Rythma

Rythma

amiodarone

Manufacturer:

Therapharma

Distributor:

United Lab
Full Prescribing Info
Contents
Amiodarone HCl.
Action
Pharmacotherapeutic Group: Antiarrhythmics (class III).
Pharmacology: Pharmacodynamics: Tablet: In myocardial tissue, amiodarone HCl inhibits the potassium efflux during stage III of the action potential and thus, selectively prolongs the duration of repolarization and the refractory period of the action potential (class III effect as defined by Vaughan Williams). This leads to depression of ectopias and re-entry mechanisms without impaired contractile force of the myocardium.
Amiodarone HCl reduces conduction velocity and extends the refractory time in accessory atrioventricular paths. The prolongation of the slow diastolic depolarization in the pacemaker potential leads to a depressed automatism in the pacemaker tissue with deceleration of the heart rate which is atropine-resistant.
Amiodarone HCl exhibits a dose-dependent, non-competitive inhibition of α- and β-adrenergic activities, which is hemodynamically expressed by a coronary-dilative and vasodilative effect and also by improvement in the oxygen balance.
Amiodarone HCl administered orally does not show any significantly negative inotropic effect. In case of IV administration, reduced contractility may occur particularly after injection.
Injection: Amiodarone is both an antiarrhythmic and a potent vasodilator. Amiodarone is considered a "broad-spectrum" antiarrhythmic with multiple and complex electrophysiological effects. Although its exact mechanism of action is not completely known, amiodarone is considered a class III compound using the traditional Vaughn-Williams classification scheme for antiarrhythmic compounds.
Like the other class III antiarrhythmics, bretylium and sotalol, amiodarone acts directly on the myocardium to delay repolarization and increase the duration of the action potential. Delayed repolarization is a result of inhibition of potassium ion fluxes that normally occur during phase 2 and 3 of the action potential. This results in prolongation of the effective refractory period in all cardiac tissue (eg, atria, ventricles, AV node and His-Purkinje system). Amiodarone exerts this antifibrillatory effect without significantly altering the myocardial membrane potential.
By definition, class III agents act only on the repolarization phase of the action potential and therefore, should leave conduction unchanged. However, amiodarone has also been shown to inhibit the inward sodium currents which is a use-dependent class I activity. The result of this cellular action is a slowing of the upstroke velocity of phase 0 which reduces the rate of membrane depolarization and impulse conduction. Amiodarone also depresses the automaticity of both the sino-atrial (SA) and atrio-ventricular (AV) nodes directly (class II effect), and slows conduction in the His-Purkinje system and in the accessory pathway of patients with Wolff-Parkinson-White syndrome.
Amiodarone HCl also noncompetitively inhibits α- and β-receptors, and possesses both vagolytic and calcium-channel blocking properties. Rythma relaxes both smooth and cardiac muscles, causing decreases in coronary and peripheral vascular resistance, left ventricular end-diastolic pressure (LVEDP) and systolic blood pressure, thereby decreasing afterload.
Pharmacokinetics: Tablet: After oral administration, approximately 50% of amiodarone HCl is absorbed in the gastrointestinal tract. After administration of 1 single dose, plasma levels are reached after 3-7 hrs. Accumulation of the substance at its site of action or saturation of the myocardial tissue, respectively, is decisive for therapeutic efficacy. Depending on the saturation dosage, the onset of action can be expected within a period of a few days up to 2 weeks.
Following injection, the maximum of action is achieved after 15 min. Afterwards, redistribution into tissue and rapid decrease in the plasma concentrations occur within 4 hrs. For saturation of tissue depots, therapy must be continued IV or orally.
Amiodarone HCl has a long t½ interindividually varying between 20 and 100 days. During saturation, the substance accumulates mainly in fat tissue. Steady state is attained within a period of 1 month up to several months. Due to these characteristics, the recommended saturation dosage should be administered in order to attain rapid saturation in tissue which is required for therapeutic efficacy.
The main excretion route is through liver and bile; 10% of the substance is excreted renally. Due to low renal excretion, the usual dosage can be administered to patients suffering from renal insufficiency.
After withdrawal, amiodarone HCl is still excreted for several months. Bioavailability: Mean bioavailability is 42% (22-80%).
Injection: After IV administration, amiodarone is rapidly and widely distributed. Peak serum concentrations after single 5 mg/kg 15-min IV infusions in healthy subjects range between 5 and 41 mg/L. Peak concentrations after 10-min infusions of 150 mg amiodarone HCl injection in patients with ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT) range between 7 and 26 mg/L. Due to rapid distribution, serum concentrations decline to 10% of peak values within 30-45 min after the end of the infusion.
In vitro, amiodarone is approximately 96% bound to plasma proteins, mainly to albumin and, to a lesser extent, to a high density lipoprotein that is probably β-lipoprotein.
Amiodarone is metabolized to N-desethyl amiodarone (DEA) by the cytochrome P-450 (CYP450) enzyme group, specifically cytochrome P-450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines.
