Class: Antiarrhythmic agent
- Injection, solution 50 mg/mL
- Tablets, oral 200 mg
- Injection, solution 1.5 mg/mL
- Injection, solution 1.8 mg/mL
- Tablets, oral 100 mg
- Tablets, oral 200 mg
- Tablets, oral 400 mg
Sandoz Amiodarone (Canada)
Prolongs action potential, duration, and refractory period in myocardial cells; acts as noncompetitive inhibitor of alpha- and beta-adrenergic receptors.
C max after single 5 mg/kg 15-min IV infusion ranges between 5 and 41 mg/L.Oral
Bioavailability is 35% to 65%; T max is 3 to 7 h. Food increases rate and extent of absorption.
Rapidly distributed; serum concentrations decline to 10% of peak values within 30 to 45 min after the end of the infusion.Oral
Vd is approximately 60 L/kg.Oral/IV
Crosses the placenta; excreted in breast milk. More than 96% protein bound.
Metabolized by CYP3A4 and CYP2C8 to desethylamiodarone (active).
Eliminated primarily by hepatic metabolism and biliary excretion; negligible renal excretion. Biphasic elimination with initial 50% reduction in plasma levels after 2.5 to 10 days; terminal half-life is 26 to 107 days (mean, approximately 53 days) (oral) and 20 to 47 days (IV). Cl of amiodarone and desethylamiodarone ranged between 63 to 231 mL/kg/h and 140 to 400 mL/kg/h, respectively.
2 to 3 days, but more commonly 1 to 3 wk (oral).
Special PopulationsRenal Function Impairment
Pharmacokinetics of amiodarone are not influenced by renal impairment.Hepatic Function Impairment
After a single dose of amiodarone injection in cirrhotic patients, C max was significantly lower and average concentration values were seen for desethylamiodarone, but mean amiodarone levels were unchanged.Elderly
Cl is lower and half-life is increased.Gender
The pharmacokinetics of amiodarone are similar in men and women.Severe left ventricular dysfunction
The half-life of desethylamiodarone is prolonged.
Indications and UsageOral
Treatment of life-threatening, recurrent ventricular arrhythmias (ie, ventricular fibrillation and hemodynamically unstable ventricular tachycardia) that do not respond to other antiarrhythmic agents.Parenteral
Initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy; treatment of ventricular tachycardia and fibrillation when oral amiodarone is indicated but patient is unable to take oral medication.
Conversion of atrial fibrillation and maintenance of sinus rhythm; supraventricular tachycardia; AV nodal reentry tachycardia.
Cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree AV block; when bradycardia produces syncope, unless used with pacemaker; hypersensitivity to the drug, including iodine.Parenteral
Known hypersensitivity to the drug, including iodine; marked sinus bradycardia; second- and third-degree AV block, unless functioning pacemaker is available; cardiogenic shock.
Dosage and AdministrationLife-Threatening, Recurrent Ventricular Arrhythmias
Adults PO Loading dose
800 to 1,600 mg/day for 1 to 3 wk (occasionally longer). When adequate arrhythmia control is achieved or if adverse reactions become prominent, reduce dosage to 600 to 800 mg/day for 1 mo.Maintenance dose
400 mg/day, some patients may require larger dosages of up to 600 mg/day.IV Loading dose
Approximately 1,000 mg over the first 24 h as follows: rapid administration of 150 mg over first 10 min (15 mg/min), followed by 360 mg over next 6 h (1 mg/min), then 540 mg over remaining 18 h (0.5 mg/min).Maintenance infusion
After first 24 h, continue maintenance infusion rate of 0.5 mg/min (720 mg per 24 h).Supplemental infusions
150 mg over 10 min should be given for breakthrough ventricular arrhythmias.IV to Oral Transition
Clinical monitoring is recommended when changing from IV to oral therapy.
