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Cordarone
Classes
Anti-arrhythmics, Class III
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.
Extemporaneous suspension: Shake well before administering. Measure dosage with calibrated measuring device.
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]
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
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.
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.
Adverse Reactions
bradycardia / Rapid / 0-20.0
pulmonary toxicity / Early / 0-17.0
AV block / Early / 15.0-15.0
arrhythmia exacerbation / Early / 2.0-5.0
cardiac arrest / Early / 2.5-3.5
asystole / Rapid / 2.9-2.9
ventricular tachycardia / Early / 2.4-2.4
heart failure / Delayed / 2.1-2.1
atrial fibrillation / Early / 0-2.0
ventricular fibrillation / Early / 0-2.0
torsade de pointes / Rapid / 0-2.0
acute respiratory distress syndrome (ARDS) / Early / 2.0-2.0
pulmonary edema / Early / 0-2.0
Stevens-Johnson syndrome / Delayed / 0-2.0
hepatic failure / Delayed / 0-1.0
bronchiolitis obliterans / Delayed / Incidence not known
eosinophilic pneumonia / Delayed / Incidence not known
pleural effusion / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
respiratory arrest / Rapid / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
cirrhosis / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
visual impairment / Early / Incidence not known
optic neuritis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
anaphylactic shock / Rapid / Incidence not known
cyanosis / Early / Incidence not known
periarteritis / Delayed / Incidence not known
thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
thrombosis / Delayed / Incidence not known
skin necrosis / Early / Incidence not known
increased intracranial pressure / Early / Incidence not known
akinesia / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
epididymitis / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
SIADH / Delayed / Incidence not known
hypotension / Rapid / 4.0-70.0
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
hypoxia / Early / Incidence not known
dyspnea / Early / Incidence not known
wheezing / Rapid / Incidence not known
hemoptysis / Delayed / Incidence not known
pneumonitis / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
eosinophilia / Delayed / Incidence not known
bleeding / Early / Incidence not known
phlebitis / Rapid / Incidence not known
erythema / Early / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
pseudotumor cerebri / Delayed / Incidence not known
delirium / Early / Incidence not known
involuntary movements / Delayed / Incidence not known
ataxia / Delayed / Incidence not known
hallucinations / Early / Incidence not known
confusion / Early / Incidence not known
myopathy / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
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
abdominal pain / Early / 10.0
nausea / 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
paresthesias / Delayed / Incidence not known
insomnia / Early / Incidence not known
fatigue / Early / Incidence not known
dizziness / Early / Incidence not known
tremor / Early / Incidence not known
malaise / Early / Incidence not known
headache / Early / Incidence not known
ecchymosis / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
skin discoloration / Delayed / Incidence not known
rash / Early / Incidence not known
alopecia / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
xerostomia / Early / Incidence not known
muscle cramps / Delayed / Incidence not known
weakness / Early / Incidence not known
back pain / Delayed / Incidence not known
libido decrease / Delayed / Incidence not known
Boxed Warning
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]
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]
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]
Common Brand Names
Cordarone, Nexterone, Pacerone
Dea Class
Rx
Description
Class III antiarrhythmic agent
Used for ventricular and supraventricular tachyarrhythmias
Risk of proarrhythmias less than other antiarrhythmics
Dosage And Indications
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.
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).
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.
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.
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]
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.
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.
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]
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]
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.
150 mg IV over 10 minutes as a single dose, then 1 mg/minute continuous IV infusion for 6 hours and 0.5 mg/minute for 18 hours or change to oral dosing; consider decreasing dose to 0.25 mg/minute after 24 hours. Alternatively, 300 mg IV over 1 hour as a single dose, then 10 to 50 mg/hour continuous IV infusion for 24 hours. Parenteral amiodarone is an appropriate alternative for rate control in critically ill persons without pre-excitation and may facilitate conversion to sinus rhythm in persons with atrial fibrillation.
5 mg/kg/dose IV as a single dose, then 5 mcg/kg/minute continuous IV infusion, initially. Max: 15 mcg/kg/minute. A second bolus ranging from 1 to 5 mg/kg/dose has been administered to some patients. Dosing protocols administering the bolus dose in smaller aliquots of 1 to 2 mg/kg/dose IV have been recommended in order to reduce patient exposure to plasticizers, such as DEHP, which may be leached out of IV tubing, including polyvinyl chloride (PVC) tubing, by certain formulations of amiodarone.
5 mg/kg/dose IV as a single dose, then 5 mcg/kg/minute continuous IV infusion, initially. Max: 15 mcg/kg/minute. A second bolus ranging from 1 to 5 mg/kg/dose has been administered to some patients. Dosing protocols administering the bolus dose in smaller aliquots of 1 to 2 mg/kg/dose IV have been recommended in order to reduce patient exposure to plasticizers, such as DEHP, which may be leached out of IV tubing, including polyvinyl chloride (PVC) tubing, by certain formulations of amiodarone.
400 to 800 mg/day PO in divided doses for 2 to 4 weeks to a total load of up to 10 g, then 100 to 200 mg PO once daily. Guidelines suggest oral amiodarone as a reasonable option for pharmacological cardioversion of atrial fibrillation. For maintenance of sinus rhythm, consider amiodarone only after consideration of its risks and when other agents have failed or are contraindicated. The SAFE-T trial comparing amiodarone and sotalol to restore and maintain sinus rhythm utilized an amiodarone dosing regimen of 800 mg/day PO for 14 days, then 600 mg/day for 14 days, then 300 mg/day for the first year, and 200 mg/day thereafter. Various loading and maintenance dosage regimens for oral amiodarone have been utilized. One source recommends a loading dose of 800 to 1600 mg/day PO for 1 to 3 weeks, followed by 800 mg/day for the next 2 to 4 weeks, with a maintenance dose of 300 mg/day or less. Another source describes utilizing a loading dose of 800 mg PO twice daily for 2 weeks followed by 400 mg/day for the next 2 weeks, with a maintenance dose of 200 mg/day. The Canadian Trial of Atrial Fibrillation (CTAF) utilized a dosage regimen of 10 mg/kg PO once daily for 2 weeks, followed by 300 mg once daily for 4 weeks, followed by a maintenance dose of 200 mg PO once daily. The CTAF study demonstrated greater efficacy of amiodarone compared to sotalol or propafenone in preventing recurrent atrial fibrillation.
10 to 20 mg/kg/day (Max: 1,600 mg/day) PO in 1 to 2 divided doses for 4 to 14 days, then 2 to 5 mg/kg/dose PO once daily has been reported most commonly.[53734] [53765] [62740] [62741] [62742] [62743] Mean reported maintenance doses: 6.6 to 7.7 mg/kg/day (range: 1.5 to 25 mg/kg/day).[24962] [53765] [62742] When symptoms are controlled, reduce to lowest effective dose; maintenance dose may be given 5 days/week.[53734] [62741] [62742] 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.[52873]
10 to 20 mg/kg/day PO in 1 to 2 divided doses for 4 to 14 days, then 2 to 5 mg/kg/dose PO once daily has been reported most commonly.[52869] [53734] [53765] [62740] [62741] [62742] [62743] Mean reported maintenance doses: 6.6 to 7.7 mg/kg/day (range: 1.5 to 25 mg/kg/day).[24962] [53765] [62742] Alternatively, 600 to 800 mg/1.73 m2/day PO for 4 to 14 days, then 200 to 400 mg/1.73 m2/day PO maintenance has been recommended.[24961] [62743] When symptoms are controlled, reduce to lowest effective dose; maintenance dose may be given 5 days/week.[53734] [62741] [62742] Infants may require higher mg/kg doses compared to older children. In a study, the infant maintenance dose was the same as the loading dose in absolute value, although it decreased in relative value in relation to the increase in body weight.[52871] In another study, the mean initial and maintenance dose was 15.3 mg/kg/day (261 mg/m2/day) and 8.2 mg/kg/day (204 mg/m2/day), respectively, in patients younger than 1 year. These doses were significantly higher than those required in older patients when compared on a mg/kg basis but not when compared on a mg/m2 basis. The authors recommended that dosing be based on body surface area in this age group rather than weight.[52877] 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.[52873]
10 to 20 mg/kg/day PO in 1 to 2 divided doses for 4 to 14 days, then 2 to 5 mg/kg/dose PO once daily has been reported most commonly.[52869] [53734] [53765] [62740] [62741] [62742] [62743] Mean reported maintenance doses: 7.7 mg/kg/day (range: 1.5 to 25 mg/kg/day).[24962] [53765] Alternatively, 600 to 800 mg/1.73 m2/day PO for 4 to 14 days, then 200 to 400 mg/1.73 m2/day PO has been recommended.[24961] [62743] When symptoms are controlled, reduce to lowest effective dose; maintenance dose may be given 5 days/week.[53734] [62741] [62742] In a study, the mean initial and maintenance dose was 15.3 mg/kg/day (261 mg/m2/day) and 8.2 mg/kg/day (204 mg/m2/day), respectively, in patients younger than 1 year. These doses were significantly higher than those required in older patients when compared on a mg/kg basis but not when compared on a mg/m2 basis. The authors recommended that dosing be based on body surface area in this age group rather than weight.[52877] 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.[52873]
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.
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).
200 to 400 mg PO every 8 to 12 hours for 1 to 2 weeks, then 300 to 400 mg PO once daily. Reduce dose to 200 mg PO once daily if possible.
†Indicates off-label use
Dosing Considerations
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 ImpairmentSpecific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
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; Pyrilamine: (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; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by 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; Guaifenesin; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like amiodarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If amiodarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Ibuprofen: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including ibuprofen. The metabolism of ibuprofen may be decreased.
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; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Adagrasib: (Major) Avoid concomitant use of adagrasib and amiodarone due to the potential for increased amiodarone exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for amiodarone-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Amiodarone is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
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.
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.
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.
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.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with amiodarone is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; amiodarone is a P-gp inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure. (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) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
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 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.
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.
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.
Aripiprazole: (Major) Concomitant use of aripiprazole and amiodarone increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and increases aripiprazole exposure and risk for side effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, an aripiprazole dosage reduction is necessary; management recommendations vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. Aripiprazole is CYP2D6 and CYP3A substrate, amiodarone is a weak CYP2D6 and moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. (Major) Concomitant use of aripiprazole and amiodarone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Arsenic Trioxide: (Major) 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; 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; 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: (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) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving amiodarone. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
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.
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.
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.
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: (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.
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; Dextromethorphan; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Brompheniramine; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Bumetanide: (Major) Monitor serum electrolytes if coadministration of bumetanide and amiodarone is necessary. Bumetanide therapy may cause electrolyte abnormalities (i.e., hypokalemia, hypomagnesemia) which may exaggerate the degree of QTc prolongation and increase the potential for torsade de pointes.
Bupivacaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Bupivacaine; Lidocaine: (Major) Concomitant administration of lidocaine with amiodarone has been reported to cause sinus bradycardia and seizure. Amiodarone and its main metabolite, N-monodesethylamiodarone (DEA), appear to inhibit the metabolism of lidocaine by competitively inhibiting CYP3A4. Furthermore, DEA inhibits lidocaine metabolism in a concentration-dependent manner. Also, the metabolism of amiodarone to DEA appears to be competitively inhibited by lidocaine. Close correlations between amiodarone N-monodesethylase activities and the amounts of CYP3A4 and the rates of lidocaine N-monodesethylation have been observed from analyses of in vitro data. Inhibition of lidocaine metabolism is supported by in vivo data from 6 adults. The mean systemic concentration of lidocaine over 300 minutes after receipt of lidocaine hydrochloride 1 mg/kg intravenously before amiodarone treatment is 111.7 +/- 23.2 mcg/minute/mL. In contrast, the mean systemic concentration of lidocaine over 300 minutes after cumulative amiodarone doses of 3 g and 13 g is 135.3 +/- 34.6 and 131.7 +/- 25.5 mcg/minute/mL, respectively. As expected, the systemic exposure of the lidocaine metabolite, monoethylglycinexylidide, decreases from 19.2 +/- 6.5 to 15.8 +/- 8.3 mcg/minute/mL after 3 g of amiodarone. In addition, the systemic clearance of lidocaine decreases from 7.86 +/- 1.83 to 6.31 +/- 2.21 mL/minute/kg body weight. As compared with values before amiodarone administration, the lidocaine elimination half-life and the distribution volume at steady state remain relatively unchanged. Due to the long half-life of amiodarone, clinicians should use caution when administering lidocaine to patients who are receiving or who have recently discontinued amiodarone.
Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with amiodarone is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and amiodarone is a moderate CYP2C9 inhibitor.
Buprenorphine: (Major) 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) Monitor for an increase in buspirone-related adverse reactions if coadministration with amiodarone is necessary; the effect may be more pronounced if the patient has been titrated to a stable dose of buspirone and amiodarone is added or removed from therapy. Buspirone is a sensitive CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors increased buspirone exposure by 3.4 to 6-fold and was accompanied by increased buspirone-related adverse reactions.
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.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with amiodarone may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of amiodarone could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If amiodarone is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by 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) Concomitant use of rilpivirine 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. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
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. (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.
Carbamazepine: (Moderate) Monitor carbamazepine concentrations and for decreased efficacy of amiodarone if coadministration is necessary; carbamazepine dose adjustments may be necessary. Coadministration may increase carbamazepine concentrations and decrease amiodarone plasma concentrations. Amiodarone is a CYP3A substrate and moderate CYP3A inhibitor and carbamazepine is a CYP3A substrate and strong CYP3A inducer.
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) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with amiodarone is necessary. Carvedilol is a CYP2C9 substrate and amiodarone is a CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.
Celecoxib: (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.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with amiodarone is necessary. If amiodarone is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and amiodarone is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (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 a
Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as amiodarone, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chlordiazepoxide; Amitriptyline: (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.
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; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Chlorpheniramine; 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; 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; 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; Clonidine: (Moderate) Monitor for potential bradycardia or atrioventricular block during coadministration with amiodarone. Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate.
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%.
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) Concomitant use of clofazimine 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.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with amiodarone; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor.
Clonidine: (Moderate) Monitor for potential bradycardia or atrioventricular block during coadministration with amiodarone. Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate.
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) Avoid concomitant use of colchicine and amiodarone due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and amiodarone is a dual moderate CYP3A and P-gp inhibitor. Concomitant use with other dual moderate CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 2- to 3.6-fold.
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.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with amiodarone. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
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.
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.
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.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine 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.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Dextromethorphan; Quinidine: (Major) Amiodarone coadministration increases quinidine concentrations by about 33% after 2 days, by decreasing its renal clearance or by inhibiting its hepatic metabolism. Quinidine may also be displaced from tissue and protein binding sites. Prolongation of the QT interval is well documented with quinidine, and the addition of amiodarone may increase this effect, placing the patient at an increased risk for the development of torsade de pointes. Careful clinical observation of the patient as well as close monitoring of the ECG and serum quinidine concentrations are essential with adjustment of the quinidine dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. An empiric reduction of the quinidine dose by 33-50% is suggested within 2 days following initiation of amiodarone therapy, with consideration given to immediately discontinuing of quinidine once amiodarone therapy is begun. Combination antiarrhythmic therapy is reserved for patients with refractory life-threatening arrhythmias. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with amiodarone is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and amiodarone is a CYP3A4 inhibitor.
Diclofenac: (Moderate) Monitor for an increase in diclofenac-related adverse reactions if coadministration with amiodarone is necessary; adjust the dose of diclofenac if needed. Diclofenac is a CYP2C9 substrate and amiodarone is a moderate CYP2C9 inhibitor.
Diclofenac; Misoprostol: (Moderate) Monitor for an increase in diclofenac-related adverse reactions if coadministration with amiodarone is necessary; adjust the dose of diclofenac if needed. Diclofenac is a CYP2C9 substrate and amiodarone is a moderate CYP2C9 inhibitor.
Digoxin: (Major) Amiodarone increases orally administered digoxin serum concentration by 70% when given concomitantly. When amiodarone is coadministered with intravenous (IV) digoxin, the serum concentration of digoxin is increased by 17%. Measure serum digoxin concentrations before initiating amiodarone. According to the manufacturer of amiodarone, the digoxin dose should be reduced by 50% upon initiation of amiodarone. The manufacturer of digoxin recommends measuring the serum digoxin concentration before initiating amiodarone and reducing the serum digoxin concentration by reducing the oral dose by approximately 30 to 50%, decreasing the IV digoxin dose by 15 to 30%, or modifying the dosing frequency and continue monitoring. The mechanism of the increase in digoxin serum concentration is thought to result from inhibition of gastrointestinal P-glycoprotein (increased oral bioavailability) and/or a decrease in digoxin renal or nonrenal clearance. Because of the depressant effects of digoxin on the sinus and AV node, concurrent use can potentiate amiodarone's electrophysiologic and hemodynamic effects resulting in bradycardia, sinus arrest, and AV block. Furthermore, amiodarone may induce changes in thyroid function and alter sensitivity to cardiac glycosides, and thyroid function should be monitored closely in patients receiving both drugs simultaneously. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Close monitoring of serum digoxin concentrations and heart rate is essential to avoid enhanced toxicity.
Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with amiodarone is necessary. Concurrent use may result in elevated diltiazem concentrations. Additive effects on cardiac contractility and/or AV conduction are also possible. Diltiazem is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor.
Diphenhydramine; 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) Concomitant use of rilpivirine 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. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
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) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Dorzolamide; Timolol: (Moderate) Concomitant administration of timolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of timolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
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 Liposomal: (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.
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) Avoid concomitant use of dronedarone and amiodarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after 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 increased duloxetine-related adverse effects if coadministered with amiodarone. Concurrent use may result in increased duloxetine exposure. Duloxetine is a CYP1A2 and CYP2D6 substrate and amiodarone is a CYP1A2 and CYP2D6 inhibitor.
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: (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. (Moderate) Use caution if coadministration of amiodarone with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A4 and CYP2D6 substrate and amiodarone is a moderate CYP3A4 and CYP2D6 inhibitor. The effects of concomitant administration of a moderate CYP3A4 and CYP2D6 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 and CYP2D6 inhibition.
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 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) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) 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) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Elacestrant: (Major) Avoid concomitant use of elacestrant and amiodarone due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
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 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. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with amiodarone; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; amiodarone is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
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 co ncentrations. 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) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Concomitant use of rilpivirine 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. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of rilpivirine 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. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Encorafenib: (Major) 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.
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.
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.
Ergot alkaloids: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of amiodarone is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and amiodarone is a moderate CYP3A inhibitor.
Ergotamine; 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.
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.
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.
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.
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.
Fezolinetant: (Contraindicated) Concomitant use of fezolinetant and amiodarone is contraindicated due to the risk of increased fezolinetant exposure which may increase the risk of fezolinetant-related adverse effects. Fezolinetant is a CYP1A2 substrate; amiodarone is a moderate CYP1A2 inhibitor. Concomitant use with another moderate CYP1A2 inhibitor increased fezolinetant overall exposure by 360%.
Finasteride; Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with amiodarone is necessary. Tadalafil is a CYP3A4 substrate and amiodarone is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
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) Avoid concomitant use of fingolimod and amiodarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
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) Avoid concomitant use of amiodarone and fluconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase amiodarone exposure and the risk for other amiodarone-related adverse effects; amiodarone is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
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.
Fluvastatin: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as amiodarone, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity, including myopathy and rhabdomyolysis.
Fluvoxamine: (Major) Due to the risk of QT prolongation and torsade de pointes (TdP), avoid coadministration of amiodarone and fluvoxamine if possible. 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 has been reported during fluvoxamine postmarketing use. Also, fluvoxamine is a substrate of CYP1A2 and CYP2D6. Amiodarone is an inhibitor of both CYP1A2 and CYP2D6 and could reduce fluvoxamine metabolism.
Food: (Major) Advise patients to avoid cannabis use during amiodarone treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A and CYP2C9 substrates and amiodarone is a moderate CYP3A and CYP2C9 inhibitor.
Fosamprenavir: (Moderate) Monitor for an increase in adverse reactions from both drugs during concomitant use of amiodarone and fosamprenavir. Concomitant use may increase the exposure of both drugs. Amiodarone and fosamprenavir are both CYP3A substrates and moderate CYP3A inhibitors.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as amiodarone. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade 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. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosphenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with fosphenytoin and amiodarone due to increased phenytoin steady-state concentrations. Concomitant use may also reduce amiodarone exposure and efficacy. Phenytoin is a CYP2C9 substrate and a strong CYP3A inducer; amiodarone is a CYP3A substrate and a CYP2C9 inhibitor.
Fostemsavir: (Major) 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 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. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Major) According to the manufacturer, gemifloxacin should be avoided in patients receiving Class III antiarrhythmics (such as amiodarone). Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. Amiodarone 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.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with amiodarone due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. 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.
Gilteritinib: (Major) If possible, avoid coadministration of amiodarone and gilteritinib. Monitor for QT prolongation if concurrent use is necessary. Gilteritinib 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). Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Glasdegib: (Major) Avoid coadministration of glasdegib with amiodarone due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. 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.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and amiodarone as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); amiodarone is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and amiodarone as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); amiodarone is an inhibitor of P-gp.
Goserelin: (Major) Avoid coadministration of amiodarone with goserelin if possible due to the risk of QT prolongation. Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks in patients receiving amiodarone. 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. Androgen deprivation therapy also prolongs the QT interval. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Granisetron: (Major) Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, may result in clinical consequences. 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.
Grapefruit juice: (Major) Grapefruit juice has been shown to increase amiodarone peak serum concentrations and AUC when a single dose of amiodarone was administered orally. No change in ECG or arterial blood pressure measurements were identified in this single dose study; however, the impact on chronic dosing of amiodarone was not evaluated. To prevent potential drug accumulation, it would be prudent to avoid taking oral amiodarone with grapefruit juice.