Amiodarone and possibly, DEA, cross the placenta to a limited extent. In pregnant women receiving amiodarone, ratios of umbilical venous to maternal venous plasma concentrations of amiodarone and DEA were 0.1-0.28 and 0.25-0.55, respectively.
Amiodarone and DEA are distributed into milk in concentrations substantially higher than concurrent maternal plasma concentrations. Limited data in a breastfeeding woman indicate amiodarone and DEA milk-to-plasma ratios ranging from 2.3-9.1 and 0.8-3.8, respectively.
Amiodarone's elimination is primarily by hepatic metabolism and biliary excretion. Amiodarone or DEA excretion in the urine is negligible. Neither amiodarone nor DEA is dialyzable.
After IV administration in healthy individuals, amiodarone's total plasma clearance averages approximately 1.9 mL/min/kg. Although not clearly established, total apparent plasma clearance of the drug appears to decrease with time. Factors of age, gender and renal or hepatic disease appear to have no effect on the disposition of amiodarone or DEA.
Toxicology: Tablet: Preclinical Safety Data: Acute Toxicity: Acute toxicity of amiodarone HCl seems to be relatively low, and lethal dose (LD50) values are >3 g/kg body weight. Clinical symptoms were vomiting in the dog, central nervous system (CNS) effects (sedation, tremor, convulsions, dyspnea) in rodents.
Chronic Toxicity/Subchronic Toxicity: Chronic toxicity studies revealed that amiodarone HCl has a similar toxicological potential in animals as well as in humans. Amiodarone HCl caused pulmonary damage eg, fibrosis or phospholipidosis (in hamster, rat and dog) as well as CNS disturbances (in rats). Oxidative stress and free radicals seem to be very important for inducing pulmonary damage. Furthermore, amiodarone HCl caused hepatic damage in rats. Effects of amiodarone HCl on serum lipids may be indirectly caused by alterations in the plasma concentrations of thyroid hormones.
Mutagenic and Tumorigenic Potential: Amiodarone HCl is a highly phototoxic substance. There is evidence that free cytotoxic radicals are formed via ultraviolet (UV) irradiation in the presence of amiodarone HCl. This may not only lead to acute phototoxic reactions, but also to photocancerogenic effects. These potentially severe adverse reactions of amiodarone HCl have not been investigated in experiments up to now. Therefore, the photomutagenic and photocancerogenic potential of amiodarone HCl is not known.
A cancerogenicity study in rats showed that amiodarone HCl caused increased follicular tumors of the thyroid gland (in male animals at doses from 5 mg/kg/day, in female animals at doses from 16 mg/kg/day). These effects appear to be caused by impacts of amiodarone HCl on synthesis and/or release of thyroid hormones. No cancerogenic potential can therefore be deduced from these investigations for the therapeutic use of amiodarone HCl in humans.
Reproductive Toxicity: Increased serum levels for LH and FSH pointing to testicular dysfunction were measured in male patients after longer-term treatment.
Indications/Uses
Symptomatic and tachycardiac supraventricular arrhythmias requiring treatment eg, AV-junctional tachycardia, supraventricular tachycardia associated with Wolff-Parkinson-White syndrome, paroxysmal atrial fibrillation.
Ventricular Rhythm Disorder: Recurrent ventricular fibrillation, recurrent hemodynamically unstable ventricular tachycardia in patients refractory to other therapy.
These indications apply to patients who do not respond to other antiarrhythmics or for whom other antiarrhythmics are not indicated.
Injection: Treatment of patients with rhythm disorders where a rapid response is required or where oral administration is not possible.
Dosage/Direction for Use
Tablet: In patients with ventricular arrhythmias, adjustment to the antiarrhythmic requires careful cardiologic monitoring and may only be carried out if cardiologic emergency equipment is available and monitoring control possible. During treatment, check-tests should be made at regular intervals [eg, standard electrocardiogram (ECG) at intervals of 1 month or long-term ECG at intervals of 3 months and possibly exercise ECG].
Therapy should be reviewed if individual parameters deteriorate eg, prolongation of QRS time or QT time by >25% or PQ time by >50% or QT prolongation to >500 ms or increase in the number or severity of arrhythmias.
As saturation dose, 600 mg amiodarone HCl is given for 8-10 days (equivalent to 3 tablets of amiodarone 200 mg) per day. In some cases, dosages of up to 1200 mg amiodarone HCl (equivalent to 6 tablets of amiodarone HCl 200 mg) may become necessary per day. Afterwards, reduction to a maintenance dose, usually 200 mg amiodarone HCl (equivalent to 1 tablet of amiodarone HCl 200 mg) for 5 days per week may be initiated.
In some cases, higher dosages of 200-600 mg amiodarone HCl (equivalent to 1-3 tablets of amiodarone HCl 200 mg) per day are required during long-term therapy.
For the treatment of children, the dosage should be adjusted to the body surface area or to the body weight.
Special Note: As most of adverse reactions are dose-dependent, the lowest effective maintenance dose should be administered.
Injection: Amiodarone should only be used in a special care unit with continuous monitoring of blood pressure and ECG. Rythma should be administered only by physicians who are experienced in the treatment of fatal arrhythmias and are totally familiar with the risks and benefits of amiodarone therapy.
