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Amiodarone

Pronunciation

Pronunciation

(a MEE oh da rone)

Index Terms

  • Amiodarone Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous, as hydrochloride:

Nexterone: 150 mg/100 mL (100 mL); 360 mg/200 mL (200 mL)

Generic: 150 mg/3 mL (3 mL); 450 mg/9 mL (9 mL); 900 mg/18 mL (18 mL)

Tablet, Oral, as hydrochloride:

Cordarone: 200 mg [scored]

Pacerone: 100 mg

Pacerone: 200 mg [scored; contains fd&c red #40, fd&c yellow #6 (sunset yellow)]

Pacerone: 400 mg [scored; contains fd&c yellow #10 aluminum lake]

Generic: 100 mg, 200 mg, 400 mg

Brand Names: U.S.

  • Cordarone
  • Nexterone
  • Pacerone

Pharmacologic Category

  • Antiarrhythmic Agent, Class III

Pharmacology

Class III antiarrhythmic agent which inhibits adrenergic stimulation (alpha- and beta-blocking properties), affects sodium, potassium, and calcium channels, prolongs the action potential and refractory period in myocardial tissue; decreases AV conduction and sinus node function

Absorption

Oral: Slow and variable

Distribution

IV: Rapid redistribution with a decrease to 10% of peak values within 30 to 45 minutes after completion of infusion

IV single dose: Vdss: Mean range: 40 to 84 L/kg

Vd: 66 L/kg (range: 18 to 148 L/kg)

Metabolism

Hepatic via CYP2C8 and 3A4 to active N-desethylamiodarone metabolite; possible enterohepatic recirculation

Excretion

Feces; urine (<1% as unchanged drug)

Onset of Action

Oral: 2 days to 3 weeks; IV: (electrophysiologic effects) within hours; antiarrhythmic effects: 2 to 3 days to 1 to 3 weeks; mean onset of effect may be shorter in children vs adults and in patients receiving IV loading doses; Peak effect: 1 week to 5 months

Time to Peak

Oral: Serum: 3 to 7 hours

Duration of Action

After discontinuing therapy: Variable, 2 weeks to months: Children: Less than a few weeks; Adults: Several months

Note: Duration after discontinuation may be shorter in children than adults

Half-Life Elimination

Note: Half-life is shortened in children vs adults

Amiodarone:

Single dose: 58 days (range: 15 to 142 days)

Oral chronic therapy: Mean range:: 40 to 55 days (range: 26 to 107 days)

IV single dose: Mean range: 9 to 36 days

N-desethylamiodarone (active metabolite):

Single dose: 36 days (range 14 to 75 days)

Oral chronic therapy: 61 days

IV single dose: Mean range: 9 to 30 days

Protein Binding

>96%

Special Populations: Hepatic Function Impairment

After a single dose of amiodarone injection in cirrhotic patients, Cmax was significantly lower and average concentration values were seen for desethylamiodarone, but mean amiodarone levels were unchanged.

Special Populations: Elderly

Clearance is lower and half-life is increased.

Special Populations Note

The half-life of desethylamiodarone is prolonged in severe left ventricular dysfunction:

Use: Labeled Indications

Management of life-threatening recurrent ventricular fibrillation (VF) or recurrent hemodynamically-unstable ventricular tachycardia (VT) refractory to other antiarrhythmic agents or in patients intolerant of other agents used for these conditions

Use: Unlabeled

Atrial fibrillation (AF): Pharmacologic conversion of AF to and maintenance of normal sinus rhythm; treatment of AF in patients with heart failure without preexcitation who require heart rate control or in patients with hypertrophic cardiomyopathy; prevention of postoperative AF or atrial flutter associated with cardiothoracic surgery; rate control in critically ill patients without preexcitation

Paroxysmal supraventricular tachycardia (SVT) (not initial drug of choice)

