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    Anti-arrhythmics, Class III

    BOXED WARNING

    Apheresis, arrhythmia exacerbation, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, requires an experienced clinician, rheumatoid arthritis, sick sinus syndrome, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    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.[28224] [52809] 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.[28432] [28457] [56592] 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.[28224] [52809] 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.[28224] [52809] 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.[28224] 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.[52809]

    Amiodarone-induced lung toxicity, chronic obstructive pulmonary disease (COPD), pneumonitis, pulmonary disease, pulmonary fibrosis, respiratory distress syndrome, respiratory insufficiency, surgery

    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.[28224] [52809]

    Amiodarone-induced liver toxicity, hepatic disease, hepatitis, hepatotoxicity

    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.[28224] 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.[52809]

    DEA CLASS

    Rx

    DESCRIPTION

    Class III antiarrhythmic agent
    Used for ventricular and supraventricular tachyarrhythmias
    Risk of proarrhythmias less than other antiarrhythmics

    COMMON BRAND NAMES

    Cordarone, Nexterone, Pacerone

    HOW SUPPLIED

    Amiodarone/Amiodarone Hydrochloride/Cordarone/Nexterone Intravenous Inj Sol: 1mL, 50mg, 100mL, 150mg, 200mL, 360mg
    Amiodarone/Amiodarone Hydrochloride/Cordarone/Pacerone Oral Tab: 100mg, 200mg, 400mg

    DOSAGE & INDICATIONS

    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.[63999] Guidelines recommend amiodarone for patients who are unresponsive to CPR, defibrillation, and a vasopressor.[45649] [60266] [63999]

    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.[45649] [60266]

    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.[43713] [60636] [64000]

    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, followed by 1 mg/minute continuous IV infusion for 6 hours then 0.5 mg/minute continuous IV infusion for 18 hours. After 24 hours, change to oral dosing or consider decreasing rate to 0.25 mg/minute. Clinical practice 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.

    Neonates, Infants, Children, and Adolescents

    5 mg/kg/dose IV as a bolus/loading dose infused over 1 hour followed by a continuous infusion of 5 mcg/kg/minute IV titrated to a maximum of 15 mcg/kg/min IV. A second bolus ranging from 1 to 5 mg/kg/dose has been administered to some patients (Max initial bolus: 10 mg/kg IV). Dosing protocols administering the bolus dose in smaller aliquots of 1 to 2 mg/kg/dose IV over 5 to 10 minutes 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. Clinical practice 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. Results from the SAFE-T trial indicate the superiority of amiodarone over sotalol for maintaining sinus rhythm in patients with persistent atrial fibrillation. 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 mg/kg/day PO for 7 to 10 days followed by 3 to 5 mg/kg/day PO once daily has been used in 13 patients ranging in age from 2 years to 15 years. Combination therapy with propranolol was used in 2 patients; ten of 13 patients had complete response to therapy. In another report, amiodarone 10 mg/kg PO for 10 days followed-up by a maintenance dose of 5 mg/kg/day (7.5 mg/kg/day in children younger than 2 years) was administered. The dose was maintained for at least 1 month and if the arrhythmia did not recur, attempts to decrease the dose were made every 3 to 4 months. Once a stable dose was achieved, it was administered 5 days/week. If amiodarone was initially effective but the arrhythmia later recurred, the dose was titrated up to a max of 25 mg/kg/day. The mean maintenance dose was 7.7 mg/kg/day (range 1.5 to 25 mg/kg/day) with a mean duration of therapy of 2.3 years. Alternatively, an initial dose of 800 mg/1.73 m2 PO per day for 2 weeks has been used, followed by 400 mg/1.73 m2 PO per day, given 5 days per week. Patients received the drug for an average of 4.1 months with partial or complete response occurring in 93% of patients. 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 and Infants

    A loading dose of 10 or 20 mg/kg/day PO divided twice daily for 7 to 10 days followed-up by a maintenance dose of 5 to 20 mg/kg/day PO has been administered. Propranolol (2 to 4 mg/kg/day) was added in patients who did not initially respond to amiodarone. In one study, the dose for the load was given at the discretion of the treating physician, but those infants with tachycardias that were difficult to control were typically given the higher dose. In another study, the mean initial doses for arrhythmia suppression and maintenance based on body weight and body surface area in patients younger than 1 year of age with various arrhythmias were 15.3 mg/kg/day and 8.2 mg/kg/day and 261 mg/m2/day and 204 mg/m2/day, respectively. These doses were significantly higher than doses required in patients older than 1 year of age 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. Alternatively, an initial dose of 800 mg/1.73 m2 PO per day for 2 weeks, followed-up by 400 mg/1.73 m2 PO per day given 5 days per week, has been used in a study in pediatric patients with various arrhythmias (n = 135, age 0 to 15 years). 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 patients 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 heart failure patients, its effect on mortality remains inconclusive. Because of the neutral effects on mortality, guidelines recommend the use of amiodarone for the treatment of arrhythmias in patients with heart failure.

    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).

    †Indicates off-label use

    MAXIMUM DOSAGE

    No specific maximum dosage guidelines are available. Amiodarone dosage is individualized according to clinical goals, phase of dosage titration, and close monitoring of efficacy and safety parameters.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.[28224]

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    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.[52902]

    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.[45649] [55927] For pediatric patients with pulseless ventricular tachycardia or fibrillation, amiodarone may be given undiluted.[64934] 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.[52887]
    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.[52809]
    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.[64020]
    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.[52809] [52887]
    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.[52809]
    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.[52809] Nexterone premixed solution is for single-use only; discard any unused portion.[52887]
     
    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.[52809]
    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.[52868] Nexterone premixed containers do not contain polysorbate 80.[52887]
    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.[52887]
     
    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.[43713] [45649] [60636] 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.[52809] [52887]
    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.