Carefully adjust dosage according to individual requirements and response, patient tolerance, and the patient's general condition and cardiovascular status.
The recommended IV amiodarone HCl starting dose over the first 24 hrs is approximately 1000 mg, administered by the infusion regimen as follows. (See Table 1.)

Click on icon to see table/diagram/image

After the first 24 hrs, continue a maintenance infusion rate of 0.5 mg/min (ie, 720 mg over 24 hrs).
In the event of breakthrough episodes of ventricular fibrillation or hemodynamically unstable ventricular tachycardia, supplemental amiodarone HCl infusions of 150 mg administered over 10 min at a rate of 15 mg/min may be given.
Clinical trials on amiodarone HCl IV reported that a maintenance infusion of up to 0.5 mg/min can be administered with caution for 2-3 weeks, regardless of patient's age, renal function or left ventricular function. There has been limited experience on the use of amiodarone HCl IV for >3 weeks.
Administration: Tablet: It should be taken unchewed during or after meals together with sufficient liquid. The attending physician decides on the duration of administration.
Injection: Amiodarone IV should never be administered via a peripheral vein. It should always be administered exclusively as an infusion through a central venous catheter. Injection via the peripheral venous route, even at a very slow rate can cause local effects eg, superficial phlebitis, and may aggravate hypotension, heart failure, myocardiopathy or severe respiratory insufficiency.
For infusions lasting >1 hr, the concentration should not exceed 2 mg/mL unless administered via a central venous catheter. Infusions lasting >2 hrs must be administered in polyolefin or glass bottles containing D5W. Use of evacuated glass containers for admixing amiodarone is not recommended as incompatibility with a buffer in the container may cause precipitation.
Amiodarone injection should only be administered using a volumetric infusion pump. An in-line filter should be used during administration.
Polyvinyl chloride (PVC) tubing should be used during IV administration. The recommended dosing regimens have taken into account the amount of amiodarone adsorbed to PVC tubing.
Admixture Incompatibility: Amiodarone IV in D5W, in a concentration of 4 mg/mL, is incompatible and forms a precipitate with the following drugs: Aminophylline, cefamandole, cefazolin, mezlocillin. A concentration of 3 mg/mL amiodarone IV in D5W forms a precipitate with sodium bicarbonate. Amiodarone is likewise incompatible with heparin.
Conversion from IV to Oral Dosage: Use amiodarone IV for acute treatment until the patient's ventricular arrhythmias are stabilized. Patients whose arrhythmias have been successfully controlled with amiodarone IV may be transferred to oral therapy. The optimal dose for changing from IV to oral administration will depend on the IV dose already administered, as well as the bioavailability of oral amiodarone. When changing to oral therapy, clinical monitoring is recommended, particularly for elderly patients.
Table 2 as follows, provides suggested doses of oral amiodarone to be initiated after varying durations of IV administration. These recommendations are made on the basis of a comparable total body amount of amiodarone delivered by the IV and oral routes, based on 50% bioavailability of oral amiodarone. (See Table 2.)

Click on icon to see table/diagram/image

Stability: Amiodarone adsorbs to PVC tubing and the clinical trial dose administration schedule was designed to account for this adsorption. Clinical trials were conducted using PVC tubing; therefore its use is recommended.
Amiodarone has been found to leach out plasticizers, including di-ethylhexyl phthalate (DEHP) from IV tubing (including PVC tubing). The degree of leaching increases when infusing amiodarone IV at higher concentrations and lower flow rates than recommended.
Overdosage
Tablet: Little is known to date about acute overdosage with amiodarone HCl. On account of specific pharmacokinetics, overdose is possible in general only in the course of long-term therapy.
The symptoms are usually confined to sinus bradycardia, sinoauricular and nodal disturbances in stimulus conduction as well as tachycardia interrupting spontaneously. Amiodarone induced-bradycardia is atropine-resistant. Temporary pacemaker monitoring may therefore possibly be necessary.
In case of suspected overdose, the patient should be observed, because of the pharmacokinetics of amiodarone HCl, for a sufficiently long time in special view of the cardiac situation.
Neither amiodarone HCl nor its metabolites are dialyzable.
Injection: There have been reports of some fatal amiodarone overdose. Effects of unintentional IV amiodarone overdose include hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity. Hypotension and cardiogenic shock should be treated by slowing the infusion rate or with standard therapy of vasopressor drugs, inotropic agents, and volume expansion. Bradycardia and AV block may require temporary pacing. Closely monitor hepatic enzyme concentrations. Amiodarone is not dialyzable.
Contraindications
Hypersensitivity to amiodarone HCl or to any of the excipients of Rythma.
Sinus bradycardia (<55 pulse bpm) and sinoatrial heart block.
All forms of delayed conduction (sino-auricular and nodal conduction delay) including sick sinus syndrome or sinus node disease (except when amiodarone is used in conjunction with a pacemaker), AV-blocks of 2nd and 3rd degrees as well as bi-fascicular and tri-fascicular blocks if no pacemaker is used. In such circumstances, amiodarone IV may be used in a special care unit and institute electrosystolic pacing.