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.
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.
Guanfacine: (Major) Amiodarone may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon amiodarone discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and amiodarone is a moderate CYP3A4 inhibitor.
Halogenated Anesthetics: (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.
Haloperidol: (Major) QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. According to the manufacturer of haloperidol, caution is advisable when prescribing the drug concurrently with medications known to prolong the QT interval. In addition, haloperidol is a substrate for CYP3A4 and CYP2D6. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and inhibitors of CYP3A4 or CYP2D6. Therefore, it is advisable to closely monitor for adverse events when haloperidol is co-administered with drugs that inhibit CYP3A4 and CYP2D6 and prolong the QT interval, such as amiodarone. 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.
Histrelin: (Major) Avoid coadministration of amiodarone with histrelin if possible due to the risk of QT prolongation. Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks in patients receiving amiodarone. 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. Androgen deprivation therapy also prolongs the QT interval. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like amiodarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If amiodarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like amiodarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If amiodarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like amiodarone can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If amiodarone is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including ibuprofen. The metabolism of ibuprofen may be decreased.
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.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine 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.
Hydroxyzine: (Major) Concomitant use of hydroxyzine and amiodarone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Ibrutinib: (Major) If ibrutinib is coadministered with amiodarone, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dose if amiodarone is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Ibuprofen: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including ibuprofen. The metabolism of ibuprofen may be decreased.
Ibuprofen; Famotidine: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including ibuprofen. The metabolism of ibuprofen may be decreased.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. If amiodarone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a 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. (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including ibuprofen. The metabolism of ibuprofen may be decreased.
Ibuprofen; Pseudoephedrine: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including ibuprofen. The metabolism of ibuprofen may be decreased.
Ibutilide: (Contraindicated) Amiodarone should not be administered concomitantly during the first four hours post-infusion of ibutilide, due to the potential for additive Class III antiarrhythmic effects. In addition, both ibutilide and amiodarone are associated with a risk of QT prolongation and torsades de pointes (TdP).
Idelalisib: (Moderate) Coadministration of idelalisib and amiodarone may increase amiodarone concentrations resulting in amiodarone-related adverse events. Idelalisib is a strong CYP3A4 inhibitor and amiodarone is a CYP3A substrate. If concomitant use is necessary, consider serial measurement of amiodarone serum concentrations.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with amiodarone is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Amiodarone is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) The concomitant use of amiodarone and other drugs known to prolong the QT interval, such as iloperidone, 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. Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. 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.
Imatinib: (Moderate) Consider serial measurement of amiodarone serum concentration during concomitant use of imatinib. Concurrent use may increase amiodarone exposure. Higher antiarrhythmic plasma concentrations increase the potential risk of QT prolongation, torsade de pointes (TdP) or other proarrhythmias. Amiodarone is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor.
Indapamide: (Major) Indapamide may induce hypokalemia, increasing the potential for proarrhythmic effects (e.g., torsade de pointes) of amiodarone. Potassium levels should be within the normal range prior and during administration of these agents. In the absence of electrolyte imbalances, these agents can be used together safely.
Indinavir: (Contraindicated) Coadministration of indinavir and amiodarone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Indinavir 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.
Indomethacin: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including indomethacin. The metabolism of indomethacin may be decreased.
Infigratinib: (Major) Avoid concomitant use of infigratinib and amiodarone. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with amiodarone due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval 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.
Iodixanol: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Iohexol: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Iomeprol: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Iopamidol: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Iopromide: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Ioversol: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Isavuconazonium: (Major) Concomitant use of isavuconazonium with amiodarone may result in increased serum concentrations of both drugs. Amiodarone is a substrate and inhibitor of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoflurane: (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.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Certain rifamycins, including rifampin, rifabutin, and rifapentine, may induce CYP3A4 metabolism of amiodarone, resulting in decreased serum concentrations of amiodarone and its active metabolite (desethylamiodarone) and potential decreased efficacy. A possible drug interaction has been reported with rifampin and amiodarone in one patient receiving therapy with ICD and amiodarone for history of atrial and ventricular arrhythmias; this patient had evidence of reduced serum amiodarone and metabolite levels, loss of antiarrhythmic efficacy, and required hospitalization.
Isoniazid, INH; Rifampin: (Major) Certain rifamycins, including rifampin, rifabutin, and rifapentine, may induce CYP3A4 metabolism of amiodarone, resulting in decreased serum concentrations of amiodarone and its active metabolite (desethylamiodarone) and potential decreased efficacy. A possible drug interaction has been reported with rifampin and amiodarone in one patient receiving therapy with ICD and amiodarone for history of atrial and ventricular arrhythmias; this patient had evidence of reduced serum amiodarone and metabolite levels, loss of antiarrhythmic efficacy, and required hospitalization.
Isosulfan Blue: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Isradipine: (Moderate) Caution should be used when CYP3A4 inhibitors, such as amiodarone, are co-administered with isradipine (CYP3A4 substrate).
Itraconazole: (Major) Avoid coadministration of amiodarone and itraconazole due to the potential for increased amiodarone concentrations and additive effects on the QT interval. There have been reports of prolonged QT, with or without torsade de pointes (TdP) with the concomitant use of amiodarone and azole antifungals. Both itraconazole and amiodarone are associated with QT prolongation. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with amiodarone (a CYP3A4 substrate) may result in elevated amiodarone plasma concentrations and an increased risk for adverse events, including QT prolongation. According to the manufacturer, the need to administer amiodarone with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits, especially when the coadministered agent might decrease the metabolism of amiodarone. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Further, it takes approximately 7 to 14 days after discontinuing itraconazole before the plasma concentrations are undetectable. The decline in itraconazole plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Ivabradine: (Major) Avoid coadministration of ivarbadine and amiodarone as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; amiodarone is a moderate CYP3A4 inhibitor. In addition, coadministration of ivabradine with other negative chronotropes like amiodarone increases the risk for bradycardia. Increased ivabradine concentrations may further increase the risk of bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If amiodarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with amiodarone due to increased plasma concentrations of ivosidenib and additive QT prolongation. If concomitant use is unavoidable, monitor electrolyte and ECGs for QTc prolongation; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Amiodarone is a moderate CYP3A4 inhibitor and 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. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of amiodarone is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor.
Ketamine: (Major) In general, adverse cardiovascular effects such as hypotension and atropine-resistant bradycardia can occur in patients receiving amiodarone who subsequently are administered any general anesthetics, particularly volatile anesthetics. Due to the extremely long half-life of amiodarone, a drug interaction is also possible for days to weeks after discontinuation of amiodarone. For example, when fentanyl was administered to patients receiving amiodarone, the incidence of bradycardia and other adverse cardiovascular effects was much higher than in patients not on amiodarone who received fentanyl.
Ketoconazole: (Contraindicated) Use of ketoconazole/levoketoconazole and amiodarone is contraindicated due to an increased risk for ventricular arrhythmias, torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. Concomitant use may also increase the exposure of amiodarone, further increasing the risk for adverse events. Amiodarone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Labetalol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as Class III antiarrhythmics, because of the risk of AV block, bradyca rdia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) 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.
Lapatinib: (Major) Avoid coadministration of amiodarone and lapatinib if possible due to the risk of QT prolongation; lapatinib exposure may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes, as well as monitoring for an increase in lapatinib-related adverse reactions. Correct any electrolyte abnormalities prior to treatment. Lapatinib is a P-glycoprotein (P-gp) substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Amiodarone, a Class III antiarrhythmic agent and P-gp inhibitor, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with amiodarone is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Ledipasvir; Sofosbuvir: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting sofosbuvir should also undergo similar cardiac monitoring as outlined above.
Lefamulin: (Major) Avoid coadministration of lefamulin with amiodarone as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Amiodarone is a P-gp inhibitor that is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Lemborexant: (Major) Avoid coadministration of lemborexant and amiodarone as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Consider an alternative to lemborexant. Lemborexant is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Moderate) Monitor for increased amiodarone toxicity if coadministered with lenacapavir. Concomitant use may increase amiodarone exposure and the risk of adverse effects. Amiodarone is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with amiodarone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Amiodarone, a Class III antiarrhythmic agent, is also 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 also 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.
Lesinurad: (Moderate) Use lesinurad and amiodarone together with caution; amiodarone may increase the systemic exposure of lesinurad. Amiodarone is a moderate inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate. In addition, lesinurad may decrease the systemic exposure and therapeutic efficacy of amiodarone; monitor for potential reduction in efficacy. Amiodarone is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Use lesinurad and amiodarone together with caution; amiodarone may increase the systemic exposure of lesinurad. Amiodarone is a moderate inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate. In addition, lesinurad may decrease the systemic exposure and therapeutic efficacy of amiodarone; monitor for potential reduction in efficacy. Amiodarone is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Moderate) Closely monitor for amiodarone-related adverse events and frequently monitor amiodarone concentrations if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of amiodarone, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Major) Avoid coadministration of amiodarone with triptorelin if possible due to the risk of QT prolongation. Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks in patients receiving amiodarone. 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. Androgen deprivation therapy also prolongs the QT interval. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Leuprolide; Norethindrone: (Major) Avoid coadministration of amiodarone with triptorelin if possible due to the risk of QT prolongation. Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks in patients receiving amiodarone. 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. Androgen deprivation therapy also prolongs the QT interval. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Levobunolol: (Moderate) The concomitant use of ophthalmic beta-blockers in patients receiving antiarrhythmics which slow AV conduction, such as amiodarone, may result in additive negative dromotropic effects, especially in patients with pre-existing cardiac disease or left ventricular dysfunction.
Levofloxacin: (Major) Concomitant use of levofloxacin 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.
Levoketoconazole: (Contraindicated) Use of ketoconazole/levoketoconazole and amiodarone is contraindicated due to an increased risk for ventricular arrhythmias, torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. Concomitant use may also increase the exposure of amiodarone, further increasing the risk for adverse events. Amiodarone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Levothyroxine: (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Levothyroxine; Liothyronine (Porcine): (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Lidocaine: (Major) Concomitant administration of lidocaine with amiodarone has been reported to cause sinus bradycardia and seizure. Amiodarone and its main metabolite, N-monodesethylamiodarone (DEA), appear to inhibit the metabolism of lidocaine by competitively inhibiting CYP3A4. Furthermore, DEA inhibits lidocaine metabolism in a concentration-dependent manner. Also, the metabolism of amiodarone to DEA appears to be competitively inhibited by lidocaine. Close correlations between amiodarone N-monodesethylase activities and the amounts of CYP3A4 and the rates of lidocaine N-monodesethylation have been observed from analyses of in vitro data. Inhibition of lidocaine metabolism is supported by in vivo data from 6 adults. The mean systemic concentration of lidocaine over 300 minutes after receipt of lidocaine hydrochloride 1 mg/kg intravenously before amiodarone treatment is 111.7 +/- 23.2 mcg/minute/mL. In contrast, the mean systemic concentration of lidocaine over 300 minutes after cumulative amiodarone doses of 3 g and 13 g is 135.3 +/- 34.6 and 131.7 +/- 25.5 mcg/minute/mL, respectively. As expected, the systemic exposure of the lidocaine metabolite, monoethylglycinexylidide, decreases from 19.2 +/- 6.5 to 15.8 +/- 8.3 mcg/minute/mL after 3 g of amiodarone. In addition, the systemic clearance of lidocaine decreases from 7.86 +/- 1.83 to 6.31 +/- 2.21 mL/minute/kg body weight. As compared with values before amiodarone administration, the lidocaine elimination half-life and the distribution volume at steady state remain relatively unchanged. Due to the long half-life of amiodarone, clinicians should use caution when administering lidocaine to patients who are receiving or who have recently discontinued amiodarone.