PO 800 to 1,600 mg of amiodarone if duration of IV infusion less than 1 wk, 600 to 800 mg of amiodarone if duration of IV infusion 1 to 3 wk, 400 mg of amiodarone if duration of IV infusion more than 3 wk.
- For IV infusion only; initial infusion rate should not exceed 30 mg/min.
- Administer by volumetric infusion pump using polyvinyl chloride tubing and an in-line filter.
- Prepare infusions that will exceed 2 h in glass or polyolefin bottles containing 5% dextrose in water. Do not use evacuated glass containers because incompatibility of amiodarone with a buffer in container may cause precipitation.
- Injection solution (50 mg/mL): To prepare first rapid loading infusion, add 3 mL (150 mg) of IV amiodarone to 100 mL of 5% dextrose in water (concentration = 1.5 mg/mL).
- Injection solution (50 mg/mL): To prepare 6 h slow loading infusion and 18 h initial maintenance infusion, add 18 mL (900 mg) of IV amiodarone to 500 mL of 5% dextrose in water (concentration = 1.8 mg/mL)
- Injection solution (50 mg/mL): For maintenance infusions after first 24 h, use infusion solutions containing 1 to 6 mg/mL.
- Administer concentrations greater than 2 mg/mL via central venous catheter.
- Premix injection: Administer 1.5 mg/mL strength for first rapid loading infusion, followed by 1.8 mg/mL strength.
- Solution should be clear and may have a pale yellow coloration. Do not administer if solution is discolored or cloudy, or contains particulate matter.
- Amiodarone should not be combined with any product in the same IV line or premixed container.
- The premix container is for single-use only, discard any unused portion. No further dilution is required. Do not combine with any product in the same IV line or premixed container.
- IV loading infusions at much higher concentrations and rates of infusion much faster than recommended have resulted in hepatocellular necrosis and acute renal failure leading to death.
- Amiodarone has been found to leach out plasticizers, including diethylhexyl phthalate from IV tubing (including polyvinyl chloride tubing).
- Administer consistently either with food or on an empty stomach. Administer with food if GI upset occurs. Administer doses greater than 1,000 mg in divided doses with food.
- Administer maintenance doses as a single daily dose or, in patients with severe GI intolerance, divide into 2 daily doses.
- The loading phase should be performed in a hospital setting.
- Upon starting therapy, attempt to gradually discontinue prior antiarrhythmic drugs.
Store between 59° and 86°F. Protect from light, freezing, and excessive heat. Injection does not need to be protected from light during infusion.
Drug InteractionsAntiarrhythmic agents (eg, disopyramide, flecainide, procainamide, quinidine)
Amiodarone may increase serum concentrations of these antiarrhythmics. Reduce dose of antiarrhythmic with coadministration.Anticoagulants (eg, warfarin)
Potentiation of anticoagulant response is almost always seen with coadministration; reduce dose of anticoagulant by one-third to one-half. Closely monitor PT and INR.Azole antifungals (eg, itraconazole), fluoroquinolones (eg, moxifloxacin), macrolide antibiotics (eg, azithromycin, telithromycin)
QTc prolongation with or without torsades de pointes may occur when used concomitantly with amiodarone. Close clinical monitoring is warranted. Avoid coadministration of amiodarone with certain fluoroquinolones or telithromycin.Beta-blockers (eg, propranolol)
Effects of beta-blockers eliminated by hepatic metabolism may be increased. Because amiodarone has weak beta-blocking activity, concomitant use can increase risk of AV block, hypotension, bradycardia, and sinus arrest.Calcium channel blockers (eg, diltiazem, verapamil)
Use amiodarone with caution with calcium channel blockers because of the possible potentiation of bradycardia, sinus arrest, and AV block.Cardiac glycosides (eg, digoxin)
Digoxin levels are increased and may result in toxicity. Reduce digoxin dose by approximately 50% or discontinue. Clinical and laboratory monitoring is warranted.Cholestyramine
Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and half-life. Monitor the clinical response and adjust the amiodarone dose as needed.Cimetidine