Ventricular tachyarrhythmias (ACLS/PALS guidelines): Cardiac arrest with persistent VT or VF if defibrillation, CPR, and vasopressor administration have failed; control of hemodynamically-stable monomorphic VT, polymorphic VT with a normal baseline QT interval, or wide-complex tachycardia of uncertain origin; control of rapid ventricular rate due to accessory pathway conduction in pre-excited atrial arrhythmias (ACLS guidelines) or stable narrow-complex tachycardia (ACLS guidelines)

Adjunct to ICD therapy to suppress symptomatic ventricular tachyarrhythmias in otherwise optimally-treated patients with heart failure (ACC/AHA/ESC Practice Guidelines)

Contraindications

Hypersensitivity to amiodarone, iodine, or any component of the formulation; severe sinus-node dysfunction causing marked sinus bradycardia; second- and third-degree heart block (except in patients with a functioning artificial pacemaker); bradycardia causing syncope (except in patients with a functioning artificial pacemaker); cardiogenic shock

Dosing: Adult

Note: Lower loading and maintenance doses are preferable in women and all patients with low body weight.

Ventricular arrhythmias:

Prevention of recurrent life-threatening ventricular arrhythmias (eg, VF or hemodynamically unstable VT): Oral: 800 to 1600 mg daily in 1 to 2 doses for 1 to 3 weeks, then when adequate arrhythmia control is achieved, decrease to 600 to 800 mg daily in 1 to 2 doses for 1 month; maintenance: 400 mg daily

Pulseless VT or VF (ACLS 2010; ACLS 2015): IV push, I.O.: Initial: 300 mg rapid bolus; if pulseless VT or VF continues after subsequent defibrillation attempt or recurs, administer supplemental dose of 150 mg. Note: In this setting, administering undiluted is preferred (Dager 2006; Skrifvars 2004). The Handbook of Emergency Cardiovascular Care (Hazinski 2015) and the ACLS guidelines do not make any specific recommendations regarding dilution of amiodarone in this setting. Experience limited with I.O. administration of amiodarone. Maximum recommended total daily dose is 2.2 g (ACLS 2010).

Upon return of spontaneous circulation, follow with an infusion of 1 mg/minute for 6 hours, then 0.5 mg/minute for 18 hours (mean daily doses >2.1 g daily have been associated with hypotension).

Stable VT: IV: 150 mg over 10 minutes, then 1 mg/minute for 6 hours, followed by 0.5 mg/minute; continue this rate for at least 18 hours (total infusion duration: 24 hours) or until complete transition to oral (see Recommendations for conversion to oral amiodarone after IV administration).

Breakthrough stable VT: 150 mg supplemental doses in 100 mL D5W or NS over 10 minutes (mean daily doses >2.1 g/day have been associated with hypotension)

Supraventricular arrhythmias:

Atrial fibrillation:

Pharmacologic cardioversion (off-label use):

Oral: 600 to 800 mg daily in divided doses until 10 g total, then 200 mg daily as maintenance (AHA/ACC/HRS [January 2014]). Although not supported by clinical evidence, a maintenance dose of 100 mg daily is commonly used especially for the elderly or patients with low body mass (Zimetbaum 2007). Note: Other regimens have been described and may be used clinically:

800 mg daily for 14 days, followed by 600 mg daily for the next 14 days, then 300 mg daily for the remainder of the first year, then 200 mg daily thereafter (Singh 2005)

or

10 mg/kg/day for 14 days, followed by 300 mg daily for 4 weeks, followed by maintenance dosage of 200 mg daily (Roy 2000)

IV: 150 mg over 10 minutes, then 1 mg/minute for 6 hours, then 0.5 mg/minute for 18 hours or change to oral maintenance dosing (eg, 100 to 200 mg once daily) (AHA/ACC/HRS [January 2014]).

