AMIODARONE HCL (Generic for PACERONE)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May be taken without regard to meals. Administer consistently with or without food due to the variable effect of food on oral absorption. To minimize gastrointestinal side effects, administer with meals.

Oral Liquid Formulations
-Extemporaneous suspension: Shake well before administering. Measure dosage with calibrated measuring device.

Extemporaneous Compounding-Oral
Extemporaneous 5 mg/mL amiodarone oral suspension preparation:
-Crush five (5) 200 mg amiodarone tablets in a mortar and grind to a fine powder.
-Mix together a 1:1 mixture of a vehicle consisting of 100 mL of Ora-Plus and 100 mL of Ora-Sweet or Ora-Sweet SF.
-Add an adequate amount of bicarbonate solution (5 g/100 mL in distilled water) to the vehicle mixture to adjust the pH to between 6 and 7.
-Add a small amount of the vehicle mixture to the crushed tablets and mix to form a uniform paste.
-Add geometric amounts of the vehicle to almost the desired volume while mixing.
-Transfer the contents of the mortar to a graduated cylinder and add remaining vehicle to a total volume of 200 mL.
-Storage: The resulting suspension is stable for 42 days at 25 degrees C or 91 days at 4 degrees C when stored in plastic bottles.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Intravenous Administration
Dilution
-For rapid infusion during CPR (i.e., pulseless ventricular tachycardia or fibrillation): May be given undiluted. However, dilution may be necessary for accurate measurement and administration of small doses.
-Dilute amiodarone in 5% Dextrose Injection only.
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 1.8 mg/mL or 3.6 mg/mL.
-Amiodarone can be diluted to a final concentration of 1 to 6 mg/mL.
-For infusions lasting more than 1 hour, do not exceed a concentration of more than 2 mg/mL unless administered via a central venous catheter. Intravenous amiodarone concentrations of more than 3 mg/mL have been associated with a high incidence of peripheral vein phlebitis.
-Infusions lasting more than 2 hours must be administered in polyolefin or glass bottles containing 5% Dextrose Injection. Do not use evacuated glass containers for admixing, as incompatibility with a buffer in the container may cause precipitation.
-Storage: Amiodarone diluted in 5% Dextrose Injection is stable at concentrations of 1 to 6 mg/mL for 2 hours in polyvinyl chloride (PVC) and for 24 hours in polyolefin or glass bottles at room temperature.

General Administration
-Only administer using a volumetric infusion pump. Use an in-line filter during administration.
-Administer via a central venous catheter whenever possible.
-Use PVC tubing during administration.
-A warning by the FDA has noted the concern that IV amiodarone has been found to leach out plasticizers, such as di-(2-ethylhexyl)phthalate (DEHP) from IV tubing including PVC tubing, which may lead to safety concerns for pediatric patients. Conventional amiodarone injection contains polysorbate 80, which is also known to leach DEHP from PVC tubing. The degree of leaching increases when infusing high concentrations and low flow rates. It is important to administer at recommended dosage and infusion rates. Nexterone premixed containers do not contain polysorbate 80.
-Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is complete.

IV Infusion During CPR
-Perfusing rhythms: Administer over 20 to 60 minutes. In children with cardiac disease, administer over 30 to 60 minutes to decrease the risk of hemodynamic compromise.
-Pulseless ventricular fibrillation/tachycardia: Administer via IV push.
-If administered peripherally via IV push, follow the injection with a fluid bolus to promote drug flow into the central circulation. Briefly elevate the extremity during and after administration.

IV Infusion for Treatment of Tachyarrhythmias
-Administer loading dose over 1 hour; then, start a continuous IV infusion at a rate of 5 to 15 mcg/kg/minute.
-Dividing bolus doses into smaller aliquots (e.g., 1 mg/kg) and administering each aliquot over 5 to 10 minutes has been recommended to reduce patient exposure to plasticizers.

Other Injectable Administration
Intraosseous Administration
NOTE: Amiodarone is not FDA-approved for intraosseous administration.
-During cardiopulmonary resuscitation, the same dosage may be given via the intraosseous route if IV access is unsuccessful or not feasible.

Despite its superior efficacy as an antiarrhythmic agent, the use of amiodarone is limited by its multitude of adverse reactions. In general, the incidence of systemic adverse reactions is lower with chronic use in pediatric patients compared to adults. Adverse reaction rates of 8% to 33% have been reported in the majority of pediatric studies of chronic amiodarone therapy; however, 1 small study of 30 pediatric patients reported an adverse reaction rate of 90%. The overall reported incidence of adverse reactions in adult patients is 30% to 93%, with serious adverse reactions reported in 9% to 26%. Adverse reactions in pediatric patients appear to be unrelated to dose; however, the incidence of reactions does appear to be age-dependent, increasing with increasing age. In 1 study, adverse reactions were reported in 4% of patients younger than 10 years compared to 44% of patients older than 10 years.