Lidocaine; Epinephrine: (Major) Concomitant administration of lidocaine with amiodarone has been reported to cause sinus bradycardia and seizure. Amiodarone and its main metabolite, N-monodesethylamiodarone (DEA), appear to inhibit the metabolism of lidocaine by competitively inhibiting CYP3A4. Furthermore, DEA inhibits lidocaine metabolism in a concentration-dependent manner. Also, the metabolism of amiodarone to DEA appears to be competitively inhibited by lidocaine. Close correlations between amiodarone N-monodesethylase activities and the amounts of CYP3A4 and the rates of lidocaine N-monodesethylation have been observed from analyses of in vitro data. Inhibition of lidocaine metabolism is supported by in vivo data from 6 adults. The mean systemic concentration of lidocaine over 300 minutes after receipt of lidocaine hydrochloride 1 mg/kg intravenously before amiodarone treatment is 111.7 +/- 23.2 mcg/minute/mL. In contrast, the mean systemic concentration of lidocaine over 300 minutes after cumulative amiodarone doses of 3 g and 13 g is 135.3 +/- 34.6 and 131.7 +/- 25.5 mcg/minute/mL, respectively. As expected, the systemic exposure of the lidocaine metabolite, monoethylglycinexylidide, decreases from 19.2 +/- 6.5 to 15.8 +/- 8.3 mcg/minute/mL after 3 g of amiodarone. In addition, the systemic clearance of lidocaine decreases from 7.86 +/- 1.83 to 6.31 +/- 2.21 mL/minute/kg body weight. As compared with values before amiodarone administration, the lidocaine elimination half-life and the distribution volume at steady state remain relatively unchanged. Due to the long half-life of amiodarone, clinicians should use caution when administering lidocaine to patients who are receiving or who have recently discontinued amiodarone. (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Lidocaine; Prilocaine: (Major) Concomitant administration of lidocaine with amiodarone has been reported to cause sinus bradycardia and seizure. Amiodarone and its main metabolite, N-monodesethylamiodarone (DEA), appear to inhibit the metabolism of lidocaine by competitively inhibiting CYP3A4. Furthermore, DEA inhibits lidocaine metabolism in a concentration-dependent manner. Also, the metabolism of amiodarone to DEA appears to be competitively inhibited by lidocaine. Close correlations between amiodarone N-monodesethylase activities and the amounts of CYP3A4 and the rates of lidocaine N-monodesethylation have been observed from analyses of in vitro data. Inhibition of lidocaine metabolism is supported by in vivo data from 6 adults. The mean systemic concentration of lidocaine over 300 minutes after receipt of lidocaine hydrochloride 1 mg/kg intravenously before amiodarone treatment is 111.7 +/- 23.2 mcg/minute/mL. In contrast, the mean systemic concentration of lidocaine over 300 minutes after cumulative amiodarone doses of 3 g and 13 g is 135.3 +/- 34.6 and 131.7 +/- 25.5 mcg/minute/mL, respectively. As expected, the systemic exposure of the lidocaine metabolite, monoethylglycinexylidide, decreases from 19.2 +/- 6.5 to 15.8 +/- 8.3 mcg/minute/mL after 3 g of amiodarone. In addition, the systemic clearance of lidocaine decreases from 7.86 +/- 1.83 to 6.31 +/- 2.21 mL/minute/kg body weight. As compared with values before amiodarone administration, the lidocaine elimination half-life and the distribution volume at steady state remain relatively unchanged. Due to the long half-life of amiodarone, clinicians should use caution when administering lidocaine to patients who are receiving or who have recently discontinued amiodarone.
Liothyronine: (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Lithium: (Major) Concomitant use of amiodarone and lithium increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Lofexidine: (Major) Avoid coadministration of lofexidine and amiodarone if possible, due to the potential for additive QT prolongation and torsade de pointes (TdP) and other serious adverse effects. Monitor ECG for QT prolongation and monitor for orthostatic hypotension and bradycardia if coadministration is required. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of TdP. Amiodarone, a CYP2D6 inhibitor and Class III antiarrhythmic agent, is associated with a well established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Lomitapide: (Major) Concomitant use of lomitapide and amiodarone may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Amiodarone is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. In addition, caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as amiodarone. The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and amiodarone is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, a CYP2C9 substrate and strong CYP3A4 inhibitor; amiodarone is a CYP3A4 substrate, a moderate CYP2C9 inhibitor, and moderate CYP3A4 inhibitor.
Loperamide: (Major) Concomitant use of amiodarone and loperamide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase the exposure of loperamide, further increasing the risk for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. Loperamide is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Major) Concomitant use of amiodarone and loperamide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase the exposure of loperamide, further increasing the risk for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. Loperamide is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with amiodarone due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. (Major) 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.
Lorlatinib: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with lorlatinib is necessary; concomitant use may decrease amiodarone plasma concentrations. Amiodarone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
Losartan: (Moderate) Closely monitor blood pressure during coadministration of losartan and amiodarone; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; amiodarone is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure during coadministration of losartan and amiodarone; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; amiodarone is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.
Lovastatin: (Major) In general, in patients taking amiodarone, the lovastatin adult dose should not exceed 40 mg/day PO. Lovastatin doses greater than 40 mg/day should only be used in patients taking amiodarone in whom the benefit is expected to outweigh the increased risk of myopathy. Amiodarone may inhibit lovastatin metabolism via hepatic CYP3A4 isoenzymes. Monitor for signs and symptoms of myopathy in patients receiving amiodarone concurrently with any dose of lovastatin.
Lumacaftor; Ivacaftor: (Major) If amiodarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of amiodarone is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
Lurasidone: (Major) Amiodarone is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of lurasidone and amiodarone may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and amiodarone due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as amiodarone. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP.
Macitentan: (Major) Avoid coadministration of macitentan with amiodarone due to the potential for increases in macitentan exposure and adverse effects. Macitentan is a CYP3A4 and CYP2C9 substrate and amiodarone is a dual moderate CYP3A4 and CYP2C9 inhibitor. Concomitant use is predicted to increase macitentan exposure approximately 4-fold.
Maprotiline: (Major) If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Additionally, amiodarone may also inhibit the CYP2D6 metabolism of maprotiline. The need to coadminister maprotiline with amiodarone should be done with a careful assessment of risk versus benefit; consider alternative therapy to maprotiline.
Maraviroc: (Moderate) Use caution if coadministration of maraviroc with amiodarone is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A4/P-glycoprotein (P-gp) substrate and amiodarone is a CYP3A4/P-gp inhibitor. Monitor for an increase in adverse effects with concomitant use.
Mavacamten: (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting amiodarone therapy. Avoid initiation of amiodarone in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable amiodarone therapy. Expect additive negative inotropic effects during concomitant use of mavacamten and amiodarone. If concomitant therapy with amiodarone is initiated, or if the dose is increased, monitor left ventricular ejection fraction closely until stable doses and clinical response have been achieved. Monitor for decreased efficacy of amiodarone if coadministration with mavacamten is necessary. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions, and may decrease plasma concentrations of amiodarone. Mavacamten is a substrate and moderate inducer of CYP3A and amiodarone is a substrate and moderate inhibitor of CYP3A. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%.
Meclizine: (Moderate) Meclizine is metabolized by CYP2D6, amiodarone is a CYP2D6 inhibitor. Concomitant use may increase meclizine plasma concentrations which may intensify its sedative and anticholinergic effects.
Mefloquine: (Major) There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. In addition, mefloquine is metabolized by CYP3A4 and P-glycoprotein (P-gp). Inhibitors of these enzymes that also prolong the QT interval, such as amiodarone, may decrease the clearance of mefloquine and increase mefloquine systemic exposure further increasing the risk for QT prolongation.
Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with amiodarone is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and amiodarone is a moderate CYP2C9 inhibitor.
Metformin; Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Amiodarone is an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
Metformin; 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.
Methadone: (Major) The need to coadminister methadone with amiodarone should be done with extreme caution and a careful assessment of treatment risks versus benefits. At high doses, methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses averaging approximately 400 mg/day in adult patients. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with inhibitors of these enzymes, such as amiodarone, may result in increased serum concentrations of methadone.
Methamphetamine: (Minor) Amiodarone inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering amiodarone with other CYP2D6 substrates, such as methamphetamine, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
Methimazole: (Moderate) In hyperthyroid patients, the combination of amiodarone and methimazole has been associated with a greater decrease in serum triiodothyronine and thyroxine levels, as compared to the administration of methimazole alone. This may be due to increased iodide release associated with amiodarone. Monitor serum T3 and T4 levels in patients receiving combination therapy.
Methohexital: (Major) In general, adverse cardiovascular effects such as hypotension and atropine resistant bradycardia can occur in patients receiving amiodarone who subsequently are administered any general anesthetics, particularly volatile anesthetics. Due to the extremely long half life of amiodarone, a drug interaction is also possible for days to weeks after discontinuation of amiodarone.
Metoprolol: (Moderate) Concomitant administration of metoprolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of metoprolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant administration of metoprolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of metoprolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Metronidazole: (Major) Concomitant use of 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.
Mexiletine: (Major) Mexiletine is primarily metabolized by CYP2D6 isoenzymes, with a secondary pathway by CYP1A2. Amiodarone inhibits both of these enzymes. However, one study showed no effect of amiodarone on mexiletine clearance in patients with supraventricular arrhythmias.
Midazolam: (Moderate) Coadministration of amiodarone, a CYP3A4 inhibitor, and midazolam, a CYP3A4 substrate, may result in increased serum concentrations of midazolam. The sedative effects of midazolam may be potentiated and prolonged. Monitor patients closely and consider a midazolam dosage reduction in patients receiving concurrent amiodarone therapy.
Midostaurin: (Major) Concomitant use of midostaurin 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.
