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Tablet: Concomitant administration of amiodarone HCl and cardiac glycosides may lead to automatism disturbances (excessive bradycardia) and disturbances in the atrioventricular conduction due to the synergistic effect of both preparations.
Concomitant administration of amiodarone HCl and digoxin may lead to an increase in the digoxin serum concentration (due to lowered digoxin clearance). Therefore, symptoms of a digitalis overdosage in these patients should be closely monitored and digoxin plasma levels should be determined as a precautionary measure. If necessary, the dose should be adjusted.
Amiodarone HCl can intensify the anticoagulant effect of vitamin K antagonists (phenprocoumon and warfarin) and hence increase the bleeding risk. During and after therapy with amiodarone HCl, Quick's value should therefore be monitored more frequently, and the dose of the vitamin K antagonists should be adjusted if necessary.
When administered concomitantly with phenytoin, amiodarone HCl may increase the serum concentration of phenytoin and precipitate symptoms of phenytoin overdose (eg, visual disturbances, tremor, vertigo). As soon as corresponding symptoms occur, the phenytoin dose should therefore be reduced. Phenytoin plasma levels should be determined if necessary.
Amiodarone HCl can increase the ciclosporin serum concentrations and decrease the clearance of ciclosporin by more than 50%. If both agents are administered concomitantly, the dose of ciclosporin should therefore be adjusted.
Amiodarone HCl can increase the plasma levels of other antiarrhythmics (eg, quinidine, procainamide, flecainide).
There is the risk of an excessive QT prolongation combined with an increased risk of ventricular arrhythmias including torsades de pointes when concomitantly administered with antiarrhythmics class I (especially quinidine-like substances) and other antiarrhythmics class III (eg, sotalol) as well as with other medicinal products prolonging the QT time (eg, vincamine, sulpiride, pentamidine IV and erythromycin IV). Concomitant administration of these medicinal products is therefore contraindicated.
In the scope of the controlled clinical SEARCH Study, an increased risk of myopathy/rhabdomyolysis was observed when amiodarone and simvastatin were used concomitantly (at a daily dose of 80 mg) (see Precautions).
Concomitant administration of potassium-depleting diuretics (eg, hydrochlorothiazide, furosemide), laxatives, systemic corticosteroids, tetracosactide or amphotericin B IV and amiodarone HCl increases the risk of the occurrence of hypokalemically induced arrhythmias (including torsades de pointes).
Concomitant administration of amiodarone HCl and calcium antagonists of the verapamil and diltiazem type or β-adrenergic blocking agents may lead to excessive bradycardia, higher grade atrioventricular conduction disturbances and to additive cardiodepressive effects. Calcium antagonists of the verapamil and diltiazem type or β-adrenergic blocking agents should therefore not be combined with amiodarone HCl.
Rare cases of atropine-resistant bradycardia, fall in blood pressure, conduction disturbances and reduced cardiac output have been observed in patients on therapy with amiodarone HCl undergoing general anesthesia.
In isolated cases, severe respiratory complications (shock lung, ARDS) occur, for the most part directly after surgical procedures. A possible intensification of the toxic effect of oxygen has been assumed. The anaesthetist should therefore be informed prior to surgical procedures about amiodarone HCl therapy.
Injection: Drugs/Food/Dietary or Herbal Supplements Affecting Microsomal Enzymes: Amiodarone is metabolized by the cytochrome P-450 (CYP450) microsomal enzyme system, principally the isoenzymes CYP3A4 and CYP2C8. Amiodarone also inhibits CYP2D6, CYP1A2, CYP2C9, and CYP3A4 isoenzymes. Inhibition of these isoenzymes by amiodarone may result in unexpectedly high plasma concentrations of other drugs which are metabolized by these isoenzymes.
HIV Protease Inhibitors: HIV protease inhibitors (eg, ritonavir, amprenavir, indinavir) are known to inhibit CYP3A4 to varying degrees. Monitor for amiodarone toxicity and do serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy.
Loratadine: A nonsedating antihistamine, is metabolized primarily by CYP3A4. QT interval prolongation and torsades de pointes have been reported with the co-administration of loratadine and amiodarone.
Cimetidine: Inhibits CYP3A4 and can increase serum amiodarone levels.
Trazodone: An antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and torsades de pointes have been reported with the co-administration of trazodone and amiodarone.