Cardiovascular adverse reactions of amiodarone are difficult to differentiate from extensions of its normal pharmacologic activity. Amiodarone may cause AV block, sinoatrial block, and/or intraventricular block, precipitating serious new cardiac arrhythmias. Amiodarone can cause arrhythmia exacerbation or new ventricular fibrillation (VF), incessant ventricular tachycardia (VT), increased resistance to cardioversion, and torsade de pointes (TdP) associated with QT prolongation. A review of published reports reveals that proarrhythmic events have been reported in 2.7% to 11.6% of pediatric patients receiving amiodarone and include sinoatrial node dysfunction, complete atrioventricular block, VF, and TdP. In a study of 61 pediatric patients (aged 30 days to 15 years), AV block was reported in 15% of patients. Bradycardia has been reported in 2.5% to 20% of pediatric patients receiving intravenous amiodarone. Bradycardia may require a pacemaker for rate control. With intravenous amiodarone, bradycardia and AV block may respond to slowing of the infusion rate. Congestive heart failure, cardiac arrhythmias, SA node dysfunction, flushing, and edema were commonly reported in adults receiving oral amiodarone; cardiac conduction abnormalities were uncommon. In adult clinical trials for intravenous amiodarone, asystole/cardiac arrest/pulseless electrical activity (2.9%; range 2.% to 3.5%), congestive heart failure (2.1%), bradycardia (4.9% or less), VT (2.4%), and AV block were among the most important adverse reactions reported. Ventricular fibrillation, atrial fibrillation, nodal arrhythmia, QT prolongation, and TdP occurred in less than 2% of patients. Sinus node dysfunction (sinus arrest, sinoatrial block), bradycardia (sometimes fatal), intraventricular conduction disorders including bundle branch block and infra-HIS block, ventricular extrasystoles, and antegrade conduction via an accessory pathway have been reported during postmarketing use. Some formulations of IV amiodarone contain benzyl alcohol, which can cause adverse reactions in neonates. There have been reports of fatal 'gasping syndrome' in neonates after the administration of IV solutions containing benzyl alcohol; symptoms include a striking onset of gasping respiration, low blood pressure, bradycardia, and cardiovascular collapse.

Pulmonary toxicity (hypersensitivity pneumonitis including eosinophilic pneumonia, interstitial/alveolar pneumonitis, or pulmonary fibrosis) is a well-recognized complication of long-term amiodarone use, manifesting in up to 17% of adult patients and fatal approximately 10% of the time. Advise patients to report symptoms of cough, fever, or progressive dyspnea. Obtain a baseline chest x-ray and pulmonary function tests, including diffusion capacity, upon initiation of oral therapy; repeat history, physical exam, and chest x-ray every 3 to 6 months or if symptoms occur. Consider an alternative antiarrhythmic if the patient experiences signs or symptoms of pulmonary toxicity. Prednisone (adult dose = 40 to 60 mg/day) tapered over several weeks may be helpful. Acute-onset (days to weeks) pulmonary toxicity can also occur in patients treated with intravenous amiodarone. Pulmonary infiltrates and masses on chest x-ray, bronchospasm, wheezing, fever (2%), pulmonary edema (less than 2%), dyspnea, cough, hemoptysis, and hypoxia have been reported in adults; some cases progressed to respiratory arrest or death. Pulmonary toxicity due to amiodarone has rarely been reported in pediatric patients; pulmonary adverse reactions were not reported in 2 large studies (n = 230) of chronic amiodarone treatment in pediatric and young adult patients (mean follow-up 5 to 28 months). Pulmonary toxicity may be dose-related. In a study of 573 adult patients receiving maintenance amiodarone doses of 50 to 800 mg/day, there were no cases of pulmonary toxicity in patients receiving less than 305 mg/day; however, there have been postmarketing reports with low dose amiodarone therapy. Acute respiratory distress syndrome (ARDS) was reported in 2% of adult patients during clinical trials involving 48 hours of intravenous amiodarone therapy. Cases of ARDS have also been reported postoperatively in adult patients receiving oral amiodarone who have undergone cardiac or noncardiac surgery. Patients typically respond to vigorous respiratory therapy, however, in rare instances, ARDS has been fatal. Bronchiolitis obliterans organizing pneumonia, pulmonary alveolar hemorrhage, interstitial pneumonitis, pulmonary phospholipidoisis, pleural effusion, and pleuritis have been reported with postmarketing use.


Nausea and vomiting are very common, while constipation, anorexia, abdominal pain, abnormal taste and smell, and abnormal salivation are common with oral amiodarone therapy. Nausea (3.9%), vomiting (less than 2%), and diarrhea (less than 2%) have also been reported with intravenous use in adults. Xerostomia has been associated with postmarketing amiodarone use.