Concomitant treatment with medicinal products inducing torsades de pointes (see Interactions).
Tablet: Preexisting QT prolongation; hypokalemia.
Concomitant treatment with monoamine oxidase (MAO) inhibitors.
Concurrent use of simvastatin at a daily dose >20 mg.
Injection: Evidence or history of thyroid dysfunction. Thyroid function tests should be performed in all patients prior to amiodarone therapy.
Circulatory collapse, severe arterial hypotension.
Use in Pregnancy & Lactation: Pregnancy Category D: Amiodarone is contraindicated during pregnancy because there have been reports of neonatal hypo- or hyperthyroidism from amiodarone use.
Amiodarone is excreted in breastmilk in significant quantities and is therefore contraindicated in breastfeeding.
Warnings
Injection: Amiodarone is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity, the most important of which is pulmonary toxicity (ie, hypersensitivity pneumonitis or interstitial/alveolar pneumonitis). Mild liver injury is likewise common as evidenced by abnormal liver enzymes. Overt liver disease can occur and has been fatal in a few cases. (See Adverse Reactions.)
Hospitalized patients with indicated arrhythmias while amiodarone loading dose is being given.
Special Precautions
Tablet: Data of the SEARCH study verify an increased risk of myopathy or rhabdomyolysis in combined use of amiodarone and simvastatin, which varies with the daily dose of simvastatin. The pharmacological mechanism on which this interaction is based is not known.
Indication for concurrent therapy of amiodarone with a statin should therefore be made with special caution. As no risk of myopathy or rhabdomyolysis is assumed only in case of a combined daily dose of amiodarone with simvastatin at low daily dose ≤20 mg, this simvastatin dose should not be exceeded.
Other statins, not simvastatin, should be used at low dosage in concurrent therapy with amiodarone.
Eyes: During treatment with amiodarone HCl, regular ophthalmic examinations are indicated-including fundoscopy and examinations by means of a slit-lamp (see Adverse Reactions).
Skin: Exposure to sunlight should be avoided during therapy with amiodarone HCl; this also applies to UV light applications and solaria. If this is not possible, uncovered skin areas, particularly the face, should be protected by application of an ointment with a high protection factor. Even after withdrawal of amiodarone HCl, a light protector is necessary for some more time.
Thyroid Gland: Due to the risk of developing a thyroid dysfunction (hyperthyroidism or hypothyroidism) on treatment with amiodarone HCl, thyroid function should be examined prior to the onset of treatment. During therapy and up to 1 year after withdrawing from therapy, these examinations should be repeated at regular intervals and the patients examined for clinical symptoms of hyperthyroidism or hypothyroidism.
Amiodarone HCl inhibits the transformation of thyroxine (T4) into triiodothyronine (T3) and may lead to increased T4 values as well as to decreased T3 values in clinically inconspicuous (euthyroid) patients. This finding constellation alone should not result in discontinuing therapy.
The clinical diagnosis of hypothyroidism is confirmed by proof of evidently increased ultrasensitive thyroid-stimulating hormone (TSH) value as well as decreased T4 value. By proof of hypothyroidism, the amiodarone HCl dosage should be reduced, if possible, and/or substitution with L-thyroxine started. In isolated cases, discontinuation of amiodarone HCl may be required.
The clinical diagnosis of hyperthyroidism is confirmed by proof of evidently decreased ultrasensitive TSH as well as increased T3 and T4 values. By proof of hyperthyroidism, the dosage should be reduced, if possible, or amiodarone HCl discontinued; in severe cases, treatment with thyroid depressants, β-adrenergic blocking agents and/or corticosteroids should be initiated.
On account of its iodine content, amiodarone HCl falsifies classic thyroid tests (iodine binding test).
Lung: There is the risk of developing severe inflammatory pneumopathy (hypersensitivity pneumonitis, alveolar or interstitial pneumonitis) during therapy with amiodarone HCl. Thoracic roentgenography and pulmonary function test should therefore be performed prior to the onset of treatment. These examinations should be repeated at intervals of approximately 3-6 months in the further therapeutic course. These examinations should also be carried out if dyspnea (symptom of a possible pulmotoxic effect) occurs.
In patients with severe hepatopathies, pulmonary function is possibly more frequently to be monitored, as these patients have a worse prognosis if pulmotoxic effects occur. By proof of hypersensitivity pneumonitis, amiodarone HCl is to be withdrawn immediately and therapy with corticosteroids initiated. By proof of alveolar/interstitial pneumonia, treatment should be carried out with corticosteroids and the dose reduced or, if possible, amiodarone HCl should be discontinued.
Liver: Liver values should be monitored at regular intervals, particularly at higher dosage. In cases of persistent clinically relevantly increased liver enzymes, cholestatic icterus or hepatomegaly, discontinuation of amiodarone HCl should be taken into consideration.