Mifepristone: (Major) Avoid use of mifepristone with QT interval prolonging drugs. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used. Although specific drug interactions with mifepristone have not been studied, the use of mifepristone with CYP3A inhibitors may result in increased mifepristone concentrations and an increased risk of QT prolongation. Amiodarone is a CYP3A4 inhibitor and is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as amiodarone. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Mirtazapine: (Major) Concomitant use of amiodarone and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with amiodarone and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
Mitotane: (Major) Use caution if mitotane and amiodarone are used concomitantly, and monitor for decreased efficacy of amiodarone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amiodarone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amiodarone.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and amiodarone; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. Mobocertinib is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
Moxifloxacin: (Major) Concomitant use of amiodarone and moxifloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Nadolol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with amiodarone. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; amiodarone is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and amiodarone due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with amiodarone is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and amiodarone. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and amiodarone is a moderate CYP3A and P-gp inhibitor.
Naproxen: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including naproxen. The metabolism of naproxen may be decreased.
Naproxen; Esomeprazole: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including naproxen. The metabolism of naproxen may be decreased.
Naproxen; Pseudoephedrine: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including naproxen. The metabolism of naproxen may be decreased.
Nateglinide: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including nateglinide. The metabolism of nateglinide may be decreased.
Nebivolol: (Moderate) Concomitant administration of nebivolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of nebivolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Nebivolol; Valsartan: (Moderate) Concomitant administration of nebivolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of nebivolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Nefazodone: (Major) Administer amiodarone and nefazodone together with caution. Nefazodone is a potent inhibitor of CYP3A4, and amiodarone is a substrate of CYP3A4. Clinically significant increases in plasma concentrations of other CYP3A4 substrates (e.g., alprazolam, atorvastatin, lovastatin, simvastatin, triazolam) have been reported. If nefazodone and amiodarone are administered concomitantly, increased amiodarone plasma concentrations may occur, which could result in a potential for serious or life-threatening reactions, including cardiac arrhythmias. Furthermore, due to the long half-life of amiodarone, a drug interactions is possible for days to weeks after discontinuation of amiodarone.
Nelfinavir: (Contraindicated) Coadministration of nelfinavir and amiodarone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Nelfinavir 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.
Neratinib: (Major) Avoid concomitant use of amiodarone with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and amiodarone is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A4/P-gp inhibitor may increase neratinib exposure by 299%.
Nevirapine: (Minor) Monitor for decreased efficacy of amiodarone if coadministration with nevirapine is necessary; concomitant use may decrease amiodarone plasma concentrations. Amiodarone is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Niacin; 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.
Nicardipine: (Moderate) Caution should be used when CYP3A4 inhibitors, such as amiodarone, are co-administered with nicardipine, which is a CYP3A4 substrate and inhibitor.
Nifedipine: (Moderate) Amiodarone is a CYP3A4 inhibitor, which theoretically may decrease hepatic clearance and enhance oral bioavailability of nifedipine (CYP3A4 substrate).
Nilotinib: (Major) Avoid the concomitant use of nilotinib with amiodarone as significant prolongation of the QT interval may occur. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Sudden deaths and QT prolongation have been reported with nilotinib therapy. Both amiodarone and nilotinib are moderate inhibitors and substrates of CYP3A4; therefore, levels of either agent may be increased resulting in increased toxicity.
Nimodipine: (Moderate) CYP3A4 inhibitors which theoretically may decrease hepatic metabolism of nimodipine include amiodarone.
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as amiodarone, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Amiodarone is a moderate inhibitor of P-gp and CYP3A4; nintedanib is a P-gp substrate, and also a minor substrate of CYP3A4. Administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and amiodarone is contraindicated; consider an alternative COVID-19 therapy. Coadministration may increase amiodarone exposure resulting in increased toxicity. Amiodarone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) 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.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with amiodarone due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and amiodarone is a CYP3A4 inhibitor.
Non-Ionic Contrast Media: (Major) When injected directly into coronary arteries, contrast media can cause bradycardia and QT interval prolongation; these reactions tend to be less common with nonionic low-osmolar contrast media. In a retrospective review of 21 patients on amiodarone therapy who underwent cardiac catheterization with iohexol, the QTc interval was significantly prolonged 12-24 hours post catheterization from a baseline QTc interval of 433 msec (95%CI 419-483 msec) to 480 msec (95%CI, 422-483 msec) (p< 0.001). No significant change in the QTc interval was seen in non-amiodarone treated control patients. Until more data are available, clinicians should closely monitor patients taking amiodarone during cardiac catheterization with radiopaque contrast agents; EKG monitoring during intra-coronary artery injection of radiopaque contrast agents is recommended.
Ofloxacin: (Major) Concomitant use of ofloxacin 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.
Olanzapine: (Major) Concomitant use of olanzapine 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.
Olanzapine; 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. (Major) Concomitant use of olanzapine 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.
Olanzapine; Samidorphan: (Major) Concomitant use of olanzapine 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.
Olaparib: (Major) Avoid coadministration of olaparib with amiodarone due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after amiodarone is discontinued. Olaparib is a CYP3A substrate and amiodarone is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and amiodarone is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and amiodarone may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If amiodarone is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministr ation with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and amiodarone. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold.
Omeprazole; Amoxicillin; Rifabutin: (Major) Certain rifamycins, including rifampin, rifabutin, and rifapentine, may induce CYP3A4 metabolism of amiodarone, resulting in decreased serum concentrations of amiodarone and its active metabolite (desethylamiodarone) and potential decreased efficacy. A possible drug interaction has been reported with rifampin and amiodarone in one patient receiving therapy with ICD and amiodarone for history of atrial and ventricular arrhythmias; this patient had evidence of reduced serum amiodarone and metabolite levels, loss of antiarrhythmic efficacy, and required hospitalization.
Ondansetron: (Major) If possible, avoid coadministration of amiodarone and ondansetron. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. 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, amiodarone may inhibit ondansetron metabolism via multiple pathways (CYP1A2, CYP2D6, CYP3A4, P-glycoprotein), increasing the potential for ondansetron-related adverse events.
Oritavancin: (Moderate) Amiodarone is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of amiodarone may be reduced if these drugs are administered concurrently.
Orlistat: (Major) In one pharmacokinetic study of healthy volunteers, administration of orlistat 120 mg three times daily for 13 days and a single orlistat dose of 120 mg on the morning of Day 14 in addition to a single dose of 1200 mg amiodarone on Day 4 resulted in a 23% to 27% reduction in the systemic exposure to amiodarone and its metabolite desethylamiodarone. The effect of initiating treatment with orlistat in patients stable on amiodarone therapy has not been studied; however, a reduced therapeutic effect of amiodarone is possible. The clinical response to amiodarone should be monitored closely if orlistat is initiated during chronic amiodarone therapy.
Osilodrostat: (Major) Concomitant use of osilodrostat 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 discontinuation.
Osimertinib: (Major) Concomitant use of osimertinib 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.
Ospemifene: (Major) Avoid the use of ospemifene in a patient taking amiodarone, if possible. Amiodarone inhibits CYP2C9 and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by these two CYP450 enzymes, including ospemifene. The increase in serum concentration may increase the risk of ospemifene-related adverse reactions, including hot flashes, changes in vaginal bleeding, and a risk for thromboembolism or stroke. Consider an alternative to ospemifene therapy.
Oxaliplatin: (Major) Concomitant use of oxaliplatin 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.
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.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking amiodarone due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. 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.
Pacritinib: (Major) Avoid concurrent use of pacritinib with amiodarone due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Paliperidone: (Major) Concomitant use of paliperidone 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.
Palovarotene: (Major) Avoid concomitant use of palovarotene and amiodarone due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Panobinostat: (Major) Concomitant use of panobinostat 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.
Paricalcitol: (Moderate) Concomitant use of amiodarone, a CYP3A4 inhibitor, and paricalcitol, a CYP3A4 substrate, may result in increased paricalcitol concentrations. A paricalcitol dose reduction may be necessary if these drugs are used together.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with amiodarone is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and amiodarone is a moderate CYP2D6 inhibitor.
Pasireotide: (Major) Concomitant use of pasireotide 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.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and amiodarone have been reported to prolong the QT interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. If pazopanib and amiodarone must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a substrate for CYP3A4 and P-glycoprotein (P-gp) and a weak inhibitor of CYP3A4. Amiodarone is a CYP3A4 and P-gp inhibitor and a CYP3A4 substrate. Concurrent administration may result in increased concentrations of pazopanib and/or amiodarone. Use caution if concurrent administration is necessary.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and amiodarone due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If amiodarone is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of amiodarone. Pemigatinib is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Pentamidine: (Major) Concomitant use of pentamidine 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.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Perphenazine: (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. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (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. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and amiodarone due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease amiodarone plasma concentrations and reduce its efficacy. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If amiodarone is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of amiodarone. Additionally, monitor for evidence of hepatotoxicity if coadministration is necessary and avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer, amiodarone is a CYP3A substrate and moderate CYP3A inhibitor, and both medications have been associated with hepatotoxicity. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenylephrine: (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Phenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with amiodarone due to increased phenytoin steady-state concentrations. Concomitant use may also reduce amiodarone exposure and efficacy. Phenytoin is a CYP2C9 substrate and a strong CYP3A inducer; amiodarone is a CYP3A substrate and a CYP2C9 inhibitor.
Pimavanserin: (Major) Concomitant use of pimavanserin 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.
Pimozide: (Contraindicated) Avoid concomitant use of pimozide and amiodarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Pindolol: (Moderate) Amiodarone prolongs AV nodal refractory period and decreases sinus node automaticity. Because beta-blockers have similar effects, concomitant administration of beta-blockers with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. While combination amiodarone and beta-blockers should be used cautiously and with close monitoring, it should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Pirfenidone: (Major) Avoid the coadministration of amiodarone and pirfenidone. Concomitant use may result in increased plasma concentrations of pirfenidone. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1 and should not be used concomitantly with drugs that are moderate or strong inhibitors of both CYP1A2 and another enzyme involved in its metabolism. Amiodarone inhibits CYP1A2, CYP2C9, and CYP2D6.
Piroxicam: (Minor) Amiodarone inhibits cytochrome P450 2C9. Caution is recommended when administering amiodarone with other CYP2C9 substrates including piroxicam.
Pitolisant: (Major) Concomitant use of pitolisant 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 discontinuation.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking amiodarone due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. 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.
Porfimer: (Major) Avoid coadministration of porfimer with amiodarone due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like amiodarone may increase the risk of a photosensitivity reaction.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and amiodarone is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Both posaconazole and amiodarone are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of amiodarone. Further, amiodarone is an inhibitor of the drug efflux protein, P-glycoprotein (P-gp), for which posaconazole is a substrate and an inhibitor. This complex interaction may ultimately result in altered plasma concentrations of both posaconazole and amiodarone. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as amiodarone.
Pralsetinib: (Major) Avoid concomitant use of amiodarone with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A and P-gp substrate and amiodarone is a combined moderate CYP3A and P-gp inhibitor. Coadministration with another combined moderate CYP3A and P-gp inhibitor increased the overall exposure of pralsetinib by 108%.