Amiodarone plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions. Monitor amiodarone concentrations and the clinical response.Clopidogrel
Coadministration may result in ineffective inhibition of platelet aggregation. Closely monitor platelet function.Clozapine
Plasma concentrations of clozapine may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Additional plasma concentration and clinical monitoring is warranted.Cyclosporine
Concomitant use has produced persistently elevated plasma cyclosporine concentrations, resulting in elevated creatinine despite reduction in dose of cyclosporine. Closely monitor cyclosporine concentrations and the clinical response.Dabigatran
Pharmacologic effects and plasma concentrations of dabigatran may be increased. Monitor for bleeding.Dextromethorphan
Long-term use (more than 2 wk) of amiodarone administration impairs metabolism of dextromethorphan. Monitor the patient for dextromethorphan-induced adverse reactions.Fentanyl
May cause hypotension, bradycardia, and decreased cardiac output. Monitor hemodynamic and pulmonary function.Fingolimod, loratadine, trazodone
Risk of arrhythmias may be increased. Close clinical monitoring is warranted.General anesthetics (eg, inhalation agents)
Amiodarone administration prior to surgery under general anesthetics may increase the risk of cardiopulmonary and hemodynamic complications. Close cardiac and pulmonary monitoring during and after anesthesia is warranted.Grapefruit juice
Amiodarone plasma concentrations may be elevated, increasing the risk of adverse effects. Patients taking oral amiodarone should avoid grapefruit juice.HMG-CoA reductase inhibitors (eg, atorvastatin, simvastatin)
Atorvastatin and simvastatin plasma levels may be elevated, increasing the risk of adverse reactions (eg, myopathy, rhabdomyolysis). When coadministered with amiodarone, lower starting and maintenance doses should be considered. The dose of simvastatin should not exceed 20 mg/day. Close clinical monitoring is warranted.Hydantoins (eg, phenytoin)
Long-term use (more than 2 wk) of amiodarone impairs phenytoin metabolism. Increased phenytoin concentrations with symptoms of toxicity may occur. Also, amiodarone serum levels may be decreased. Monitor drug concentrations and observe the patient for toxicity or loss of therapeutic effect. Because effects may be delayed for several weeks, long-term monitoring is necessary.Iohexol
The risk of life-threatening cardiac arrhythmias may be increased. If coadministration cannot be avoided, use with caution.Lidocaine
Lidocaine plasma concentrations may be elevated, increasing the risk of seizures. Monitor cardiac function and observe patients for symptoms of lidocaine toxicity.Methotrexate
Long-term use (more than 2 wk) of amiodarone impairs metabolism of methotrexate. Methotrexate toxicity may be increased. Monitor for methotrexate toxicity.Orlistat
Amiodarone plasma concentrations and pharmacologic effects may be decreased. Monitor patients for a decrease in amiodarone response.Protease inhibitors (eg, ritonavir)
Amiodarone plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions. Monitor for amiodarone toxicity. Ritonavir and nelfinavir are contraindicated in patients receiving amiodarone.Quinupristin/Dalfopristin
The risk of QT interval prolongation and cardiac arrhythmias caused by amiodarone may be increased. Coadministration is not recommended.Rifamycins (eg, rifampin)
Plasma levels of amiodarone and the metabolite, desethylamiodarone, may be reduced, decreasing the pharmacologic effect. Closely monitor cardiac function and amiodarone serum concentrations when starting or stopping a rifamycin.Sirolimus, tacrolimus
Concentrations of these agents may be elevated, increasing the risk of adverse reactions. If coadministration cannot be avoided, consider decreasing the dose of these agents and frequently monitoring blood concentrations.St. John's wort
Amiodarone plasma levels may be reduced, decreasing the pharmacologic effects. Avoid coadministration.Theophylline
Increased theophylline concentrations with toxicity may occur. Monitor serum theophylline concentrations and observe the patient for signs of toxicity.Vardenafil
The risk of life-threatening cardiac arrhythmias, including torsades de pointes, may be increased. Coadministration is not recommended.