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: Statins (CYP3A4 substrate) in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis.
Antihypertensives: Amiodarone should be used with caution in patients receiving β-receptor blocking agents (eg, propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (eg, 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 3-4 days, the dose of the anticoagulant should be reduced by 1/3 to ½, and prothrombin times should be monitored closely. A similar effect has been reported with fluindione, an oral vitamin K antagonist, when administered concomitantly with amiodarone.
Clopidogrel: An inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and Amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.
Antibiotics: Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone.
Fentanyl (CYP3A4 Substrate): In combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.
In isolated cases, severe respiratory complications (shock lung, ARDS) occur, for the most part directly after surgical procedures. A possible intensification of the toxic effect of oxygen has been assumed. The anaesthetist should therefore be informed prior to surgical procedures about amiodarone HCl therapy.
Lidocaine (CYP3A4 Substrate): It has been reported to cause sinus bradycardia when given in combination with amiodarone. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of amiodarone IV.
Dextromethorphan: It is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6 with resulting impairment in metabolism.
St. John's Wort (Hypericum perforatum): It induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John's wort in patients receiving amiodarone could result in reduced amiodarone levels.
Grapefruit Juice: When given to healthy volunteers, it increased amiodarone area under the concentration-time curve (AUC) by 50% and peak plasma concentration (Cmax) by 84%, and decreased desethylamiodarone (DEA) to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased amiodarone plasma levels; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from amiodarone IV to oral amiodarone.
Drugs Affecting the QT Interval: Amiodarone prolongs QTc interval. Potentially serious cardiac arrhythmias, including torsades de pointes, could occur if amiodarone is administered concomitantly with other drugs that prolong the QTc interval (eg, cisapride, halofantrine, pimozide, disopyramide, fluoroquinolones, macrolide antibiotics, azole antifungal agents).
Cardiac Glycoside (Digoxin): Amiodarone given concomitantly with digoxin increases serum digoxin concentration by 70% after 1 day. On initiation of amiodarone, review the need for digitalis therapy and reduce the dose by approximately 50% or discontinue digoxin. Closely monitor serum digoxin levels and observe patients for clinical evidence of toxicity. These precautions should be applied to digitoxin as well.
Antiarrhythmics: Concomitant use of amiodarone with other antiarrhythmic agents (eg, disopyramide, mexiletine, propafenone, flecainide, procainamide, quinidine, bepridil, sotalol, diphemanil) generally should be reserved for patients with life-threatening arrhythmias who do not respond completely to either a single antiarrhythmic agent or amiodarone alone.
When combination therapy with amiodarone is necessary, it is generally recommended that dosage of currently administered antiarrhythmic agent be reduced by 30-50% several days after initiation of amiodarone therapy, since the onset of amiodarone's antiarrhythmic effect may be delayed.
Other Reported Interactions with Amiodarone: Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t½.
Chronic use (>2 weeks) of amiodarone impairs metabolism of phenytoin. It may also increase the serum concentration of phenytoin and precipitate symptoms of phenytoin overdose (eg, visual disturbances, tremor, vertigo). As soon as corresponding symptoms occur, the phenytoin dose should therefore be reduced. Phenytoin plasma levels should be determined if necessary. Also, amiodarone serum levels may be decreased.
Concomitant administration of fentanyl and amiodarone may result in hypotension, bradycardia and decreased cardiac output.
Concomitant administration with non-antiarrhythmic agents, including vincamine, sultopride, sparfloxacin, erythromycin IV and pentamidine may cause an increased risk of potentially lethal torsades de pointes.
Co-administration with agents that can produce hypokalemia and/or hypomagnesemia (eg, potassium-wasting diuretics, amphotericin B, cation exchange resins, stimulant laxatives) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, because of additive arrhythmogenic potential. Any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy.
Amiodarone HCl can increase the cyclosporin serum concentrations and decrease the clearance of cyclosporin by >50%. If both agents are administered concomitantly, the dose of cyclosporin should therefore be adjusted. Concomitant use of amiodarone and cyclosporine has also produced persistently elevated creatinine despite reduction in dose of cyclosporine.
Chronic use (>2 weeks) of amiodarone impairs metabolism of methotrexate. Methotrexate toxicity may be increased.
Concomitant administration of amiodarone and rifamycin may cause decreased serum concentrations of amiodarone and its active metabolites, reducing its pharmacologic effect.
Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.
