Amiodarone is a class III antiarrhythmic agent used for the treatment of tachyarrhythmias. Although amiodarone is FDA-approved only for the treatment of ventricular arrhythmias, it is widely used for supraventricular arrhythmias, especially for the pharmacological cardioversion of atrial fibrillation and maintenance of normal sinus rhythm. Amiodarone and sotalol are equally efficacious in converting atrial fibrillation to sinus rhythm; however, amiodarone is superior to sotalol for maintaining sinus rhythm. Amiodarone is also more effective than propafenone and other class I agents for the maintenance of sinus rhythm. Amiodarone may be considered during cardiac arrest when ventricular fibrillation or pulseless ventricular tachycardia is unresponsive to cardiopulmonary resuscitation (CPR), defibrillation, and vasopressor therapy. Amiodarone may also be considered for stable wide-complex tachycardia or polymorphic ventricular tachycardia. Guidelines suggest amiodarone as an alternative treatment for the prevention of atrial fibrillation after cardiac surgery in patients for whom first-line therapy (e.g., beta-blockers) is contraindicated. Atrial tachyarrhythmias occurred significantly less often in patients receiving oral amiodarone compared to those receiving placebo (16.1% vs. 29.5%, respectively) after nonemergent coronary artery bypass graft (CABG) surgery and/or valve replacement or repair in the PAPABEAR trial. Although amiodarone is associated with several potentially significant and sometimes fatal adverse effects, it has not been associated with proarrhythmias as frequently as other antiarrhythmics.
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 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 the remaining vehicle to a total volume of 200 mL.
-Storage: 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 cardiopulmonary resuscitation (CPR): The need for dilution is no longer specified when administering amiodarone during cardiac arrest, a situation in which any delay in therapy should be avoided. For pediatric patients with pulseless ventricular tachycardia or fibrillation, amiodarone may be given undiluted. However, dilution may be necessary for accurate measurement and administration of small doses.
-Dilute amiodarone in 5% Dextrose Injection only.
-Commercially available premixed solutions are available; no further dilution is required for premixed solutions.
-For rapid loading infusion: Add 150 mg (3 mL) of amiodarone 50 mg/mL injection to 100 mL 5% Dextrose Injection (final concentration = 1.5 mg/mL).
-For slow loading infusion: Add 900 mg (18 mL) of amiodarone 50 mg/mL injection to 500 mL 5% Dextrose Injection (final concentration = 1.8 mg/mL).
-For maintenance infusion: Dilute amiodarone 50 mg/mL injection to a final concentration of 1 to 6 mg/mL.
-ASHP Recommended Standard Concentrations for Adult Continuous Infusions: 1.5 mg/mL for peripheral line administration and 3.6 mg/mL for central line administration.
-Data regarding concentration for infusion in pediatric patients is not available.
-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. Nexterone premixed solution is for single-use only; discard any unused portion.
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. The recommended adult dosing regimens have taken into account the amount of amiodarone adsorbed to PVC tubing.
-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 Administration During CPR
-Pulseless ventricular fibrillation/tachycardia: Administer via IV push.
-When administering amiodarone peripherally via IV push, follow the injection with a 10 to 20 mL bolus of IV fluid. Elevate the extremity for 10 to 20 seconds following to facilitate drug delivery to the central circulation. Although peak drug serum concentrations are lower and onset of action is delayed when drugs are administered via peripheral vs. central sites, CPR should not be interrupted for central line placement. Drugs generally reach the central circulation within 1 to 2 minutes when administered peripherally.
-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.
IV Infusion for Treatment of Tachyarrhythmias
-For rapid IV loading infusion, breakthrough ventricular fibrillation, or hemodynamically unstable (symptomatic) ventricular tachycardia: Infuse IV at a rate of 15 mg/minute to minimize the potential for hypotension. The infusion rate should not exceed 30 mg/minute.
-For slow IV loading infusion: Infuse IV at a rate of 1 mg/minute.
-Maintenance infusion: Infuse IV at a rate of 0.5 mg/minute. Rate may be adjusted to achieve effective arrhythmia suppression.
-Pediatric patients: Administer loading dose over 1 hour; then start a continuous IV infusion at a rate of 5 to 15 mcg/kg/minute.
Other Injectable Administration
Intraosseous Administration
NOTE: Amiodarone is not FDA-approved for intraosseous administration.
-During cardiopulmonary resuscitation, the same dosage as that for IV administration may be given via the intraosseous route when IV access is not available.
Despite its superior efficacy as an antiarrhythmic agent, the use of amiodarone is limited by its multitude of adverse effects. In general, the major adverse effects of amiodarone are cumulative and dose-related and, therefore, tend to occur with long-term therapy and/or with higher doses. Adverse reactions have been reported in about 75% of patients treated with large doses (400 mg/day or more) for ventricular arrhythmias, resulting in discontinuation rates ranging from 7% to 18%.
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 causes arrhythmia exacerbation in approximately 2% to 5% of patients or cause new ventricular fibrillation (VF), incessant ventricular tachycardia (VT), increased resistance to cardioversion, and torsade de pointes (TdP) associated with QT prolongation. Oral amiodarone causes symptomatic bradycardia or sinus arrest with suppression of escape foci in 2% to 4% of patients. Bradycardia may require a pacemaker for rate control. With intravenous amiodarone, bradycardia and AV block may respond to slowing of the infusion rate. In clinical trials for intravenous amiodarone, asystole/cardiac arrest/pulseless electrical activity (2.9%; range 2.5% 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. Congestive heart failure, cardiac arrhythmias, SA node dysfunction, flushing, and edema were commonly reported in adults receiving oral amiodarone; cardiac conduction abnormalities were uncommon. 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. 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 AV 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 IV amiodarone. 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 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 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; some case progressed to respiratory arrest or death. 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 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.
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.
Hypotension is the most common adverse reaction associated with intravenous amiodarone and has been reported in 16% of adult patients and 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. Some cases of hypotension may be refractory and result in a fatal outcome. 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.
Amiodarone causes hyperthyroidism in about 2% of patients, which may lead to potentially fatal thyrotoxicosis and/or arrhythmia breakthrough or exacerbation. Congential hyperthyroidism is also a risk if amiodarone must be administered to a pregnant woman. Because of these associated risks, if amiodarone-induced hyperthyroidism is identified the dose or infusion-rate should be decreased and aggressive medical treatment initiated (antithyroid drugs, beta-adrenergic blockers, and/or temporary corticosteroid therapy); discontinuing amiodarone may also be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of the substantial quantities of preformed thyroid hormone stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Treatment may be followed by a transient period of hypo-thyroidism. Amiodarone may induce hyperthyroidism by iodine load (type 1 amiodarone-induced thyrotoxicosis (AIT); in particular in patients with underlying autonomous thyroid nodules or latent Grave's disease); direct amiodarone-induced destructive thyroiditis that occurs in individuals with no underlying thyroid disease (type 2 AIT), resulting in the release of preformed thyroid hormone into the bloodstream from damaged thyroid follicular epithelium; or as a mixed form resulting from both pathogenic mechanisms (excessive thyroid hormone production and thyroid destruction). Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 concentrations, decreased T3 concentrations, and increased concentrations of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine. The risk of hyperthyroidism may be higher among patients with prior inadequate dietary iodine intake. Even with short term or 1 time IV administration, high plasma iodide concentrations, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or months because of the slow elimination of amiodarone and its metabolites. Thyrotoxicosis and arrhythmia with fatal outcome has been reported in the presence of pre-existing hyperthyroidism, even after a single IV dose. If any new signs of arrhythmia appear, consider the possibility of hyperthyroidism. In postmarketing surveillance, thyroid nodules and/or thyroid cancer, some accompanied by hyperthyroidism, have been reported.
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.
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 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.
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.
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.
Amiodarone causes photosensitivity/solar dermatitis in approximately 10% of 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.
Nausea and vomiting are very common, while constipation, anorexia, abdominal pain, abnormal taste and smell, and abnormal salivation are common with oral amiodarone therapy. If gastrointestinal intolerance occurs, dividing the dose and administering with meals may help. Nausea (3.9%), vomiting (less than 2%), and diarrhea (less than 2%) have also been reported with intravenous use. Xerostomia has been associated with postmarketing amiodarone use.
Myopathy, rhabdomyolysis, muscle weakness, muscle cramps/spasms, back pain, and lupus-like symptoms have been reported during postmarketing surveillance of amiodarone.
Libido decrease has been reported in adult patients receiving oral amiodarone. Impotence (erectile dysfunction) and epididymitis were reported in postmarketing surveillance.
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.
Abnormal kidney function (less than 2%), increased blood creatinine, renal impairment, renal insufficiency, and acute renal failure (unspecified) have been reported with amiodarone therapy.
Syndrome of inappropriate antidiuretic hormone (SIADH) has been associated with amiodarone use 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 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 less than 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 preexisting 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 where possible 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 concentration imbalances. Females, people 65 years and older, 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, such as amiodarone, may affect pacing or defibrillating thresholds in patients with implanted pacemakers or defibrillators; assess thresholds at the beginning of and during amiodarone treatment. 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.
Use amiodarone with extreme caution in patients with preexisting pulmonary disease (i.e., chronic obstructive pulmonary disease (COPD), 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 initiation of amiodarone. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics, laxatives, systemic corticosteroids, intravenous amphotericin B, or other drugs affecting electrolyte levels. Electrolyte imbalance may predispose the patient to the development of proarrhythmias 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.
Use amiodarone with caution in any patient with a significant neurological disease or disorder, including peripheral neuropathy, due to the potential neurotoxic and central nervous system effects of the drug. Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but resolution has been slow and incomplete.
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 after 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.
Amiodarone crosses the placenta and can cause fetal harm when administered to a pregnant woman. Inform the patient of the potential hazard to the fetus if amiodarone is administered during pregnancy or if the patient becomes pregnant while taking amiodarone. Reported risks include neonatal bradycardia; QT prolongation; periodic ventricular extrasystoles; neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure; neonatal hyperthyroxinemia; neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia; jerk nystagmus with synchronous head titubation; fetal growth retardation; and premature birth. When pregnant rabbits were administered amiodarone at doses approximately 2.7 times the maximum recommended human maintenance dose (MRHD), abortions occurred in more than 90% of the animals. Doses of 0.8 times the MRHD were associated with slight displacement of the testes and increased incidence of incomplete ossification of some skull and digital bones. At doses 1.6 times the MRHD, fetal body weights were reduced, and at doses 3.2 times the MRHD, fetal resorption was increased.
Amiodarone and a major metabolite, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have been shown to be less viable and have reduced body-weight gains. Weigh the risk of exposing the infant to amiodarone and DEA against the potential benefit of arrhythmia suppression in the mother. When amiodarone therapy is indicated, discontinue breast-feeding.
Geriatric subjects over 65 years of age have a slower clearance of amiodarone compared to younger subjects, with a prolongation in half-life from about 20 days to 47 days. Older adults may also be more sensitive to the thyrotoxic and neurotoxic effects of amiodarone. Insufficient data are available to evaluate the dose-response of amiodarone in geriatric patients. Initiate amiodarone cautiously in elderly patients, starting at the lower end of the adult dosage range; monitor clinical response closely. According to the Beers Criteria, amiodarone is considered a potentially inappropriate medication in geriatric patients; avoid as first-line treatment of atrial fibrillation unless the patient has concomitant heart failure or substantial left ventricular hypertrophy (LVH). Amiodarone is effective for maintaining sinus rhythm but has greater toxicities than other antiarrhythmics used for atrial fibrillation. It may be reasonable to use amiodarone for atrial fibrillation in patients with concomitant heart failure or LVH if rhythm control is preferred over rate control.