    STORAGE

    Cordarone:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Nexterone:
    - Avoid excessive heat (above 104 degrees F)
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from freezing
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in carton until time of use
    Pacerone:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Iodine hypersensitivity

    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.[28224] [52809]

    Cardiogenic shock, heart failure, hypotension, hypovolemia, ventricular dysfunction

    Amiodarone is contraindicated for use in cardiogenic shock due to its adverse effect profile which includes hypotension, heart failure, and cardiogenic shock.[28224] [52809] 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%).[26331] [32361] [32365] [32885] 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.[52809] Rare episodes of hypotension occurring upon the discontinuation of cardiopulmonary bypass have been reported in patients receiving amiodarone.[28224]

    Goiter, hyperthyroidism, hypothyroidism, thyroid disease, thyrotoxicosis

    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.[28224] [52809]

    Apheresis, arrhythmia exacerbation, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, requires an experienced clinician, rheumatoid arthritis, sick sinus syndrome, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    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.[28224] [52809] 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.[28432] [28457] [56592] 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.[28224] [52809] 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.[28224] [52809] 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.[28224] 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.[52809]

    Amiodarone-induced lung toxicity, chronic obstructive pulmonary disease (COPD), pneumonitis, pulmonary disease, pulmonary fibrosis, respiratory distress syndrome, respiratory insufficiency, surgery

    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.[28224] [52809]

    Amiodarone-induced liver toxicity, hepatic disease, hepatitis, hepatotoxicity

    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.[28224] 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.[52809]

    Diarrhea, electrolyte imbalance

    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.

    Ocular surgery, optic neuritis, visual disturbance

    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.[28224] [52887] [52809] Most manufacturers of corneal refractive laser surgery devices contraindicate the use of this type of ocular surgery in patients taking amiodarone.[52887] [52809]

    Geriatric

    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. Elderly patients may be more sensitive to the thyrotoxic and neurotoxic effects of amiodarone. Insufficient data are available to evaluate the dose-response of amiodarone in elderly 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 (PIM) in geriatric patients; avoid as first-line treatment of atrial fibrillation unless the patient has heart failure or substantial left ventricular hypertrophy. Amiodarone is effective for maintaining sinus rhythm but has greater toxicities than other antiarrhythmics used for atrial fibrillation. Amiodarone may be a reasonable first-line agent in patients with concomitant heart failure or substantial left ventricular hypertrophy if rhythm control is preferred over rate control. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs); antiarrhythmics can have serious adverse effects (e.g., impairment of mental function, appetite, behavior, heart function, or falls) in older individuals. The literature suggests that in many higher risk individuals, alternative approaches for treating atrial fibrillation are equally effective and less toxic. It is essential to carefully consider risks and benefits, use the lowest possible dose for the shortest possible duration, closely monitor patients receiving long-term treatments, and seek and identify adverse consequences. Toxicity increases with higher doses and longer duration of use. Clinically significant interactions may occur, such as with digoxin or warfarin.

    Neurological disease, peripheral neuropathy

    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.

    Sunlight (UV) exposure

    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.

    Halothane anesthesia

    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.[28224] [52809]

    Children, infants, neonates

    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.[52868] 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.[52809] This warning is not associated with Nexterone, a formulation of amiodarone injection that is free of polysorbate 80 and benzyl alcohol.[52887]

    Pregnancy

    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.

    Breast-feeding

    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.