Pretomanid: (Major) Avoid coadministration of pretomanid with amiodarone, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
Prilocaine; Epinephrine: (Moderate) Monitor patients who receive epinephrine while concomitantly taking antiarrhythmics for the development of arrhythmias. Epinephrine may produce ventricular arrhythmias in patients who are on drugs that may sensitize the heart to arrhythmias.
Primaquine: (Major) Concomitant use of primaquine 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.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and amiodarone due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and amiodarone is a dual moderate CYP3A and P-gp inhibitor. Concomitant use with other dual moderate CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 2- to 3.6-fold.
Procainamide: (Major) Amiodarone may increase procainamide serum concentrations, with potential for drug toxicity. Procainamide and N-acetylprocainamide or NAPA (a pharmacologically active metabolite) serum concentrations increase by approximately 55 and 33%, respectively, during the first 7 days of concomitant amiodarone therapy. The precise pharmacokinetic mechanism of this interaction has not been elucidated, although a reduction the renal clearance of both parent and metabolite, as well as a reduction in hepatic metabolism seem likely. Additive electrophysiologic activity occurs with combination therapy and prolonged QT and QRS intervals or acceleration of preexisting ventricular tachycardia may result. Careful clinical observation of the patient as well as close monitoring of the ECG and serum procainamide and NAPA concentrations is essential with adjustment of the procainamide dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. If amiodarone is to be coadministered with procainamide, the manufacturer recommends reducing the procainamide dosage by 33%. Combination antiarrhythmic therapy is reserved for patients with refractory life-threatening arrhythmias. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Prochlorperazine: (Minor) The concomitant use of amiodarone and other drugs known to prolong the QT interval should only be done after careful assessment of risks versus benefits. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Prochlorperazine is associated with a possible risk for QT prolongation.
Promethazine: (Major) 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.
Promethazine; Dextromethorphan: (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.
Promethazine; Phenylephrine: (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) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
Propafenone: (Major) The use of propafenone with other antiarrhythmics has not been well-studied. Class III antiarrhythmics are associated with QT prolongation and ventricular arrhythmias, including torsades de pointes (TdP). The concurrent use of amiodarone with propafenone is not recommended by the manufacturer, In addition to potential for additive effects on cardiac conduction and repolarization, amiodarone is a CYP2D6 inhibitor and may inhibit the metabolism of propafenone (CYP2D6 substrate). In general, combination therapy with Class III and Class IC antiarrhythmics has been reported to increase the risk of proarrhythmias. In one pediatric trial, combined therapy with amiodarone and propafenone resulted in electrocardiographic abnormalities. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Propofol: (Major) In general, adverse cardiovascular effects such as hypotension and atropine-resistant bradycardia can occur in patients receiving amiodarone who subsequently are administered any general anesthetics, particularly volatile anesthetics. Due to the extremely long half-life of amiodarone, a drug interaction is also possible for days to weeks after discontinuation of amiodarone. For example, when fentanyl was administered to patients receiving amiodarone, the incidence of bradycardia and other adverse cardiovascular effects was much higher than in patients not on amiodarone who received fentanyl.
Propranolol: (Moderate) Concomitant administration of propranolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of propranolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant administration of propranolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of propranolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Propylthiouracil, PTU: (Moderate) Amiodarone contains iodine and excess intake of iodine/iodide can decrease the efficacy of propylthiouracil. Clinicians should consider the possibility of reduced response to propylthiouracil if amiodarone is used concomitantly.
Quazepam: (Moderate) Amiodarone is a CYP3A4 inhibitor and may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity.
Quetiapine: (Major) Concomitant use of amiodarone and quetiapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Quinidine: (Major) Amiodarone coadministration increases quinidine concentrations by about 33% after 2 days, by decreasing its renal clearance or by inhibiting its hepatic metabolism. Quinidine may also be displaced from tissue and protein binding sites. Prolongation of the QT interval is well documented with quinidine, and the addition of amiodarone may increase this effect, placing the patient at an increased risk for the development of torsade de pointes. Careful clinical observation of the patient as well as close monitoring of the ECG and serum quinidine concentrations are essential with adjustment of the quinidine dosing regimen performed as necessary to avoid enhanced toxicity or pharmacodynamic effects. An empiric reduction of the quinidine dose by 33-50% is suggested within 2 days following initiation of amiodarone therapy, with consideration given to immediately discontinuing of quinidine once amiodarone therapy is begun. Combination antiarrhythmic therapy is reserved for patients with refractory life-threatening arrhythmias. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Quinine: (Major) Concurrent use of quinine and amiodarone should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Amiodarone, a Class III antiarrhythmic agent, is also 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, concentrations of both drugs may be increased during concomitant use. Amiodarone is a CYP3A4 substrate and P-glycoprotein (P-gp) inhibitor and quinine is a CYP3A4 inhibitor and P-gp substrate.
Quizartinib: (Major) Concomitant use of quizartinib 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.
Ramelteon: (Moderate) Caution is recommended during concomitant use of ramelteon and amiodarone. Because ramelteon is metabolized by CYP3A4 and CYP1A2, use with CYP3A4 and CYP1A2 inhibitors, such as amiodarone, may increase exposure to ramelteon and the potential for adverse effects. If amiodarone must be administered with ramelteon, monitor the patient closely for toxicity due to increased ramelteon concentrations.
Ranolazine: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with amiodarone is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A and P-gp substrate and amiodarone is a moderate CYP3A inhibitor and inhibitor of P-gp. Coadministration with another moderate CYP3A inhibitor increased plasma levels of ranolazine by 50% to 130%.
Rasagiline: (Major) Do not exceed a rasagiline dose of 0.5 mg once daily when coadministered with amiodarone. Coadministration may result in increased rasagiline concentrations. Rasagiline is primarily metabolized by CYP1A2; amiodarone is a moderate CYP1A2 inhibitor. When rasagiline was administered with a strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%.
Red Yeast Rice: (Contraindicated) As an inhibitor of hepatic CYP3A4 isoenzymes, amiodarone has the potential to increase serum concentrations of HMG-CoA reductase inhibitors that are CYP3A4 substrates. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with amiodarone. Monitor for signs and symptoms of myopathy in patients receiving amiodarone concurrently with red yeast rice.
Relugolix: (Major) Avoid concomitant use of relugolix and oral amiodarone. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer amiodarone at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of amiodarone is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Relugolix is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral amiodarone. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer amiodarone at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of amiodarone is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Relugolix is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor.
Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Amiodarone is an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
Ribociclib: (Major) Avoid coadministration of ribociclib with amiodarone due to an increased risk for QT prolongation and torsade de pointes (TdP). The systemic exposure to amiodarone may also increase resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Amiodarone, a Class III antiarrhythmic agent, is a CYP3A4 substrate that is also associated with a well-established risk of QT prolongation; although the frequency is less with amiodarone than with other Class III agents, amiodarone is additionally still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with amiodarone due to an increased risk for QT prolongation and torsade de pointes (TdP). The systemic exposure to amiodarone may also increase resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Amiodarone, a Class III antiarrhythmic agent, is a CYP3A4 substrate that is also associated with a well-established risk of QT prolongation; although the frequency is less with amiodarone than with other Class III agents, amiodarone is additionally still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Rifabutin: (Major) Certain rifamycins, including rifampin, rifabutin, and rifapentine, may induce CYP3A4 metabolism of amiodarone, resulting in decreased serum concentrations of amiodarone and its active metabolite (desethylamiodarone) and potential decreased efficacy. A possible drug interaction has been reported with rifampin and amiodarone in one patient receiving therapy with ICD and amiodarone for history of atrial and ventricular arrhythmias; this patient had evidence of reduced serum amiodarone and metabolite levels, loss of antiarrhythmic efficacy, and required hospitalization.
Rifampin: (Major) Certain rifamycins, including rifampin, rifabutin, and rifapentine, may induce CYP3A4 metabolism of amiodarone, resulting in decreased serum concentrations of amiodarone and its active metabolite (desethylamiodarone) and potential decreased efficacy. A possible drug interaction has been reported with rifampin and amiodarone in one patient receiving therapy with ICD and amiodarone for history of atrial and ventricular arrhythmias; this patient had evidence of reduced serum amiodarone and metabolite levels, loss of antiarrhythmic efficacy, and required hospitalization.
Rifapentine: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with rifapentine is necessary. Coadministration may decrease amiodarone plasma concentrations. Amiodarone is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with amiodarone is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and amiodarone is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Major) Concomitant use of rilpivirine 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. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Riluzole: (Moderate) Coadministration of riluzole with amiodarone may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and hepatotoxicity. Monitor for signs and symptoms of hepatic injury during coadministration. Discontinue riluzole if clinical signs of liver dysfunction are present. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with amiodarone; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate; amiodarone is a moderate CYP3A4 inhibitor and P-gp inhibitor.
Risperidone: (Major) Concomitant use of risperidone 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.
Ritlecitinib: (Moderate) If concomitant use of ritlecitinib 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; ritlecitinib is a moderate CYP3A inhibitor.
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.
Rivaroxaban: (Moderate) Avoid coadministration of rivaroxaban and amiodarone in patients with renal impairment (CrCL 15 to 79 mL/minute) unless the potential benefit justifies the potential risk. Rivaroxaban is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and amiodarone is a P-gp and moderate CYP3A4 inhibitor. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A4/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCL 50 to 79 mL/minute) and by 99% in patients with moderate renal impairment (CrCL 30 to 49 mL/minute) compared to patients with normal renal function (CrCL greater than 80 mL/minute); similar trends in pharmacodynamic effects were also observed.
Romidepsin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and amiodarone, a CYP3A4 inhibitor and a P-gp inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. In addition, romidepsin has been reported to prolong the QT interval. Amiodarone also prolongs the QT interval. If romidepsin and amiodarone must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
Ropinirole: (Moderate) Amiodarone inhibits cytochrome P450 CYP1A2 isoenzymes, which can potentially lead to increased plasma concentrations of CYP1A2 substrates like ropinirole.
Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as amiodarone, may occur during concurrent use with rufinamide.
Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as amiodarone, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
Saquinavir: (Contraindicated) The concurrent use of amiodarone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Amiodarone and saquinavir are both substrates and inhibitors of CYP3A4. The coadministration of saquinavir/ritonavir and amiodarone results in increased plasma concentrations of both amiodarone and saquinavir, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as all Class III antiarrhythmics.
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.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone, a CYP3A4 substrate and a moderate CYP3A4 inhibitor, such as amiodarone, may increase the serum concentration of segesterone.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and amiodarone due to the risk of additive QT prolongation and increased selpercatinib exposure resulting in increased treatment-related adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If amiodarone is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of amiodarone. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-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). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase selpercatinib exposure by 60% to 99%.
Selumetinib: (Major) Avoid coadministration of selumetinib and amiodarone due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If amiodarone is discontinued, resume the original selumetinib dose after 3 elimination half-lives of amiodarone. Selumetinib is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Sertraline: (Major) Concomitant use of sertraline 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.