Very high concentrations of amiodarone and desethylamiodarone may be found in testes. There are reports of an elevated follicle-stimulating hormone and luteinizing hormone levels, suggestive of testicular dysfunction, in men on long-term amiodarone treatment. Consider the long half-life of amiodarone and its metabolite while planning pregnancy after discontinuation of amiodarone treatment. Amiodarone reduces fertility in animal models (males and females) at approximately 1.4 times the maximum human recommended dosage; the potential for infertility in humans is unknown.
For the treatment of life-threatening recurrent ventricular fibrillation or hemodynamically unstable (symptomatic) sustained ventricular tachycardia, including post-myocardial infarction (MI) patients:
NOTE: See resuscitation indication for ECC/AHA dosage and administration guidelines for ventricular fibrillation or pulseless ventricular tachycardia.
NOTE: Amiodarone is FDA-approved for the treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy.
Oral dosage:
Adults: Initially, 800 to 1600 mg/day PO in single or divided doses for a minimum of 1 to 3 weeks in a monitored setting until an initial therapeutic response is achieved (suppression of life-threatening ventricular ectopy and reduction of total ventricular ectopy), followed by 600 to 800 mg/day PO in one or divided doses for about one month. Then reduce dosage again to the lowest effective maintenance dose, usually 400 mg/day PO in one or divided doses. Some patients can be controlled on lower doses (e.g., 200 to 300 mg/day PO). Amiodarone did not increase overall mortality in two controlled clinical trials (CAMIAT and EMIAT) of post-MI patients followed up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400 mg/day. Patients in EMIAT qualified with an ejection fraction less than 40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules.
Children*: Loading doses of 10 to 15 mg/kg/day PO or 600 to 800 mg/1.73 m2/day PO should be employed for 4 to 14 days or until adequate control of arrhythmias or prominent adverse effects occur. The loading dose should be given in 1 to 2 divided doses per day. Dosage should then be reduced to 5 mg/kg/day or 200 to 400 mg/1.73 m2 given PO once daily for several weeks. If arrhythmias do not recur, reduce to lowest effective dose possible. Use the minimal effective dose, which is usually about 2.5 mg/kg/day. Doses for children less than 1 year should be calculated based on BSA (body surface area).
Intravenous dosage:
Adults: If the patient is being treated for pulseless ventricular tachycardia/fibrillation or stable ventricular tachycardia during the emergency ACLS setting, see dosage guidelines for CPR. The approved IV dosage recommended by the manufacturer for life-threatening ventricular arrhythmias for the first 24 hours is the following infusion regimen: initial IV rapid infusion of 150 mg over the first 10 minutes. Then begin a slow IV infusion of 1 mg/min for the next 6 hours (total dose infused = 360 mg). Then, the infusion rate is lowered to 0.5 mg/min for the next 18 hours (total dose infused = 540 mg). After the first 24 hours, a maintenance IV infusion of 0.5 mg/minute (720 mg/day) is recommended. Adjust infusion rate to achieve effective arrhythmia suppression. Intravenous amiodarone is not intended for maintenance therapy and should not be administered for longer than 3 weeks. NOTE: The dose of amiodarone may be individualized, however, during controlled clinical trials doses more than 2100 mg were associated with an increased risk of hypotension.
Conversion from intravenous to oral therapy:
Adults: If the duration of IV infusion was less than 1 week, the initial oral dose is 800 to 1600 mg/day PO. If the duration of IV infusion was 1 to 3 weeks, the initial oral dose is 600 to 800 mg/day PO. If the duration of IV infusion was longer than 3 weeks, the initial oral dose is 400 mg/day PO.
For the treatment of ventricular arrhythmias during cardiopulmonary resuscitation* (CPR):
-for cardiac arrest associated with ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT) unresponsive to CPR:
Intravenous and Intraosseous* dosage:
Adults: 300 mg IV, which may be followed by 150 mg IV. The same dosage may be given via the intraosseous route when IV access is not available. Guidelines recommend amiodarone for patients who are unresponsive to CPR, defibrillation, and a vasopressor.
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). May administer IV push for ventricular fibrillation or pulseless ventricular tachycardia. The same dosage may be given via the intraosseous route when IV access is not available.
Neonates: 5 mg/kg/dose IV; may repeat dose twice up to 15 mg/kg IV (Max single dose: 300 mg IV). May administer IV push for ventricular fibrillation or pulseless ventricular tachycardia. The same dosage may be given via the intraosseous route when IV access is not available.
-for hemodynamically stable ventricular tachycardia (monomorphic or polymorphic) or wide-complex tachycardia of unknown origin during CPR (perfusing ventricular arrhythmias):
Intravenous or Intraosseous* dosage:
Adults: 150 mg IV over 10 minutes, followed by 1 mg/minute continuous IV infusion for 6 hours then 0.5 mg/minute continuous IV infusion for 18 hours. Supplemental 150 mg IV doses may be repeated every 10 minutes as needed. Max cumulative dosage: 2.2 g/24 hours. The same dosage may be given via the intraosseous route when IV access is not available.
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). 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.
Neonates: 5 mg/kg/dose IV; may repeat dose twice up to 15 mg/kg IV (Max single dose: 300 mg IV). 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.
For the treatment of atrial fibrillation*, atrial flutter*, or paroxysmal supraventricular tachycardia (PSVT)*:
Intravenous dosage:
Adults: 150 mg IV over 10 minutes as a single dose, then 1 mg/minute continuous IV infusion for 6 hours and 0.5 mg/minute for 18 hours or change to oral dosing; consider decreasing dose to 0.25 mg/minute after 24 hours. Alternatively, 300 mg IV over 1 hour as a single dose, then 10 to 50 mg/hour continuous IV infusion for 24 hours. Parenteral amiodarone is an appropriate alternative for rate control in critically ill persons without pre-excitation and may facilitate conversion to sinus rhythm in persons with atrial fibrillation.
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.
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.
Oral dosage:
Adults: 400 to 800 mg/day PO in divided doses for 2 to 4 weeks to a total load of up to 10 g, then 100 to 200 mg PO once daily. Guidelines suggest oral amiodarone as a reasonable option for pharmacological cardioversion of atrial fibrillation. For maintenance of sinus rhythm, consider amiodarone only after consideration of its risks and when other agents have failed or are contraindicated. The SAFE-T trial comparing amiodarone and sotalol to restore and maintain sinus rhythm utilized an amiodarone dosing regimen of 800 mg/day PO for 14 days, then 600 mg/day for 14 days, then 300 mg/day for the first year, and 200 mg/day thereafter. Various loading and maintenance dosage regimens for oral amiodarone have been utilized. One source recommends a loading dose of 800 to 1600 mg/day PO for 1 to 3 weeks, followed by 800 mg/day for the next 2 to 4 weeks, with a maintenance dose of 300 mg/day or less. Another source describes utilizing a loading dose of 800 mg PO twice daily for 2 weeks followed by 400 mg/day for the next 2 weeks, with a maintenance dose of 200 mg/day. The Canadian Trial of Atrial Fibrillation (CTAF) utilized a dosage regimen of 10 mg/kg PO once daily for 2 weeks, followed by 300 mg once daily for 4 weeks, followed by a maintenance dose of 200 mg PO once daily. The CTAF study demonstrated greater efficacy of amiodarone compared to sotalol or propafenone in preventing recurrent atrial fibrillation.
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.
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.
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.
For the prevention of sudden cardiac death in persons with heart failure*:
Oral dosage:
Adults: 600 to 800 mg PO once daily for 7 to 14 days, then 200 to 400 mg PO once daily. Although amiodarone suppresses ventricular arrhythmias and improves left ventricular ejection fraction (LVEF) in persons with heart failure, its effect on mortality remains inconclusive. Amiodarone has demonstrated neutral effects on mortality in clinical trials of persons with reduced ejection fraction heart failure (HFrEF).
For primary atrial fibrillation prophylaxis* in patients receiving cardiac surgery*:
NOTE: Amiodarone is suggested as an alternative treatment option to other first-line treatment strategies (e.g., beta-blockers) for the prevention of atrial fibrillation after coronary artery bypass graft (CABG) surgery.
Oral dosage:
Adults: Initially, 600 mg PO once daily for 7 days preoperatively, then 200 mg once daily postoperatively until hospital discharge. In a double-blind, placebo-controlled study, the efficacy of oral amiodarone for the prevention of atrial fibrillation was assessed in patients with normal sinus rhythm who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass. Sixty-four patients received 200 mg PO three times per day for seven days (beginning an average of 13 days prior to surgery), then 200 mg once daily during hospitalization and until discharge (mean total cumulative dosage 4.8 g). Patients with a resting heart rate less than 50 bpm or uncontrolled heart failure were excluded. Postoperative atrial fibrillation occurred in 25% of patients in the amiodarone group and 53% in the placebo group (p = 0.003). Patients in the amiodarone group were hospitalized for significantly fewer days than patients assigned to placebo (6.5 vs. 7.9 days, p = 0.04). Further evidence supporting the efficacy of amiodarone in prevention of atrial fibrillation was reported in the PAPABEAR trial. Patients undergoing nonemergent CABG and/or valve replacement or repair were randomized to receive either oral amiodarone 10 mg/kg/day, in 2 divided doses, for 6 days before and 6 days after surgery for a total of 13 perioperative days, or placebo. Postoperative atrial tachyarrhythmias occurred significantly less often in the amiodarone group than the placebo group (16.1% vs. 29.5%, respectively). Although the use of amiodarone in post-CABG patients has been established as an alternative therapy, less favorable results have been documented with intraoperative amiodarone use during CABG surgery. A study of intraoperative IV amiodarone to prevent atrial fibrillation in patients undergoing CABG, showed that it did not prevent new onset of atrial fibrillation and had no beneficial effects on outcome (e.g., perioperative complications, early mortality, duration of hospital stay).
For the treatment of premature ventricular contractions (PVCs)*:
Oral dosage:
Adults: 200 to 400 mg PO every 8 to 12 hours for 1 to 2 weeks, then 300 to 400 mg PO once daily. Reduce dose to 200 mg PO once daily if possible.
Maximum Dosage Limits:
Individualize maximum amiodarone dosage according to clinical goals, phase of dosage titration, and close monitoring of efficacy and safety parameters.
-Adults
300 mg/dose IV, 1 mg/min continuous infusion, and up to 1600 mg/DAY PO.
-Geriatric
300 mg/dose IV, 1 mg/min continuous infusion, and up to 1600 mg/DAY PO.
-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.
-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.
-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.
-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.
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
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with amiodarone. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and amiodarone is a P-gp inhibitor.
Acebutolol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Acetaminophen; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with amiodarone may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of amiodarone could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A; amiodarone is a dual weak 2D6 and weak 3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like amiodarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If amiodarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. If amiodarone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like amiodarone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If amiodarone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Acetaminophen; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Adagrasib: (Major) Avoid concomitant use of amiodarone and adagrasib due to increased amiodarone exposure and an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Afatinib: (Moderate) If the concomitant use of amiodarone and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of amiodarone. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-gp substrate and amiodarone is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC of afatinib was 119% when coadministered with the same P-gp inhibitor, and 111% when the inhibitor was administered 6 hours after afatinib.