    Infertility

    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.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 2.5-20.0
    AV block / Early / 15.0-15.0
    cardiac arrest / Early / 2.0-4.0
    ventricular tachycardia / Early / 2.4-2.4
    ventricular fibrillation / Early / 0-2.0
    atrial fibrillation / Early / 0-2.0
    pulmonary edema / Early / 0-2.0
    Stevens-Johnson syndrome / Delayed / 0-2.0
    hepatic failure / Delayed / 0-1.0
    arrhythmia exacerbation / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    heart failure / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    bronchiolitis obliterans / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known
    pulmonary toxicity / Early / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    optic neuritis / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    cyanosis / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    periarteritis / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    thrombosis / Delayed / Incidence not known
    akinesia / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    epididymitis / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    hypotension / Rapid / 4.0-70.0
    hypothyroidism / Delayed / 2.0-10.0
    hyperthyroidism / Delayed / 1.0-3.0
    QT prolongation / Rapid / 0-2.0
    thrombocytopenia / Delayed / 0-2.0
    blurred vision / Early / 0-1.0
    elevated hepatic enzymes / Delayed / 10.0
    corneal deposits / Delayed / 10.0
    constipation / Delayed / 10.0
    edema / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    hemoptysis / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    hypoxia / Early / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    thyrotoxicosis / Delayed / Incidence not known
    goiter / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    erythema / Early / Incidence not known
    confusion / Early / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    delirium / Early / Incidence not known
    pseudotumor cerebri / Delayed / Incidence not known
    involuntary movements / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 25.0-25.0
    fever / Early / 2.0-2.0
    diarrhea / Early / 0-2.0
    photosensitivity / Delayed / 10.0
    vomiting / Early / 10.0
    anorexia / Delayed / 10.0
    nausea / Early / 10.0
    abdominal pain / Early / 10.0
    flushing / Rapid / Incidence not known
    cough / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    dizziness / Early / Incidence not known
    insomnia / Early / Incidence not known
    headache / Early / Incidence not known
    fatigue / Early / Incidence not known
    tremor / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    skin discoloration / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    ecchymosis / Delayed / Incidence not known
    rash / Early / Incidence not known
    xerostomia / Early / Incidence not known
    weakness / Early / Incidence not known
    libido decrease / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Contraindicated) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation including amiodarone.
    Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with amiodarone is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with amiodarone. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    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: (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.
    Acetaminophen; Caffeine: (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.
    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 dihydrocodeine. 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 CYP3A4. Amiodarone is a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (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.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (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.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (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.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. (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; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    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; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (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 CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amiodarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Acetaminophen; Dextromethorphan: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. (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; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. (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; Pseudoephedrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    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 CYP3A4 substrate, and coadministration with a moderate inhibitor 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; Propoxyphene: (Moderate) Propoxyphene is a substrate and an inhibitor of CYP2D6. Increased serum concentrations of propoxyphene would be expected from concurrent use of a CYP2D6 inhibitor, such as amiodarone.
    Aclidinium; Formoterol: (Moderate) 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. The use of amiodarone with other drugs known to prolong the QT interval, such as the long-acting beta-agonists, should only be done after careful assessment of risks versus benefits. Long-acting beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. 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 and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Albuterol: (Minor) 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 Short-acting beta-agonists may rarely be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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) 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. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. The manufacturer warns that the QT effect of alfuzosin should be considered prior to administering the drug to patients taking other medications known to prolong the QT interval. In addition, alfuzosin is primarily metabolized by CYP3A4 hepatic enzymes and amiodarone is a CYP3A4 inhibitor. Concurrent use may increase systemic exposure to alfuzosin and further increase the risk for QT prolongation.
    Aliskiren; Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics. (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    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 CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    Amisulpride: (Major) Avoid coadministration of amisulpride with amiodarone due to the risk of QT prolongation. Amisulpride causes dose- and concentration- dependent 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.
    Amitriptyline: (Major) If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Carefully asses treatmentt risks versus benefits. Amiodarone is associated with a well-established risk of QT prolongation and torsade de pointes (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 prolongationthat should be used cautiously with amiodarone include tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations) or in patients with other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of such combined therapies.
    Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Atorvastatin: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored. (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.
    Amlodipine; Benazepril: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Celecoxib: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored. (Minor) Since celecoxib is metabolized by cytochrome P450 2C9, concurrent administration with amiodarone, which can inhibit this enzyme, may result in increased levels of celecoxib. The clinical significance of this interactions has not been established.
    Amlodipine; Olmesartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Valsartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics. (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as amiodarone, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when amiodarone is coadministered with amlodipine; therapeutic response should be monitored.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). 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. If possible, avoid coadministration of amiodarone and clarithromycin. 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.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including amphotericin B.
    Amphotericin B lipid complex (ABLC): (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including amphotericin B.
    Amphotericin B liposomal (LAmB): (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including amphotericin B.
    Amphotericin B: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including amphotericin B.
    Amprenavir: (Major) Amprenavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as amiodarone, should be expected with concurrent use. Therapeutic monitoring of amiodarone concentrations is recommended.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include amiodarone.
    Apalutamide: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with apalutamide is necessary. Amiodarone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration may decrease amiodarone plasma concentrations.
    Apixaban: (Moderate) Use apixaban and amiodarone together with caution, especially in patients with significant renal dysfunction, as risk of bleeding may be increased. Amiodarone is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. One cohort study found an increased risk of major bleeding when amiodarone and a non-vitamin K oral anticoagulant were used together. The combination was associated with an adjusted incidence rate difference for major bleeding of 13.94 events per 1,000 person-years (99% CI, 9.76 to 18.13).
    Apomorphine: (Major) The concomitant use of amiodarone and other drugs known to prolong the QT interval, including apomorphine, should only be done after careful assessment of risks versus benefits. 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. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of amiodarone, a moderate CYP3A4 inhibitor, and aprepitant/fosaprepitant, a CYP3A4 substrate, due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Increased amiodarone exposure may also occur with multi-day regimens of oral aprepitant, resulting in increased amiodarone-related adverse reactions, including QT prolongation. Amiodarone is a CYP3A4 substrate and aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
    Arformoterol: (Moderate) 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. The use of amiodarone with other drugs known to prolong the QT interval, such as the long-acting beta-agonists, should only be done after careful assessment of risks versus benefits. Long-acting beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aripiprazole: (Major) Because both amiodarone and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as amiodarone. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of mild to moderate CYP3A4 and CYP2D6 inhibitors.
