Amiodarone

Package leaflet (information for patients)

Tradename
Amiodarone

Dosage form
Tablets 200 mg .

Description
Round, flat, beveled to the edge white tablets with an imprint in the form of the brand name "V" on one side.

Structure
Active ingredient: Amiodarone 200 mg .
Excipients: microcrystalline cellulose 102, calcium stearate, aerosil ® 200 (hydrophilic pyrogenic silicon dioxide).

Pharmacotherapeutic group
Antiarrhythmic agent

Pharmacological properties
Amiodarone belongs to the III class of antiarrhythmic drugs (a class of repolarization inhibitors) and has a unique mechanism of antiarrhythmic action, since in addition to the properties of class III antiarrhythmics (potassium channel blockade), it has the effects of class I antiarrhythmics (blockade of sodium channels), class IV antiarrhythmics (calcium channel blockade)) and non-competitive beta- adrenergic blocking action.
In addition to antiarrhythmic action, it has antianginal, coronal expansion, alpha and beta adrenergic blocking effects.
Antiarrhythmic properties:
- an increase in the duration of the 3rd phase of the action potential of cardiomyocytes, mainly due to blocking the ion current in the potassium channels (the effect of class III antiarrhythmic according to Williams classification);
- a decrease in the automatism of the sinus node, leading to a decrease in the heart rate;
- non-competitive blockade of alpha and beta adrenergic receptors;
- slowing down of sinoatrial, atrial and atrioventricular conduction, more pronounced with tachycardia;
- no changes in ventricular conduction;
- an increase in refractory periods and a decrease in the excitability of the myocardium of the atria and ventricles, as well as an increase in the refractory period of the atrioventricular node;
- slowing down the conduction and increasing the duration of the refractory period in additional bundles of atrioventricular conduction.
Other effects:
- lack of negative inotropic action when taken orally;
- reduction of myocardial oxygen consumption due to a moderate reduction in the peripheral resistance and heart rate cut-tion ;
- an increase in coronary blood flow due to a direct effect on the smooth muscles of the coronary arteries;
- maintaining cardiac output by reducing the pressure in the aorta and reducing peripheral resistance;
- influence on the metabolism of thyroid hormones: inhibition of the conversion of T3 to T4 (blockade of thyroxine-5-deiodinase) and blocking the capture of these hormones by cardiocytes and hepatocytes, leading to a weakening of the stimulating effect of thyroid hormones on the myocardium. Therapeutic effects are observed on average one week after the start of taking the drug (from several days to two weeks). After the termination of his reception, amiodarone is determined in blood plasma for 9 months. The possibility of maintaining the pharmacodynamic effect of amiodarone for 10-30 days after its withdrawal should be taken into account .
Pharmacokinetics
Bioavailability after oral administration in different patients ranges from 30 to 80% (average value about 50%). After a single oral administration of amiodarone, maximum plasma concentrations are reached after 3-7 hours. However, the therapeutic effect usually develops within a week after the start of taking the drug (from several days to two weeks). Amiodarone is a drug with a slow release into tissues and a high affinity for them. The connection with blood plasma proteins is 95% (62% - with albumin, 33.5% - with beta-lipoproteins). Amiodarone has a large volume of distribution. During the first days of treatment, the drug accumulates in almost all tissues, especially in adipose tissue and, in addition, in the liver, lungs, spleen and cornea. Amiodarone is metabolized in the liver by the isoenzymes CYP3A4 and CYP2C8. Its main metabolite, desethylamiodarone, is pharmacologically active and can enhance the antiarrhythmic effect of the main compound. Amiodarone and its active metabolite desethylamiodarone in vitro have the ability to inhibit isoenzymes CYP1A1, CYP1A2, CYP2C19, CYP2D6, CYP2A6, CYP2B6 and CYP2C8. Amiodarone and desethylamiodarone have also been shown to inhibit certain transporters such as P-glycoprotein (P- gp) and organic cation transporter (OC2). In vivo interaction of amiodarone with substrates of isoenzymes CYP3A4, CYP2C9, CYP2D6 and P- gp was observed .
The elimination of amiodarone begins after a few days, and the achievement of balance between the intake and elimination of the drug (reaching an equilibrium state) occurs after one or several months, depending on the individual characteristics of the patient. The main route of elimination of amiodarone is the intestine. Amiodarone and its metabolites are not excreted by hemodialysis. Amiodarone has a long half-life of c great individual variability (and therefore the selection of doses, for example, increasing or decreasing it should pom -nit that requires at least one month in order to stabilize the new plasma concentrations of amiodarone). Oral elimination takes place in 2 phases: the initial half-life (first phase) is 4-21 hours, the half-life in the second phase is 25-110 days. After prolonged oral administration, the average elimination half-life is 40 days. After discontinuation of the drug, the complete elimination of amiodarone from the body may continue for several months. Each dose of amiodarone (200 mg) contains 75 mg of iodine. Part of the iodine is released from the drug and is found in the urine in the form of iodide (6 mg per 24 hours with a daily dose of 200 mg amiodarone). Most of the iodine remaining in the composition of the drug is excreted through the intestines after passing through the liver, however, with prolonged use of amiodarone, iodine concentrations can reach 60-80% of the concentrations of amiodarone in the blood. The peculiarities of the pharmacokinetics of the drug explain the use of "loading" doses, which is aimed at the rapid achievement of the required level of tissue saturation, at which its therapeutic effect is manifested .
Pharmacokinetics in renal failure
Due to the insignificant excretion of the drug by the kidneys in patients with renal insufficiency, no dose adjustment of amiodarone is required .