Alfentanil: (Moderate) Alfentanil is a substrate of CYP3A4. Amiodarone is an inhibitor of CYP3A4. If these drugs are coadministered, monitor patients for adverse effects of alfentanil, such as hypotension, nausea, itching, and respiratory depression. Also, adverse cardiovascular effects, such as hypotension and atropine-resistant bradycardia can occur in patients receiving amiodarone who subsequently are administered anesthetics, including alfentanil. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after amiodarone discontinuation.
Alfuzosin: (Major) Concomitant use of amiodarone and alfuzosin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Alprazolam: (Major) Avoid coadministration of alprazolam and amiodarone due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with amiodarone, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and amiodarone is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amisulpride: (Major) Concomitant use of amiodarone and amisulpride increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with amiodarone is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; amiodarone is a P-gp inhibitor.
Amoxapine: (Major) Lower doses of amoxapine may be required during concurrent use of amiodarone due to the potential for increased amoxapine exposure. If amiodarone is discontinued, an increased dose of amoxapine may be necessary. Amoxapine is a CYP2D6 substrate; amiodarone is a CYP2D6 inhibitor.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of amiodarone and clarithromycin due to increased amiodarone exposure and an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Anagrelide: (Major) Concomitant use of amiodarone and anagrelide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Apalutamide: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and apalutamide. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and apalutamide is a strong CYP3A inducer.
Apomorphine: (Major) Concomitant use of amiodarone and apomorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Aprepitant, Fosaprepitant: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with aprepitant/fosaprepitant is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and aprepitant/fosaprepitant is a moderate CYP3A inhibitor.
Aripiprazole: (Major) Concomitant use of aripiprazole and amiodarone increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase aripiprazole exposure and the risk for other adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, an aripiprazole dosage reduction is necessary; management recommendations vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. Aripiprazole is CYP2D6 and CYP3A substrate, amiodarone is a weak CYP2D6 and CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Major) Concomitant use of aripiprazole and amiodarone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Arsenic Trioxide: (Major) Concomitant use of amiodarone and arsenic trioxide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Artemether; Lumefantrine: (Major) Concomitant use of amiodarone and artemether increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Major) Concomitant use of amiodarone and lumefantrine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Articaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Asenapine: (Major) Concomitant use of amiodarone and asenapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. If amiodarone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like amiodarone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If amiodarone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Avoid concomitant use of amiodarone and atazanavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of amiodarone and atazanavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. (Major) Avoid concomitant use of amiodarone and cobicistat due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor.
Atenolol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Atenolol; Chlorthalidone: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Atomoxetine: (Major) Concomitant use of amiodarone and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with amiodarone is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; amiodarone is a P-gp inhibitor.
Azithromycin: (Major) Concomitant use of amiodarone and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Bedaquiline: (Major) Concomitant use of amiodarone and bedaquiline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Bendamustine: (Major) Consider the use of an alternative therapy if amiodarone treatment is needed in patients receiving bendamustine. Concomitant use of amiodarone may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with amiodarone may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of amiodarone in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If amiodarone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Amiodarone is an inhibitor of CYP3A4 and CYP2D6.
Berotralstat: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with berotralstat is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Betaxolol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving amiodarone. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving amiodarone. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; amiodarone is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3-fold.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with amiodarone may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and amiodarone is a P-gp inhibitor.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of amiodarone and metronidazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of amiodarone and metronidazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Bisoprolol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Bosentan: (Moderate) Use caution if coadministration of amiodarone with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions. Administration of bosentan with both amiodarone and a strong or moderate CYP3A inhibitor is not recommended. Bosentan is a CYP3A and CYP2C9 substrate; amiodarone is a moderate CYP2C9 inhibitor.
Brimonidine; Timolol: (Moderate) Concomitant administration of timolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of timolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Brompheniramine; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Bumetanide: (Major) Monitor serum electrolytes if coadministration of bumetanide and amiodarone is necessary. Bumetanide therapy may cause electrolyte abnormalities (i.e., hypokalemia, hypomagnesemia) which may exaggerate the degree of QTc prolongation and increase the potential for torsade de pointes.
Bupivacaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Bupivacaine; Lidocaine: (Major) Concomitant administration of lidocaine with amiodarone has been reported to cause sinus bradycardia and seizure. Amiodarone and its main metabolite, N-monodesethylamiodarone (DEA), appear to inhibit the metabolism of lidocaine by competitively inhibiting CYP3A4. Furthermore, DEA inhibits lidocaine metabolism in a concentration-dependent manner. Also, the metabolism of amiodarone to DEA appears to be competitively inhibited by lidocaine. Close correlations between amiodarone N-monodesethylase activities and the amounts of CYP3A4 and the rates of lidocaine N-monodesethylation have been observed from analyses of in vitro data. Inhibition of lidocaine metabolism is supported by in vivo data from 6 adults. The mean systemic concentration of lidocaine over 300 minutes after receipt of lidocaine hydrochloride 1 mg/kg intravenously before amiodarone treatment is 111.7 +/- 23.2 mcg/minute/mL. In contrast, the mean systemic concentration of lidocaine over 300 minutes after cumulative amiodarone doses of 3 g and 13 g is 135.3 +/- 34.6 and 131.7 +/- 25.5 mcg/minute/mL, respectively. As expected, the systemic exposure of the lidocaine metabolite, monoethylglycinexylidide, decreases from 19.2 +/- 6.5 to 15.8 +/- 8.3 mcg/minute/mL after 3 g of amiodarone. In addition, the systemic clearance of lidocaine decreases from 7.86 +/- 1.83 to 6.31 +/- 2.21 mL/minute/kg body weight. As compared with values before amiodarone administration, the lidocaine elimination half-life and the distribution volume at steady state remain relatively unchanged. Due to the long half-life of amiodarone, clinicians should use caution when administering lidocaine to patients who are receiving or who have recently discontinued amiodarone.
Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with amiodarone is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and amiodarone is a moderate CYP2C9 inhibitor.
Buprenorphine: (Major) Concomitant use of amiodarone and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use can also increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when amiodarone is added after a stable buprenorphine dose is achieved. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping amiodarone, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If amiodarone is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a CYP3A substrate, amiodarone is a CYP3A4 inhibitor, and both medications have been associated with QT/QTc prolongation.
Buprenorphine; Naloxone: (Major) Concomitant use of amiodarone and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use can also increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when amiodarone is added after a stable buprenorphine dose is achieved. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping amiodarone, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If amiodarone is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a CYP3A substrate, amiodarone is a CYP3A4 inhibitor, and both medications have been associated with QT/QTc prolongation.
Butalbital; Acetaminophen; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Cabotegravir; Rilpivirine: (Major) Concomitant use of amiodarone and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor. (Minor) Amiodarone is an inhibitor of CYP1A2 isoenzymes, and could theoretically reduce CYP1A2-mediated caffeine metabolism. The clinical significance of this potential interaction is not known.
Caffeine; Sodium Benzoate: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Carbamazepine: (Moderate) Monitor for a decrease in amiodarone efficacy and an increase in carbamazepine-related adverse reactions during concomitant use of amiodarone and carbamazepine. Monitor carbamazepine concentrations closely and adjust the dose as needed. Concomitant use may decrease amiodarone exposure and increase carbamazepine exposure. Amiodarone is a CYP3A substrate and weak CYP3A inhibitor and carbamazepine is a CYP3A substrate and strong CYP3A inducer.
Carteolol: (Major) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Carvedilol: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with amiodarone is necessary. Carvedilol is a CYP2C9 substrate and amiodarone is a CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.
Celecoxib; Tramadol: (Moderate) Concurrent use of tramadol with amiodarone may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A; amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Ceritinib: (Major) Avoid concomitant use of amiodarone and ceritinib due to increased amiodarone exposure and an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, ceritinib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Chloramphenicol: (Major) Avoid concomitant use of amiodarone and chloramphenicol due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor.
Chloroquine: (Major) Concomitant use of amiodarone and chloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like amiodarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If amiodarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Chlorpromazine: (Major) Concomitant use of amiodarone and chlorpromazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase chlorpromazine exposure and the risk for other chlorpromazine-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Chlorpromazine is a CYP2D6 substrate, amiodarone is a weak CYP2D6 inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Cholestyramine: (Major) Cholestyramine can enhance amiodarone clearance presumably via reduced enterohepatic recirculation, thereby reducing amiodarone serum concentrations. This interaction between amiodarone and cholestyramine may be of benefit to temporarily reduce amiodarone serum concentrations prior to surgery and possibly limit the cardiac depressant effects of the drug in the immediate post-surgical period, although more data are needed before this recommendation can be made.
Cimetidine: (Major) Avoid concomitant use of amiodarone and cimetidine due to the risk for increased amiodarone exposure which may increase the risk for adverse effects.
Ciprofloxacin: (Major) Concomitant use of amiodarone and ciprofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase amiodarone exposure and the risk for other adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, ciprofloxacin is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Cisapride: (Contraindicated) Avoid concomitant use of amiodarone and cisapride due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase cisapride exposure and the risk for other cisapride-related adverse effects. Cisapride is a CYP3A substrate, amiodarone is a weak CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use of cisapride with CYP3A inhibitors is disallowed under the Propulsid Limited Access Program. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Citalopram: (Major) Concomitant use of amiodarone and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Clarithromycin: (Major) Avoid concomitant use of amiodarone and clarithromycin due to increased amiodarone exposure and an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Clofazimine: (Major) Concomitant use of amiodarone and clofazimine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Clomipramine: (Moderate) Monitor for an increase in clomipramine-related adverse reactions if concomitant use of amiodarone is necessary; a clomipramine dose reduction may be necessary. Concomitant use may increase clomipramine exposure; clomipramine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Clonidine: (Moderate) Monitor for potential bradycardia or atrioventricular block during coadministration with amiodarone. Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate.
Clozapine: (Major) Concomitant use of amiodarone and clozapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase clozapine exposure and the risk for clozapine-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider a clozapine dose reduction and take steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Clozapine is a CYP3A, CYP2D6, and CYP1A2 substrate; amiodarone is a weak CYP3A, CYP2D6, and CYP1A2 inhibitor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Cobicistat: (Major) Avoid concomitant use of amiodarone and cobicistat due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor.
Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with amiodarone is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; amiodarone is a P-gp inhibitor.
Codeine: (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of amiodarone and promethazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Codeine; Promethazine: (Major) Concomitant use of amiodarone and promethazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Colchicine: (Major) Avoid concomitant use of colchicine and amiodarone due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and amiodarone is a P-gp inhibitor.
Conivaptan: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with conivaptan is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
Crizotinib: (Major) Concomitant use of amiodarone and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase amiodarone exposure and the risk for other adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, crizotinib is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Cyclophosphamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with amiodarone as there may be an increased risk of pulmonary toxicity.
Cyclosporine: (Moderate) Cyclosporine is a CYP3A4 substrate. Amiodarone is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, which may reduce cyclosporine dosage requirements or cause cyclosporine toxicity.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with amiodarone is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-gp substrate and amiodarone is a P-gp inhibitor.