Asymptomatic elevated hepatic enzymes are seen frequently with amiodarone therapy. These effects are mild and usually return to normal after dosage reduction. Obtain baseline and periodic liver transaminases in patients receiving amiodarone. Discontinue or reduce the dose of oral amiodarone if transaminases exceed 3 times the upper limit of normal (ULN) or double in a patient with elevated baseline values. Obtain follow-up tests and treat appropriately. Consider reducing the rate of administration or discontinue intravenous amiodarone if hepatic injury occurs. Fatal hepatotoxicity (cholestasis, cirrhosis, hepatic failure, hepatitis) has occurred and is accompanied by severely elevated hepatic enzymes. Histology has resembled that of alcoholic hepatitis or cirrhosis. Acute hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone. Of note, elevations in liver function tests (LFTs) often occur in patients with ventricular tachycardia or fibrillation, multiple electrical defibrillations, congestive heart failure, or recent myocardial infarction, which may complicate interpretation of changes in LFTs. Baseline LFT elevations are not a contraindication to intravenous amiodarone treatment. Elevated bilirubin concentrations (hyperbilirubinemia), hepatitis, cholestasis, cholestatic hepatitis, jaundice, cirrhosis, and pancreatitis have been reported with amiodarone use.

Coagulation abnormalities were reported commonly in adult patients receiving oral amiodarone during clinical trials. Thrombocytopenia was reported in less than 2% of those receiving intravenous amiodarone. Granuloma, agranulocytosis, aplastic anemia, hemolytic anemia, neutropenia, and pancytopenia have been reported during postmarketing surveillance.

Hypotension is the most common adverse reaction associated with intravenous amiodarone and has been reported in 4% to 70% of pediatric patients. Hypotension may respond to a reduced infusion rate, volume expansion, or calcium administration; some patients may require increased catecholamine support. Hypotension is observed most frequently within the first few hours of the infusion, is not dose-related, but appears to be related to the infusion rate. Some formulations of IV amiodarone contain polysorbate 80 and benzyl alcohol as excipients, both of which have been associated with hypotension. The incidence of drug-related hypotension was much lower (2%) in an analysis of 4 clinical trials in adult patients receiving bolus doses (administered over approximately 2 minutes) of an amiodarone formulation free of polysorbate 80 or benzyl alcohol. Fatal cases of hypotension have been reported during postmarketing experience with amiodarone.

Fatigue, malaise, tremor, abnormal involuntary movements, ataxia, poor coordination and gait, dizziness, paresthesias, insomnia, headache, sleep disturbances, and peripheral neuropathy are common with amiodarone use. Peripheral neuropathy may be irreversible. Parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with amiodarone discontinuation), hallucinations, confusion, disorientation, delirium, increased intracranial pressure, demyelinating polyneuropathy, and pseudotumor cerebri have been reported during postmarketing surveillance of amiodarone.

Myopathy, rhabdomyolysis, muscle weakness, muscle cramps/spasms, back pain, and lupus-like symptoms have been reported during postmarketing surveillance of amiodarone.

Amiodarone has a complex effect on thyroid hormone metabolism and frequently alters thyroid function tests during chronic therapy. Amiodarone can cause either hyper- or hypothyroidism, with hypothyroidism occurring in approximately 2% to 10% of adult patients during therapy and being most prevalent in areas with high iodine intake. Severe hypothyroidism and myxedema coma, sometimes fatal, have been reported. Additionally, although use during pregnancy is uncommon, there have been a small number of reports of congenital goiter/hypothyroidism associated with maternal amiodarone use. Monitor thyroid function at baseline and periodically thereafter, particularly in patients with preexisting thyroid disease. Manage hypothyroidism with amiodarone dosage reduction or discontinuance and thyroid hormone supplementation. Thyroid nodules/thyroid cancer in patients treated with amiodarone have been reported with postmarketing surveillance.

Angioedema and anaphylactic/anaphylactoid reactions, including anaphylactic shock and cardiac arrest, have been reported with amiodarone use. Manifestations reported with intravenous use include hypotension, tachycardia, hypoxia, cyanosis, rash, flushing, hyperhidrosis, and cold sweats. Hypersensitivity reactions may also involve cutaneous or mucosal bleeding, fever, arthralgia, eosinophilia, hives, thrombotic thrombocytopenic purpura (TTP), or severe periarteritis.

Local injection site reaction has occurred with intravenous amiodarone administration and may include thrombosis, phlebitis, thrombophlebitis, cellulitis, pain, induration, edema, inflammation, itching, erythema, pigment changes, hypoesthesia, skin sloughing, extravasation possibly leading to venous/infusion site skin necrosis, intravascular amiodarone deposition/mass (developed in the superior vena cava around a central venous catheter after long-term [28 days] central line administration), and granuloma. Injection site reactions have been observed in 5 (25%) of 20 pediatric patients receiving IV amiodarone via a peripheral vein. Intravenous administration of amiodarone concentrations more than 3 mg/mL have been associated with a high incidence of peripheral vein phlebitis; however, concentrations of 2.5 mg/mL or less appear to be less irritating. Infusions that will be administered over longer than 1 hour should not exceed a concentration of 2 mg/mL unless a central venous catheter is used.