Indications for use
Relapse prevention
• Life-threatening ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation (treatment should be initiated in a hospital with close cardiac monitoring).
• Supraventricular paroxysmal tachycardia:
- documented attacks of recurrent persistent supraventricular paroxysmal tachycardia in patients with organic heart diseases;
- documented attacks of recurrent persistent supraventricular paroxysmal tachycardia in patients without organic heart disease, when antiarrhythmic drugs of other classes are ineffective or there are contraindications to their use;
- documented attacks of recurrent persistent supraventricular paroxysmal tachycardia in patients with Wolff-Parkinson-White syndrome.
• Atrial fibrillation (atrial fibrillation) and atrial flutter.
Prevention of sudden arrhythmic death in high-risk patients
Patients after a recent myocardial infarction, having more than 10 ventricular extrasystoles in 1 hour, clinical manifestations of chronic heart failure and a reduced left ventricular ejection fraction (less than 40%).
Amiodarone can be used to treat rhythm disturbances in patients with coronary artery disease and / or impaired left ventricular function.

Method of administration and dosage
The drug should only be taken as directed by a doctor!
Amiodarone tablets are taken orally, before meals and washed down
enough water.
Loading ("saturating") dose
Various saturation schemes can be used.
In a hospital, the initial dose, divided into several doses, ranges from 600-800 mg (up to a maximum of 1200 mg) per day until a total dose of 10 g is reached (usually within 5-8 days).
On an outpatient basis, the initial dose, divided into several doses, is from 600 to 800 mg per day until a total dose of 10 g is reached (usually within 10-14 days).
The maintenance dose can vary in different patients from 100 to 400 mg / day. The minimum effective dose should be used in accordance with the individual therapeutic effect.
Since amiodarone has a very long half-life, it can be taken every other day or taken 2 days a week off.
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
The frequency of the possible side effects listed below is determined according to the classification of the World Health Organization as follows: very often (> 1/10), often (> 1/100 to <1/10), infrequently (> 1/1000 to <1 / 100), rare (> 1/10000 to <1/1000), very rare (<1/10000), not known (cannot be estimated based on available data).
From the side of the heart: often - bradycardia, usually moderate, the severity of which depends on the dose of the drug; infrequently - conduction disturbances (sinoatrial block, atrioventricular block of various degrees), arrhythmogenic action (there are reports of new arrhythmias, or worsening of existing ones, in some cases - with subsequent cardiac arrest). In the light of the available data, it is impossible to determine whether this is caused by the use of the drug, or is associated with the severity of cardiovascular disease, or is a consequence of treatment failure. These effects are observed mainly in cases of the use of the drug Amiodarone in conjunction with drugs that lengthen the period of repolarization of the ventricles of the heart (QTc interval) or in violation of water and electrolyte balance (see the section "Interaction with other drugs"); very rarely - severe bradycardia or, in exceptional cases, stopping the sinus node, which were noted in some patients (patients with sinus node dysfunction and elderly patients); frequency unknown - progression of chronic heart failure (with prolonged use); ventricular "pirouette" tachycardia (see the sections "Interaction with other medicinal products", subsection "Pharmacodynamic interaction" and "Special instructions").
On the part of the digestive system: very often - nausea, vomiting, dysgeusia (dullness or loss of taste), usually occurring when taking a loading dose and passing after a dose reduction.
From the liver and biliary tract: very often - an isolated increase in the activity of transaminases in the blood serum, usually moderate (1.5-3 times the normal value), observed at the beginning of treatment and decreasing with dose reduction or even spontaneously: often - acute liver damage with an increase in the activity of transaminases and / or jaundice, including the development of liver failure, sometimes fatal (see section "Special instructions"), very rarely - chronic liver disease (pseudo-alcoholic hepatitis, cirrhosis), sometimes fatal. Even with a moderate increase in the activity of transaminases in the blood, observed after treatment lasted for more than 6 months, chronic liver damage should be suspected.