Daclatasvir: (Major) Coadministration of amiodarone with daclatasvir plus sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, some requiring pacemaker intervention, have been reported when amiodarone was administered with sofosbuvir and another direct-acting antiviral, including daclatasvir. One patient developed a fatal cardiac arrest after receiving amiodarone with ledipasvir; sofosbuvir. Bradycardia generally occurs within hours to days; however, cases have been observed up to 2 weeks after initiating the hepatitis C virus (HCV) treatment regimen. The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting the HCV regimen should also undergo similar cardiac monitoring as outlined above.
Danazol: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with danazol is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and danazol is a moderate CYP3A inhibitor.
Darunavir: (Major) Avoid concomitant use of amiodarone and darunavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Darunavir; Cobicistat: (Major) Avoid concomitant use of amiodarone and cobicistat due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Major) Avoid concomitant use of amiodarone and darunavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of amiodarone and cobicistat due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Major) Avoid concomitant use of amiodarone and darunavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. (Moderate) Coadministration of tenofovir alafenamide with amiodarone may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and amiodarone is a P-gp inhibitor.
Dasatinib: (Major) Concomitant use of amiodarone and dasatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Degarelix: (Major) Concomitant use of amiodarone and androgen deprivation therapy (i.e., degarelix) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Delavirdine: (Major) Avoid concomitant use of amiodarone and delavirdine due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor.
Desflurane: (Major) Concomitant use of amiodarone and halogenated anesthetics increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Dexmedetomidine: (Major) Concomitant use of amiodarone and dexmedetomidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Dextromethorphan; Quinidine: (Major) Amiodarone coadministration increases quinidine concentrations by about 33% after 2 days, by decreasing its renal clearance or by inhibiting its hepatic metabolism. Quinidine may also be displaced from tissue and protein binding sites. Prolongation of the QT interval is well documented with quinidine, and the addition of amiodarone may increase this effect, placing the patient at an increased risk for the development of torsade de pointes. Careful clinical observation of the patient as well as close monitoring of the ECG and serum quinidine concentrations are essential with adjustment of the quinidine dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. An empiric reduction of the quinidine dose by 33-50% is suggested within 2 days following initiation of amiodarone therapy, with consideration given to immediately discontinuing of quinidine once amiodarone therapy is begun. Combination antiarrhythmic therapy is reserved for patients with refractory life-threatening arrhythmias. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with amiodarone is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and amiodarone is a CYP3A inhibitor.
Diclofenac: (Moderate) Monitor for an increase in diclofenac-related adverse effects if concomitant use with amiodarone is necessary; a diclofenac dosage decrease may be required based on response. Concomitant use may increase diclofenac exposure. Diclofenac is a CYP2C9 substrate and amiodarone is a CYP2C9 inhibitor.
Diclofenac; Misoprostol: (Moderate) Monitor for an increase in diclofenac-related adverse effects if concomitant use with amiodarone is necessary; a diclofenac dosage decrease may be required based on response. Concomitant use may increase diclofenac exposure. Diclofenac is a CYP2C9 substrate and amiodarone is a CYP2C9 inhibitor.
Digoxin: (Major) Amiodarone increases orally administered digoxin serum concentration by 70% when given concomitantly. When amiodarone is coadministered with intravenous (IV) digoxin, the serum concentration of digoxin is increased by 17%. Measure serum digoxin concentrations before initiating amiodarone. According to the manufacturer of amiodarone, the digoxin dose should be reduced by 50% upon initiation of amiodarone. The manufacturer of digoxin recommends measuring the serum digoxin concentration before initiating amiodarone and reducing the serum digoxin concentration by reducing the oral dose by approximately 30 to 50%, decreasing the IV digoxin dose by 15 to 30%, or modifying the dosing frequency and continue monitoring. The mechanism of the increase in digoxin serum concentration is thought to result from inhibition of gastrointestinal P-glycoprotein (increased oral bioavailability) and/or a decrease in digoxin renal or nonrenal clearance. Because of the depressant effects of digoxin on the sinus and AV node, concurrent use can potentiate amiodarone's electrophysiologic and hemodynamic effects resulting in bradycardia, sinus arrest, and AV block. Furthermore, amiodarone may induce changes in thyroid function and alter sensitivity to cardiac glycosides, and thyroid function should be monitored closely in patients receiving both drugs simultaneously. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Close monitoring of serum digoxin concentrations and heart rate is essential to avoid enhanced toxicity.
Dihydroergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of ergotamine and amiodarone. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor.
Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with amiodarone is necessary. Concurrent use may result in elevated diltiazem concentrations. Additive effects on cardiac contractility and/or AV conduction are also possible. Diltiazem is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor.
Diphenhydramine; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Disopyramide: (Major) Avoid concomitant use of amiodarone and disopyramide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase disopyramide exposure and the risk for other disopyramide-related adverse effects. Disopyramide is a CYP3A substrate, amiodarone is a weak CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A inhibitors. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Dofetilide: (Major) Avoid concomitant use of amiodarone and dofetilide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase dofetilide exposure and the risk for other dofetilide-related adverse effects. Dofetilide is a CYP3A substrate, amiodarone is a weak CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Dolasetron: (Major) Concomitant use of amiodarone and dolasetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with amiodarone. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and amiodarone is a P-gp inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with amiodarone. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and amiodarone is a P-gp inhibitor.
Dolutegravir; Rilpivirine: (Major) Concomitant use of amiodarone and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with amiodarone. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and amiodarone is a P-gp inhibitor.
Donepezil: (Major) Concomitant use of amiodarone and donepezil increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Donepezil; Memantine: (Major) Concomitant use of amiodarone and donepezil increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Dorzolamide; Timolol: (Moderate) Concomitant administration of timolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of timolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Doxorubicin Liposomal: (Major) Avoid coadministration of amiodarone with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and amiodarone is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of amiodarone with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and amiodarone is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Moderate) Monitor for increased toxicity (e.g., feeling high, dizziness, confusion, somnolence) of dronabinol if coadministered with amiodarone. Coadministration may increase the exposure of dronabinol. Dronabinol is a CYP2C9 substrate; amiodarone is a moderate CYP2C9 inhibitor.
Dronedarone: (Contraindicated) Avoid concomitant use of amiodarone and dronedarone due to increased amiodarone exposure and an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Amiodarone is a CYP3A substrate, dronedarone is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Droperidol: (Major) Concomitant use of amiodarone and droperidol increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Duloxetine: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with amiodarone. Concurrent use may result in increased duloxetine exposure. Duloxetine is a CYP1A2 and CYP2D6 substrate and amiodarone is a CYP1A2 and CYP2D6 inhibitor.
Duvelisib: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with duvelisib is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and duvelisib is a moderate CYP3A inhibitor.
Edoxaban: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of amiodarone is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and amiodarone is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with amiodarone. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of amiodarone. Increased concentrations of edoxaban may occur during concomitant use of amiodarone; monitor for increased adverse effects of edoxaban.
Efavirenz: (Major) Concomitant use of amiodarone and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of amiodarone and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of amiodarone and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Eliglustat: (Major) Coadministration of amiodarone and eliglustat is not recommended. Eliglustat is a CYP2D6 and CYP3A substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Amiodarone is an inhibitor of CYP2D6 and a weak inhibitor of CYP3A and is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Amiodarone-mediated inhibition of CYP2D6 and CYP3A in a patient receiving eliglustat may result in unexpectedly high plasma concentrations of eliglustat, further increasing the risk of serious adverse events (e.g., cardiac arrhythmias).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of amiodarone and cobicistat due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Moderate) Coadministration of tenofovir alafenamide with amiodarone may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and amiodarone is a P-gp inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of amiodarone and cobicistat due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Concomitant use of amiodarone and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Moderate) Coadministration of tenofovir alafenamide with amiodarone may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and amiodarone is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of amiodarone and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with amiodarone may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and amiodarone is a P-gp inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Encorafenib: (Major) Concomitant use of amiodarone and encorafenib may decrease amiodarone exposure and efficacy and increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Entrectinib: (Major) Concomitant use of amiodarone and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Enzalutamide: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and enzalutamide. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and enzalutamide is a strong CYP3A inducer.
Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and amiodarone due to the risk for increased plasma concentrations of erdafitinib. If concomitant use is necessary, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. Erdafitinib is a CYP2C9 substrate and amiodarone is a moderate CYP2C9 inhibitor.
Ergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of ergotamine and amiodarone. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor.
Ergotamine; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of amiodarone is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor. (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of ergotamine and amiodarone. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor.
Eribulin: (Major) Concomitant use of amiodarone and eribulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Erlotinib: (Major) Avoid coadministration of erlotinib with amiodarone if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A and to a lesser extent by CYP1A2; amiodarone is a CYP3A and CYP1A2 inhibitor. Coadministration with a moderate CYP3A/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
Erythromycin: (Major) Concomitant use of amiodarone and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase amiodarone exposure and the risk for other amiodarone-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, erythromycin is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Escitalopram: (Major) Concomitant use of amiodarone and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Esmolol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Ethiodized Oil: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Etrasimod: (Major) Concomitant use of amiodarone and etrasimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions if concomitant use of amiodarone is necessary. Etravirine is a CYP2C9 substrate and amiodarone is a moderate CYP2C9 inhibitor.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with amiodarone is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Ezetimibe; Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amiodarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amiodarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amiodarone and simvastatin against the potential risks. Amiodarone increases the simvastatin exposure by approximately 2-fold.
Fedratinib: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with fedratinib is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
Felodipine: (Moderate) Concurrent use of felodipine and amiodarone should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and amiodarone is a weak CYP3A inhibitor. Concurrent use of another weak CYP3A inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. If amiodarone is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amiodarone can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amiodarone is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fexinidazole: (Major) Concomitant use of amiodarone and fexinidazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Fezolinetant: (Contraindicated) Concomitant use of fezolinetant and amiodarone is contraindicated due to the risk of increased fezolinetant exposure which may increase the risk of fezolinetant-related adverse effects. Fezolinetant is a CYP1A2 substrate; amiodarone is a weak CYP1A2 inhibitor. Concomitant use with another weak CYP1A2 inhibitor increased fezolinetant overall exposure by 100%.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or amiodarone; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and amiodarone is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Fingolimod: (Major) Concomitant use of amiodarone and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Flecainide: (Major) Flecainide has been used in combination with amiodarone in specialized settings to treat refractory arrhythmias. Combination therapy with Class III and Class IC antiarrhythmics has been reported to increase the risk of proarrhythmias. Close monitoring of therapeutic response is warranted for patients receiving combination therapy, including serum drug concentration monitoring. Amiodarone inhibits the hepatic metabolism of flecainide via CYP2D6 inhibition. When amiodarone is added to flecainide therapy, plasma flecainide levels may increase two-fold or more in some patients, if flecainide dosage is not reduced. When flecainide is given in the presence of amiodarone, reduce the usual flecainide dose by 50% and monitor the patient closely for adverse effects. Serum drug concentration monitoring is strongly recommended to guide dosage with such combination therapy. Coadministration of amiodarone with drugs that prolong the QT interval should be done with a careful assessment of risks versus benefits. Although rare, cases of QT prolongation and torsade de pointes (TdP) have been reported during flecainide therapy; causality has not been established. Based on theoretical considerations, the manufacturer recommends allowing at least 2 to 4 plasma half-lives to elapse following flecainide discontinuation before switching to another antiarrhythmic drug.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A inhibitors, including amiodarone, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A inhibitors and flibanserin should be discussed with the patient.