    Arsenic Trioxide: (Major) 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). QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. If possible, avoid coadministration or discontinue drugs that are known to prolong the QT interval prior to initiating arsenic trioxide therapy. 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.
    Artemether; Lumefantrine: (Major) Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with other drugs that prolong the QT interval such as amiodarone should be avoided. Consider ECG monitoring if amiodarone must be used with or after artemether; lumefantrine treatment. 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. Additionally, amiodarone is a substrate and inhibitor of the CYP3A4 isoenzyme. Both components of artemether; lumefantrine are CYP3A4 substrates; therefore, concomitant use may increase the serum concentrations of artemether; lumefantrine, thereby potentiating QT prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    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) Avoid coadministration of amiodarone and asenapine. Both agents have been associated with QT prolongation and coadministration may result in additive effects on the QT interval. In addition, in vitro studies indicate that CYP1A2 is a primary metabolic pathway of asenapine. Inhibitors of this isoenzyme, such as amiodarone, may decrease the elimination of asenapine.
    Aspirin, ASA; Butalbital; Caffeine: (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.
    Aspirin, ASA; Butalbital; 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 CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amiodarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (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.
    Aspirin, ASA; Caffeine: (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.
    Aspirin, ASA; 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 dihydrocodeine. 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 CYP3A4. Amiodarone is a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (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.
    Aspirin, ASA; Caffeine; Orphenadrine: (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.
    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 CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amiodarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 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 CYP3A4 substrate, and coadministration with a moderate inhibitor 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) Therapeutic monitoring of amiodarone concentrations is recommended when administered concurrently with atazanavir. If atazanavir is boosted with ritonavir, concurrent use of amiodarone is contraindicated. Use of all 3 drugs together may significantly increase amiodarone concentrations and increase the risk for serious or life-threatening cardiac arrhythmias. Atazanavir and ritonavir are CYP3A4 inhibitors; amiodarone is metabolized by this enzyme.
    Atazanavir; Cobicistat: (Major) Therapeutic monitoring of amiodarone concentrations is recommended when administered concurrently with atazanavir. If atazanavir is boosted with ritonavir, concurrent use of amiodarone is contraindicated. Use of all 3 drugs together may significantly increase amiodarone concentrations and increase the risk for serious or life-threatening cardiac arrhythmias. Atazanavir and ritonavir are CYP3A4 inhibitors; amiodarone is metabolized by this enzyme. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of amiodarone with cobicistat. Amiodarone is a substrate and inhibitor of CYP3A4 and an inhibitor CYP2D6, cobicistat is a substrate and strong inhibitor of CYP3A and CYP2D6. Concurrent use may result in elevated concentration of both drugs.
    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: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics. (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) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Both atomoxetine and amiodarone are considered drugs with a possible risk of torsade de pointes (TdP); therefore, the combination should be used cautiously and with close monitoring. In addition, because atomoxetine is primarily metabolized by CYP2D6, concurrent use of CYP2D6 inhibitors such as amiodarone may theoretically increase the risk of atomoxetine-induced adverse effects. Monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation).
    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.
    Atorvastatin; Ezetimibe: (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.
    Avanafil: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including amiodarone, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Avapritinib: (Major) Avoid coadministration of avapritinib with amiodarone due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
    Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), reduce the starting dose of avatrombopag to 20 mg PO 3 times weekly when used concomitantly with amiodarone. In patients starting amiodarone while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inhibitors such as amiodarone increase avatrombopag exposure, increasing the risk of avatrombopag toxicity.
    Azilsartan; Chlorthalidone: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    Azithromycin: (Major) Concomitant use of azithromycin 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.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when coadministering bedaquiline and amiodarone. Both drugs are associated with QT prolongation. Furthermore, amiodarone may inhibit the CYP3A4 metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline electrocardiogram (ECG). An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as amiodarone, may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    Bendamustine: (Major) Consider the use of an alternative therapy if amiodarone treatment is needed in patients receiving bendamustine. 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.
    Bendroflumethiazide; Nadolol: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics. (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.
    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: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking amiodarone. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, consider serial measurement of amiodarone serum concentrations as coadministration may increase amiodarone concentrations resulting in amiodarone-related adverse events. Berotralstat is a P-gp substrate and moderate CYP3A4 inhibitor; amiodarone is a CYP3A4 substrate and P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
    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. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; amiodarone inhibits P-gp.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole 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.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole 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.
    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: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics. (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.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering amiodarone with boceprevir due to an increased potential for serious and/or life-threatening amiodarone-related adverse events. If amiodarone dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of amiodarone and boceprevir. Both amiodarone and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. Additionally amiodarone is an inhibitor of P-glycoprotein (PGP), an efflux transporter partially responsible for the metabolism of boceprevir. When used in combination, the plasma concentrations of both medications may be elevated.
    Bortezomib: (Minor) Amiodarone inhibits CYP3A4 and may increase the exposure to bortezomib and increase the risk for toxicity.
    Bosentan: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including amiodarone.
    Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Amiodarone is a moderate inhibitor of CYP3A4. If amiodarone is used in combination with brexpiprazole and a moderate to strong CYP2D6 inhibitor, the brexpiprazole dose should be reduced and the patient should be carefully monitored for brexpiprazole-related adverse reactions. A reduction of the brexpiprazole dose to 25% of the usual dose is also recommended in patients who are poor metabolizers of CYP2D6 and are receiving a moderate CYP3A4 inhibitor.
    Brigatinib: (Major) Avoid coadministration of brigatinib with amiodarone if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of amiodarone, resume the brigatinib dose that was tolerated prior to initiation of amiodarone. Brigatinib is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    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.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of amiodarone. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; amiodarone is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
    Brompheniramine; Carbetapentane; 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; Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. (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; Guaifenesin; 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.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (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.
    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.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Budesonide: (Major) Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia, including corticosteroids. Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy.
    Budesonide; Formoterol: (Major) Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia, including corticosteroids. Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. (Moderate) 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. The use of amiodarone with other drugs known to prolong the QT interval, such as the long-acting beta-agonists, should only be done after careful assessment of risks versus benefits. Long-acting beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Budesonide; Glycopyrrolate; Formoterol: (Major) Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia, including corticosteroids. Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. (Moderate) 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. The use of amiodarone with other drugs known to prolong the QT interval, such as the long-acting beta-agonists, should only be done after careful assessment of risks versus benefits. Long-acting beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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; 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) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Antiarrhythmics with an established risk for QT prolongation and TdP include disopyramide, flecainide, propafenone, quinidine (including dextromethorphan; quinidine), procainamide, amiodarone, ibutilide, and sotalol. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as amiodarone may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Buprenorphine; Naloxone: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Antiarrhythmics with an established risk for QT prolongation and TdP include disopyramide, flecainide, propafenone, quinidine (including dextromethorphan; quinidine), procainamide, amiodarone, ibutilide, and sotalol. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as amiodarone may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Buspirone: (Moderate) CYP3A4 inhibitors, such as amiodarone,may decrease systemic clearance of buspirone leading to increased or prolonged effects. If this combination is used, a low dose of buspirone, such as 2.5 mg PO twice daily, is recommended initially. Subsequent dosage adjustments should be based on clinical response.