From the respiratory system, chest and mediastinal organs: often - pulmonary toxicity, sometimes fatal (alveolar / interstitial pneumonitis or fibrosis, pleurisy, obliterating bronchiolitis with pneumonia). Although these changes can lead to the development of pulmonary fibrosis, they are generally reversible with early withdrawal of amiodarone or with or without the use of glucocorticosteroids . Clinical manifestations usually disappear within 3-4 weeks. The restoration of the radiological picture and lung function occurs more slowly (after several months). The appearance in a patient taking amiodarone of severe shortness of breath or dry cough, both accompanied and not accompanied by a deterioration in general condition (increased fatigue, weight loss, increased body temperature) requires chest X-ray and, if necessary, discontinuation of the drug; very rarely - bronchospasm in patients with severe respiratory failure, especially in patients with bronchial asthma; acute respiratory distress syndrome in adults, sometimes with a fatal outcome and usually developing immediately after surgery (the possibility of interaction with high oxygen concentrations is assumed) (see section "Special instructions"), the frequency is unknown - pulmonary hemorrhage.
Disturbances from the organ of vision: very often - microdeposits in the corneal epithelium, consisting of complex lipids, including lipofuscin, they are usually limited to the pupil area and do not require discontinuation of treatment and disappear after drug withdrawal. Sometimes they can cause visual disturbances in the form of a colored halo or blurred contours in bright light, very rarely - several cases of optic neuritis / optic neuropathy have been described . Their connection with taking amiodarone has not yet been established. However, since optic neuritis can lead to blindness, if blurred vision or decreased visual acuity appears while taking Amiodarone, it is recommended to conduct a complete ophthalmological examination, including fundoscopy, and if optic neuritis is detected, stop taking amiodarone .
Disorders from the endocrine system: often - hypothyroidism with its classic manifestations: increased body weight, chilliness, apathy, decreased activity, drowsiness, excessive bradycardia compared to the expected effect of amiodarone (The diagnosis is confirmed by the detection of an increased concentration of thyroid-stimulating hormone (TSH) in blood serum (with with a hypersensitive TSH test). Normalization of thyroid function is usually observed within 1-3 months after stopping treatment. In life-threatening situations, treatment with amiodarone can be continued, with the simultaneous additional use of L-thyroxine under the control of TSH concentration in serum.); hyperthyroidism, sometimes fatal, the appearance of which is possible during and after treatment (cases of hyperthyroidism that developed several months after the withdrawal of amiodarone have been described). Hyperthyroidism is more secretive with fewer symptoms: minor unexplained weight loss, decreased antiarrhythmic and / or antianginal efficacy; mental disorders in elderly patients or even the phenomenon of thyrotoxicosis. The diagnosis is confirmed by the detection of a reduced serum TSH concentration (determined using a hypersensitive TSH assay). If hyperthyroidism is detected, amiodarone should be discontinued. Normalization of thyroid function usually occurs within a few months after drug withdrawal. In this case, the clinical symptoms are normalized earlier (after 3-4 weeks) than the normalization of the concentration of thyroid hormones occurs. Severe cases can be fatal and therefore require urgent medical attention. Treatment in each case is selected individually. If the patient's condition worsens, both because of the thyrotoxicosis itself, and in connection with a dangerous imbalance between myocardial oxygen demand and its delivery, it is recommended to start treatment immediately: the use of antithyroid drugs (which may not always be effective in this case), glucocorticoid treatment - steroids (1 mg / kg), which lasts a long time (3 months), the use of beta-blockers; very rarely - syndrome of impaired secretion of antidiuretic hormone.
From the side of the skin and subcutaneous tissues: very often - photosensitization ; often - in the case of prolonged use of the drug in high daily doses, grayish or bluish skin pigmentation may be observed; after stopping treatment, this pigmentation slowly disappears; very rarely - cases of erythema may occur during radiation therapy; skin rash, usually nonspecific, exfoliative dermatitis; alopecia ; frequency unknown - urticaria.
From the nervous system: often - tremors or other extrapyramidal symptoms; sleep disorders, including nightmares; infrequently - sensorimotor peripheral neuropathies and / or myopathy, usually reversible within a few months after discontinuation of the drug, but sometimes not completely, very rarely - cerebellar ataxia, benign intracranial hypertension (pseudotumor of the brain), headache.
From the side of the vessels: very rarely - vasculitis .
On the part of the genitals and mammary gland: very rarely - epididymitis, impotence.
On the part of the blood and lymphatic system: very rarely - hemolytic anemia, aplastic anemia, thrombocytopenia.
From the immune system: the frequency is unknown - angioedema (Quincke's edema).
Laboratory and instrumental data: very rarely - an increase in the concentration of creatinine in the blood serum.
General disorders: frequency unknown - formation of granulomas, including bone marrow granulomas.