Fluconazole: (Contraindicated) Avoid concomitant use of amiodarone and fluconazole due to increased amiodarone exposure and an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Amiodarone is a CYP3A substrate, fluconazole is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Fluoxetine: (Major) Concomitant use of amiodarone and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase fluoxetine exposure and the risk for other fluoxetine-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Fluoxetine is a CYP2D6 substrate, amiodarone is a weak CYP2D6 inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Fluphenazine: (Minor) The concomitant use of amiodarone and other drugs known to prolong the QT interval should only be done after careful assessment of risks versus benefits. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Drugs with a possible risk for QT prolongation include fluphenazine.
Fluvoxamine: (Major) Concomitant use of amiodarone and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase amiodarone exposure and the risk for other amiodarone-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, fluvoxamine is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Food: (Major) Advise patients to avoid cannabis use during amiodarone treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are a CYP2C9 substrates and amiodarone is a CYP2C9 inhibitor.
Fosamprenavir: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with fosamprenavir is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor.
Foscarnet: (Major) Concomitant use of amiodarone and foscarnet increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Fosphenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with fosphenytoin and amiodarone due to increased phenytoin steady-state concentrations. Concomitant use may also reduce amiodarone exposure and efficacy. Phenytoin is a CYP2C9 substrate and a strong CYP3A inducer; amiodarone is a CYP3A substrate and a CYP2C9 inhibitor.
Fostemsavir: (Major) Concomitant use of amiodarone and fostemsavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with fostemsavir is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 4 times the recommended daily dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Gemifloxacin: (Major) Concomitant use of amiodarone and gemifloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Gemtuzumab Ozogamicin: (Major) Concomitant use of amiodarone and gemtuzumab ozogamicin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Gilteritinib: (Major) Concomitant use of amiodarone and gilteritinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Glasdegib: (Major) Concomitant use of amiodarone and glasdegib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and amiodarone as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a substrate of P-gp and amiodarone is a P-gp inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of amiodarone is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of P-gp and amiodarone is a P-gp inhibitor.
Goserelin: (Major) Concomitant use of amiodarone and androgen deprivation therapy (i.e., goserelin) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Granisetron: (Major) Concomitant use of amiodarone and granisetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during amiodarone treatment due to the risk of increased amiodarone exposure and adverse reactions. Amiodarone is a CYP3A substrate and grapefruit juice is a CYP3A inhibitor.
Guaifenesin; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Halogenated Anesthetics: (Major) Concomitant use of amiodarone and halogenated anesthetics increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Haloperidol: (Major) Concomitant use of amiodarone and haloperidol increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The intravenous route may carry a higher risk for haloperidol-induced QT/QTc prolongation than other routes of administration. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Histrelin: (Major) Concomitant use of amiodarone and androgen deprivation therapy (i.e., histrelin) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like amiodarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If amiodarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like amiodarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If amiodarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like amiodarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If amiodarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydroxychloroquine: (Major) Concomitant use of amiodarone and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Hydroxyzine: (Major) Concomitant use of hydroxyzine and amiodarone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. If amiodarone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like amiodarone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If amiodarone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ibutilide: (Major) Concomitant use of amiodarone and ibutilide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Idelalisib: (Major) Avoid concomitant use of amiodarone and idelalisib due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor.
Iloperidone: (Major) Concomitant use of amiodarone and iloperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Imatinib: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with imatinib is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor.
Indinavir: (Major) Avoid concomitant use of amiodarone and indinavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and indinavir is a strong CYP3A inhibitor.
Inotuzumab Ozogamicin: (Major) Concomitant use of amiodarone and inotuzumab ozogamicin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Iodixanol: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Iohexol: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Iomeprol: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Iopamidol: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Iopromide: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Ioversol: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Isavuconazonium: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with isavuconazonium is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and isavuconazonium is a moderate CYP3A inhibitor.
Isoflurane: (Major) Concomitant use of amiodarone and halogenated anesthetics increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and rifampin. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and rifampin is a strong CYP3A inducer.
Isoniazid, INH; Rifampin: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and rifampin. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and rifampin is a strong CYP3A inducer.
Isosulfan Blue: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Isradipine: (Minor) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with amiodarone is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and amiodarone is a weak CYP3A inhibitor.
Itraconazole: (Major) Avoid coadministration of amiodarone and itraconazole due to the potential for increased amiodarone concentrations and additive effects on the QT interval. There have been reports of prolonged QT, with or without torsade de pointes (TdP) with the concomitant use of amiodarone and azole antifungals. Both itraconazole and amiodarone are associated with QT prolongation. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with amiodarone (a CYP3A4 substrate) may result in elevated amiodarone plasma concentrations and an increased risk for adverse events, including QT prolongation. According to the manufacturer, the need to administer amiodarone with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits, especially when the coadministered agent might decrease the metabolism of amiodarone. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Further, it takes approximately 7 to 14 days after discontinuing itraconazole before the plasma concentrations are undetectable. The decline in itraconazole plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Ivabradine: (Major) Avoid coadministration of ivarbadine and amiodarone as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; amiodarone is a moderate CYP3A4 inhibitor. In addition, coadministration of ivabradine with other negative chronotropes like amiodarone increases the risk for bradycardia. Increased ivabradine concentrations may further increase the risk of bradycardia exacerbation and conduction disturbances.
Ivosidenib: (Major) Concomitant use of amiodarone and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of amiodarone is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and amiodarone is a weak CYP3A inhibitor.
Ketamine: (Major) In general, adverse cardiovascular effects such as hypotension and atropine-resistant bradycardia can occur in patients receiving amiodarone who subsequently are administered any general anesthetics, particularly volatile anesthetics. Due to the extremely long half-life of amiodarone, a drug interaction is also possible for days to weeks after discontinuation of amiodarone. For example, when fentanyl was administered to patients receiving amiodarone, the incidence of bradycardia and other adverse cardiovascular effects was much higher than in patients not on amiodarone who received fentanyl.
Ketoconazole: (Contraindicated) Use of ketoconazole/levoketoconazole and amiodarone is contraindicated due to an increased risk for ventricular arrhythmias, torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. Concomitant use may also increase the exposure of amiodarone, further increasing the risk for adverse events. Amiodarone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Labetalol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as Class III antiarrhythmics, because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of amiodarone and clarithromycin due to increased amiodarone exposure and an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Lapatinib: (Major) Avoid coadministration of amiodarone and lapatinib if possible due to the risk of QT prolongation; lapatinib exposure may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes, as well as monitoring for an increase in lapatinib-related adverse reactions. Correct any electrolyte abnormalities prior to treatment. Lapatinib is a P-glycoprotein (P-gp) substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Amiodarone, a Class III antiarrhythmic agent and P-gp inhibitor, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Ledipasvir; Sofosbuvir: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting sofosbuvir should also undergo similar cardiac monitoring as outlined above.
Lefamulin: (Major) Avoid coadministration of lefamulin with amiodarone as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Amiodarone is a P-gp inhibitor that is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Lemborexant: (Major) Limit the dose of lemborexant to 5 mg PO once daily if coadministered with amiodarone as concomitant use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; amiodarone is a weak CYP3A inhibitor. Coadministration with a weak CYP3A inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Lenacapavir: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with lenacapavir is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor.
Lenvatinib: (Major) Concomitant use of amiodarone and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Letermovir: (Moderate) Closely monitor for amiodarone-related adverse events and frequently monitor amiodarone concentrations if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of amiodarone, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Major) Concomitant use of amiodarone and androgen deprivation therapy (i.e., leuprolide) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Leuprolide; Norethindrone: (Major) Concomitant use of amiodarone and androgen deprivation therapy (i.e., leuprolide) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Levobunolol: (Moderate) The concomitant use of ophthalmic beta-blockers in patients receiving antiarrhythmics which slow AV conduction, such as amiodarone, may result in additive negative dromotropic effects, especially in patients with pre-existing cardiac disease or left ventricular dysfunction.
Levofloxacin: (Major) Concomitant use of amiodarone and levofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Levoketoconazole: (Contraindicated) Use of ketoconazole/levoketoconazole and amiodarone is contraindicated due to an increased risk for ventricular arrhythmias, torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. Concomitant use may also increase the exposure of amiodarone, further increasing the risk for adverse events. Amiodarone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Levothyroxine: (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Levothyroxine; Liothyronine (Porcine): (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Lidocaine: (Major) Concomitant administration of lidocaine with amiodarone has been reported to cause sinus bradycardia and seizure. Amiodarone and its main metabolite, N-monodesethylamiodarone (DEA), appear to inhibit the metabolism of lidocaine by competitively inhibiting CYP3A4. Furthermore, DEA inhibits lidocaine metabolism in a concentration-dependent manner. Also, the metabolism of amiodarone to DEA appears to be competitively inhibited by lidocaine. Close correlations between amiodarone N-monodesethylase activities and the amounts of CYP3A4 and the rates of lidocaine N-monodesethylation have been observed from analyses of in vitro data. Inhibition of lidocaine metabolism is supported by in vivo data from 6 adults. The mean systemic concentration of lidocaine over 300 minutes after receipt of lidocaine hydrochloride 1 mg/kg intravenously before amiodarone treatment is 111.7 +/- 23.2 mcg/minute/mL. In contrast, the mean systemic concentration of lidocaine over 300 minutes after cumulative amiodarone doses of 3 g and 13 g is 135.3 +/- 34.6 and 131.7 +/- 25.5 mcg/minute/mL, respectively. As expected, the systemic exposure of the lidocaine metabolite, monoethylglycinexylidide, decreases from 19.2 +/- 6.5 to 15.8 +/- 8.3 mcg/minute/mL after 3 g of amiodarone. In addition, the systemic clearance of lidocaine decreases from 7.86 +/- 1.83 to 6.31 +/- 2.21 mL/minute/kg body weight. As compared with values before amiodarone administration, the lidocaine elimination half-life and the distribution volume at steady state remain relatively unchanged. Due to the long half-life of amiodarone, clinicians should use caution when administering lidocaine to patients who are receiving or who have recently discontinued amiodarone.