Visual disturbances are common with amiodarone use. Cases of optic neuropathy and optic neuritis, typically resulting in visual impairment but sometimes resulting in permanent blindness, have been reported in patients receiving amiodarone and may occur at any time during therapy. If symptoms of visual impairment appear (e.g., change in visual acuity, blurred vision, decrease in peripheral vision), consider discontinuing amiodarone and promptly refer the patient for ophthalmic examination. Corneal deposits (microdeposits) appear in the majority of patients receiving amiodarone and lead to symptoms such as visual halos and blurred vision in up to 10% of adult patients. Dose reduction or drug discontinuation can reverse corneal microdeposits; however, asymptomatic microdeposits alone are not a reason to reduce the dose or discontinue treatment. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during amiodarone therapy.

Epididymitis has been associated with amiodarone therapy during postmarketing experience.

Syndrome of inappropriate antidiuretic hormone (SIADH) has been associated with amiodarone use during postmarketing surveillance.

Abnormal kidney function (less than 2%), increased blood creatinine, renal impairment, renal insufficiency, and acute renal failure (unspecified) have been reported with amiodarone therapy.

Amiodarone has a complex effect on thyroid hormone metabolism and frequently alters thyroid function tests during chronic therapy. Amiodarone can cause either hypo- or hyperthyroidism, with hyperthyroidism occurring in approximately 2% of adult patients during therapy. Additionally, although use during pregnancy is uncommon, there have been a small number of reports of congenital hyperthyroidism associated with maternal amiodarone use. Monitor thyroid function at baseline and periodically thereafter, particularly in patients with preexisting thyroid disease. Hyperthyroidism may lead to thyrotoxicosis and arrhythmia exacerbation (sometimes fatal); if new signs of arrhythmia appear during amiodarone therapy, consider hyperthyroidism. Manage symptoms with antithyroid drugs, beta-blockers, and temporary steroid therapy. The action of antithyroid drugs may be delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated; low radioiodine uptake is associated with amiodarone-induced hyperthyroidism. Amiodarone-induced hyperthyroidism may be followed by transient hypothyroidism. Experience with thyroidectomy as a treatment option for amiodarone-induced thyrotoxicosis is limited; thyroid storm may be induced with this treatment option.

Amiodarone causes photosensitivity/solar dermatitis in approximately 10% of adult patients. Sunscreen and protective clothing may offer some protection. During long-term treatment, a blue-gray skin discoloration may occur. Some reversal may occur with drug discontinuation. Less common dermatologic reactions include rash, spontaneous ecchymosis, alopecia, and Stevens-Johnson syndrome (less than 2%). Cases of vasculitis, flushing, erythema multiforme, exfoliative dermatitis, bullous dermatitis, eczema, granuloma, pruritus, urticaria, skin cancer, drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (sometimes fatal) have been reported during postmarketing surveillance.

Adverse reactions and drug interactions can persist for several weeks after amiodarone discontinuation due to the long half-life of amiodarone and its active metabolite.

Amiodarone is contraindicated in patients with a known hypersensitivity to the drug or any of its components. Due to the incorporation of iodine into its chemical structure, it is contraindicated in patients with iodine hypersensitivity.

Amiodarone is contraindicated in patients with sick sinus syndrome, second- or third-degree AV block (without a functioning pacemaker), and bradycardia leading to syncope (without a functioning pacemaker). Treat patients with a known predisposition to bradycardia or AV block with intravenous amiodarone in a setting where a temporary pacemaker is available. Initiate oral amiodarone in a clinical setting where continuous electrocardiograms and cardiac resuscitation are available. Oral amiodarone is only indicated for use in patients with life-threatening arrhythmias due to the potential for drug toxicity; use requires an experienced clinician who is familiar with the drug's risks and experienced in the treatment of life-threatening arrhythmias. While there are no black box warnings for the intravenous formulation, it is recommended that only experienced clinicians familiar with drug's risks and benefits, as well as, the treatment of life-threatening arrhythmias administer amiodarone therapy.

Amiodarone is contraindicated for use in cardiogenic shock due to its adverse effect profile which includes hypotension, heart failure, and cardiogenic shock. In general, due to potential negative inotropic effects, use amiodarone cautiously in patients with congestive heart failure or left ventricular dysfunction (LVD). However, amiodarone may be preferred to alternative antiarrhythmics in patients with severe ventricular impairment due to its lower incidence of adverse hemodynamic and proarrhythmic effects relative to other antiarrhythmic agents. When antiarrhythmic therapy is necessary, amiodarone may be useful for the treatment of atrial and ventricular arrhythmias in patients with heart failure or LVD (EF < 40%). Use intravenous amiodarone with caution in patients at risk for hypotension; monitor blood pressure closely and use volume expansion with blood or plasma when appropriate in patients with pre-existing hypotension or hypovolemia. Rare episodes of hypotension occurring upon the discontinuation of cardiopulmonary bypass have been reported in patients receiving amiodarone.

Amiodarone can cause hypothyroidism or hyperthyroidism. Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine concentrations, decreased T3 concentrations, and increased concentrations of inactive reverse T3 in euthyroid patients. Monitor thyroid function at baseline and periodically thereafter, particularly in patients with preexisting thyroid disease (e.g., thyrotoxicosis, thyroid nodules, goiter, or other thyroid dysfunction). Hyperthyroidism may induce arrhythmia breakthrough; consider hyperthyroidism if new signs of arrhythmia appear.