Contraindication
• Hypersensitivity to iodine, amiodarone or excipients of the drug.
• Lactose intolerance (lactase deficiency), glucose-galactose malabsorption syndrome (the drug contains lactose).
• Syndrome of weakness of the sinus node (sinus bradycardia, sinoatrial block), except for cases of their correction by an artificial pacemaker (danger of "stopping" the sinus node).
• Atrioventricular block II-III degree, in the absence of an artificial pacemaker (pacemaker).
• Hypokalemia, hypomagnesemia .
• Combination with drugs that can lengthen the QT interval and cause the development of paroxysmal tachycardia, including ventricular " pirouette " tachycardia (see the section "Interaction with other medicinal products"):
- antiarrhythmic drugs: class IA (quinidine, hydroquinidine, disopyramide, procainamide); class III antiarrhythmics (dofetilide, ibutilide, bretilium tosylate); sotalol ;
- other (non-antiarrhythmic) drugs such as bepridil ; vincamine ; some neuroleptics: phenothiazines (Chlorpromazine, tsiamemazin, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulprid, tiapride, veraliprid), butyrophenones (droperidol, haloperidol), sertindole, pimozide ; cisapride ; tricyclic antidepressants; macrolide antibiotics (in particular, intravenous erythromycin, spiramycin); azoles ; antimalarial drugs (quinine, chloroquine, mefloquine, halofantrine); pentamidine for parenteral administration; diphemanil methyl sulfate ; mizolastine ; astemizole, terfenadine ; fluoroquinolones .
• Congenital or acquired lengthening of the QT interval.
• Thyroid dysfunction (hypothyroidism, hyperthyroidism).
• Interstitial lung disease.
• Pregnancy (see "Use during pregnancy and lactation").
• Lactation period (see "Use during pregnancy and lactation").
• Age under 18 years (efficacy and safety have not been established).
Carefully
With decompensated or severe chronic (III-IV functional class according to the NYHA classification) heart failure, liver failure, bronchial asthma, severe respiratory failure, in elderly patients (high risk of severe bradycardia), with atrioventricular block I degree.
Application during pregnancy and lactation

Overdose
Symptoms: When very large doses are taken by mouth, several cases of sinus bradycardia, cardiac arrest, attacks of ventricular tachycardia, paroxysmal ventricular "pirouette" tachycardia and liver damage have been reported. Perhaps a slowdown in atrioventricular conduction, an increase in already existing heart failure.
Treatment should be symptomatic: gastric lavage, the use of activated charcoal (if the drug has recently been taken), in other cases, symptomatic therapy is carried out: with bradycardia - beta- adrenostimulants or the installation of a pacemaker, with ventricular "pirouette" tachycardia - intravenous administration of magnesium salts or cardiostimulation .
Neither amiodarone nor its metabolites are removed by hemodialysis.
There is no specific antidote.