Maintenance of sinus rhythm (off-label use): Oral: 400 to 600 mg daily in divided doses for 2 to 4 weeks followed by a maintenance dose of 100 to 200 mg once daily (AHA/ACC/HRS [January 2014])

Prevention of postoperative atrial fibrillation and atrial flutter associated with cardiothoracic surgery (off-label use): Note: A variety of regimens have been used in clinical trials, including oral and intravenous regimens:

Oral: 200 mg 3 times daily for 7 days prior to surgery, followed by 200 mg daily until hospital discharge (Daoud, 1997).

IV:

Preoperative regimen: 150 mg loading dose, followed by 0.4 mg/kg/hour (~0.5 mg/minute for a 70 kg patient) for 3 days prior to surgery and for 5 days postoperative (Lee 2000).

Postoperative regimen: Starting at postop recovery, 1000 mg infused over 24 hours for 2 days (Guarnieri, 1999).

Rate control (off-label use): IV: 300 mg over 1 hour, then 10 to 50 mg/hour over 24 hours followed by an oral maintenance dose; usual maintenance dose: 100 to 200 mg once daily. Note: Amiodarone requires a longer time to achieve rate control as compared to nondihydropyridine calcium channel blockers (eg, diltiazem) (7 hours vs 3 hours, respectively) (AHA/ACC/HRS [January 2014])

Supraventricular tachycardia (eg, AVNRT, AVRT): Note: Amiodarone is an effective therapeutic option with a variety of potential uses in the management of supraventricular tachycardia; however, safety risks limit its therapeutic use. In many cases, amiodarone is reserved for use in patients who have failed other therapies or who have structural heart disease, including left ventricular dysfunction. In general, most patients do not require chronic long-term treatment with antiarrhythmic therapy.

Pharmacologic cardioversion (off-label use):

Oral: 600 to 800 mg daily in divided doses until 10 g total, then may administer 200 mg daily as maintenance (ACC/AHA/ESC [Blomström-Lundqvist 2003]; AHA/ACC/HRS [January 2014]).

IV: 150 mg over 10 minutes, then 1 mg/minute for 6 hours, then 0.5 mg/minute for 18 hours or may change to oral dosing (ACC/AHA/ESC [Blomström-Lundqvist 2003]; AHA/ACC/HRS [January 2014]).

Recommendations for conversion to oral amiodarone after IV administration: Use the following as a guide:

<1-week IV infusion: 800 to 1600 mg daily

1- to 3-week IV infusion: 600 to 800 mg daily

>3-week IV infusion: 400 mg

Note: Conversion from IV to oral therapy has not been formally evaluated. Some experts recommend a 1 to 2 day overlap when converting from IV to oral therapy especially when treating ventricular arrhythmias.

Recommendations for conversion to intravenous amiodarone after oral administration: During long-term amiodarone therapy (ie, ≥4 months), the mean plasma-elimination half-life of the active metabolite of amiodarone is 61 days. Replacement therapy may not be necessary in such patients if oral therapy is discontinued for a period <2 weeks, since any changes in serum amiodarone concentrations during this period may not be clinically significant.

Dosing: Geriatric

Refer to adult dosing. No specific guidelines available. Dose selection should be cautious, at low end of dosage range, and titration should be slower to evaluate response. Although not supported by clinical evidence, a maintenance dose of 100 mg daily is commonly used especially for the elderly or patients with low body mass (Zimetbaum 2007).

Dosing: Pediatric

Pulseless VT or VF (PALS dosing): Infants, Children, and Adolescents: IV, I.O.: 5 mg/kg (maximum: 300 mg per dose) rapid bolus; may repeat twice up to a maximum total dose of 15 mg/kg during acute treatment (PALS 2010).

Perfusing tachycardias (PALS dosing): Infants, Children, and Adolescents: IV, I.O.: Loading dose: 5 mg/kg (maximum: 300 mg per dose) over 20 to 60 minutes; may repeat twice up to maximum total dose of 15 mg/kg during acute treatment (PALS 2010).