Sevoflurane: (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.
Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with amiodarone is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A4 inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amiodarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amiodarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amiodarone and simvastatin against the potential risks. Amiodarone increases the simvastatin exposure by approximately 2-fold.
Siponimod: (Major) Concomitant use of siponimod and amiodarone is not recommended due to a significant increase in siponimod exposure. Additionally, both drugs are associated with QT prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Siponimod is a CYP2C9 and CYP3A4 substrate; amiodarone is a moderate CYP2C9/CYP3A4 dual inhibitor. Coadministration with another moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amiodarone. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and amiodarone is a moderate CYP3A and P-gp inhibitor. Concomitant use of other moderate CYP3A and P-gp inhibitors increased sirolimus overall exposure by 2.2- to 4.2-fold.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate 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.
Sofosbuvir: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting sofosbuvir should also undergo similar cardiac monitoring as outlined above.
Sofosbuvir; Velpatasvir: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting sofosbuvir should also undergo similar cardiac monitoring as outlined above.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting sofosbuvir should also undergo similar cardiac monitoring as outlined above.
Solifenacin: (Major) Concomitant use of solifenacin 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.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and amiodarone; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and amiodarone is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than14 days.
Sorafenib: (Major) Concomitant use of sorafenib 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.
Sotalol: (Major) Sotalol administration is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Drugs that prolong the QT interval should be used with extreme caution in combination with sotalol. Ventricular tachycardia, including torsade de pointes and monomorphic ventricular tachycardia can occur with excessive prolongation of the QT interval. Before initiating sotalol, the previous Class I and Class III antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of (2-3) p lasma half-lives for the discontinued drug. Class III antiarrhythmics (e.g., amiodarone, dofetilide) are associated with QT prolongation and ventricular arrhythmias; concurrent exposure with sotalol could increase the risk of drug-induced proarrhythmias. Because of unpredictable pharmacokinetics with amiodarone, sotalol should not be initiated following discontinuation of amiodarone therapy until the QTc interval has normalized. In clinical trials, patients were not allowed to receive sotalol if they had received amiodarone for > 1 month in the previous 3 months.
Sotorasib: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with sotorasib is necessary; concomitant use may decrease amiodarone plasma concentrations. Amiodarone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with amiodarone is necessary. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%.
St. John's Wort, Hypericum perforatum: (Major) Avoid use of St. John's wort in patients taking amiodarone if possible. Monitor for decreased efficacy of amiodarone if coadministration with St. John's Wort is necessary. Reduced amiodarone serum levels are expected, which can compromise amiodarone efficacy. Amiodarone is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if amiodarone must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. If amiodarone is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a moderate CYP3A4 inhibitor like amiodarone can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If amiodarone is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfonylureas: (Minor) Amiodarone inhibits cytochrome P450 2C9. Caution is recommended when administering amiodarone with other CYP2C9 substrates including sulfonylureas.
Sumatriptan; Naproxen: (Minor) Amiodarone inhibits CYP2C9. Caution is recommended when administering amiodarone with CYP2C9 substrates including naproxen. The metabolism of naproxen may be decreased.
Sunitinib: (Major) Concomitant use of sunitinib 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.
Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with amiodarone. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
Tacrolimus: (Major) Amiodarone and tacrolimus both prolong the QT interval; also, both drugs are metabolized by CYP3A4, and amiodarone is also a CYP3A4 inhibitor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are subtrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of torsade de pointes may be increased.
Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with amiodarone is necessary. Tadalafil is a CYP3A4 substrate and amiodarone is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Talazoparib: (Major) Avoid coadministration of amiodarone with talazoparib when used for the treatment of breast cancer due to increased talazoparib exposure. If concomitant use is unavoidable, reduce the dose of talazoparib to 0.75 mg PO once daily. If amiodarone is discontinued, wait at least 3 to 5 half-lives of amiodarone before increasing the dose of talazoparib to the prior dose used before amiodarone therapy. A talazoparib dose reduction is not necessary for patients with prostate cancer; monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a P-gp substrate and amiodarone is a P-gp inhibitor. In clinical trials, coadministration with amiodarone increased talazoparib exposure by 45%.
Tamoxifen: (Major) Concomitant use of tamoxifen 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 discontinuation of amiodarone.
Tamsulosin: (Moderate) Use caution if coadministration of amiodarone with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A4 and CYP2D6 substrate and amiodarone is a moderate CYP3A4 and CYP2D6 inhibitor. The effects of concomitant administration of a moderate CYP3A4 and CYP2D6 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 and CYP2D6 inhibition.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with amiodarone as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If amiodarone is discontinued, wait at least 3 half-lives of amiodarone before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telavancin: (Major) Concomitant use of telavancin 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.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with amiodarone is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor. Concomitant use may lead to increased concentrations of temsirolimus.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with amiodarone may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and amiodarone is a P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and amiodarone is a P-gp inhibitor.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering amiodarone. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may substantially increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9 and CYP3A4; amiodarone is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
Tetrabenazine: (Major) Concomitant use of tetrabenazine 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 atomoxetine, a drug interaction is possible for days to weeks after drug discontinuation.
Tezacaftor; Ivacaftor: (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. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Thalidomide: (Moderate) Thalidomide and other agents that cause peripheral neuropathy such as amiodarone should be used cautiously due to the potential for additive effects.
Theophylline, Aminophylline: (Moderate) Amiodarone inhibits cytochrome P450 CYP1A2 isoenzymes, which can potentially lead to increased plasma concentrations of CYP1A2 substrates like aminophylline. (Moderate) Amiodarone inhibits cytochrome P450 CYP1A2 isoenzymes, which can potentially lead to increased plasma concentrations of CYP1A2 substrates like theophylline.
Thioridazine: (Contraindicated) Avoid concomitant use of thioridazine and amiodarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Thiothixene: (Contraindicated) Amiodarone prolongs the QT interval and could lead to additive orthostatic hypotension and/or prolonged QT syndrome and torsade de pointes when combined with thiothixene and use should be done with caution and close monitoring, if not avoided.
Thyroid hormones: (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Ticagrelor: (Moderate) Coadministration of ticagrelor and amiodarone may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
Timolol: (Moderate) Concomitant administration of timolol with amiodarone may cause additive electrophysiologic effects (slow sinus rate or worsen AV block), resulting in symptomatic bradycardia, sinus arrest, and atrioventricular block. This is particularly likely in patients with preexisting partial AV block or sinus node dysfunction. Because amiodarone is an inhibitor of CYP2D6, decreased clearance of timolol, which is a CYP2D6 substrate, is also possible. Caution and close monitoring are recommended during coadministration; a dose reduction of one or both drugs may be needed based on response. It should be noted that post-hoc analysis of amiodarone therapy in patients after acute myocardial infarction in two clinical trials revealed that amiodarone in addition to a beta-blocker significantly lowered the incidence of cardiac and arrhythmic death or resuscitated cardiac arrest when compared with amiodarone or beta-blocker therapy alone.
Tipranavir: (Contraindicated) Coadministration of tipranavir and amiodarone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Tipranavir inhibits the CYP3A4 metabolism of amiodarone resulting in elevated amiodarone plasma concentrations.
Tizanidine: (Major) Avoid concomitant use of tizanidine and amiodarone as increased serum concentrations of tizanidine may occur. If use together is necessary, initiate tizanidine with the 2 mg dose and increase daily in 2 to 4 mg increments based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Tolterodine: (Major) Avoid the concomitant use of amiodarone with other agents that prolong the QT interval, such as tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Amiodarone is an inhibitor of CYP3A4 and CYP2D6, and tolterodine is a CYP3A4 and CYP2D6 substrate; administering these drugs together may result in increased tolterodine concentrations.
Tolvaptan: (Major) Avoid coadministration of amiodarone when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with amiodarone. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
Topotecan: (Major) Avoid coadministration of amiodarone with oral topotecan due to increased topotecan exposure; amiodarone may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and amiodarone is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Toremifene: (Major) Concomitant use of toremifene 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.
Torsemide: (Moderate) 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. In addition, monitor the diuretic effect and blood pressure if torsemide and amiodarone are administered together. The torsemide dose may need to be reduced. The concomitant use of torsemide and amiodarone can decrease torsemide clearance and increase torsemide plasma concentrations. Torsemide is a substrate of CYP2C9; amiodarone inhibits CYP2C9.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with amiodarone is necessary. If amiodarone is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and amiodarone is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with amiodarone is necessary. If amiodarone is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and amiodarone is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with amiodarone. Coadministration may increase the exposure of verapamil. Additive effects on cardiac contractility and/or AV conduction are also possible. Verapamil is a substrate of CYP3A4 and amiodarone is a moderate CYP3A4 inhibitor.
Trazodone: (Major) Concomitant use of amiodarone and trazodone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Tretinoin, ATRA: (Moderate) Monitor for pseudotumor cerebri (benign intracranial hypertension) during concomitant amiodarone and tretinoin use due to increased risk for the condition. Both lithium and tretinoin are associated with pseudotumor cerebri.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with amiodarone and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and amiodarone is a moderate CYP3A inhibitor.
Triclabendazole: (Major) Concomitant use of triclabendazole 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.
Trifluoperazine: (Minor) The concomitant use of amiodarone and other drugs known to prolong the QT interval should only be done after careful assessment of risks versus benefits. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Triptorelin: (Major) Concomitant use of triptorelin 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.
Tucatinib: (Moderate) If concomitant use of tucatinib with amiodarone is necessary, consider serial measurement of amiodarone serum concentrations. Coadministration may increase amiodarone concentrations resulting in amiodarone-related adverse events. Tucatinib is a strong CYP3A4 inhibitor and amiodarone is a CYP3A substrate.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with amiodarone. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-gp substrate; amiodarone is a moderate CYP3A4 inhibitor and a P-gp inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Vandetanib: (Major) Concomitant use of vandetanib 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.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with amiodarone due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Vardenafil is primarily metabolized by CYP3A and amiodarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the AUC of vardenafil by 4-fold.
Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as amiodarone, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval 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. Also, amiodarone is a CYP3A4 substrate/inhibitor and a P-glycoprotein (P-gp) inhibitor, while vemurafenib is CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. Decreased amiodarone and increased vemurafenib concentrations may occur with concomitant use.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with amiodarone due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of amiodarone. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; amiodarone is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Venlafaxine: (Major) Concomitant use of amiodarone and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with amiodarone. Coadministration may increase the exposure of verapamil. Additive effects on cardiac contractility and/or AV conduction are also possible. Verapamil is a substrate of CYP3A4 and amiodarone is a moderate CYP3A4 inhibitor.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with amiodarone is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like amiodarone may increase the risk of a photosensitivity reaction.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with amiodarone is necessary. Vinblastine is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vincristine Liposomal: (Major) Amiodarone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
Vincristine: (Major) Amiodarone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amiodarone is necessary. Vinorelbine is a CYP3A4 substrate and amiodarone is a moderate CYP3A4 inhibitor.