Precautions
Since the side effects of amiodarone are dose-dependent, patients should be treated with the lowest effective doses to minimize the possibility of their occurrence.
Patients should be advised to avoid exposure to direct sunlight or to take protective measures (eg sunscreen, wearing appropriate clothing) during treatment.
Treatment monitoring
Before you start taking Amiodarone, it is recommended to conduct an ECG study and determine the content of potassium in the blood. Hypokalemia must be corrected before starting Amiodarone . During treatment, it is necessary to regularly monitor the ECG (every 3 months) and the level of transaminases and other indicators of liver function. In addition, due to the fact that amiodarone can cause hypothyroidism or hyperthyroidism, especially in patients with a history of thyroid disease, before taking Amiodarone, a clinical and laboratory (serum TSH concentration, determined using an ultrasensitive TSH test) should be examined for the subject of detecting dysfunctions and diseases of the thyroid gland. During treatment with amiodarone and for several months after its termination, the patient should be regularly examined to identify clinical or laboratory signs of changes in thyroid function. If thyroid dysfunction is suspected, it is necessary to determine the concentration of TSH in the blood serum (using an ultrasensitive test for TSH).
In patients receiving long-term treatment for rhythm disturbances, cases of increased ventricular defibrillation rate and / or increased threshold for pacemaker or implanted defibrillator have been reported, which may reduce the effectiveness of these devices. Therefore, before starting or during treatment with Amiodarone, you should regularly check their correct functioning.
Regardless of the presence or absence of pulmonary symptoms during treatment with Amiodarone, it is recommended to conduct an X-ray examination of the lungs and pulmonary function tests every 6 months.
The onset of shortness of breath or dry cough, both isolated and accompanied by a worsening of the general condition (increased fatigue, weight loss, fever), can indicate pulmonary toxicity, such as interstitial pneumonitis, the suspicion of which requires an X-ray examination of the lungs and carrying out pulmonary functional tests.
Due to the lengthening of the period of repolarization of the ventricles of the heart, the pharmacological action of the drug Amiodarone causes certain ECG changes: lengthening of the QT interval, QTc (corrected), U waves may appear. An increase in the QTc interval of no more than 450 ms or no more than 25% of the initial value is permissible . These changes are not a manifestation of the toxic effect of the drug, however, they require monitoring to adjust the dose and assess the possible proarrhythmogenic effect of the drug Amiodarone .
With the development of atrioventricular block II and III degree, sinoatrial blockade or double-beam intraventricular block, treatment should be discontinued. In the event of grade I atrioventricular block, surveillance should be intensified.
Although the occurrence of arrhythmias or the aggravation of existing rhythm disturbances, sometimes fatal, has been noted, the proarrhythmogenic effect of amiodarone is mild, less than that of most antiarrhythmic drugs, and usually manifests itself in the context of factors that increase the duration of the QT interval, such as interactions with other drugs and / or violations of the content of electrolytes in the blood (see sections "Side effects" and "Interaction with other medicinal products"). Despite the ability of amiodarone increase Chiva duration interval QT, it has shown low activity in respect of provoking ventricular "the twisting" tachycardia.
In case of blurry vision or a decrease in visual acuity, an ophthalmologic examination, including an examination of the fundus, is urgently needed. With the development of neuropathy or optic neuritis caused by amiodarone, the drug must be discontinued due to the risk of blindness.
Since Amiodarone contains iodine, its intake can disrupt the absorption of radioactive iodine and distort the results of a radioisotope study of the thyroid gland, however, taking the drug does not affect the accuracy of determining the content of T3, T4 and TSH in the blood plasma. Amiodarone inhibits the peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and can cause isolated biochemical changes (an increase in the concentration of free T4 in the blood serum, with a slightly reduced or even normal concentration of free T3 in the blood serum) in clinically euthyroid patients, which is not the cause to cancel Amiodarone .
The development of hypothyroidism can be suspected when the following clinical signs, usually mild, appear: weight gain, cold intolerance, decreased activity, excessive bradycardia (see section "Side Effects"). Before surgery, the anesthesiologist should be informed that the patient is taking Amiodarone .
Long- term treatment with amiodarone may increase the hemodynamic risk inherent in local or general anesthesia. This applies in particular to its bradycardic and hypotensive effects, decreased cardiac output and conduction disturbances.
In addition, acute respiratory distress syndrome was noted in patients taking Amiodarone in rare cases immediately after surgery . With artificial ventilation of the lungs, such patients require careful monitoring.
It is recommended to carefully monitor the functional "liver" tests (control of the activity of "liver" transaminases) before starting the use of Amiodarone and regularly during treatment with the drug. When taking Amiodarone, acute liver dysfunction (including hepatocellular failure or liver failure, sometimes fatal) and chronic liver damage are possible. Therefore, treatment with Amiodarone should be discontinued when the activity of "hepatic" transaminases increases, which is 3 times higher than the upper limit of the norm.
Clinical and laboratory signs of chronic liver failure when taking Amiodarone orally can be minimally pronounced (hepatomegaly, increased transaminase activity, 5 times higher than the upper limit of the norm) and reversible after discontinuation of the drug, however, cases of death have been reported in liver damage.