Amiodarone can worsen cardiac arrhythmias, a risk that may be enhanced by the presence of concomitant antiarrhythmics. Initiate amiodarone in a clinical setting where continuous electrocardiograms and cardiac resuscitation are available. The types of arrhythmia exacerbation reported in adult patients include new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (and torsade de pointes [TdP]). In addition, amiodarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in adult patients. Avoid amiodarone in patients with congenital long QT syndrome, acquired QT prolongation syndromes, or a history of TdP. The need to coadminister amiodarone with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits. Use amiodarone with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds in patients with implanted pacemakers or defibrillators; assess thresholds at the beginning of and during amiodarone treatment.

Use amiodarone with extreme caution in patients with preexisting pulmonary disease (i.e., chronic lung disease (CLD), reduced diffusion capacity, respiratory insufficiency). Potentially fatal amiodarone-induced lung toxicity may occur during therapy (hypersensitivity pneumonitis or interstitial/alveolar pulmonary fibrosis). Rates of pulmonary toxicity as high as 17% with fatal outcomes in about 10% of cases have been reported for oral amiodarone. Obtain baseline pulmonary function tests, including diffusion capacity, and a chest x-ray upon initiation of oral therapy; repeat history, physical exam, and chest x-ray every 3 to 6 months or if symptoms occur. Consider an alternative antiarrhythmic if the patient experiences signs or symptoms of pulmonary toxicity. Acute respiratory distress syndrome (ARDS) has been reported postoperatively in patients receiving oral amiodarone who have undergone cardiac or noncardiac surgery. Although most patients respond to vigorous respiratory therapy, death has been reported rarely. Closely monitor FiO2 and determinants of oxygen delivery to the tissues (e.g., SaO2 and PaO2) in patients receiving amiodarone undergoing surgery.

Use amiodarone cautiously in patients with preexisting structurally degenerative hepatic disease (e.g., cirrhosis), as the metabolism and/or elimination of amiodarone and active metabolite DEA could be reduced, potentially increasing the risk of amiodarone-induced liver toxicity. Asymptomatic elevations of hepatic enzyme concentrations are seen frequently. However, fatal hepatotoxicity (e.g., hepatic failure, hepatitis) may also occur. Obtain baseline and periodic liver transaminases in patients receiving amiodarone. Discontinue or reduce the dose of oral amiodarone if transaminases exceed 3 times the upper limit of normal (ULN) or double in a patient with elevated baseline values. Obtain follow-up tests and treat appropriately. In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of intravenous amiodarone therapy. Carefully monitor patients. If evidence of progressive hepatic injury occurs, consider reducing the administration rate or withdrawing amiodarone.

Correct any electrolyte imbalance including hypokalemia, hypomagnesemia, or hypocalcemia prior to amiodarone initiation. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant drugs that affect electrolyte concentrations (e.g., diuretics, laxatives, systemic corticosteroids, amphotericin B). Electrolyte imbalance may predispose the patient to the development of arrhythmias as well as potentially decrease the efficacy of amiodarone.

Optic neuropathy and optic neuritis, usually resulting in visual disturbance and sometimes in permanent blindness, have been reported in patients treated with amiodarone and may occur at any time during therapy. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended in all patients during administration of amiodarone. If symptoms of visual impairment appear (e.g., change in visual acuity, decrease in peripheral vision), consider discontinuing amiodarone and promptly refer the patient for ophthalmic examination. Most manufacturers of corneal refractive laser surgery devices contraindicate the use of this type of ocular surgery in patients taking amiodarone.

Amiodarone can cause photosensitivity, especially in fair-skinned patients or those with excessive sunlight (UV) exposure. Advise patients to wear sunscreen and protective clothing, both of which may offer some protection. During long-term treatment, a blue-gray discoloration of the sun-exposed skin may occur. Some reversal of discoloration may occur with drug discontinuation.

Close perioperative monitoring is recommended in patients who are on amiodarone therapy and are undergoing surgery that requires general anesthesia. These patients may be more sensitive to the myocardial depressant and conduction effects of halothane anesthesia.

Intravenous (IV) amiodarone has been found to leach out plasticizers, such as DEHP from IV tubing, including polyvinyl chloride (PVC) tubing, which may lead to safety concerns for neonates, infants, and children. The degree of leaching increases when infusing amiodarone at high concentrations and low flow rates. An expert panel concluded that, based on data from animal studies, there was concern that exposure to DEHP may adversely affect male reproductive tract development during fetal, infant, and toddler stages of development if the exposure in these immature stages is several fold higher than in adults, a situation that might be associated with intensive medical procedures such as those used in critically ill infants. The maximum anticipated exposure to DEHP following IV amiodarone administration under conditions of pediatric administration is estimated to be about 1.9 mg/kg/day for a 3 kg infant, which produces a safety margin of between about two-fold and seven-fold. If the use of IV amiodarone in pediatric patients is medically warranted, in order to reduce the potential exposure of these patients to plasticizers, alternative methods of dosing and administration (e.g., bolus IV dosing in 1mg/kg aliquots) may be considered. An additional precaution for amiodarone is that some IV formulations may contain the preservative benzyl alcohol, which can cause adverse effects in neonates. There have been reports of fatal 'gasping syndrome' in neonates after the administration of IV solutions containing benzyl alcohol; symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. This warning is not associated with Nexterone, a formulation of amiodarone injection that is free of polysorbate 80 and benzyl alcohol.