Dosing: Renal Impairment

No dosage adjustment necessary.

Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary

Peritoneal dialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary

Dosing: Hepatic Impairment

Dosage adjustment is probably necessary in substantial hepatic impairment. No specific guidelines available. If hepatic enzymes exceed 3 times normal or double in a patient with an elevated baseline, consider decreasing the dose or discontinuing amiodarone.

Extemporaneously Prepared

A 5 mg/mL oral suspension may be made with tablets and either a 1:1 mixture of Ora-Sweet® and Ora-Plus® or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus® adjusted to a pH between 6-7 using a sodium bicarbonate solution (5 g/100 mL of distilled water). Crush five 200 mg tablets in a mortar and reduce to a fine powder. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 200 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 200 mL. Label “shake well” and “protect from light”. Stable for 42 days at room temperature or 91 days refrigerated (preferred) (Nahata, 2004).

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Oral: Administer consistently with regard to meals. Take in divided doses with meals if GI upset occurs or if taking large daily dose. If GI intolerance occurs with single-dose therapy, use twice daily dosing.

IV: For infusions >1 hour, use concentrations ≤2 mg/mL unless a central venous catheter is used; commercially-prepared premixed solutions in concentrations of 1.5 mg/mL and 1.8 mg/mL are available. Use only volumetric infusion pump; use of drop counting may lead to underdosage. Administer through an IV line located as centrally as possible. For continuous infusions, an in-line filter has been recommended during administration to reduce the incidence of phlebitis. During pulseless VT/VF, administering undiluted is preferred (Dager 2006; Skrifvars 2004). The Handbook of Emergency Cardiovascular Care (Hazinski 2015) and the ACLS guidelines do not make any specific recommendations regarding dilution of amiodarone in this setting.

Adjust administration rate to urgency (give more slowly when perfusing arrhythmia present). Slow the infusion rate if hypotension or bradycardia develops. Infusions >2 hours must be administered in a non-PVC container (eg, glass or polyolefin). PVC tubing is recommended for administration regardless of infusion duration. Incompatible with heparin; flush with saline prior to and following infusion. Note: IV administration at lower flow rates (potentially associated with use in pediatrics) and higher concentrations than recommended may result in leaching of plasticizers (DEHP) from intravenous tubing. DEHP may adversely affect male reproductive tract development. Alternative means of dosing and administration (1 mg/kg aliquots) may need to be considered.

Dietary Considerations

Take consistently with regard to meals. Amiodarone is a potential source of large amounts of inorganic iodine; ~3 mg of inorganic iodine per 100 mg of amiodarone is released into the systemic circulation. Recommended daily allowance for iodine in adults is 150 mcg.

Grapefruit juice is not recommended.

Compatibility

Y-site administration: Incompatible with aminophylline, ampicillin and sulbactam, argatroban, bivalirudin, cefamandole nafate, cefazolin, ceftazidime, digoxin, furosemide, heparin, imipenem and cilastatin, magnesium, micafungin, pantoprazole, piperacillin, piperacillin and tazobactam, potassium phosphate, sodium bicarbonate, sodium nitroprusside, sodium phosphate.

Storage

Tablets: Store at 20°C to 25°C (68°F to 77°F); protect from light.

Injection: Store undiluted vials and premixed solutions (Nexterone) at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light during storage; protect from excessive heat. There is no need to protect solutions from light during administration. When vial contents are admixed in D5W to a final concentration of 1-6 mg/mL, amiodarone is stable for 24 hours in glass or polyolefin bottles and for 2 hours in polyvinyl chloride (PVC) bags; do not use evacuated glass containers as buffer may cause precipitation. Nexterone is available as premixed solutions. Although amiodarone adsorbs to PVC tubing, all clinical studies used PVC tubing and the recommended doses account for adsorption; in adults, PVC tubing is recommended. Discard any unused portions of premixed solutions.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Agalsidase Alfa: Amiodarone may diminish the therapeutic effect of Agalsidase Alfa. Avoid combination