Interaction with other medicinal products
Pharmacodynamic interaction
Drugs that can cause bidirectional ventricular tachycardia or prolong the QT interval
Drugs That Can Cause Ventricular Pirouette Tachycardia
Combination therapy with drugs that can cause ventricular pirouette tachycardia is contraindicated as the risk of potentially lethal ventricular tachycardia increases.
- Antiarrhythmic drugs: class IA (quinidine, hydroquinidine, disopyramide, procainamide), sotalol, bepridil .
- Other (non-antiarrhythmic) drugs such as: vincamine ; some neuroleptics: phenothiazines (Chlorpromazine, tsiamemazin, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulprid, tiapride, veraliprid), butyrophenones (droperidol, haloperidol), sertindole, pimozide ; tricyclic antidepressants; cisapride ; macrolide antibiotics (intravenous erythromycin, spiramycin); azoles ; antimalarial drugs (quinine, chloroquine, mefloquine, halofantrine, lumefantrine); pentamidine for parenteral administration; diphemanil methyl sulfate ; mizolastine ; astemizole ; terfenadine .
Medicines that can prolong the QT interval
Joint administration of amiodarone with drugs that can increase the duration of the QT interval should be based on a careful assessment for each patient of the ratio of the expected benefit and potential risk (the possibility of an increase in the risk of developing ventricular "pirouette" tachycardia) (see section "Special instructions"), when using such combinations, it is necessary to constantly monitor the ECG of patients (to detect prolongation of the QT interval), the content of potassium and magnesium in the blood.
In patients taking amiodarone, the use of fluoroquinolones, including moxifloxacin, should be avoided .
Medicines that slow down the heart rate (HR) or cause automatic or conduction problems
Combination therapy with these drugs is not recommended. Beta-blockers, blockers of "slow" calcium channels, which slow down the heart rate (verapamil, diltiazem), can cause violations of automatism (development of excessive bradycardia) and conduction.
Medicines that can cause hypokalemia
non-recommended combination
With laxatives that stimulate intestinal motility, which can cause hypokalemia, which increases the risk of developing ventricular "pirouette" tachycardia. When combined with amiodarone, laxatives of other groups should be used.
Combinations requiring caution when using:
- with diuretics that cause hypokalemia (in monotherapy or in combination with other drugs);
- with systemic corticosteroids (glucocorticosteroids, mineralocorticosteroids), tetracazactide ;
- with amphotericin B (intravenous administration).
It is necessary to prevent the development of hypokalemia, and in case of its occurrence, restore to the normal level of potassium in the blood, monitor the content of electrolytes in the blood and ECG (for possible prolongation of the QT interval), and in the event of ventricular "pirouette" tachycardia, antiarrhythmic drugs should not be used (ventricular pacing should be started, possibly intravenous administration of magnesium salts).
Medicines for inhalation anesthesia
It was reported about the possibility of the development of the following severe complications in patients taking amiodarone when they received general anesthesia: bradycardia (resistant to the administration of atropine), arterial hypotension, conduction disorders, and a decrease in cardiac output. There have been very rare cases of severe complications from the respiratory system, sometimes fatal (acute respiratory distress syndrome in adults), which developed immediately after surgery, the occurrence of which is associated with high oxygen concentrations.
Medicines that slow down the heart rate (clonidine, guanfacine, cholinesterase inhibitors (donepezil, galantamine, rivastigmine, tacrine, ambenonium chloride, pyridostigmine bromide, neostigmine bromide), pilocarpine)
The risk of developing excessive bradycardia (cumulative effects).
Effect of amiodarone on other drugs
Amiodarone and / or its metabolite desethylamiodarone inhibit the isoenzymes CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6 and P- gp and may increase the systemic exposure of drugs that are their substrates. Due to the long half-life of amiodarone, this interaction can be observed even several months after stopping it.
Drugs that are P- gp substrates
Amiodarone is a P- gp inhibitor . It is expected that its coadministration with drugs that are substrates of P- gp will lead to an increase in the systemic exposure of the latter.
Cardiac glycosides (digitalis medications)