Lidocaine; Epinephrine: (Major) Concomitant administration of lidocaine with amiodarone has been reported to cause sinus bradycardia and seizure. Amiodarone and its main metabolite, N-monodesethylamiodarone (DEA), appear to inhibit the metabolism of lidocaine by competitively inhibiting CYP3A4. Furthermore, DEA inhibits lidocaine metabolism in a concentration-dependent manner. Also, the metabolism of amiodarone to DEA appears to be competitively inhibited by lidocaine. Close correlations between amiodarone N-monodesethylase activities and the amounts of CYP3A4 and the rates of lidocaine N-monodesethylation have been observed from analyses of in vitro data. Inhibition of lidocaine metabolism is supported by in vivo data from 6 adults. The mean systemic concentration of lidocaine over 300 minutes after receipt of lidocaine hydrochloride 1 mg/kg intravenously before amiodarone treatment is 111.7 +/- 23.2 mcg/minute/mL. In contrast, the mean systemic concentration of lidocaine over 300 minutes after cumulative amiodarone doses of 3 g and 13 g is 135.3 +/- 34.6 and 131.7 +/- 25.5 mcg/minute/mL, respectively. As expected, the systemic exposure of the lidocaine metabolite, monoethylglycinexylidide, decreases from 19.2 +/- 6.5 to 15.8 +/- 8.3 mcg/minute/mL after 3 g of amiodarone. In addition, the systemic clearance of lidocaine decreases from 7.86 +/- 1.83 to 6.31 +/- 2.21 mL/minute/kg body weight. As compared with values before amiodarone administration, the lidocaine elimination half-life and the distribution volume at steady state remain relatively unchanged. Due to the long half-life of amiodarone, clinicians should use caution when administering lidocaine to patients who are receiving or who have recently discontinued amiodarone. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Lidocaine; Prilocaine: (Major) Concomitant administration of lidocaine with amiodarone has been reported to cause sinus bradycardia and seizure. Amiodarone and its main metabolite, N-monodesethylamiodarone (DEA), appear to inhibit the metabolism of lidocaine by competitively inhibiting CYP3A4. Furthermore, DEA inhibits lidocaine metabolism in a concentration-dependent manner. Also, the metabolism of amiodarone to DEA appears to be competitively inhibited by lidocaine. Close correlations between amiodarone N-monodesethylase activities and the amounts of CYP3A4 and the rates of lidocaine N-monodesethylation have been observed from analyses of in vitro data. Inhibition of lidocaine metabolism is supported by in vivo data from 6 adults. The mean systemic concentration of lidocaine over 300 minutes after receipt of lidocaine hydrochloride 1 mg/kg intravenously before amiodarone treatment is 111.7 +/- 23.2 mcg/minute/mL. In contrast, the mean systemic concentration of lidocaine over 300 minutes after cumulative amiodarone doses of 3 g and 13 g is 135.3 +/- 34.6 and 131.7 +/- 25.5 mcg/minute/mL, respectively. As expected, the systemic exposure of the lidocaine metabolite, monoethylglycinexylidide, decreases from 19.2 +/- 6.5 to 15.8 +/- 8.3 mcg/minute/mL after 3 g of amiodarone. In addition, the systemic clearance of lidocaine decreases from 7.86 +/- 1.83 to 6.31 +/- 2.21 mL/minute/kg body weight. As compared with values before amiodarone administration, the lidocaine elimination half-life and the distribution volume at steady state remain relatively unchanged. Due to the long half-life of amiodarone, clinicians should use caution when administering lidocaine to patients who are receiving or who have recently discontinued amiodarone.
Liothyronine: (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Lithium: (Major) Concomitant use of amiodarone and lithium increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Lofexidine: (Major) Avoid coadministration of lofexidine and amiodarone if possible, due to the potential for additive QT prolongation and torsade de pointes (TdP) and other serious adverse effects. Monitor ECG for QT prolongation and monitor for orthostatic hypotension and bradycardia if coadministration is required. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of TdP. Amiodarone, a CYP2D6 inhibitor and Class III antiarrhythmic agent, is associated with a well established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with amiodarone is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Lomitapide is a CYP3A substrate and amiodarone is a weak CYP3A inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A inhibitors.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and amiodarone is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, a CYP2C9 substrate and strong CYP3A4 inhibitor; amiodarone is a CYP3A4 substrate, a moderate CYP2C9 inhibitor, and moderate CYP3A4 inhibitor.
Loperamide: (Major) Concomitant use of amiodarone and loperamide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase the exposure of loperamide, further increasing the risk for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. Loperamide is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Major) Concomitant use of amiodarone and loperamide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase the exposure of loperamide, further increasing the risk for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. Loperamide is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with amiodarone due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. (Major) Avoid concomitant use of amiodarone and ritonavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
Losartan: (Moderate) Closely monitor blood pressure during coadministration of losartan and amiodarone; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; amiodarone is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure during coadministration of losartan and amiodarone; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; amiodarone is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.
Lovastatin: (Major) In general, in patients taking amiodarone, the lovastatin adult dose should not exceed 40 mg/day PO. Lovastatin doses greater than 40 mg/day should only be used in patients taking amiodarone in whom the benefit is expected to outweigh the increased risk of myopathy. Amiodarone may inhibit lovastatin metabolism via hepatic CYP3A4 isoenzymes. Monitor for signs and symptoms of myopathy in patients receiving amiodarone concurrently with any dose of lovastatin.
Lumacaftor; Ivacaftor: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and lumacaftor; ivacaftor. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer.
Lumacaftor; Ivacaftor: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and lumacaftor; ivacaftor. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer.
Macimorelin: (Major) Concomitant use of amiodarone and macimorelin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Macitentan: (Major) Avoid coadministration of macitentan with amiodarone due to the potential for increases in macitentan exposure and adverse effects. Macitentan is a CYP3A4 and CYP2C9 substrate and amiodarone is a dual moderate CYP3A4 and CYP2C9 inhibitor. Concomitant use is predicted to increase macitentan exposure approximately 4-fold.
Macitentan; Tadalafil: (Major) Avoid coadministration of macitentan with amiodarone due to the potential for increases in macitentan exposure and adverse effects. Macitentan is a CYP3A4 and CYP2C9 substrate and amiodarone is a dual moderate CYP3A4 and CYP2C9 inhibitor. Concomitant use is predicted to increase macitentan exposure approximately 4-fold.
Maprotiline: (Major) If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Additionally, amiodarone may also inhibit the CYP2D6 metabolism of maprotiline. The need to coadminister maprotiline with amiodarone should be done with a careful assessment of risk versus benefit; consider alternative therapy to maprotiline.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with amiodarone is necessary. Concomitant use may increase maraviroc exposure. Maraviroc is a P-gp substrate; amiodarone is a P-gp inhibitor.
Meclizine: (Moderate) Monitor for meclizine-related adverse effects, such as drowsiness and anticholinergic effects, when coadministered with amiodarone. Concomitant use may increase the exposure to meclizine. Meclizine is a CYP2D6 substrate and amiodarone is a CYP2D6 inhibitor.
Mefloquine: (Major) There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. In addition, mefloquine is metabolized by CYP3A4 and P-glycoprotein (P-gp). Inhibitors of these enzymes that also prolong the QT interval, such as amiodarone, may decrease the clearance of mefloquine and increase mefloquine systemic exposure further increasing the risk for QT prolongation.
Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with amiodarone is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and amiodarone is a moderate CYP2C9 inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. If amiodarone is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and amiodarone is a weak CYP3A inhibitor. Concomitant use with amiodarone can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Methadone: (Major) The need to coadminister methadone with amiodarone should be done with extreme caution and a careful assessment of treatment risks versus benefits. At high doses, methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses averaging approximately 400 mg/day in adult patients. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with inhibitors of these enzymes, such as amiodarone, may result in increased serum concentrations of methadone.
Methimazole: (Moderate) In hyperthyroid patients, the combination of amiodarone and methimazole has been associated with a greater decrease in serum triiodothyronine and thyroxine levels, as compared to the administration of methimazole alone. This may be due to increased iodide release associated with amiodarone. Monitor serum T3 and T4 levels in patients receiving combination therapy.
Methohexital: (Major) In general, adverse cardiovascular effects such as hypotension and atropine resistant bradycardia can occur in patients receiving amiodarone who subsequently are administered any general anesthetics, particularly volatile anesthetics. Due to the extremely long half life of amiodarone, a drug interaction is also possible for days to weeks after discontinuation of amiodarone.
Methylergonovine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of methylergonovine and amiodarone. Concomitant use may increase methylergonovine exposure. Methylergonovine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor.
Metoprolol: (Moderate) Concomitant administration of metoprolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of metoprolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant administration of metoprolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of metoprolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Metronidazole: (Major) Concomitant use of amiodarone and metronidazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Mexiletine: (Major) Mexiletine is primarily metabolized by CYP2D6 isoenzymes, with a secondary pathway by CYP1A2. Amiodarone inhibits both of these enzymes. However, one study showed no effect of amiodarone on mexiletine clearance in patients with supraventricular arrhythmias.
Midazolam: (Moderate) Use caution when midazolam is coadministered with amiodarone. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and amiodarone is a weak CYP3A inhibitor.
Midostaurin: (Major) Concomitant use of amiodarone and midostaurin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Mifepristone: (Major) Avoid use of mifepristone with QT interval prolonging drugs. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used. Although specific drug interactions with mifepristone have not been studied, the use of mifepristone with CYP3A inhibitors may result in increased mifepristone concentrations and an increased risk of QT prolongation. Amiodarone is a CYP3A4 inhibitor and is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Mirtazapine: (Major) Concomitant use of amiodarone and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Mitotane: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and mitotane. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and mitotane is a strong CYP3A inducer.
Mobocertinib: (Major) Concomitant use of amiodarone and mobocertinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with amiodarone is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with amiodarone is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Moxifloxacin: (Major) Concomitant use of amiodarone and moxifloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Nadolol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Naldemedine: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with amiodarone. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; amiodarone is a P-gp inhibitor.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and amiodarone. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and amiodarone is a weak CYP3A and P-gp inhibitor.
Nateglinide: (Moderate) Monitor for an increase in nateglinide-related adverse effects, such as hypoglycemia, if concomitant use with amiodarone is necessary; a nateglinide dosage reduction may be required. Concomitant use may increase nateglinide exposure. Nateglinide is a CYP2C9 substrate and amiodarone is a moderate CYP2C9 inhibitor. Concomitant use with another moderate CYP2C9 inhibitor increased nateglinide overall exposure by 48%.
Nebivolol: (Moderate) Concomitant administration of nebivolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of nebivolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Nebivolol; Valsartan: (Moderate) Concomitant administration of nebivolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of nebivolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Nefazodone: (Major) Avoid concomitant use of amiodarone and nefazodone due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor.
Nelfinavir: (Major) Avoid concomitant use of amiodarone and nelfinavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with netupitant is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor.
Nilotinib: (Major) Avoid the concomitant use of nilotinib with amiodarone as significant prolongation of the QT interval may occur. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Sudden deaths and QT prolongation have been reported with nilotinib therapy. Both amiodarone and nilotinib are moderate inhibitors and substrates of CYP3A4; therefore, levels of either agent may be increased resulting in increased toxicity.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with amiodarone is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A substrate and amiodarone is a weak CYP3A inhibitor.
Nintedanib: (Moderate) Monitor for nintedanib-related adverse reactions if concomitant use of amiodarone is necessary. Concomitant use may increase nintedanib exposure. Nintedanib is a P-gp substrate, and a minor substrate of CYP3A and amiodarone is a dual P-gp and CYP3A inhibitor. Coadministration with another dual P-gp and CYP3A inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and amiodarone is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase amiodarone exposure resulting in increased toxicity. Amiodarone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) Avoid concomitant use of amiodarone and ritonavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
Nirogacestat: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with nirogacestat is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with amiodarone due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and amiodarone is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Non-Ionic Contrast Media: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Ofloxacin: (Major) Concomitant use of amiodarone and ofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Olanzapine: (Major) Concomitant use of amiodarone and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Olanzapine; Fluoxetine: (Major) Concomitant use of amiodarone and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase fluoxetine exposure and the risk for other fluoxetine-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Fluoxetine is a CYP2D6 substrate, amiodarone is a weak CYP2D6 inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Major) Concomitant use of amiodarone and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Olanzapine; Samidorphan: (Major) Concomitant use of amiodarone and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Ondansetron: (Major) Concomitant use of amiodarone and ondansetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Orlistat: (Major) In one pharmacokinetic study of healthy volunteers, administration of orlistat 120 mg three times daily for 13 days and a single orlistat dose of 120 mg on the morning of Day 14 in addition to a single dose of 1200 mg amiodarone on Day 4 resulted in a 23% to 27% reduction in the systemic exposure to amiodarone and its metabolite desethylamiodarone. The effect of initiating treatment with orlistat in patients stable on amiodarone therapy has not been studied; however, a reduced therapeutic effect of amiodarone is possible. The clinical response to amiodarone should be monitored closely if orlistat is initiated during chronic amiodarone therapy.