Agalsidase Beta: Amiodarone may diminish the therapeutic effect of Agalsidase Beta. Avoid combination

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Antiarrhythmic Agents (Class Ia): Amiodarone may enhance the QTc-prolonging effect of Antiarrhythmic Agents (Class Ia). Amiodarone may increase the serum concentration of Antiarrhythmic Agents (Class Ia). Management: Avoid whenever possible. While considered contraindicated in some places, amiodarone U.S. prescribing information suggests that use could be considered under some circumstances, with careful monitoring. Reduce quinidine or procainamide dose by one third. Avoid combination

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Artesunate: CYP2A6 Inhibitors may decrease serum concentrations of the active metabolite(s) of Artesunate. CYP2A6 Inhibitors may increase the serum concentration of Artesunate. Avoid combination

Atazanavir: May increase the serum concentration of Amiodarone. Monitor therapy

Azithromycin (Systemic): May enhance the QTc-prolonging effect of Amiodarone. Management: The concomitant use of amiodarone, which has a high risk for QTc prolongation, with azithromycin, which may also prolong the QT interval, should be avoided. Avoid combination

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta-Blockers: Amiodarone may enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Bile Acid Sequestrants: May decrease the bioavailability of Amiodarone. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Boceprevir: May increase the serum concentration of Amiodarone. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the bradycardic effect of Amiodarone. Sinus arrest has been reported. Consider therapy modification

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Cardiac Glycosides: Amiodarone may increase the serum concentration of Cardiac Glycosides. Management: Reduce the dose of cardiac glycosides by 30% to 50% or reduce the frequency of administration when initiating concomitant amiodarone therapy. Monitor for increased serum concentrations and toxic effects of cardiac glycosides. Consider therapy modification

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cimetidine: May increase the serum concentration of Amiodarone. Management: Consider alternatives to cimetidine. If this combination cannot be avoided, monitor for increased amiodarone concentrations/effects with cimetidine initiation/dose increase or decreased concentrations/effects with cimetidine discontinuation/dose decrease. Consider therapy modification

Clopidogrel: Amiodarone may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Monitor therapy

Cobicistat: May increase the serum concentration of Amiodarone. Monitor therapy

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Cyclophosphamide: May enhance the adverse/toxic effect of Amiodarone. Specifically, the risk of pulmonary toxicity may be enhanced. Monitor therapy

CycloSPORINE (Systemic): Amiodarone may decrease the metabolism of CycloSPORINE (Systemic). Consider therapy modification

CYP2A6 Substrates: CYP2A6 Inhibitors (Moderate) may decrease the metabolism of CYP2A6 Substrates. Monitor therapy

CYP2C8 Inducers (Strong): May increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C8 Inhibitors (Strong): May decrease the metabolism of CYP2C8 Substrates. Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabigatran Etexilate: Amiodarone may increase the serum concentration of Dabigatran Etexilate. Management: Dose reductions and/or avoidance of this combination may be necessary. Specific recommendations vary by U.S. vs. Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C8 Substrates. Management: Seek alternatives to the CYP2C8 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Daclatasvir: May enhance the bradycardic effect of Amiodarone. Avoid combination

Darunavir: May increase the serum concentration of Amiodarone. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Etravirine: May decrease the serum concentration of Amiodarone. Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Fingolimod: May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class III). Avoid combination