The possibility of violations of automatism (pronounced bradycardia) and atrioventricular conduction. In addition, the combination of digoxin with amiodarone may increase the concentration of digoxin in the blood plasma (due to a decrease in its clearance). Therefore, when combining digoxin with amiodarone, it is necessary to determine the concentration of digoxin in the blood and monitor possible clinical and electrocardiographic manifestations of digitalis intoxication. Reducing digoxin doses may be required .
Dabigatran
Caution must be exercised while using amiodarone with dabigatran due to the risk of bleeding. Dosage adjustment of dabigatran may be required according to the directions in its instructions for use.
Drugs that are substrates of the isoenzyme CYP2C9
Amiodarone increases the concentration in the blood of drugs that are substrates of the CYP2C9 isoenzyme, such as warfarin or phenytoin, by inhibiting cytochrome P450 2C9.
Warfarin
When warfarin is combined with amiodarone, the effects of an indirect anticoagulant may increase, which increases the risk of bleeding. Prothrombin time should be monitored more often (by determining the International Normalized Ratio) and the dose of indirect anticoagulants should be adjusted, both during treatment with amiodarone and after stopping it.
Phenytoin
When phenytoin is combined with amiodarone, an overdose of phenytoin may develop, which can lead to the appearance of neurological symptoms; clinical monitoring is necessary and, at the first signs of an overdose, a decrease in the dose of phenytoin, it is desirable to determine the concentration of phenytoin in the blood plasma.
Drugs that are substrates of the isoenzyme CYP2D6
Flecainide Amiodarone increases the plasma concentration of flecainide by inhibiting the isoenzyme CYP2D6. In this connection, correction of doses of flecainide is required .
Drugs that are substrates of the isoenzyme CYP3A4
When amiodarone, an inhibitor of the CYP3A4 isoenzyme, is combined with these drugs, their plasma concentrations may increase, which may lead to an increase in their toxicity and / or an increase in pharmacodynamic effects and may require a decrease in their doses. These drugs are listed below. Cyclosporine . The combination of cyclosporine with amiodarone can increase the concentration of cyclosporine in the blood plasma, dose adjustment is necessary.
Fentanyl . The combination with amiodarone may increase the pharmacodynamic effects of fentanyl and increase the risk of developing its toxic effects. Inhibitors GMG CoA - reductase inhibitors (statins) (simvastatin, atorvastatin and lovastatin)
Increasing the risk of muscle toxicity of statins when taken simultaneously with amiodarone, it is recommended to use statins that are not metabolized by the isoenzyme CYP3A4.
Other drugs metabolized by the CYP3A4 isoenzyme: lidocaine (risk of developing sinus bradycardia and neurological symptoms), tacrolimus (risk of nephrotoxicity), sildenafil (risk of increased side effects), midazolam (risk of psychomotor effects), triazolam, dihydroergotamine, ergocyrgotamine .. Medicinal product that is a substrate of CYP2D6 and CYP3A4 isoenzymes
Dextromethorphan . Amiodarone inhibits the isoenzymes CYP2D6 and CYP3A4 and can theoretically increase the plasma concentration of dectromethorphan .
Clopidogrel . Clopidogrel, which is an inactive thienopyrimidine drug that is metabolized in the liver to form active metabolites. There is a possible interaction between clopidogrel and amiodarone, which can lead to a decrease in the effectiveness of clopidogrel .
Effect of other drugs on amiodarone
Inhibitors of isoenzymes CYP3A4 and CYP2C8 may have the potential to inhibit the metabolism of amiodarone and increase its concentration in the blood and, accordingly, its pharmacodynamic and side effects.
It is recommended to avoid taking inhibitors of the isoenzyme CYP3A4 (for example, grapefruit juice and certain medications such as cimetidine and HIV protease inhibitors (including indinavir)) during amiodarone therapy . Inhibitors of HIV protease, when used simultaneously with amiodarone, can increase the concentration of amiodarone in the blood.
CYP3A4 isoenzyme inducers
Rifampicin . Rifampicin is a potent inducer of the CYP3A4 isoenzyme; when used together with amiodarone, it can reduce the plasma concentrations of amiodarone and deethylamiodarone .
Hypericum perforatum drugs
St. John's wort is a strong inducer of the isoenzyme CYP3A4. In this regard, it is theoretically possible to reduce the plasma concentration of amiodarone and reduce its effect (there are no clinical data).

