Pacerone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically
cytochromes P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines.
Pacerone is also known to be an inhibitor of CYP3A4. Therefore, amiodarone has the potential for interactions with
drugs or substances that may be substrates, inhibitors or inducers of CYP3A4. While only a limited number of in vivo
drug-drug interactions with amiodarone have been reported, chiefly with the oral formulation, the potential for other
interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as
other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma
concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions
exists not only with concomitant medication but also with drugs administered after discontinuation of amiodarone.
Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit these isoenzymes
may decrease the metabolism and increase serum concentration of amiodarone. Reported examples include the
Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone
200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3
mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and
serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be
Histamine H2 antagonists:
Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels.
Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, resulting in
increased plasma levels of amiodarone. Grapefruit juice should not be taken during treatment with oral amiodarone.
This information should be considered when changing from intravenous amiodarone to oral amiodarone .
Pacerone may suppress certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This
inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450
enzymes. Reported examples of this interaction include the following:
Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce
persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in
dose of cyclosporine.
HMG-CoA Reductase Inhibitors:
Simvastatin (CYP3A4 substrate) in combination with amiodarone has been associated with reports of
Cardiac glycosides: In patients receiving digoxin therapy, administration of oral amiodarone
regularly results in an increase in serum digoxin concentration that may reach toxic levels with resultant clinical
toxicity. Pacerone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day.
On administration of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by
approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored
and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin
administration as well.
Antiarrhythmics: Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide,
and phenytoin, have been used concurrently with amiodarone. There have been case reports of increased
steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin
decreases serum amiodarone levels. Pacerone taken concomitantly with quinidine increases quinidine serum
concentration by 33% after two days. Pacerone taken concomitantly with procainamide for less than seven days
increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and
procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of
flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of
flecainide should be adjusted when these drugs are administered concomitantly. In general, any added
antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring. Combination of amiodarone
with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who
are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to oral
amiodarone, the dose levels of previously administered agents should be reduced by 30 to 50% several days after the
addition of oral amiodarone. The continued need for the other antiarrhythmic agent should be reviewed after the
effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is
continued, these patients should be particularly carefully monitored for adverse effects, especially conduction
disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who
require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual
Antihypertensives: Pacerone should be used with caution in patients receiving ß-receptor
blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a
CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus
arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients
with severe bradycardia or sinus arrest.
Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response
is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the
concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days,
the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be
Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the
synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in
efficacy. Reported examples of this interaction include the following:
Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown
to result in decreases in serum concentrations of amiodarone and desethylamiodarone.
Other substances, including herbal preparations:
St. Johnís Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is
the potential that the use of St. Johnís Wort in patients receiving amiodarone could result in reduced
Other reported interactions with amiodarone:
Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac
Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given
for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant
administration of intravenous amiodarone.
Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Pacerone inhibits CYP2D6.
Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and
Disopyramide increases QT prolongation which could cause arrhythmia.
Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have
been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide
antibiotics, or azoles were administered concomitantly.
Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with
propranolol, diltiazem, and verapamil.
Volatile Anesthetic Agents:.
In addition to the interactions noted above, chronic (> 2 weeks) oral Cordarone administration impairs
metabolism of phenytoin, dextromethorphan, and methotrexate.
Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being
treated with Cordarone I.V., as these disorders can exaggerate the degree of QTc prolongation and increase the
potential for TdP. Special attention should be given to electrolyte and acid-base balance in patients experiencing
severe or prolonged diarrhea or in patients receiving concomitant diuretics.