Cardiovascular System: Electrocardiogram alterations, imposing as QT prolongation (in dependence of prolonged repolarisation) possibly in connection with the development of U-wave as well as prolongation and deformation of the T-wave, demonstrate the pharmacological activity of amiodarone HCl. There is an increased risk of torsades de pointes in case of an excessive QT prolongation.
Others: The possibility of a syndrome of inappropriate (increased) secretion of antidiuretic hormone (SIADH) should be considered in patients experiencing asthenia during treatment with amiodarone: Sodium levels and osmolality in serum, as well as osmolality and sodium concentration in urine should be measured.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take amiodarone 200 mg.
Injection: Hypotension occurring with IV amiodarone therapy should be treated initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion.
The pharmacological action of amiodarone includes ECG changes: QT prolongation (related to prolonged repolarization) with the possible development of U-waves; these changes do not reflect toxicity.
In the elderly, heart rate may decrease markedly.
Treatment should be discontinued in case of onset of 2nd and 3rd degree A-V block, sinoatrial block, or bifascicular block.
Amiodarone contains iodine and thus may interfere with radioiodine uptake. However, thyroid function tests T3, T4, ultrasensitive TSH (usTSH) remain interpretable.
Dyspnea or non-productive cough may be related to pulmonary toxicity.
Before treatment initiation, perform an ECG, usTSH assay and serum potassium measurement.
Undesirable effects are usually dose-related; therefore, careful attention should be paid to determine the minimum effective maintenance dose in order to avoid or minimize undesirable effects.
Patients should be instructed to avoid exposure to sun or to use protective measures during therapy since amiodarone may induce photosensitization.
Amiodarone may induce thyroid disorders particularly in patients with personal or family history of thyroid disorders. Therefore, clinical and biological monitoring is recommended before starting treatment, during treatment and for several months after treatment discontinuation. Serum usTSH level should be measured when regular dysfunction is suspected.
Effects on the Ability to Drive or Operate Machinery: Tablet: Treatment with this medicinal product requires regular medical monitoring. Even when this medicinal product is used according to the instructions, reactivity may be changed in such a way that the ability to drive, to operate machinery or to work in an unsafe posture is impaired. This applies to a higher extent at the onset of therapy, when increasing the dosage and changing the preparation as well as in combination with alcohol.
Use in Pregnancy & Lactation: Tablet: There is no sufficient experience regarding safe administration during pregnancy.
Amiodarone HCl and N-demethyl amiodarone pass the placenta and reach concentrations in the child of 10-25% of the maternal plasma concentration. Growth disturbances, premature births and thyroid dysfunctions in the neonate are the most frequent complications. Hypothyroidism, bradycardia and prolonged QT intervals have been ascertained in approximately 10% of neonates. In isolated cases, thyroid enlargement or cardiac murmur have been found. The malformation rate does not seem to be increased; however, the possibility of cardiac defects should be taken into consideration.
Due to the long t½ of amiodarone HCl, women who want to become pregnant should plan the beginning of a pregnancy 6 months after ending therapy at the earliest in order to avoid any exposure of the child in early pregnancy.
Transition into mother's milk is proven for the active substance and the active metabolite. Measurable plasma levels are reached in breast-fed children. If treatment is necessary in the lactation period or if amiodarone HCl has been taken during pregnancy, breastfeeding should be refrained from.
Use in Children: Injection: The safety and effectiveness of amiodarone in children have not been established.
Use in Elderly: Injection: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy
Use In Pregnancy & Lactation
Pregnancy Category D: Amiodarone is contraindicated during pregnancy because there have been reports of neonatal hypo- or hyperthyroidism from amiodarone use.
Amiodarone is excreted in breastmilk in significant quantities and is therefore contraindicated in breastfeeding.
Tablet: There is no sufficient experience regarding safe administration during pregnancy.
Amiodarone HCl and N-demethyl amiodarone pass the placenta and reach concentrations in the child of 10-25% of the maternal plasma concentration. Growth disturbances, premature births and thyroid dysfunctions in the neonate are the most frequent complications. Hypothyroidism, bradycardia and prolonged QT intervals have been ascertained in approximately 10% of neonates. In isolated cases, thyroid enlargement or cardiac murmur have been found. The malformation rate does not seem to be increased; however, the possibility of cardiac defects should be taken into consideration.
Due to the long t½ of amiodarone HCl, women who want to become pregnant should plan the beginning of a pregnancy 6 months after ending therapy at the earliest in order to avoid any exposure of the child in early pregnancy.
Transition into mother's milk is proven for the active substance and the active metabolite. Measurable plasma levels are reached in breast-fed children. If treatment is necessary in the lactation period or if amiodarone HCl has been taken during pregnancy, breastfeeding should be refrained from.
Adverse Reactions
Tablet: Eyes: Microdeposits at the anterior surface of the cornea are found in almost every patient, are usually limited to the area below the pupil and may occasionally lead to visual disturbances (blurring of vision, visual halos). They usually regress 6-12 months after discontinuation of amiodarone HCl. Some cases of optic neuritis, which caused permanent blindness in isolated cases, have been reported. During treatment with amiodarone HCl, regular ophthalmic examinations (including fundoscopy and examinations by means of a slit-lamp) are therefore indicated.