    Butalbital; Acetaminophen; Caffeine: (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.
    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 CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amiodarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (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.
    Cabotegravir; Rilpivirine: (Major) The concomitant use of amiodarone and rilpivirine should only be done after careful assessment of risks versus benefits. If possible, avoid coadministration. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR 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.
    Caffeine: (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: (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.
    Candesartan; Hydrochlorothiazide, HCTZ: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    Carbamazepine: (Moderate) Adjust amiodarone and carbamazepine doses as needed based on efficacy and tolerability. Consider monitoring amiodarone serum concentrations during concurrent use. Coadministration of amiodarone and carbamazepine may result in decreased amiodarone exposure and/or increased carbamazepine exposure. Carbamazepine is a CYP3A4 substrate and strong CYP3A4 inducer; amiodarone is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbetapentane; Phenylephrine; Pyrilamine: (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.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Carbinoxamine; Hydrocodone; Phenylephrine: (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. (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.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (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.
    Carbinoxamine; 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.
    Cariprazine: (Moderate) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Amiodarone is an inhibitor of CYP3A4 and may reduce the hepatic metabolism of CYP3A4 substrates, although the impact of moderate CYP3A4 inhibitors on cariprazine metabolism has not been studied. Monitoring for adverse effects, such as CNS effects and extrapyramidal symptoms, is advisable during coadministration.
    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) 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. In addition, amiodarone is an inhibitor of CYP2D6, CYP2C9, and P-glycoprotein. Carvedilol is a substrate of CYP2D6, CYP2C9, and P-glycoprotein. Concomitant administration of amiodarone and carvedilol increased the concentration of the S(-) enantiomer of carvedilol by at least 2-fold. Caution is advised as metoprolol, another beta-blocker metabolized by CYP2D6, in combination with amiodarone has resulted in severe sinus bradycardia. While the combination 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. Patients receiving amiodarone concurrently with carvedilol should be monitored for bradycardia or heart block, especially when one agent is added to pre-existing treatment with the other.
    Celecoxib: (Minor) Since celecoxib is metabolized by cytochrome P450 2C9, concurrent administration with amiodarone, which can inhibit this enzyme, may result in increased levels of celecoxib. The clinical significance of this interactions has not been established.
    Cenobamate: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with cenobamate is necessary; concomitant use may decrease amiodarone plasma concentrations. Amiodarone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
    Ceritinib: (Major) Avoid coadministration of amiodarone with ceritinib if possible due to the risk of QT prolongation; exposure to amiodarone may also be increased. Because amiodarone has an extremely long half-life, an interaction is possible for days to weeks after discontinuation of amiodarone. If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; also consider serial measurement of amiodarone serum concentrations. An interruption of ceritinib therapy, dose reduction, or discontinuation of ceritinib therapy may be necessary if QT prolongation occurs. Amiodarone, a Class III antiarrhythmic agent, is a CYP3A4 substrate associated with a well-established risk of QT prolongation; although the frequency of torsade de pointes (TdP) is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Ceritinib is a strong CYP3A4 inhibitor associated with concentration-dependent QT prolongation.
    Cerivastatin: (Contraindicated) Amiodarone may inhibit hepatic CYP3A4 isoenzymes, and therefore has the potential to increase serum concentrations of cerivastatin. Monitor for signs and symptoms of myopathy in patients receiving amiodarone concurrently with these HMG-CoA reductase inhibitors.
    Chlophedianol; 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.
    Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as amiodarone, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Chlordiazepoxide; Amitriptyline: (Major) If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Carefully asses treatmentt risks versus benefits. Amiodarone is associated with a well-established risk of QT prolongation and torsade de pointes (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 prolongationthat should be used cautiously with amiodarone include tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations) or in patients with other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of such combined therapies. (Moderate) CYP3A4 inhibitors, such as amiodarone, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Chlordiazepoxide; Clidinium: (Moderate) CYP3A4 inhibitors, such as amiodarone, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Chloroquine: (Major) Avoid coadministration of chloroquine with amiodarone due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. 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.
    Chlorothiazide: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    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 CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amiodarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Dextromethorphan: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. (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; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (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 dihydrocodeine. 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 CYP3A4. Amiodarone is a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-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.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (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 dihydrocodeine. 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 CYP3A4. Amiodarone is a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (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; 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; Hydrocodone; Phenylephrine: (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. (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; Pseudoephedrine: (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; Ibuprofen; Pseudoephedrine: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including ibuprofen. The metabolism of ibuprofen may be decreased.
    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) Phenothiazines have been associated with a risk of QT prolongation and/or torsade de pointes (TdP). This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine. Agents that prolong the QT interval could lead to torsade de pointes when combined with a phenothiazine, and therefore are generally not recommended for combined use. 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.
    Chlorthalidone: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    Chlorthalidone; Clonidine: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics. (Moderate) Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate including amiodarone. Monitor for potential bradycardia or atrioventricular block during coadministration.
    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.
    Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with amiodarone, and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate. Amiodarone is a moderate CYP3A4 inhibitor both in vitro and in vivo. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%.
    Cimetidine: (Moderate) Cimetidine may decrease the CYP3A4 metabolism of amiodarone, potentially resulting in increased plasma concentrations of amiodarone and the active metabolite.
    Cinacalcet: (Moderate) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Therefore, caution is recommended when coadministering cinacalcet with other CYP3A4 enzyme inhibitors, such as amiodarone.
    Ciprofloxacin: (Major) Concomitant use of ciprofloxacin 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.
    Cisapride: (Contraindicated) Post-marketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Amiodarone has the potential to inhibit the metabolism of cisapride through CYP3A4 and thus, should not be used with cisapride. In addition, 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.
    Citalopram: (Major) Concomitant use of citalopram 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.
    Clarithromycin: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). 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. If possible, avoid coadministration of amiodarone and clarithromycin. 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.
    Clofazimine: (Major) Avoid coadministration of amiodarone and clofazimine due to the risk of additive QT prolongation and torsade de pointes (TdP). If coadministration is necessary, monitor ECGs for QT prolongation. 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. QT prolongation and TdP have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clomipramine: (Major) If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Carefully asses treatmentt risks versus benefits. Amiodarone is associated with a well-established risk of QT prolongation and torsade de pointes (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 prolongationthat should be used cautiously with amiodarone include tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations) or in patients with other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of such combined therapies.
    Clonazepam: (Moderate) Amiodarone is a CYP3A4 inhibitor and may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity.