Laboratory Test Interactions
Amiodarone alters the results of thyroid function tests, causing an increase in serum T 4 and serum reverse T 3 levels, and a decline in serum T 3 levels.
Hypotension (20%); bradycardia (6%); cardiac arrest (4%); ventricular tachycardia (2%); cardiac arrhythmias, CHF, flushing, SA node dysfunction (1% to 3%); atrial fibrillation, nodal arrhythmia, prolonged QT interval, sinus bradycardia, ventricular fibrillation (less than 2%); asystole/cardiac arrest/electromechanical dissociation, AV block, cardiac conduction abnormalities, cardiogenic shock, sinus arrest, vasculitis (postmarketing).
Abnormal gait/ataxia, dizziness, fatigue, lack of coordination, malaise, paresthesias, tremor/abnormal involuntary movement (4% to 9%); decreased libido, headache, insomnia, sleep disturbances (1% to 3%); confusional states, delirium, demyelinating polyneuropathy, disorientation, hallucinations, parkinsonian symptoms (eg, akathisia, bradykinesia), pseudotumor cerebri (postmarketing).
Photosensitivity/solar dermatitis (4% to 9%); Stevens-Johnson syndrome (less than 2%); drug rash with eosinophilic and systemic symptoms (sometimes fatal), eczema, erythema multiforme, exfoliative dermatitis, pruritus, skin cancer, TEN (sometimes fatal), urticaria (postmarketing).
Visual disturbances, including eye discomfort, lens opacities, macular degeneration, optic neuropathy and/or neuritis (progressing to corneal degeneration), papilledema, permanent blindness, photosensitivity, scotoma (4% to 9%); abnormal smell sensation (1% to 3%); corneal microdeposits; dry eyes; halos; photophobia.
Hyperthyroidism, hypothyroidism (1% to 3%); thyroid cancer, thyroid nodules (postmarketing).
Nausea, vomiting (10% to 33%); anorexia, constipation (4% to 9%); abdominal pain, abnormal salivation, abnormal taste (1% to 3%); diarrhea (less than 2%); pancreatitis (postmarketing).
Abnormal kidney function (less than 2%); acute renal failure, epididymitis, impotence, renal impairment, renal insufficiency (postmarketing).
Coagulation abnormalities (1% to 3%); thrombocytopenia (less than 2%); agranulocytosis, aplastic anemia, granuloma, hemolytic anemia, neutropenia, pancytopenia, thrombocytopenia (postmarketing).
Abnormal LFTs (4% to 9%); nonspecific hepatic disorders (1% to 3%); increased ALT and AST (less than 2%); cholestatic hepatitis, cirrhosis, hepatitis (postmarketing).
Cellulitis, edema, erythema, necrosis, pain, phlebitis, pigment changes, skin sloughing, thrombophlebitis, venous thrombosis at injection site (postmarketing).
Muscle weakness, myopathy, rhabdomyolysis (postmarketing).
Pulmonary inflammation or fibrosis (4% to 9%); lung edema, respiratory disorder (less than 2%); alveolar hemorrhage, bronchospasm, possibly fatal respiratory disorders (including ARDS, arrest, distress, and failure), bronchiolitis obliterans organizing pneumonia (possibly fatal), cough, dyspnea, eosinophilic pneumonia, hemoptysis, hypoxia, pleural effusion, pleuritis, pulmonary infiltrates and/or mass, wheezing (postmarketing).
Fever (3%); edema (1% to 3%); shock (less than 2%); anaphylactic/anaphylactoid reaction, angioedema, SIADH (postmarketing).
Amiodarone is intended for use only in patients with the indicated life-threatening arrhythmias.