Skin: Occasionally, photosensitization with increased tendency to sunburns may occur, which can lead to erythema and rash. During longer-term treatment, especially body areas exposed to sunlight, may become hyperpigmented with black-violet to slate-grey discoloration of the skin (pseudocyanosis). The discoloration slowly recedes within 1-4 years after discontinuing the preparation. Cases of erythematous development on radiation therapy have been reported. Cases of erythema nodosum and rarely specific exanthemas including rare cases of exfoliative dermatitis have been reported. (For preventive measures see Precautions.)
Thyroid Gland: Amiodarone HCl inhibits the transformation of T4 into T3 and may lead to increased T4 values, as well as to decreased T3 values in clinically inconspicuous (euthyroid) patients. Occasionally, thyroid dysfunctions (hyperthyroidism or hypothyroidism) occur.
The following symptoms may point to thyroid dysfunction: In Hypothyroidism: Weight gain, exhaustion, extreme bradycardia exceeding the effect expected on amiodarone HCl.
In Hyperthyroidism: Weight loss, tachycardia, tremor, nervousness, increased diaphoresis and heat intolerance, recurrence of arrhythmias or angina pectoris, cardiac insufficiency.
Severe hyperthyroidism, in isolated cases leading to death, has been described.
For examinations during the course of therapy, diagnostic and therapeutic measures (see Warnings and Precautions).
Lung: As a result of the pulmonary toxicity of amiodarone HCl, atypical pneumonia as symptom of a hypersensitivity reaction (hypersensitivity pneumonitis), alveolar or interstitial pneumonitis or fibroses, pleuritis, bronchiolitis obliterans with pneumonia/BOOP may occur. If amiodarone HCl is discontinued in good time, the previously mentioned pulmonary alterations subside. Isolated cases with lethal course have been reported. Mostly after surgical procedures, several cases of shock lung acute respiratory distress syndrome (ARDS), which were fatal in isolated cases, occurred.
For examinations during the course of therapy, diagnostic and therapeutic measures (see Precautions).
Gastrointestinal Tract/Liver: Nausea and vomiting frequently occur. Occasionally, abdominal pain, sensation of repletion, constipation and anorexia occur.
Occasionally, isolated increases in serum transaminases occur, which are usually not very pronounced.
Rare cases of acute hepatitis (in isolated cases leading to death), cholestatic icterus or hepatocirrhosis have been described. In cases of persistent clinically relevant increases in liver enzymes, cholestetic icterus or hepatomegalia, discontinuation of amiodarone HCl should be taken into consideration.
Heart: As a result of the pharmacological effect of amiodarone HCl, sinus bradycardia, which may be more pronounced in elderly patients or in cases of disturbed sinus node function, or in exceptional cases, sinus node arrest may occur. The ECG shows the following alterations: QT prolongation, occurrence of U-wave, prolongation or deformation of the T-wave. Therapy must be withdrawn if pronounced bradycardia or sinus node arrest occurs.
In rare cases, conduction disturbances occurred (SA block, AV block); in isolated cases, the occurrence of asystole has been observed. Pro-arrhythmic effects in the form of alterations or aggravations of arrhythmias have been observed which can lead to highly impaired cardiac activity with the possible consequence of cardiac arrest. Isolated cases of torsades de pointes and ventricular fibrillation/flutter have been described.
Other Adverse Reactions: Occasionally, fatigue, headache, dyssomnia, nightmares, vertigo, diminished libido, myasthenia, tremor, impaired coordination, paresthesia, peripheral neuropathy or ataxia occur.
Rarely, dysgeusia, as well as reversible alopecia occur.
Rarely, hypersensitivity reactions as well as vasculitis, thrombocytopenia, transiently impaired renal function and epididymitis may occur.
Isolated cases of hemolytic or aplastic anemia, as well as intracranial increase in pressure (cerebral pseudo-tumor) have been reported.
Isolated cases of a syndrome of inappropriate (increased) secretion of antidiuretic hormone (SIADH) with hyponatremia have been described in connection with amiodarone.
Injection: The most important adverse effects of amiodarone IV were hypotension, asystole/cardiac arrest/electromechanical dissociation (EMD), cardiogenic shock, congestive heart failure (CHF), bradycardia, liver function test abnormalities, ventricular tachycardia (VT) and AV block.
The most common treatment-emergent adverse events during amiodarone IV therapy which are considered to be possibly drug-related are as follows. Body as a Whole: Fever.
Cardiovascular System: Bradycardia, CHF, heart arrest, hypotension (sometimes fatal), VT, atrial fibrillation, nodal arrhythmia, prolonged QT interval, shock, sinus bradycardia, ventricular fibrillation, sinus arrest, angioedema.
Digestive System: Abnormal liver function tests, nausea, abnormal kidney function, diarrhea, increased alanine transaminase (ALT), increased aspartate aminotransferase (AST), vomiting, hepatitis, cirrhosis, pancreatitis.
Respiratory: Lung edema, respiratory disorder, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pleuritis.