    Clonidine: (Moderate) Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate including amiodarone. Monitor for potential bradycardia or atrioventricular block during coadministration.
    Clorazepate: (Moderate) Amiodarone is a CYP3A4 inhibitor and may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity.
    Clozapine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as amiodarone. In addition, amiodarone is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP2D6 or CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of amiodarone with cobicistat. Amiodarone is a substrate and inhibitor of CYP3A4 and an inhibitor CYP2D6, cobicistat is a substrate and strong inhibitor of CYP3A and CYP2D6. Concurrent use may result in elevated concentration of both drugs.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic amiodarone therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of amiodarone is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of amiodarone, resume cobimetinib at the previous dose. Use an alternative to amiodarone in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; amiodarone is a moderate inhibitor of both P-gp and CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
    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 CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amiodarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 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 CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amiodarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 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 CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amiodarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Phenylephrine; Promethazine: (Major) 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, especially when the coadministered agent might decrease the metabolism of amiodarone. 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. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with amiodarone include promethazine. Promethazine carries a possible risk of QT prolongation. Additionally, amiodarone inhibits CYP2D6 and may theoretically increase concentrations of promethazine, which is metabolized by CYP2D6. Monitor for side effects like sedation and changes in heart rate or rhythm. (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 CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amiodarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 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) 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, especially when the coadministered agent might decrease the metabolism of amiodarone. 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. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with amiodarone include promethazine. Promethazine carries a possible risk of QT prolongation. Additionally, amiodarone inhibits CYP2D6 and may theoretically increase concentrations of promethazine, which is metabolized by CYP2D6. Monitor for side effects like sedation and changes in heart rate or rhythm. (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 CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amiodarone is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and amiodarone in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Amiodarone can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a moderate CYP3A4 inhibitor like amiodarone in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
    Conivaptan: (Moderate) If concomitant use of conivaptan with amiodarone is necessary, consider serial measurement of amiodarone serum concentrations. Coadministration may increase amiodarone concentrations resulting in amiodarone-related adverse events. Amiodarone is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor.
    Crizotinib: (Major) Avoid concomitant use of amiodarone and crizotinib due to the risk of additive QT prolongation and torsade de pointes (TdP); exposure to both drugs may also increase. If concomitant use is necessary, monitor ECGs for QT prolongation and monitor electrolytes; consider serial measurement of amiodarone serum concentrations. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Both drugs are CYP3A4 substrates and moderate inhibitors. Crizotinib has been associated with concentration-dependent QT prolongation. Amiodarone is a Class III antiarrhythmic agent that is also associated with a well-established risk of QT prolongation and TdP, although the frequency of TdP is less than with other Class III agents.
    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) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with amiodarone, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. 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 with P-gp inhibitors like amiodarone in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with amiodarone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. Coadministration of dabigatran and a single oral dose of 600 mg amiodarone resulted in an increase in dabigatran AUC and Cmax by 58% and 50%, respectively. In addition, coadministration resulted in a 65% increase in renal clearance of dabigatran. Due to the long half-life of amiodarone, the increase in renal clearance may persist after discontinuation of amiodarone. Data from the RE-LY trial indicate no significant changes in dabigatran trough concentrations were seen in patients who received concomitant therapy with amiodarone. In clinical studies, dabigatran was found to have no effect on the pharmacokinetics of amiodarone. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    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) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates, including amiodarone.
    Dapagliflozin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and amiodarone are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as amiodarone.
    Darifenacin: (Moderate) Amiodarone, an inhibitor of both CYP3A4 and CYP2D6, may decrease the metabolism of darifenacin and increase serum concentrations. Patients should be monitored for increased anticholinergic effects if these drugs are used concomitantly; dosage adjustments of darifenacin may be necessary.
    Darunavir: (Major) Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, like amiodarone, is expected with concurrent use. Coadminister with extreme caution, therapeutic monitoring of antiarrhythmic concentrations is recommended.
    Darunavir; Cobicistat: (Major) Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, like amiodarone, is expected with concurrent use. Coadminister with extreme caution, therapeutic monitoring of antiarrhythmic concentrations is recommended. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of amiodarone with cobicistat. Amiodarone is a substrate and inhibitor of CYP3A4 and an inhibitor CYP2D6, cobicistat is a substrate and strong inhibitor of CYP3A and CYP2D6. Concurrent use may result in elevated concentration of both drugs.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, like amiodarone, is expected with concurrent use. Coadminister with extreme caution, therapeutic monitoring of antiarrhythmic concentrations is recommended. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of amiodarone with cobicistat. Amiodarone is a substrate and inhibitor of CYP3A4 and an inhibitor CYP2D6, cobicistat is a substrate and strong inhibitor of CYP3A and CYP2D6. Concurrent use may result in elevated concentration of both drugs.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of HIV treatment doses of ritonavir and amiodarone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Cautious consideration may be given to administering amiodarone with boosting doses of ritonavir. Ritonavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as amiodarone, should be expected with concurrent use.
    Dasatinib: (Major) Avoid coadministration of amiodarone and dasatinib due to the potential for QT prolongation and torsade de pointes (TdP). In vitro studies have shown that dasatinib has the potential to prolong the QT interval. 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.
    Deferasirox: (Moderate) Deferasirox inhibits CYP2C8. Amiodarone is a substrate for CYP2C8. The concomitant administration of deferasirox and the CYP2C8 substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide Cmax by 62% and an increase in AUC 2.3-fold. Although specific drug interaction studies of deferasirox and amiodarone are not available, a similar interaction may occur. The dose of amiodarone may need to be decreased if coadministered with deferasirox.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with amiodarone. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; amiodarone is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold. Additionally, use caution with coadministration of amiodarone with drugs which may induce hypokalemia or hypomagnesemia, including deflazacort. Antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia; any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy.
    Degarelix: (Major) If possible, avoid coadministration of amiodarone with degarelix due to the risk of QT prolongation. 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. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
    Delavirdine: (Major) Delavirdine is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as amiodarone, should be expected with concurrent use. Coadministration of delavirdine with amiodarone should be done with caution. Therapeutic monitoring of amiodarone concentrations is recommended.
    Desflurane: (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. Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated anesthetics, which may include QT prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is also possible for days to weeks after discontinuation of amiodarone.
    Desipramine: (Major) If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Carefully asses treatmentt risks versus benefits. Amiodarone is associated with a well-established risk of QT prolongation and torsade de pointes (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 prolongationthat should be used cautiously with amiodarone include tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations) or in patients with other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of such combined therapies.
    Deutetrabenazine: (Major) Avoid coadministration of amiodarone and drugs known to prolong the QT interval, if possible. 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. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    Dexamethasone: (Major) Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia, including corticosteroids. Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Dextromethorphan: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. (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: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. (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; Potassium Guaiacolsulfonate: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    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. (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Diazepam: (Moderate) Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes, such as amiodarone. Monitor patients closely.
