- means for inhalation anesthesia, an oxygenotherapy increase risk of development of bradycardia (resistant to atropine), arterial hypotension, disturbance of conductivity, decrease in the IOC;

- Amiodaronum can suppress absorption of Natrii iodidum (131-I, 123-I) and sodium of a pertekhnetat (99mTc) a thyroid gland;

- combined use with lithium increases risk of a hypothyroidism;

- Amiodaronum increases toxicity of a methotrexate;

- rifampicin reduces Amiodaronum level in blood serum (acceleration of metabolism in a liver);

- Amiodaronum slows down metabolism of a budesonid that as a result can lead to emergence of a syndrome of Cushing;

- inhibitors of HIV proteases (ампренавир, индинавир, нелфинавир, ритонавир) – increase concentration of Amiodaronum in blood serum, risk of development of arrhythmias;

- симвастатин (strengthening of risk of the side effects depending on a dose) like a rabdomioliz. The dose of a simvastatin should not exceed 20 mg a day. If at such dose it is not possible to reach therapeutic effect, it is necessary to pass to other statine which is not entering interactions of this kind;

- the medicines causing a photosensitization have the additive photosensitizing effect;

- grapefruit juice raises AUC and Cmax of Amiodaronum for 50% and 84% respectively;

- fentanyl – risk of development of bradycardia, decrease in the ABP and cordial emission;

- lidocaine for local local anesthesia and Amiodaronum inside – risk of development of a sinus bradycardia;

- Disopyramidum, ftorkhinolona, makrolidny antibiotics, azoles – risk of lengthening of an interval of QT;

- with the drugs which are metabolized by means of P450 3A4 cytochrome: fentanyl, lidocaine, такролимус, sildenafit, midazolam, to triazoles, ergotamine, statines.

Contraindications:

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

- sinus bradycardia and sinuatrial blockade;

- a sick sinus syndrome (in the absence of a pacemaker);

- an atrioventricular block of the II-III degree, disturbance of intra ventricular conductivity (two - and trekhpuchkovy blockade) in the absence of a pacemaker;

- cardiogenic shock, a collapse, the expressed arterial hypotension;

- dysfunction of a thyroid gland (hypo - and a hyperthyroidism);

- hypopotassemia;

- the expressed heart failure;

- intersticial pulmonary diseases;

- pregnancy and period of a lactation (breastfeeding);

- children's and teenage age up to 18 years (efficiency and safety are not established).

Contraindicated combinations:

- with the drugs capable to cause polymorphic ventricular tachycardia like "pirouette";

- antiarrhytmic means of IA of a class (quinidine, Disopyramidum); antiarrhytmic means of the III class (sotaloly, dofetilidy, ibutilidy); bepridily (at their combination to Amiodaronum the risk of development of ventricular tachycardia increases, in particular potentially lethal ventricular tachycardia like "pirouette" and predisposition to a sinus bradycardia, blockade of a sinus node and disturbances of AV of conductivity increases);

- other (not antiarrhytmic) drugs, such, as, Vincaminum; some neuroleptics: fenotiazina (Chlorpromazinum, циамемазин, levomepromazinum, thioridazine, трифлуоперазин), benzamides (ami-sulprid, сультоприд, сульприд, тиаприд, вералиприд), phenyl propyl ketones (Droperidolum, haloperidol), other neuroleptics (Pimozidum); цизаприд; makrolidny antibiotics, in particular erythromycin at intravenous administration, Spheromycinum; azoles; pentamidine at parenteral administration; difemanit methyl sulfate; мизоластин (at their combination to Amiodaronum the risk of development of ventricular tachycardia, in particular potentially lethal ventricular tachycardia like "pirouette" increases);

- with MAO inhibitors.

It is necessary to be careful at use of drug for patients with a liver failure, bronchial asthma, at patients of advanced age (high risk of development of the expressed bradycardia), chronic heart failure, an atrioventricular block of the I degree.

Overdose:

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

Symptoms: lowering of arterial pressure, sinus bradycardia, arrhythmias, atrioventricular block, abnormal liver functions.

Treatment: a gastric lavage and reception of absorbent carbon if drug is accepted recently. In other cases carry out symptomatic therapy. There is no specific antidote, the hemodialysis is not effective, Amiodaronum and its metabolites are not removed at dialysis. At development of bradycardia purpose of atropine, beta1-adrenostimulyator, in hard cases – cardiostimulation is possible.

Storage conditions:

To store 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 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.

3 blister strip packagings together with the instruction on a medical use in the state and Russian languages in a pack from a cardboard.