In utero exposure to amiodarone may increase the potential for adverse cardiac, thyroid, neurodevelopmental, neurological, and growth effects in the neonate. Monitor thyroid function studies in neonates with fetal exposure to amiodarone; there have been limited reports of congenital goiter/hypothyroidism and hyperthyroidism. Other reported risks associated with in utero exposure to amiodarone include bradycardia, QT prolongation, periodic ventricular extrasystoles, hyperthyroxinemia, jerk nystagmus with synchronous head titubation, and neurodevelopmental abnormalities independent of thyroid function such as speech delay, difficulties with written language and arithmetic, delayed motor development, and ataxia. Fetal growth retardation and premature birth have also been reported.

Description: Amiodarone is a class III antiarrhythmic agent used for the treatment of tachyarrhythmias, including ventricular and supraventricular tachyarrhythmias. PALS guidelines recommend either amiodarone or lidocaine for shock-refractory ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT). Pediatric observational data has shown improved return of spontaneous circulation (ROSC) with the use of lidocaine as compared with amiodarone. Neither amiodarone nor lidocaine has been shown to improve survival to hospital discharge. Reported efficacy rates for amiodarone in pediatric patients are high (84% to 93% for SVT); however, due to the concern for serious adverse reactions with long-term use, oral amiodarone is often reserved for the treatment of life-threatening arrhythmias or arrhythmias resistant to other therapies. However, the overall incidence of systemic adverse reactions is lower with chronic use in pediatric patients compared to adults and appears to increase with increasing age. Although amiodarone is associated with several potentially significant, sometimes fatal adverse reactions, it has not been associated with proarrhythmias as frequently as other antiarrhythmics. Although not FDA-approved, amiodarone has been used in pediatric patients as young as neonates.

For the treatment of tachyarrhythmias including atrial fibrillation*, atrial flutter*, paroxysmal supraventricular tachycardia (PSVT)*, junctional ectopic tachycardia (JET)*, ventricular fibrillation*, and ventricular tachycardia*:
Intravenous dosage:
Neonates: 5 mg/kg/dose IV as a single dose, then 5 mcg/kg/minute continuous IV infusion, initially. Max: 15 mcg/kg/minute. A second bolus ranging from 1 to 5 mg/kg/dose has been administered to some patients. Dosing protocols administering the bolus dose in smaller aliquots of 1 to 2 mg/kg/dose IV have been recommended in order to reduce patient exposure to plasticizers, such as DEHP, which may be leached out of IV tubing, including polyvinyl chloride (PVC) tubing, by certain formulations of amiodarone.
Infants, Children, and Adolescents: 5 mg/kg/dose IV as a single dose, then 5 mcg/kg/minute continuous IV infusion, initially. Max: 15 mcg/kg/minute. A second bolus ranging from 1 to 5 mg/kg/dose has been administered to some patients. Dosing protocols administering the bolus dose in smaller aliquots of 1 to 2 mg/kg/dose IV have been recommended in order to reduce patient exposure to plasticizers, such as DEHP, which may be leached out of IV tubing, including polyvinyl chloride (PVC) tubing, by certain formulations of amiodarone.
Oral dosage:
Neonates: 10 to 20 mg/kg/day PO in 1 to 2 divided doses for 4 to 14 days, then 2 to 5 mg/kg/dose PO once daily has been reported most commonly. Mean reported maintenance doses: 7.7 mg/kg/day (range: 1.5 to 25 mg/kg/day). Alternatively, 600 to 800 mg/1.73 m2/day PO for 4 to 14 days, then 200 to 400 mg/1.73 m2/day PO has been recommended. When symptoms are controlled, reduce to lowest effective dose; maintenance dose may be given 5 days/week. In a study, the mean initial and maintenance dose was 15.3 mg/kg/day (261 mg/m2/day) and 8.2 mg/kg/day (204 mg/m2/day), respectively, in patients younger than 1 year. These doses were significantly higher than those required in older patients when compared on a mg/kg basis but not when compared on a mg/m2 basis. The authors recommended that dosing be based on body surface area in this age group rather than weight. Although the reported efficacy rates of amiodarone in pediatric patients are high (84% to 93% for SVT), it is often reserved for the treatment of life-threatening arrhythmias or arrhythmias resistant to other therapies due to the concern for serious adverse reactions with long-term use.
Infants: 10 to 20 mg/kg/day PO in 1 to 2 divided doses for 4 to 14 days, then 2 to 5 mg/kg/dose PO once daily has been reported most commonly. Mean reported maintenance doses: 6.6 to 7.7 mg/kg/day (range: 1.5 to 25 mg/kg/day). Alternatively, 600 to 800 mg/1.73 m2/day PO for 4 to 14 days, then 200 to 400 mg/1.73 m2/day PO maintenance has been recommended. When symptoms are controlled, reduce to lowest effective dose; maintenance dose may be given 5 days/week. Infants may require higher mg/kg doses compared to older children. In a study, the infant maintenance dose was the same as the loading dose in absolute value, although it decreased in relative value in relation to the increase in body weight. In another study, the mean initial and maintenance dose was 15.3 mg/kg/day (261 mg/m2/day) and 8.2 mg/kg/day (204 mg/m2/day), respectively, in patients younger than 1 year. These doses were significantly higher than those required in older patients when compared on a mg/kg basis but not when compared on a mg/m2 basis. The authors recommended that dosing be based on body surface area in this age group rather than weight. Although the reported efficacy rates of amiodarone in pediatric patients are high (84% to 93% for SVT), it is often reserved for the treatment of life-threatening arrhythmias or arrhythmias resistant to other therapies due to the concern for serious adverse reactions with long-term use.
Children and Adolescents: 10 to 20 mg/kg/day (Max: 1,600 mg/day) PO in 1 to 2 divided doses for 4 to 14 days, then 2 to 5 mg/kg/dose PO once daily has been reported most commonly. Mean reported maintenance doses: 6.6 to 7.7 mg/kg/day (range: 1.5 to 25 mg/kg/day). When symptoms are controlled, reduce to lowest effective dose; maintenance dose may be given 5 days/week. Although the reported efficacy rates of amiodarone in pediatric patients are high (84% to 93% for SVT), it is often reserved for the treatment of life-threatening arrhythmias or arrhythmias resistant to other therapies due to the concern for serious adverse reactions with long-term use.