Voclosporin: (Major) Avoid coadministration of amiodarone and voclosporin if possible due to the risk of QT prolongation. Voclosporin exposure and the risk for voclosporin-related adverse effects may also be increased. If concomitant use is necessary, reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening. Voclosporin is a sensitive CYP3A4 substrate that is associated with QT prolongation at supratherapeutic doses. Amiodarone is a moderate CYP3A4 inhibitor that is associated with a well-established risk of QT prolongation and torsade de pointes. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
Vonoprazan; Amoxicillin; 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.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and amiodarone. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with amiodarone, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Major) Avoid coadministration of amiodarone and voriconazole due to the potential for increased amiodarone concentrations and additive effects on the QT interval. There have been reports of prolonged QT intervals, with or without torsade de pointes (TdP), during concomitant use of amiodarone and azole antifungals. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Voriconazole has also been associated with QT prolongation and rare cases of TdP, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with amiodarone (a CYP3A4 substrate) may result in elevated amiodarone plasma concentrations and could further increase the risk for adverse events, including QT prolongation. Similarly, amiodarone may inhibit the CYP2C9 metabolism of voriconazole, and could theoretically lead to elevated plasma concentrations of voriconazole when coadministered. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Vorinostat: (Major) Concomitant use of vorinostat 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.
Voxelotor: (Moderate) If concomitant use of voxelotor 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; voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Major) Closely monitor the INR if coadministration of warfarin with amiodarone is necessary as concurrent use results in at least a doubling of prothrombin time, significantly increasing the INR in virtually all patients and can cause serious or potentially fatal hemorrhagic complications. Consider an empiric 33% to 50% reduction in warfarin dosage when amiodarone therapy is initiated. Intensive clinical observation for bleeding and frequent determination of PT and INR values are warranted. Amiodarone is a moderate CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. Amiodarone is also a CYP3A4/CYP1A2 inhibitor, and the R-enantiomer is a CYP3A4/CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Interactions may be seen as early as 4 to 6 days or as delayed as weeks following the initial administration of the drugs in combination. Given the extremely long half-life of amiodarone, the interaction may persist for weeks or even months after discontinuation of amiodarone.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with amiodarone. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of amiodarone, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
Ziprasidone: (Contraindicated) Avoid concomitant use of ziprasidone and amiodarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
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
Maximum Dosage
Individualize maximum amiodarone dosage according to clinical goals, phase of dosage titration, and close monitoring of efficacy and safety parameters.
Adults300 mg/dose IV, 1 mg/min continuous infusion, and up to 1600 mg/DAY PO.
Geriatric300 mg/dose IV, 1 mg/min continuous infusion, and up to 1600 mg/DAY PO.
Adolescents5 mg/kg/dose (Max: 300 mg/dose) IV, 15 mcg/kg/minute continuous IV infusion, and up to 25 mg/kg/DAY (Max: 1,600 mg/DAY) PO has been reported.
Children5 mg/kg/dose (Max: 300 mg/dose) IV, 15 mcg/kg/minute continuous IV infusion, and up to 25 mg/kg/DAY (Max: 1,600 mg/DAY) PO has been reported.
Infants5 mg/kg/dose IV, 15 mcg/kg/minute continuous IV infusion, and up to 25 mg/kg/DAY or 800 mg/1.73m2/DAY PO have been reported.
Neonates5 mg/kg/dose IV, 15 mcg/kg/minute continuous IV infusion, and up to 25 mg/kg/DAY or 800 mg/1.73m2/DAY PO have been reported.
Mechanism Of Action
Amiodarone is both an antiarrhythmic and a potent vasodilator. Amiodarone is considered a 'broad spectrum' antiarrhythmic with multiple and complex electrophysiologic effects. Although its exact mechanism of action is not completely known, using the traditional Vaughn-Williams classification scheme for antiarrhythmic compounds, amiodarone is considered a class III compound.
Like the other class III antiarrhythmic agents, bretylium and sotalol, amiodarone acts directly on the myocardium to delay repolarization and increase the duration of the action potential. Delayed repolarization is a result of inhibition of potassium ion fluxes that normally occur during phase 2 and 3 of the action potential.[24497] This results in prolongation of the effective refractory period in all cardiac tissue (e.g., atria, ventricles, AV node, and His-Purkinje system). Amiodarone exerts this antifibrillatory effect without significantly altering the myocardial membrane potential.
By definition, class III agents act only on the repolarization phase of the action potential and therefore should leave conduction unchanged. However, amiodarone possesses actions similar to both class II and class IV antiarrhythmics: Amiodarone is a weak sodium channel blocker (class I effect). The result of this cellular action is a slowing of the upstroke velocity of phase 0 which reduces the rate of membrane depolarization and impulse conduction. Amiodarone also depresses automaticity of both the SA and AV nodes directly (class II effect) and slows conduction in the His-Purkinje system and in the accessory pathway of patients with Wolff-Parkinson-White syndrome.[24497]
Amiodarone also noncompetitively inhibits alpha- and beta-receptors, and possesses both vagolytic and calcium-channel blocking properties. The drug relaxes both smooth and cardiac muscle, causing decreases in coronary and peripheral vascular resistance, left ventricular end-diastolic pressure (LVEDP) and systolic blood pressure, thereby decreasing afterload. Transient, dose-related increases in coronary blood flow may occur following intravenous amiodarone administration and is thought to be due to direct relaxation of coronary arteries, reductions in myocardial contractility and LVEDP. This activity may result in a decrease in myocardial oxygen demand (MVO2).
Amiodarone has a complex effect on thyroid hormone metabolism and frequently alters thyroid function tests during chronic therapy. Amiodarone can cause either hypothyroidism or hyperthyroidism, with hyperthyroidism being the most dangerous due to the risk of thyrotoxicosis. Since approximately 37% of amiodarone (by weight) is iodine, a maintenance dose of 200 to 600 mg/day results in a daily intake of organic iodide of 75 to 225 mg, at least 10% of which is deiodinated.[24731] Because the normal dietary requirement of iodine is less than 1 mg/day, therapeutic doses of amiodarone result in a massive increase in total iodine stores. In addition, amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) by inhibiting type I iodothyronine 5'-deiodinase. Amiodarone may increase T4 concentrations, decrease T3 concentrations, and increase concentrations of inactive reverse T3 (rT3) in clinically euthyroid patients.[28224] Amiodarone also inhibits entry of thyroxine and triiodothyronine into peripheral tissue. TSH usually increases, but after 3 months of continuous administration, TSH concentrations often return to normal.[24731] Because of the slow elimination of amiodarone and its metabolites and high plasma iodide concentrations, abnormal thyroid function tests may persist for several weeks or months after drug discontinuation.
Pharmacokinetics
Amiodarone is administered orally and intravenously. The therapeutic range is considered to be roughly 1 to 2.5 mcg/mL, although an absolute relationship between serum concentration and pharmacodynamic effect has not been established.
Once in the systemic circulation, amiodarone distributes extensively throughout the body including into adipose, hepatic, myocardial, pulmonary, kidney, thyroid, skin, ocular, splenic and pancreatic tissues, and concentrates in fluids including bile, semen, and saliva. As a reflection of its extensive distribution in the body, the volume of distribution averages approximately 70 L/kg. It is the extensive accumulation of amiodarone (especially in adipose tissue) which accounts for its prolonged elimination, as well as the persistence of adverse effects after discontinuation of therapy. The principle metabolite of amiodarone (DEA) distributes into the same tissues as the parent drug, albeit to a lesser extent in adipose tissue. Both amiodarone and DEA distribute into and concentrate in breast milk. Amiodarone and DEA are extensively bound (more than 99%) to plasma proteins, primarily albumin and alpha-1 acid glycoprotein.[23800]
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6, P-gp, OCT2
Amiodarone is extensively metabolized in the liver. N-desethyl-amiodarone (DEA) is the major active metabolite in humans. DEA serum concentrations above 0.05 mg/L are not usually seen until after several days of continuous infusion, but with prolonged therapy reach approximately the same concentration as amiodarone. Amiodarone is metabolized to N-desethyl-amiodarone by the cytochrome P450 (CYP450) enzyme group, specifically CYP3A4 and CYP2C8. The highly variable systemic availability of oral amiodarone may be attributed to large interindividual variability in CYP3A4 activity. In vitro, amiodarone and DEA show potential to inhibit CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6, and CYP2C8. Amiodarone and DEA also have the potential to inhibit P-glycoprotein (P-gp) and organic cation transporter (OCT2). Therefore, amiodarone has the potential to interact with substrates affected by these pathways.[28224]
Amiodarone and DEA are virtually exclusively eliminated hepatically, although biliary excretion may play a small role in the excretion of amiodarone. As a consequence of its distribution characteristics, the elimination of amiodarone occurs in a biphasic fashion, with an initial reduction of plasma concentrations of 50% occurring within 10 days. The terminal elimination half-life ranges from 26 to 107 days with a mean of around 53 days.[24497]
After oral administration, amiodarone is absorbed incompletely and slowly from the GI tract, with the absolute bioavailability ranging from 20% to 86%, but averages approximately 50%.[24497] Amiodarone may undergo metabolism in the intestinal lumen and GI mucosa and first pass metabolism in the liver, all of which occur to a variable degree, possibly explaining the variability in bioavailability. The highly variable systemic availability of oral amiodarone also may be attributed to large interindividual variability in CYP3A4 activity. A single oral dose of 400 mg of amiodarone achieves peak plasma concentrations within 3 to 7 hours. Steady state plasma concentrations are generally not reached for 1 to 5 months after continuous oral administration, with the onset of action delayed for as long as 2 to 3 months, unless aggressive loading doses are utilized.
Pregnancy And Lactation
Amiodarone crosses the placenta and can cause fetal harm when administered to a pregnant woman. Inform the patient of the potential hazard to the fetus if amiodarone is administered during pregnancy or if the patient becomes pregnant while taking amiodarone. Reported risks include neonatal bradycardia; QT prolongation; periodic ventricular extrasystoles; neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure; neonatal hyperthyroxinemia; neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia; jerk nystagmus with synchronous head titubation; fetal growth retardation; and premature birth. When pregnant rabbits were administered amiodarone at doses approximately 2.7 times the maximum recommended human maintenance dose (MRHD), abortions occurred in more than 90% of the animals. Doses of 0.8 times the MRHD were associated with slight displacement of the testes and increased incidence of incomplete ossification of some skull and digital bones. At doses 1.6 times the MRHD, fetal body weights were reduced, and at doses 3.2 times the MRHD, fetal resorption was increased.
Amiodarone and a major metabolite, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have been shown to be less viable and have reduced body-weight gains. Weigh the risk of exposing the infant to amiodarone and DEA against the potential benefit of arrhythmia suppression in the mother. When amiodarone therapy is indicated, discontinue breast-feeding.