Osilodrostat: (Major) Concomitant use of amiodarone and osilodrostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Osimertinib: (Major) Concomitant use of amiodarone and osimertinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Oxaliplatin: (Major) Concomitant use of amiodarone and oxaliplatin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. If amiodarone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like amiodarone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If amiodarone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) Concomitant use of amiodarone and ozanimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Ozanimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Pacritinib: (Major) Concomitant use of amiodarone and pacritinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Paliperidone: (Major) Concomitant use of amiodarone and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Panobinostat: (Major) Concomitant use of amiodarone and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with amiodarone is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and amiodarone is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Pasireotide: (Major) Concomitant use of amiodarone and pasireotide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and amiodarone have been reported to prolong the QT interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. If pazopanib and amiodarone must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a substrate for CYP3A4 and P-glycoprotein (P-gp) and a weak inhibitor of CYP3A4. Amiodarone is a CYP3A4 and P-gp inhibitor and a CYP3A4 substrate. Concurrent administration may result in increased concentrations of pazopanib and/or amiodarone. Use caution if concurrent administration is necessary.
Pentamidine: (Major) Concomitant use of amiodarone and systemic pentamidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Perphenazine: (Minor) QT/QTc prolongation can occur with concomitant use of amiodarone and perphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Perphenazine; Amitriptyline: (Minor) QT/QTc prolongation can occur with concomitant use of amiodarone and perphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Phenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with amiodarone due to increased phenytoin steady-state concentrations. Concomitant use may also reduce amiodarone exposure and efficacy. Phenytoin is a CYP2C9 substrate and a strong CYP3A inducer; amiodarone is a CYP3A substrate and a CYP2C9 inhibitor.
Pimavanserin: (Major) Concomitant use of amiodarone and pimavanserin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Pimozide: (Contraindicated) Avoid concomitant use of pimozide and amiodarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Pindolol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with amiodarone is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-gp substrate; amiodarone is a P-gp inhibitor.
Pitolisant: (Major) Concomitant use of amiodarone and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Ponesimod: (Major) Concomitant use of amiodarone and ponesimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Ponesimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Porfimer: (Major) Avoid coadministration of porfimer with amiodarone due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like amiodarone may increase the risk of a photosensitivity reaction.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and amiodarone is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Both posaconazole and amiodarone are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of amiodarone. Further, amiodarone is an inhibitor of the drug efflux protein, P-glycoprotein (P-gp), for which posaconazole is a substrate and an inhibitor. This complex interaction may ultimately result in altered plasma concentrations of both posaconazole and amiodarone. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as amiodarone.
Pralsetinib: (Major) Avoid concomitant use of amiodarone with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Pretomanid: (Major) Avoid coadministration of pretomanid with amiodarone, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
Prilocaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Primaquine: (Major) Concomitant use of amiodarone and primaquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and amiodarone due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and amiodarone is a P-gp inhibitor.
Procainamide: (Major) Amiodarone may increase procainamide serum concentrations, with potential for drug toxicity. Procainamide and N-acetylprocainamide or NAPA (a pharmacologically active metabolite) serum concentrations increase by approximately 55 and 33%, respectively, during the first 7 days of concomitant amiodarone therapy. The precise pharmacokinetic mechanism of this interaction has not been elucidated, although a reduction the renal clearance of both parent and metabolite, as well as a reduction in hepatic metabolism seem likely. Additive electrophysiologic activity occurs with combination therapy and prolonged QT and QRS intervals or acceleration of preexisting ventricular tachycardia may result. Careful clinical observation of the patient as well as close monitoring of the ECG and serum procainamide and NAPA concentrations is essential with adjustment of the procainamide dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. If amiodarone is to be coadministered with procainamide, the manufacturer recommends reducing the procainamide dosage by 33%. Combination antiarrhythmic therapy is reserved for patients with refractory life-threatening arrhythmias. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Prochlorperazine: (Minor) The concomitant use of amiodarone and other drugs known to prolong the QT interval should only be done after careful assessment of risks versus benefits. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Prochlorperazine is associated with a possible risk for QT prolongation.
Promethazine: (Major) Concomitant use of amiodarone and promethazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Promethazine; Dextromethorphan: (Major) Concomitant use of amiodarone and promethazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Promethazine; Phenylephrine: (Major) Concomitant use of amiodarone and promethazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Propafenone: (Major) The use of propafenone with other antiarrhythmics has not been well-studied. Class III antiarrhythmics are associated with QT prolongation and ventricular arrhythmias, including torsades de pointes (TdP). The concurrent use of amiodarone with propafenone is not recommended by the manufacturer, In addition to potential for additive effects on cardiac conduction and repolarization, amiodarone is a CYP2D6 inhibitor and may inhibit the metabolism of propafenone (CYP2D6 substrate). In general, combination therapy with Class III and Class IC antiarrhythmics has been reported to increase the risk of proarrhythmias. In one pediatric trial, combined therapy with amiodarone and propafenone resulted in electrocardiographic abnormalities. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Propofol: (Major) In general, adverse cardiovascular effects such as hypotension and atropine-resistant bradycardia can occur in patients receiving amiodarone who subsequently are administered any general anesthetics, particularly volatile anesthetics. Due to the extremely long half-life of amiodarone, a drug interaction is also possible for days to weeks after discontinuation of amiodarone. For example, when fentanyl was administered to patients receiving amiodarone, the incidence of bradycardia and other adverse cardiovascular effects was much higher than in patients not on amiodarone who received fentanyl.
Propranolol: (Moderate) Concomitant administration of propranolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of propranolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Quetiapine: (Major) Concomitant use of amiodarone and quetiapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Quinidine: (Major) Amiodarone coadministration increases quinidine concentrations by about 33% after 2 days, by decreasing its renal clearance or by inhibiting its hepatic metabolism. Quinidine may also be displaced from tissue and protein binding sites. Prolongation of the QT interval is well documented with quinidine, and the addition of amiodarone may increase this effect, placing the patient at an increased risk for the development of torsade de pointes. Careful clinical observation of the patient as well as close monitoring of the ECG and serum quinidine concentrations are essential with adjustment of the quinidine dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. An empiric reduction of the quinidine dose by 33-50% is suggested within 2 days following initiation of amiodarone therapy, with consideration given to immediately discontinuing of quinidine once amiodarone therapy is begun. Combination antiarrhythmic therapy is reserved for patients with refractory life-threatening arrhythmias. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Quinine: (Major) Concomitant use of amiodarone and quinine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Quizartinib: (Major) Concomitant use of amiodarone and quizartinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Ranolazine: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with amiodarone is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A and P-gp substrate and amiodarone is a moderate CYP3A inhibitor and inhibitor of P-gp. Coadministration with another moderate CYP3A inhibitor increased plasma levels of ranolazine by 50% to 130%.
Rasagiline: (Moderate) Monitor for dopaminergic adverse effects during concurrent use of rasagiline and amiodarone. Coadministration may result in increased rasagiline concentrations. A dose reduction of rasagiline may be necessary. Rasagiline is primarily metabolized by CYP1A2; amiodarone is a weak CYP1A2 inhibitor.
Red Yeast Rice: (Contraindicated) As an inhibitor of hepatic CYP3A4 isoenzymes, amiodarone has the potential to increase serum concentrations of HMG-CoA reductase inhibitors that are CYP3A4 substrates. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with amiodarone. Monitor for signs and symptoms of myopathy in patients receiving amiodarone concurrently with red yeast rice.
Relugolix: (Major) Avoid concomitant use of relugolix and oral amiodarone. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer amiodarone at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of amiodarone is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Relugolix is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral amiodarone. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer amiodarone at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of amiodarone is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Relugolix is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with amiodarone due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a P-gp substrate and amiodarone is a P-gp inhibitor.
Ribociclib: (Major) Avoid coadministration of ribociclib with amiodarone due to an increased risk for QT prolongation and torsade de pointes (TdP). The systemic exposure to amiodarone may also increase resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Amiodarone, a Class III antiarrhythmic agent, is a CYP3A4 substrate that is also associated with a well-established risk of QT prolongation; although the frequency is less with amiodarone than with other Class III agents, amiodarone is additionally still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with amiodarone due to an increased risk for QT prolongation and torsade de pointes (TdP). The systemic exposure to amiodarone may also increase resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Amiodarone, a Class III antiarrhythmic agent, is a CYP3A4 substrate that is also associated with a well-established risk of QT prolongation; although the frequency is less with amiodarone than with other Class III agents, amiodarone is additionally still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Rifampin: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and rifampin. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and rifampin is a strong CYP3A inducer.
Rifapentine: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and rifapentine. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and rifapentine is a strong CYP3A inducer.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with amiodarone is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Major) Concomitant use of amiodarone and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with amiodarone; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and amiodarone is a P-gp inhibitor.
Risperidone: (Major) Concomitant use of amiodarone and risperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Ritlecitinib: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with ritlecitinib is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Major) Avoid concomitant use of amiodarone and ritonavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
Rivaroxaban: (Moderate) Avoid coadministration of rivaroxaban and amiodarone in patients with renal impairment (CrCL 15 to 79 mL/minute) unless the potential benefit justifies the potential risk. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and amiodarone is a P-gp and moderate CYP3A4 inhibitor. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A4/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCL 50 to 79 mL/minute) and by 99% in patients with moderate renal impairment (CrCL 30 to 49 mL/minute) compared to patients with normal renal function (CrCL greater than 80 mL/minute); similar trends in pharmacodynamic effects were also observed.
Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with amiodarone is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A and CYP1A2 substrate and amiodarone is a CYP3A/CYP1A2 inhibitor. Coadministration with other dual CYP3A/CYP1A2 inhibitors increased the exposure of roflumilast by 85% to 156%.
Romidepsin: (Major) Concomitant use of amiodarone and romidepsin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Saquinavir: (Contraindicated) The concurrent use of amiodarone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Amiodarone and saquinavir are both substrates and inhibitors of CYP3A4. The coadministration of saquinavir/ritonavir and amiodarone results in increased plasma concentrations of both amiodarone and saquinavir, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as all Class III antiarrhythmics.
Selpercatinib: (Major) Concomitant use of amiodarone and selpercatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Sertraline: (Major) Concomitant use of amiodarone and sertraline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Sevoflurane: (Major) Concomitant use of amiodarone and halogenated anesthetics increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Silodosin: (Major) Avoid coadministration of silodosin and amiodarone due to the potential for increased silodosin exposure. In vitro data indicate that silodosin is a P-gp substrate; amiodarone is a P-gp inhibitor.
Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amiodarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amiodarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amiodarone and simvastatin against the potential risks. Amiodarone increases the simvastatin exposure by approximately 2-fold.
Siponimod: (Major) Concomitant use of siponimod and amiodarone is not recommended due to a significant increase in siponimod exposure. Additionally, both drugs are associated with QT prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Siponimod is a CYP2C9 and CYP3A4 substrate; amiodarone is a moderate CYP2C9/CYP3A4 dual inhibitor. Coadministration with another moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amiodarone. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and amiodarone is a weak CYP3A and P-gp inhibitor.