For the treatment of ventricular arrhythmias during cardiopulmonary resuscitation* (CPR):
Intravenous and Intraosseous dosage:
Neonates, Infants, Children, and Adolescents: 5 mg/kg/dose IV; may repeat dose twice up to 15 mg/kg IV (Max single dose: 300 mg IV). Adjust administration rate to urgency. May administer IV push for ventricular fibrillation or pulseless ventricular tachycardia; slower administration (e.g., over 20 to 60 minutes) is recommended for patients with a perfusing rhythm. The same dosage may be given via the intraosseous route when IV access is not available.

Therapeutic Drug Monitoring:
The mean serum concentrations of amiodarone required for initial arrhythmia suppression (mean dose 10.1 mg/kg/day PO) and maintenance therapy (mean dose 6 mg/kg/day PO) were 0.98 and 0.84 mg/L, respectively, in 30 pediatric patients (age range 1 week to 14 years). The manufacturer recommends a usual therapeutic range of 1 to 2.5 mg/L for chronic oral dosing in adults; however, the relationship of plasma concentrations to efficacy or the occurrence of adverse reactions is not well established. Other experts have stated the monitoring of serum concentrations is not clinically useful due to the long half-life of the drug.

Maximum Dosage Limits:
Individualize maximum amiodarone dosage according to clinical goals, phase of dosage titration, and close monitoring of efficacy and safety parameters.
-Neonates
5 mg/kg/dose IV, 15 mcg/kg/minute continuous IV infusion, and up to 25 mg/kg/DAY or 800 mg/1.73m2/DAY PO have been reported.
-Infants
5 mg/kg/dose IV, 15 mcg/kg/minute continuous IV infusion, and up to 25 mg/kg/DAY or 800 mg/1.73m2/DAY PO have been reported.
-Children
5 mg/kg/dose (Max: 300 mg/dose) IV, 15 mcg/kg/minute continuous IV infusion, and up to 25 mg/kg/DAY (Max: 1,600 mg/DAY) PO has been reported.
-Adolescents
5 mg/kg/dose (Max: 300 mg/dose) IV, 15 mcg/kg/minute continuous IV infusion, and up to 25 mg/kg/DAY (Max: 1,600 mg/DAY) PO has been reported.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; however, cautious monitoring of drug efficacy and safety (e.g., hepatic function) is prudent. Amiodarone and DEA (active metabolite) are primarily eliminated by hepatic metabolism.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Amiodarone is both an antiarrhythmic and a potent vasodilator. Amiodarone is considered a 'broad spectrum' antiarrhythmic with multiple and complex electrophysiologic effects. Although its exact mechanism of action is not completely known, using the traditional Vaughn-Williams classification scheme for antiarrhythmic compounds, amiodarone is considered a class III compound.

Like the other class III antiarrhythmic agents, 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 (e.g., 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 possesses actions similar to both class II and class IV antiarrhythmics. Amiodarone is a weak sodium channel blocker (class I effect). 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 automaticity of both the SA and 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 also noncompetitively inhibits alpha- and beta-receptors, and possesses both vagolytic and calcium-channel blocking properties. The drug relaxes both smooth and cardiac muscle, causing decreases in coronary and peripheral vascular resistance, left ventricular end-diastolic pressure (LVEDP) and systolic blood pressure, thereby decreasing afterload. Transient, dose-related increases in coronary blood flow may occur following intravenous amiodarone administration, and is thought to be due to direct relaxation of coronary arteries, reductions in myocardial contractility and LVEDP. This activity may result in a decrease in myocardial oxygen demand (MVO2).