Potentially fatal pulmonary toxicities include hypersensitivity pneumonitis or interstitial/alveolar pneumonitis. Rates of clinically manifested disease are as high as 10% to 17% in some series of patients with ventricular arrhythmias given dosages around 400 mg/day. Pulmonary toxicity has been fatal approximately 10% of the time.
Overt liver disease can occur and has been fatal in a few cases.
Proarrhythmic effects, significant heart block, and sinus bradycardia have occurred. Patients must be hospitalized during loading-dose administration.
Even in patients at high risk of arrhythmic death in whom toxicity of amiodarone is an acceptable risk, every effort should be made to utilize alternative agents first because of the major management problems posed by amiodarone that could be life-threatening in a population at risk of sudden death.
Because absorption and elimination are variable, maintenance-dose selection is difficult and dosage reduction or discontinuation of treatment is not unusual. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. Attempts to substitute other antiarrhythmic agents when amiodarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden.
Monitor effectiveness in long-term prevention of ventricular tachycardia and ventricular fibrillation using ambulatory monitoring, programmed electrical stimulation, or a combination of these, as appropriate. Monitor for hypotension, especially during the first few hours of IV infusion. Close perioperative monitoring is recommended in patients undergoing general anesthesia. Closely monitor FiO 2 and the determinants of oxygen delivery to the tissues (eg, SaO 2 , PaO 2 ). Close clinical monitoring is recommended during the loading phase.Hepatic
Obtain liver enzymes before starting therapy and periodically thereafter during long-term therapy.Ophthalmic
Perform regular ophthalmic exams, including funduscopy and slit-lamp exam.Pulmonary
Obtain baseline chest x-ray and pulmonary function tests, including diffusion capacity before initiating therapy. Repeat chest x-ray, history, and physical exam every 3 to 6 mo thereafter.QTc prolongation
Monitor for QTc prolongation during IV infusion of amiodarone.Thyroid
Monitor thyroid function before starting therapy and periodically thereafter, especially in elderly patients and any patient with history of thyroid nodules, goiter, or other thyroid dysfunction.
Category D . May cause fetal harm.
Excreted in breast milk. Breast-feeding is not recommended.
Safety and efficacy not established.
Cautiously make dose selection, usually starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and renal function, and of comorbidity.
Angioedema, arthralgias, cutaneous/mucosal hemorrhage, eosinophilia, fever, rash, severe periarteritis, thrombotic thrombocytopenic purpura, or urticaria may occur.
Occurs in approximately 10% of patients.
Adult respiratory distress syndrome
Has been reported in patients receiving IV amiodarone who have experienced lung injuries from trauma, shock, prolonged cardiopulmonary resuscitation, and aspiration pneumonia. Postoperative occurrences of ARDS have been reported in patients receiving oral amiodarone who have undergone cardiac or noncardiac surgery. In rare instances, the outcome has been fatal.
Benzyl alcohol, which may be contained in IV amiodarone products as a preservative, has been associated with fatal gasping syndrome in neonates (children younger than 1 mo).
Bradycardia and AV block
Occurs with IV amiodarone but is not dose related. Insertion of temporary pacemaker may be required. Treat patients with known predisposition to bradycardia or AV block in a setting where a temporary pacemaker is available.
Corneal refractive laser surgery
Most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking amiodarone.
Correct any potassium or magnesium deficiency before starting amiodarone therapy.
Usually appears earlier in the course of therapy; rechallenging with amiodarone results in a more rapid occurrence of greater severity. If this occurs, discontinue amiodarone and institute treatment with steroids.
Hypotension is the most common adverse reaction seen with IV amiodarone; it most often occurs during the first several hours of treatment and appears to be related to rate of infusion. Monitor infusion rate closely and do not exceed recommended rates of infusion.
May result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis, or fibrosis in lung biopsy specimens.