    Diclofenac: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as amiodarone; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Diclofenac; Misoprostol: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as amiodarone; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (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 dihydrocodeine. 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 CYP3A4. Amiodarone is a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Dihydroergotamine: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as amiodarone, may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Diltiazem: (Major) Based on the pharmacology of amiodarone and diltiazem, additive effects on cardiac contractility and/or AV conduction are possible. Concurrent use of amiodarone and diltiazem may result in bradycardia and depressed cardiac output; monitor clinical response. In addition, amiodarone is both a substrate and inhibitor of CYP3A4 metabolism, and may potentially interact with diltiazem via CYP3A4 metabolic pathways.
    Diphenhydramine; Hydrocodone; Phenylephrine: (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. (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.
    Diphenhydramine; Ibuprofen: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including ibuprofen. The metabolism of ibuprofen may be decreased.
    Diphenhydramine; Naproxen: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including naproxen. The metabolism of naproxen may be decreased.
    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) Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP) and is a substrate for CYP3A4. Life-threatening interactions have been reported with the coadministration of disopyramide with clarithromycin and erythromycin, both have a possible risk for QT prolongation and TdP and inhibit CYP3A4. The coadministration of disopyramide and CYP3A4 inhibitors may result in a potentially fatal interaction. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation andTdP and is a CYP3A4 inhibitor. 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.
    Dofetilide: (Major) Coadministration of dofetilide and amiodarone is not recommended as concurrent use may increase the risk of QT prolongation. Class III antiarrhythmic agents, such as amiodarone, should be withheld for at least 3 half-lives prior to initiating dofetilide therapy. Both dofetilide and amiodarone are 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. In clinical trials, dofetilide was administered to patients previously treated with oral amiodarone only if serum amiodarone concentrations were below 0.3 mg/L or amiodarone had been withdrawn for at least three months.
    Dolasetron: (Major) Dolasetron has been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Use of dolasetron injection for the prevention of chemotherapy-induced nausea and vomiting is contraindicated because the risk of QT prolongation is higher with the doses required for this indication; when the injection is used at lower doses (i.e., those approved for post-operative nausea and vomiting) or when the oral formulation is used, the risk of QT prolongation is lower and caution is advised. 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, especially when the coadministered agent might decrease the metabolism of amiodarone. 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.
    Dolutegravir; Rilpivirine: (Major) The concomitant use of amiodarone and rilpivirine should only be done after careful assessment of risks versus benefits. If possible, avoid coadministration. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR 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.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Amiodarone has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, amiodarone inhibits CYP2D6, one of the isoenzymes involved in the metabolism of donepezil. In theory, co-administration of amiodarone and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Amiodarone has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, amiodarone inhibits CYP2D6, one of the isoenzymes involved in the metabolism of donepezil. In theory, co-administration of amiodarone and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as amiodarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    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.
    Doxepin: (Major) If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Carefully asses treatmentt risks versus benefits. Amiodarone is associated with a well-established risk of QT prolongation and torsade de pointes (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 prolongationthat should be used cautiously with amiodarone include tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations) or in patients with other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of such combined therapies.
    Doxercalciferol: (Moderate) Amiodarone inhibits CYP450 and may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if amiodarone is coadministered with doxercalciferol.
    Doxorubicin: (Major) Avoid the concomitant use of doxorubicin and amiodarone; use of these drugs together may increase doxorubicin concentrations and increase the risk of doxorubicin-induced toxicity. Doxorubicin is a substrate of CYP2D6, CYP3A4, and P-glycoprotein (P-gp); amiodarone is a CYP2D6 inhibitor, a CYP3A4 substrate and inhibitor, and a P-gp inhibitor.
    Dronabinol: (Major) Use caution if coadministration of dronabinol with amiodarone is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; amiodarone is a moderate inhibitor of CYP2C9 and 3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated. 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.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. According to the revised 2001 labeling for droperidol, any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. 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, especially when the coadministered agent might decrease the metabolism of amiodarone. 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.
    Duloxetine: (Moderate) Monitor for adverse effects associated with increased exposure to duloxetine if amiodarone is coadministered. Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of amiodarone and duloxetine may increase the risk of hypotension; monitor blood pressure if the combination is necessary. Amiodarone is a CYP1A2 and CYP2D6 inhibitor, while duloxetine is a CYP1A2 and CYP2D6 substrate.
    Dutasteride: (Moderate) Dutasteride is metabolized by CYP3A4 and CYP3A5 isoenzymes. The clearance of dutasteride may be reduced when co-administered with CYP3A4 inhibitors, such as amiodarone.
    Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of amiodarone. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as amiodarone, should be avoided. (Moderate) Dutasteride is metabolized by CYP3A4 and CYP3A5 isoenzymes. The clearance of dutasteride may be reduced when co-administered with CYP3A4 inhibitors, such as amiodarone.
    Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib and amiodarone during coadministration. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; amiodarone is also a substrate and moderate inhibitor of CYP3A.
    Edoxaban: (Moderate) Coadministration of edoxaban and amiodarone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of amiodarone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Major) If possible, avoid coadministration of efavirenz and amiodarone, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. 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, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as amiodarone. It would be prudent to monitor for changes in amiodarone efficacy.
    Efavirenz; Emtricitabine; Tenofovir: (Major) If possible, avoid coadministration of efavirenz and amiodarone, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. 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, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as amiodarone. It would be prudent to monitor for changes in amiodarone efficacy. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as amiodarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) If possible, avoid coadministration of efavirenz and amiodarone, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. 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, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as amiodarone. It would be prudent to monitor for changes in amiodarone efficacy. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as amiodarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elagolix: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with elagolix is necessary. Coadministration may decrease amiodarone plasma concentrations. Amiodarone is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer.
    Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with elagolix is necessary. Coadministration may decrease amiodarone plasma concentrations. Amiodarone is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with amiodarone may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amiodarone is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with amiodarone. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and amiodarone is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the elexacaftor; tezacaftor; ivacaftor dosing schedule when coadministered with amiodarone; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor; tezacaftor; ivacaftor combination tablets every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., elexacaftor; tezacaftor; ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive CYP3A4 substrate); amiodarone is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2-fold, respectively. (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with amiodarone; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor combination tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); amiodarone is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If amiodarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    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: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of amiodarone with cobicistat. Amiodarone is a substrate and inhibitor of CYP3A4 and an inhibitor CYP2D6, cobicistat is a substrate and strong inhibitor of CYP3A and CYP2D6. Concurrent use may result in elevated concentration of both drugs.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of amiodarone with cobicistat. Amiodarone is a substrate and inhibitor of CYP3A4 and an inhibitor CYP2D6, cobicistat is a substrate and strong inhibitor of CYP3A and CYP2D6. Concurrent use may result in elevated concentration of both drugs. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as amiodarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) The concomitant use of amiodarone and rilpivirine should only be done after careful assessment of risks versus benefits. If possible, avoid coadministration. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR 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.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) The concomitant use of amiodarone and rilpivirine should only be done after careful assessment of risks versus benefits. If possible, avoid coadministration. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR 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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as amiodarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as amiodarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Enalapril; Felodipine: (Moderate) Amiodarone is a CYP3A4 inhibitor, which theoretically may decrease hepatic clearance and enhance oral bioavailability of felodipine, a CYP3A4 substrate.