Gastrointestinal: Nausea, vomiting, constipation, abdominal pain, abnormal salivation, anorexia, epigastric burning or fullness, and pancreatitis.
Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, exfoliative dermatitis, skin cancer, pruritus, injection site reactions (pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis and skin sloughing).
Neurologic: Hallucination, confusional state, disorientation, delirium.
Hematologic: Thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, agranulocytosis.
Thyroid: Thyroid nodules/thyroid cancer.
Others: Anaphylactic/anaphylactoid reaction (including shock), renal impairment, renal insufficiency, acute renal failure, pseudotumor cerebri, syndrome of inappropriate antidiuretic hormone secretion (SIADH), vasculitis, granuloma, myopathy, muscle weakness, rhabdomyolysis, epididymitis and impotence.
Drug Interactions
Tablet: Concomitant administration of amiodarone HCl and cardiac glycosides may lead to automatism disturbances (excessive bradycardia) and disturbances in the atrioventricular conduction due to the synergistic effect of both preparations.
Concomitant administration of amiodarone HCl and digoxin may lead to an increase in the digoxin serum concentration (due to lowered digoxin clearance). Therefore, symptoms of a digitalis overdosage in these patients should be closely monitored and digoxin plasma levels should be determined as a precautionary measure. If necessary, the dose should be adjusted.
Amiodarone HCl can intensify the anticoagulant effect of vitamin K antagonists (phenprocoumon and warfarin) and hence increase the bleeding risk. During and after therapy with amiodarone HCl, Quick's value should therefore be monitored more frequently, and the dose of the vitamin K antagonists should be adjusted if necessary.
When administered concomitantly with phenytoin, amiodarone HCl may increase the serum concentration of phenytoin and precipitate symptoms of phenytoin overdose (eg, visual disturbances, tremor, vertigo). As soon as corresponding symptoms occur, the phenytoin dose should therefore be reduced. Phenytoin plasma levels should be determined if necessary.
Amiodarone HCl can increase the ciclosporin serum concentrations and decrease the clearance of ciclosporin by more than 50%. If both agents are administered concomitantly, the dose of ciclosporin should therefore be adjusted.
Amiodarone HCl can increase the plasma levels of other antiarrhythmics (eg, quinidine, procainamide, flecainide).
There is the risk of an excessive QT prolongation combined with an increased risk of ventricular arrhythmias including torsades de pointes when concomitantly administered with antiarrhythmics class I (especially quinidine-like substances) and other antiarrhythmics class III (eg, sotalol) as well as with other medicinal products prolonging the QT time (eg, vincamine, sulpiride, pentamidine IV and erythromycin IV). Concomitant administration of these medicinal products is therefore contraindicated.
In the scope of the controlled clinical SEARCH Study, an increased risk of myopathy/rhabdomyolysis was observed when amiodarone and simvastatin were used concomitantly (at a daily dose of 80 mg) (see Precautions).
Concomitant administration of potassium-depleting diuretics (eg, hydrochlorothiazide, furosemide), laxatives, systemic corticosteroids, tetracosactide or amphotericin B IV and amiodarone HCl increases the risk of the occurrence of hypokalemically induced arrhythmias (including torsades de pointes).
Concomitant administration of amiodarone HCl and calcium antagonists of the verapamil and diltiazem type or β-adrenergic blocking agents may lead to excessive bradycardia, higher grade atrioventricular conduction disturbances and to additive cardiodepressive effects. Calcium antagonists of the verapamil and diltiazem type or β-adrenergic blocking agents should therefore not be combined with amiodarone HCl.
Rare cases of atropine-resistant bradycardia, fall in blood pressure, conduction disturbances and reduced cardiac output have been observed in patients on therapy with amiodarone HCl undergoing general anesthesia.
In isolated cases, severe respiratory complications (shock lung, ARDS) occur, for the most part directly after surgical procedures. A possible intensification of the toxic effect of oxygen has been assumed. The anaesthetist should therefore be informed prior to surgical procedures about amiodarone HCl therapy.
Injection: Drugs/Food/Dietary or Herbal Supplements Affecting Microsomal Enzymes: Amiodarone is metabolized by the cytochrome P-450 (CYP450) microsomal enzyme system, principally the isoenzymes CYP3A4 and CYP2C8. Amiodarone also inhibits CYP2D6, CYP1A2, CYP2C9, and CYP3A4 isoenzymes. Inhibition of these isoenzymes by amiodarone may result in unexpectedly high plasma concentrations of other drugs which are metabolized by these isoenzymes.
HIV Protease Inhibitors: HIV protease inhibitors (eg, ritonavir, amprenavir, indinavir) are known to inhibit CYP3A4 to varying degrees. Monitor for amiodarone toxicity and do serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy.
Loratadine: A nonsedating antihistamine, is metabolized primarily by CYP3A4. QT interval prolongation and torsades de pointes have been reported with the co-administration of loratadine and amiodarone.
Cimetidine: Inhibits CYP3A4 and can increase serum amiodarone levels.