Sodium Stibogluconate: (Major) Concomitant use of amiodarone and sodium stibogluconate increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Sofosbuvir: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting sofosbuvir should also undergo similar cardiac monitoring as outlined above.
Sofosbuvir; Velpatasvir: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting sofosbuvir should also undergo similar cardiac monitoring as outlined above.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting sofosbuvir should also undergo similar cardiac monitoring as outlined above.
Solifenacin: (Major) Concomitant use of amiodarone and solifenacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Sorafenib: (Major) Concomitant use of amiodarone and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Sotalol: (Major) Sotalol administration is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Drugs that prolong the QT interval should be used with extreme caution in combination with sotalol. Ventricular tachycardia, including torsade de pointes and monomorphic ventricular tachycardia can occur with excessive prolongation of the QT interval. Before initiating sotalol, the previous Class I and Class III antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of (2-3) plasma half-lives for the discontinued drug. Class III antiarrhythmics (e.g., amiodarone, dofetilide) are associated with QT prolongation and ventricular arrhythmias; concurrent exposure with sotalol could increase the risk of drug-induced proarrhythmias. Because of unpredictable pharmacokinetics with amiodarone, sotalol should not be initiated following discontinuation of amiodarone therapy until the QTc interval has normalized. In clinical trials, patients were not allowed to receive sotalol if they had received amiodarone for > 1 month in the previous 3 months.
St. John's Wort, Hypericum perforatum: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and St. John's wort. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and St. John's wort is a strong CYP3A inducer.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if amiodarone must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. If amiodarone is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a weak CYP3A inhibitor like amiodarone can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If amiodarone is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sunitinib: (Major) Concomitant use of amiodarone and sunitinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Tacrolimus: (Major) Amiodarone and tacrolimus both prolong the QT interval; also, both drugs are metabolized by CYP3A4, and amiodarone is also a CYP3A4 inhibitor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are subtrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of torsade de pointes may be increased.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with amiodarone is necessary. Talazoparib is a P-gp substrate and amiodarone is a P-gp inhibitor.
Tamoxifen: (Major) Concomitant use of amiodarone and tamoxifen increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Telavancin: (Major) Concomitant use of amiodarone and telavancin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with amiodarone is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with amiodarone may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and amiodarone is a P-gp inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with amiodarone may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and amiodarone is a P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Terbinafine: (Moderate) Monitor for an increase in terbinafine-related adverse reactions if coadministration with amiodarone is necessary. Terbinafine is a CYP2C9 and CYP3A substrate; amiodarone is a dual moderate CYP2C9 and weak CYP3A inhibitor. Coadministration with a moderate CYP2C9 and moderate CYP3A inhibitor increased the Cmax and AUC of terbinafine by 52% and 69%, respectively.
Tetrabenazine: (Major) Concomitant use of amiodarone and tetrabenazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Thalidomide: (Moderate) Thalidomide and other agents that cause peripheral neuropathy such as amiodarone should be used cautiously due to the potential for additive effects.
Theophylline, Aminophylline: (Moderate) Amiodarone inhibits cytochrome P450 CYP1A2 isoenzymes, which can potentially lead to increased plasma concentrations of CYP1A2 substrates like aminophylline. (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with amiodarone is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and amiodarone is a CYP1A2 inhibitor.
Thioridazine: (Contraindicated) Avoid concomitant use of thioridazine and amiodarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Thyroid hormones: (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with amiodarone as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and amiodarone is a P-gp inhibitor.
Timolol: (Moderate) Concomitant administration of timolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of timolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Tipranavir: (Contraindicated) Coadministration of tipranavir and amiodarone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Tipranavir inhibits the CYP3A4 metabolism of amiodarone resulting in elevated amiodarone plasma concentrations.
Tizanidine: (Major) Avoid concomitant use of tizanidine and amiodarone as increased tizanidine exposure may occur. If use together is necessary, initiate tizanidine at 2 mg and increase by 2 to 4 mg/day based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate and amiodarone is a weak CYP1A2 inhibitor.
Tolterodine: (Major) Concomitant use of amiodarone and tolterodine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Topotecan: (Major) Avoid coadministration of amiodarone with oral topotecan due to increased topotecan exposure; amiodarone may be administered with intravenous topotecan. Coadministration increases the risk of topotecan-related adverse reactions. Oral topotecan is a P-gp substrate and amiodarone is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Toremifene: (Major) Concomitant use of amiodarone and toremifene increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Tramadol: (Moderate) Concurrent use of tramadol with amiodarone may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A; amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Tramadol; Acetaminophen: (Moderate) Concurrent use of tramadol with amiodarone may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A; amiodarone is a dual weak CYP2D6 and weak CYP3A inhibitor. CYP3A inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with amiodarone. Coadministration may increase the exposure of verapamil. Additive effects on cardiac contractility and/or AV conduction are also possible. Verapamil is a substrate of CYP3A4 and amiodarone is a moderate CYP3A4 inhibitor.
Trazodone: (Major) Concomitant use of amiodarone and trazodone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with amiodarone. Coadministration may increase the exposure of triazolam. Triazolam is a sensitive CYP3A substrate and amiodarone is a weak CYP3A inhibitor.
Triclabendazole: (Major) Concomitant use of amiodarone and triclabendazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Trifluoperazine: (Minor) The concomitant use of amiodarone and other drugs known to prolong the QT interval should only be done after careful assessment of risks versus benefits. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Triptorelin: (Major) Concomitant use of amiodarone and androgen deprivation therapy (i.e., triptorelin) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Tucatinib: (Major) Avoid concomitant use of amiodarone and tucatinib due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with amiodarone. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-gp substrate; amiodarone is a moderate CYP3A4 inhibitor and a P-gp inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Vandetanib: (Major) Concomitant use of amiodarone and vandetanib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Vardenafil: (Major) Concomitant use of amiodarone and vardenafil increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Vemurafenib: (Major) Concomitant use of amiodarone and vemurafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with amiodarone due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of amiodarone. Venetoclax is a P-gp substrate; amiodarone is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Venlafaxine: (Major) Concomitant use of amiodarone and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with amiodarone. Coadministration may increase the exposure of verapamil. Additive effects on cardiac contractility and/or AV conduction are also possible. Verapamil is a substrate of CYP3A4 and amiodarone is a moderate CYP3A4 inhibitor.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with amiodarone is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like amiodarone may increase the risk of a photosensitivity reaction.
Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of amiodarone is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and amiodarone is a P-gp inhibitor.
Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of amiodarone is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and amiodarone is a P-gp inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amiodarone is necessary. Vinorelbine is a CYP3A substrate and amiodarone is a weak CYP3A inhibitor.
Voclosporin: (Major) Concomitant use of amiodarone and voclosporin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with voclosporin is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of amiodarone and clarithromycin due to increased amiodarone exposure and an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Voriconazole: (Major) Avoid coadministration of amiodarone and voriconazole due to the potential for increased amiodarone concentrations and additive effects on the QT interval. There have been reports of prolonged QT intervals, with or without torsade de pointes (TdP), during concomitant use of amiodarone and azole antifungals. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Voriconazole has also been associated with QT prolongation and rare cases of TdP, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with amiodarone (a CYP3A4 substrate) may result in elevated amiodarone plasma concentrations and could further increase the risk for adverse events, including QT prolongation. Similarly, amiodarone may inhibit the CYP2C9 metabolism of voriconazole, and could theoretically lead to elevated plasma concentrations of voriconazole when coadministered. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Vorinostat: (Major) Concomitant use of amiodarone and vorinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Voxelotor: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with voxelotor is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Major) Closely monitor the INR if coadministration of warfarin with amiodarone is necessary as concurrent use results in at least a doubling of prothrombin time, significantly increasing the INR in virtually all patients and can cause serious or potentially fatal hemorrhagic complications. Consider an empiric 33% to 50% reduction in warfarin dosage when amiodarone therapy is initiated. Intensive clinical observation for bleeding and frequent determination of PT and INR values are warranted. Amiodarone is a moderate CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. Amiodarone is also a CYP3A4/CYP1A2 inhibitor, and the R-enantiomer is a CYP3A4/CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Interactions may be seen as early as 4 to 6 days or as delayed as weeks following the initial administration of the drugs in combination. Given the extremely long half-life of amiodarone, the interaction may persist for weeks or even months after discontinuation of amiodarone.
Ziprasidone: (Contraindicated) Avoid concomitant use of ziprasidone and amiodarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
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. Since approximately 37% of amiodarone (by weight) is iodine, a maintenance dose of 200 to 600 mg/day results in a daily intake of organic iodide of 75 to 225 mg, at least 10% of which is deiodinated. Because the normal dietary requirement of iodine is less than 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.
Amiodarone is administered orally and intravenously. The therapeutic range is considered to be roughly 1 to 2.5 mcg/mL, although an absolute relationship between serum concentration and pharmacodynamic effect has not been established.
Once in the systemic circulation, amiodarone distributes extensively throughout the body including into adipose, hepatic, myocardial, pulmonary, kidney, thyroid, skin, ocular, splenic and pancreatic tissues, and concentrates in fluids including bile, semen, and saliva. As a reflection of its extensive distribution in the body, the volume of distribution averages approximately 70 L/kg. It is the extensive accumulation of amiodarone (especially in adipose tissue) which accounts for its prolonged elimination, as well as the persistence of adverse effects after discontinuation of therapy. The principle metabolite of amiodarone (DEA) distributes into the same tissues as the parent drug, albeit to a lesser extent in adipose tissue. Both amiodarone and DEA distribute into and concentrate in breast milk. Amiodarone and DEA are extensively bound (more than 99%) to plasma proteins, primarily albumin and alpha-1 acid glycoprotein.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6, P-gp, OCT2
Amiodarone is extensively metabolized in the liver. N-desethyl-amiodarone (DEA) is the major active metabolite 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 is metabolized to N-desethyl-amiodarone by the cytochrome P450 (CYP450) enzyme group, specifically CYP3A4 and CYP2C8. The highly variable systemic availability of oral amiodarone may be attributed to large interindividual variability in CYP3A4 activity. In vitro, amiodarone and DEA show potential to inhibit CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6, and CYP2C8. Amiodarone and DEA also have the potential to inhibit P-glycoprotein (P-gp) and organic cation transporter (OCT2). Therefore, amiodarone has the potential to interact with substrates affected by these pathways.
Amiodarone and DEA are virtually exclusively eliminated hepatically, although biliary excretion may play a small role in the excretion of amiodarone. 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 10 days. The terminal elimination half-life ranges from 26 to 107 days with a mean of around 53 days.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration, amiodarone is absorbed incompletely and slowly from the GI tract, with the absolute bioavailability ranging from 20% to 86%, but averages approximately 50%. Amiodarone may undergo metabolism in the intestinal lumen and GI mucosa and first pass metabolism in the liver, all of which occur to a variable degree, possibly explaining the variability in bioavailability. The highly variable systemic availability of oral amiodarone also may be attributed to large interindividual variability in CYP3A4 activity. A single oral dose of 400 mg of amiodarone achieves peak plasma concentrations within 3 to 7 hours. Steady state plasma concentrations are generally not reached for 1 to 5 months after continuous oral administration, with the onset of action delayed for as long as 2 to 3 months, unless aggressive loading doses are utilized.
-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.
Geriatric
Elderly subjects aged older than 65 years have a slower clearance of amiodarone compared to younger adults, with a prolongation in half-life from about 20 days to 47 days.