Flecainide: Amiodarone may enhance the QTc-prolonging effect of Flecainide. Amiodarone may increase the serum concentration of Flecainide. Management: Decrease flecainide dose by 50% in the presence of amiodarone. Monitor for adverse effects of flecainide and consider monitoring for elevated serum concentrations during concomitant therapy. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fosamprenavir: May increase the serum concentration of Amiodarone. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: May enhance the QTc-prolonging effect of Amiodarone. Fosphenytoin may decrease the serum concentration of Amiodarone. Amiodarone may increase the serum concentration of Fosphenytoin. Management: Seek alternatives when possible. Monitor patients receiving this combination for QT interval prolongation or changes in cardiac rhythm, and for decreased serum concentrations/effects of amiodarone and increased concentrations/effects of phenytoin. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May decrease serum concentrations of the active metabolite(s) of Amiodarone. Grapefruit Juice may increase the serum concentration of Amiodarone. Avoid combination

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

HMG-CoA Reductase Inhibitors: Amiodarone may decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Dose of HMG-CoA reductase inhibitor may need to be reduced (limit simvastatin adult maximum dose to 20 mg/day, limit lovastatin adult maximum dose to 40 mg/day). Exceptions: Pitavastatin; Pravastatin. Consider therapy modification

Hydrocodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Hydrocodone. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Indinavir: May increase the serum concentration of Amiodarone. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Ledipasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ledipasvir. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lidocaine (Systemic): Amiodarone may increase the serum concentration of Lidocaine (Systemic). Monitor therapy

Lidocaine (Topical): May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class III). Antiarrhythmic Agents (Class III) may increase the serum concentration of Lidocaine (Topical). This mechanism specifically applies to amiodarone and dronedarone. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Lopinavir: May enhance the QTc-prolonging effect of Amiodarone. Lopinavir may increase the serum concentration of Amiodarone. More specifically, Lopinavir/Ritonavir may increase the serum concentration of Amiodarone. Management: If this combination cannot be avoided, monitor for increased amiodarone serum concentrations and effects as well as for evidence of QT interval prolongation. Avoid combination

Loratadine: Amiodarone may increase the serum concentration of Loratadine. Management: Due to reported QT interval prolongation and Torsades de Pointes with this combination, consider an alternative to loratadine when possible. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Metoprolol: CYP2D6 Inhibitors may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification

Mifepristone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Mipomersen: Amiodarone may enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Monitor therapy

Nelfinavir: May increase the serum concentration of Amiodarone. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of Amiodarone. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of Amiodarone. Management: Canadian labeling recommends avoiding this combination. Monitor therapy

Orlistat: May decrease the serum concentration of Amiodarone. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phenytoin: May decrease the serum concentration of Amiodarone. Amiodarone may increase the serum concentration of Phenytoin. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Propafenone: Amiodarone may enhance the adverse/toxic effect of Propafenone. Specifically, the combination may result in altered cardiac conduction and repolarization. Amiodarone may increase the serum concentration of Propafenone. Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Rifampin: May decrease serum concentrations of the active metabolite(s) of Amiodarone. Specifically, desethylamiodarone concentrations may decrease. Rifampin may decrease the serum concentration of Amiodarone. Management: Seek alternatives. When used together, monitor closely for decreased amiodarone concentrations/effects. Dose adjustment may be needed. Consider therapy modification

Rifaximin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rifaximin. Monitor therapy

Ritonavir: May increase the serum concentration of Amiodarone. Management: Ritonavir US prescribing information lists this combination as contraindicated. Amiodarone use should be avoided with lopinavir/ritonavir, but if the combination must be used, monitor closely for increased amiodarone serum concentrations and effects. Avoid combination

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Saquinavir: May enhance the QTc-prolonging effect of Amiodarone. Saquinavir may increase the serum concentration of Amiodarone. Avoid combination

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Iodide I131: Amiodarone may diminish the therapeutic effect of Sodium Iodide I131. Consider therapy modification

Sofosbuvir: May enhance the bradycardic effect of Amiodarone. Avoid combination

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification

Tegafur: CYP2A6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tegafur. Specifically, CYP2A6 inhibitors may inhibit the conversion of tegafur into its active metabolite, 5-fluorouracil. Avoid combination