Trazodone: An antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and torsades de pointes have been reported with the co-administration of trazodone and amiodarone.
Cyclosporine (CYP3A4 substrate): Administered in combination with oral amiodarone, has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine.
HMG-CoA Reductase Inhibitors: Statins (CYP3A4 substrate) in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis.
Antihypertensives: Amiodarone should be used with caution in patients receiving β-receptor blocking agents (eg, propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (eg, verapamil, a CYP3A4 substrate and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest.
Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3-4 days, the dose of the anticoagulant should be reduced by 1/3 to ½, and prothrombin times should be monitored closely. A similar effect has been reported with fluindione, an oral vitamin K antagonist, when administered concomitantly with amiodarone.
Clopidogrel: An inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and Amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.
Antibiotics: Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone.
Fentanyl (CYP3A4 Substrate): In combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.
In isolated cases, severe respiratory complications (shock lung, ARDS) occur, for the most part directly after surgical procedures. A possible intensification of the toxic effect of oxygen has been assumed. The anaesthetist should therefore be informed prior to surgical procedures about amiodarone HCl therapy.
Lidocaine (CYP3A4 Substrate): It has been reported to cause sinus bradycardia when given in combination with amiodarone. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of amiodarone IV.
Dextromethorphan: It is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6 with resulting impairment in metabolism.
St. John's Wort (Hypericum perforatum): It induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John's wort in patients receiving amiodarone could result in reduced amiodarone levels.
Grapefruit Juice: When given to healthy volunteers, it increased amiodarone area under the concentration-time curve (AUC) by 50% and peak plasma concentration (Cmax) by 84%, and decreased desethylamiodarone (DEA) to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased amiodarone plasma levels; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from amiodarone IV to oral amiodarone.
Drugs Affecting the QT Interval: Amiodarone prolongs QTc interval. Potentially serious cardiac arrhythmias, including torsades de pointes, could occur if amiodarone is administered concomitantly with other drugs that prolong the QTc interval (eg, cisapride, halofantrine, pimozide, disopyramide, fluoroquinolones, macrolide antibiotics, azole antifungal agents).
Cardiac Glycoside (Digoxin): Amiodarone given concomitantly with digoxin increases serum digoxin concentration by 70% after 1 day. On initiation of amiodarone, review the need for digitalis therapy and reduce the dose by approximately 50% or discontinue digoxin. Closely monitor serum digoxin levels and observe patients for clinical evidence of toxicity. These precautions should be applied to digitoxin as well.
Antiarrhythmics: Concomitant use of amiodarone with other antiarrhythmic agents (eg, disopyramide, mexiletine, propafenone, flecainide, procainamide, quinidine, bepridil, sotalol, diphemanil) generally should be reserved for patients with life-threatening arrhythmias who do not respond completely to either a single antiarrhythmic agent or amiodarone alone.
When combination therapy with amiodarone is necessary, it is generally recommended that dosage of currently administered antiarrhythmic agent be reduced by 30-50% several days after initiation of amiodarone therapy, since the onset of amiodarone's antiarrhythmic effect may be delayed.
Other Reported Interactions with Amiodarone: Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t½.
Chronic use (>2 weeks) of amiodarone impairs metabolism of phenytoin. It may also increase the serum concentration of phenytoin and precipitate symptoms of phenytoin overdose (eg, visual disturbances, tremor, vertigo). As soon as corresponding symptoms occur, the phenytoin dose should therefore be reduced. Phenytoin plasma levels should be determined if necessary. Also, amiodarone serum levels may be decreased.
Concomitant administration of fentanyl and amiodarone may result in hypotension, bradycardia and decreased cardiac output.
Concomitant administration with non-antiarrhythmic agents, including vincamine, sultopride, sparfloxacin, erythromycin IV and pentamidine may cause an increased risk of potentially lethal torsades de pointes.
Co-administration with agents that can produce hypokalemia and/or hypomagnesemia (eg, potassium-wasting diuretics, amphotericin B, cation exchange resins, stimulant laxatives) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, because of additive arrhythmogenic potential. Any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy.
Amiodarone HCl can increase the cyclosporin serum concentrations and decrease the clearance of cyclosporin by >50%. If both agents are administered concomitantly, the dose of cyclosporin should therefore be adjusted. Concomitant use of amiodarone and cyclosporine has also produced persistently elevated creatinine despite reduction in dose of cyclosporine.
Chronic use (>2 weeks) of amiodarone impairs metabolism of methotrexate. Methotrexate toxicity may be increased.
Concomitant administration of amiodarone and rifamycin may cause decreased serum concentrations of amiodarone and its active metabolites, reducing its pharmacologic effect.
Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.
Storage
Tablet: Store at temperatures not exceeding 25°C.
Injection: Store at temperatures not exceeding 30°C.
MIMS Class
ATC Classification
C01BD01 - amiodarone ; Belongs to class III antiarrhythmics.
Presentation/Packing
Tab 200 mg (white, round, biconvex with one-sided score notch) x 30's. Inj (amp) 50 mg/mL (sterile, clear, colorless to yellowish) x 3 mL x 6's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in