Amiodarone has a complex effect on thyroid hormone metabolism and frequently alters thyroid function tests during chronic therapy. Amiodarone can cause either hypothyroidism or hyperthyroidism, with hyperthyroidism being the most dangerous due to the risk of thyrotoxicosis. Approximately 37% of amiodarone (by weight) is iodine, at least 10% of which is deiodinated. Because the normal dietary requirement of iodine is < 1 mg/day, therapeutic doses of amiodarone result in a massive increase in total iodine stores. In addition, amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) by inhibiting type I iodothyronine 5'-deiodinase. Amiodarone may increase T4 concentrations, decrease T3 concentrations, and increase concentrations of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone also inhibits entry of thyroxine and triiodothyronine into peripheral tissue. TSH usually increases, but after 3 months of continuous administration, TSH concentrations often return to normal. Because of the slow elimination of amiodarone and its metabolites and high plasma iodide concentrations, abnormal thyroid function tests may persist for several weeks or months after drug discontinuation.

Pharmacokinetics: Amiodarone is administered orally and intravenously. Once in the systemic circulation, amiodarone distributes extensively throughout the body in various sites, especially adipose tissue and highly perfused organs (e.g., liver, lung, spleen). As a reflection of its extensive distribution in the body, the volume of distribution of amiodarone averages approximately 60 L/kg in adults. It is the extensive accumulation of amiodarone (especially in adipose tissue) which accounts for its prolonged elimination, as well as the persistence of adverse reactions after discontinuation of therapy. The principle metabolite of amiodarone, N-desethyl-amiodarone (DEA), distributes into the same tissues as the parent drug, albeit to a lesser extent in adipose tissue. Amiodarone and DEA are extensively bound (more than 96%) to plasma proteins, primarily albumin and alpha-1 acid glycoprotein.

Amiodarone is extensively metabolized in the liver, specifically via CYP3A and CYP2C8. DEA is the major active metabolite of amiodarone in humans. DEA serum concentrations above 0.05 mg/L are not usually seen until after several days of continuous infusion, but with prolonged therapy reach approximately the same concentration as amiodarone. Amiodarone and DEA are almost exclusively eliminated hepatically, although biliary excretion may play a small role in the excretion of amiodarone.

Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2A6, CYP2B6, CYP2D6, P-gp, OCT2
Amiodarone is metabolized to N-desethyl-amiodarone (DEA) by the cytochrome P450 (CYP450) enzyme group, specifically CYP3A4 and CYP2C8. Amiodarone is an inhibitor of several drug elimination pathways, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6, and CYP2C8 mediated metabolism; therefore, amiodarone has the potential to interact with substrates affected by these pathways. Amiodarone also has the potential to inhibit drug transporters such as P-glycoprotein (P-gp) and organic cation transporter (OCT2).


-Route-Specific Pharmacokinetics
Oral Route
Amiodarone is absorbed incompletely and slowly from the GI tract, with a bioavailability of approximately 50%. Cmax is attained 3 to 7 hours after a single dose. Plasma concentrations with chronic administration are dose proportional with a mean 0.5 mg/L increase for each 100 mg/day (dose range: 100 to 600 mg/day). Food increases the rate and extent of absorption. After the consumption of a high-fat meal, AUC and Cmax increased by 2.3 and 3.8 times, respectively, and Tmax decreased by 37% in adult volunteers. Mean AUC and Cmax of DEA (the major metabolite) increased by 55% and 32%, respectively; there was no change in the Tmax. The onset of action after chronic oral dosing appears to be shorter in pediatric patients (1 to 16 days) compared to adult patients (1 to 3 weeks). As a consequence of its distribution characteristics, the elimination of amiodarone occurs in a biphasic fashion, with an initial reduction of plasma concentrations of 50% occurring within 2.5 to 10 days. The terminal elimination half-life in adults ranges from 26 to 107 days with a mean of around 53 days.

Intravenous Route
The onset and duration of action are shorter after intravenous (IV) administration of amiodarone compared to oral administration. The onset and duration of action in adult patients were reported as 1 to 30 minutes and 1 to 3 hours, respectively, after a single IV bolus. The terminal elimination half-life was 9 to 36 days and 9 to 30 days for amiodarone and the active metabolite DEA, respectively, after a single dose of 5 mg/kg IV in healthy adult volunteers.


-Special Populations
Pediatrics
Infants, Children, and Adolescents
Limited data indicate that the clearance of amiodarone may be faster in pediatric patients than adults. The half-life in 3 pediatric patients (age range 30 days to 16 years) receiving IV amiodarone ranged from 6.9 to 11.4 days. The onset of action and delay before relapse of arrhythmia after treatment discontinuation with oral amiodarone were also faster in pediatric patients (age range 0 to 15 years) compared to that usually seen in adults, occurring at a mean of 4.1 days (range 1 to 16 days) and 3.3 weeks, respectively.