    Enalapril; Hydrochlorothiazide, HCTZ: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    Encainide: (Major) Combination therapy with encainide and amiodarone has been reported to significantly increase the risk of proarrhythmias, necessitating close monitoring. In addition, encainide is significantly metabolized by CYP2D6 isoenzymes, and amiodarone is an inhibitor of CYP2D6.
    Encorafenib: (Major) Avoid coadministration of encorafenib and amiodarone due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of amiodarone; monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If amiodarone is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of amiodarone. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; amiodarone is a moderate CYP3A4 inhibitor that is associated with a well established risk of QT prolongation and torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Enflurane: (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. Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated anesthetics, which may include QT prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is also possible for days to weeks after discontinuation of amiodarone.
    Entrectinib: (Major) Avoid coadministration of entrectinib with amiodarone due to the risk of QT prolongation. Entrectinib has been 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.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with enzalutamide is necessary. Consider monitoring amiodarone serum concentrations during concurrent use. Coadministration may decrease amiodarone plasma concentrations. Amiodarone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 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.
    Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Amiodarone is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Major) Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and, or hypomagnesemia including thiazide diuretics.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib and amiodarone due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If amiodarone is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP2C9 substrate and amiodarone is a moderate CYP2C9 inhibitor.
    Ergonovine: (Major) Coadministration of certain ergot alkaloids with inhibitors of CYP3A4, such as amiodarone, may potentially increase the risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities and/or other serious effects). Coadministration should be done cautiously until further data are available regarding the combination of these drugs with ergonovine.
    Ergotamine: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as amiodarone, may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Ergotamine; Caffeine: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as amiodarone, may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible. (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.
    Eribulin: (Major) 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, especially when the coadministered agent might decrease the metabolism of amiodarone. If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Eribulin has been associated with QT prolongation. 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 eribulin and amiodarone must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    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 CYP3A4 and to a lesser extent by CYP1A2. amiodarone is a CYP3A4 and CYP1A2 inhibitor. Coadministration with another moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
    Erythromycin: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). 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 to potential pharmacokinetic interactions, erythromycin may cause QT prolongation and exhibit additive electrophysiologic effects with Class III antiarrhythmics. Concurrent use of erythromycin with amiodarone should be avoided. In addition, erythromycin may theoretically increase plasma concentrations of amiodarone via inhibition of CYP3A4. Higher antiarrhythmic plasma concentrations increase the potential risk of QT prolongation, TdP or other proarrhythmias.
    Erythromycin; Sulfisoxazole: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). 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 to potential pharmacokinetic interactions, erythromycin may cause QT prolongation and exhibit additive electrophysiologic effects with Class III antiarrhythmics. Concurrent use of erythromycin with amiodarone should be avoided. In addition, erythromycin may theoretically increase plasma concentrations of amiodarone via inhibition of CYP3A4. Higher antiarrhythmic plasma concentrations increase the potential risk of QT prolongation, TdP or other proarrhythmias.
    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.
    Eslicarbazepine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amiodarone, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of amiodarone if coadministered with eslicarbazepine.
    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.
    Estazolam: (Moderate) Amiodarone is a CYP3A4 inhibitor. and may inhibit the metabolism of oxidized benzodiazepines including estazolam.
    Eszopiclone: (Moderate) Monitor for eszopiclone adverse effects, such as CNS depression, during coadministration with amiodarone. A decreased dose of eszopiclone may be warranted. The plasma concentrations of eszopiclone may be elevated when administered concurrently with amiodarone. Amiodarone is a CYP3A4 inhibitor, while eszopiclone is a CYP3A4 substrate.
    Ethacrynic Acid: (Moderate) Monitor serum electrolytes if coadministration of ethacrynic acid and amiodarone is necessary. Ethacrynic acid 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.
    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.
    Etomidate: (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.
    Etravirine: (Major) Etravirine is an inducer of CYP3A4; amiodarone concentrations may be decreased with coadministration. Coadminister these drugs with caution. It is recommended to monitor amiodarone concentrations when possible.
    Everolimus: (Major) Coadministration of everolimus with amiodarone requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of amiodarone and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Amiodarone is a moderate CYP3A4 and P-gp inhibitor. Coadministration with other moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
    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.
    Ezogabine: (Major) 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, especially when the coadministered agent might decrease the metabolism of amiodarone. If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Ezogabine has been associated with QT prolongation. 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 coadministration is necessary, the manufacturer of ezogabine recommends caution during concurrent use with amiodarone.
    Famotidine; Ibuprofen: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including ibuprofen. The metabolism of ibuprofen may be decreased.
    Fedratinib: (Moderate) If concomitant use of fedratinib with amiodarone is necessary, consider serial measurement of amiodarone serum concentrations. Coadministration may increase amiodarone concentrations resulting in amiodarone-related adverse events. Fedratinib is a moderate CYP3A4 inhibitor and amiodarone is a CYP3A substrate.
    Felodipine: (Moderate) Amiodarone is a CYP3A4 inhibitor, which theoretically may decrease hepatic clearance and enhance oral bioavailability of felodipine, a CYP3A4 substrate.
    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.
    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 CYP3A inhibitor. Coadministration with amiodarone increased overall exposure to finerenone by 21%.
    Fingolimod: (Contraindicated) Fingolimod is contraindicated in patients requiring treatment with amiodarone, a Class III antiarrhythmic. Fingolimod treatment results in decreased heart rate and may prolong the QT interval. Amiodarone is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). 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: (Contraindicated) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as amiodarone, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
    Fluconazole: (Contraindicated) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). The concurrent use of fluconazole and other drugs that prolong the QT and are CYP3A4 substrates, such as amiodarone, is contraindicated due to the risk of life-threatening arrhythmias such as TdP. Coadministration of fluconazole with amiodarone may result in an elevated plasma concentration of the interacting drug, causing an increased risk for adverse events, such as QT prolongation.
    Fluoxetine: (Major) Concomitant use of amiodarone and fluoxetine 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.
    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.
    Flurazepam: (Moderate) Amiodarone is a CYP3A4 inhibitor and may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity.
    Flurbiprofen: (Minor) Amiodarone inhibits cytochrome P450 2C9. Caution is recommended when administering amiodarone with other CYP2C9 substrates, such as flurbiprofen, that have a narrow therapeutic range or where large increase in concentrations may be associated with adverse reactions.
    Fluticasone; Salmeterol: (Moderate) 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. The use of amiodarone with other drugs known to prolong the QT interval, such as the long-acting beta-agonists, should only be done after careful assessment of risks versus benefits. Long-acting beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) 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. The use of amiodarone with other drugs known to prolong the QT interval, such as the long-acting beta-agonists, should only be done after careful assessment of risks versus benefits. Long-acting beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) 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. The use of amiodarone with other drugs known to prolong the QT interval, such as the long-acting beta-agonists, should only be done after careful assessment of risks versus benefits. Long-acting beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluvastatin: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as amiodarone, and fluvastatin, a CYP2C9 substrate