Hepatic enzyme elevations occur frequently in patients on oral amiodarone, but most patients are asymptomatic. If liver enzyme increase exceeds 3 × ULN, or doubles in patient with elevated baseline, consider discontinuing amiodarone or reducing the dose. Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death have been associated with administration of IV amiodarone at a much higher loading-dose concentration and much faster rate of infusion than recommended.
Neonatal hypo- or hyperthyroidism
Congenital goiter/hypothyroidism and hyperthyroidism have been reported in children exposed in utero to amiodarone.
Optic neuropathy or neuritis, resulting in visual impairment (in some cases progressing to permanent blindness), has been reported. Appearance of optic neuropathy or neuritis calls for reevaluation of amiodarone therapy. Corneal microdeposits appear in majority of adults and may cause visual halos or blurred vision. Corneal microdeposits are reversible upon dose reduction or termination of treatment.
Rare cases of peripheral neuropathy have been reported during long-term amiodarone administration. Discontinuation of amiodarone results in slow and incomplete resolution of symptoms.
Acute-onset (days to weeks) pulmonary injury (bronchospasm, cough, dyspnea, fever, hemoptysis, hypoxia, pulmonary infiltrates and/or mass on x-ray, wheezing) has been reported. Some cases have progressed to respiratory failure and/or death. Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops. Any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and history, physical exam, chest x-ray, and pulmonary function tests (with diffusion capacity) should be repeated and evaluated. Reduce dose or, preferably, withdraw amiodarone if pulmonary toxicity is suspected.
A blue-gray discoloration of exposed skin may occur during long-term treatment. Risk may be increased in patients with fair complexion or those with excessive sun exposure.
Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving amiodarone have been reported.
Can cause hypo- or hyperthyroidism. Arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism. Thyrotoxicosis may also occur.
Carefully assess potential risks and benefits of coadministering amiodarone with any drug known to prolong the QTc interval, or when treating patients with thyroid dysfunction, because of the possibility of arrhythmia breakthrough or exacerbation of arrhythmia.
AV block, bradycardia, cardiogenic shock, hepatotoxicity, hypotension.
- Advise patient or caregiver to read the Medication Guide carefully before starting therapy, and to read and check for new information each time the medication is refilled.
- Advise patient or caregiver that injectable amiodarone will be prepared and administered by a health care provider in a medical setting.
- Advise patient to take each dose consistently either with or without food. Advise patient to take with food if stomach upset occurs.
- Instruct patient to avoid drinking grapefruit juice while taking amiodarone.
- Instruct patient not to change the dose or stop taking this medicine unless advised by health care provider.
- Advise patient that if medication is stopped because of adverse effects, adverse effects may persist for a long time because the amiodarone stays in the body for months after treatment is stopped.
- Instruct patient to contact health care provider or seek medical assistance right away if any of the following occur: blurred vision, seeing halos, or eyes sensitive to sunlight; chest pain, coughing, or spitting up blood; difficulty breathing, unexplained shortness of breath, or wheezing; feeling light-headed or faint; feeling more tired than usual; feeling of pins and needles or numbness in hands, legs, or feet; heart pounding, skipping beats, or beating very fast or very slowly; muscle weakness, uncontrolled movements, poor coordination, or trouble walking; passing brown or dark-colored urine; persistent nausea, stomach pain, or vomiting; yellowing of the skin or eyes.
- Advise patient to notify health care provider if any of the following occur: bluish discoloration of skin, heat or cold intolerance, restlessness, swelling or lump in neck, thinning hair, unexplained sweating, unexplained weight loss or gain, weakness, or any other bothersome adverse effect or unexplained feelings.
- Advise patient to avoid unnecessary exposure to direct and indirect sunlight or tanning lamps and to use sunscreen and wear protective clothing to avoid photosensitivity reactions during therapy.
- Caution women of childbearing potential to avoid becoming pregnant during treatment with amiodarone.
- Instruct women not to breast-feed while on amiodarone therapy because the drug may pass into their breast milk and potentially cause harm to the infant.
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