Special instructions
Amiodarone is prescribed with caution in case of electrolyte imbalance. there are isolated reports of the development or progression of arrhythmias (up to cardiac arrest). However, at present, it is not possible to differentiate between changes associated with taking the drug and changes associated with existing heart diseases or resulting from insufficient effectiveness of treatment.
It should be borne in mind that when using Ami odaron, ECG changes are possible:
lengthening of the QT interval with the possible appearance of a U wave.
It should be borne in mind that elderly patients have a more pronounced decrease in heart rate. If atrioventricular block of II and III degree or bifascicular block appears, treatment with Amiodarone should be discontinued.
It should be borne in mind that after discontinuation of the drug, the pharmacodynamic effect persists for 10-30 days.
Amiodarone contains iodine (200 mg contains 75 mg of iodine), so it may affect the results of tests for the accumulation of radioactive iodine in the thyroid gland. Before starting treatment, during it and for several months after the end of treatment, it is necessary to carry out studies of thyroid function.
During treatment, an ophthalmological examination should be carried out, liver function should be monitored, and an x-ray examination of the lungs should be performed. Patients should avoid sun exposure or use effective protective measures to avoid the development of photosensitization .
It should be borne in mind that there have been rare cases of acute respiratory distress syndrome in adults immediately after surgery. Therefore, before the operation, the anesthesiologist must be informed that the patient is taking Amiodarone . During pregnancy and lactation, treatment with amiodarone is contraindicated.
Amiodarone does not affect the ability to drive vehicles and other mechanisms.

Pregnancy and elbowing
Pregnancy
The currently available clinical information is insufficient to determine the possibility or impossibility of the occurrence of malformations in the embryo when using amiodarone in the first trimester of pregnancy.
Since the fetal thyroid gland begins to bind iodine only from the 14th week of pregnancy (amenorrhea), the effect of amiodarone on it is not expected if it is used earlier. Excess iodine when using the drug after this period can lead to the appearance of laboratory symptoms of hypothyroidism in a newborn or even to the formation of a clinically significant goiter. Due to the effect of the drug on the fetal thyroid gland, amiodarone is contraindicated during pregnancy, except in special cases when the expected benefit outweighs the risks (with life-threatening ventricular heart rhythm disturbances).
Breastfeeding period
Amiodarone is excreted in breast milk in significant quantities, so it is contraindicated during breastfeeding. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Influence on the ability to drive vehicles and work with mechanisms
Does not affect.

Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ° C, out of the reach of children.

Shelf life
3 years. Do not use after the expiration date printed on the package.

Vacation conditions
On prescription.

Packaging
Amiodarone 200 mg Tablets. There are 25 tablets in a blister. 2 blisters are packed in a cardboard box together with an enclosed leaflet.