Telaprevir: May enhance the adverse/toxic effect of Amiodarone. Telaprevir may increase the serum concentration of Amiodarone. Monitor therapy

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

Tipranavir: May increase the serum concentration of Amiodarone. Avoid combination

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin K Antagonists (eg, warfarin): Amiodarone may enhance the anticoagulant effect of Vitamin K Antagonists. Amiodarone may increase the serum concentration of Vitamin K Antagonists. Management: Monitor patients extra closely for evidence of increased anticoagulant effects if amiodarone is started. Consider empiric reduction of 30% to 50% in warfarin dose, though no specific guidelines on dose adjustment have been published. Consider therapy modification

Adverse Reactions

Frequency not always defined.

Cardiovascular: Hypotension (IV: 16%, refractory in rare cases), bradycardia (2% to 5%), atrioventricular block (<2% to 5%), cardiac arrest (3%), cardiac arrhythmia (1% to 3%), cardiac failure (1% to 3%), ventricular tachycardia (2%), asystole (≤2%; IV), atrial fibrillation (<2%), cardiogenic shock (<2%), torsades de pointes (<2%, rare), ventricular fibrillation (<2%), atrioventricular dissociation, cardiac conduction disturbance, edema, flushing, peripheral thrombophlebitis (IV, with concentrations >3 mg/mL), pulseless electrical activity (PEA)

Central nervous system: Abnormal gait (4% to 40%), ataxia (4% to 40%), dizziness (4% to 40%), fatigue (4% to 40%), involuntary body movements (4% to 40%), malaise (4% to 40%), peripheral neuropathy (4% to 40%), memory impairment (3% to 40%), paresthesia (4% to 9%), altered sense of smell (1% to 3%), headache (1% to 3%), insomnia (1% to 3%), sleep disorder (1% to 3%)

Dermatologic: Blue-gray skin pigmentation (oral: ≤15% with prolonged exposure to amiodarone), skin photosensitivity (4% to 10%)

Endocrine & metabolic: Hypothyroidism (1% to 10%), decreased libido (1% to 3%), hyperthyroidism (1% to 3%)

Gastrointestinal: Nausea (oral: 10% to 33%; IV: 4%), vomiting (10% to 33%), anorexia (≤25%), constipation (≤25%), altered salivation (1% to 3%), dysgeusia (1% to 3%), abdominal pain (1% to 3%), diarrhea (<2%)

Hematologic & oncologic: Blood coagulation disorder (1% to 3%)

Hepatic: Increased serum transaminases (IV: <2% to 54%; oral: 3% to 9%), abnormal hepatic function tests (4% to 9%), hepatic disease (1% to 3%)

Neuromuscular & skeletal: Tremor (≤40%)

Ophthalmic: Corneal deposits (>90%; causes visual disturbance in <10%), visual halos (≤10%), visual disturbance (2% to 9%), optic neuritis (1%), photophobia

Respiratory: Pulmonary toxicity (2% to 17%), pulmonary edema (IV: <2%), hypersensitivity pneumonitis, interstitial pneumonitis, pulmonary fibrosis

Miscellaneous: Fever

<1% (Limited to important or life-threatening): Acute pancreatitis, acute renal failure, agranulocytosis, alopecia, anaphylactic shock, anaphylactoid reaction, anaphylaxis, aplastic anemia, bronchiolitis obliterans organizing pneumonia, bullous dermatitis, cholestatic hepatitis, cholestasis, delirium, demyelinating polyneuropathy, disorientation, DRESS syndrome, drug-induced Parkinson disease, eosinophilic pneumonia, epididymitis (noninfectious), erythema multiforme, exfoliation of skin, granuloma, hallucination, hemolytic anemia, hemoptysis, hepatic cirrhosis, hepatic failure, hepatitis, hepatotoxicity (idiosyncratic) (Chalasani 2014), hypoesthesia, hypotension, hypoxia, impotence, increased intracranial pressure, increased lactate dehydrogenase, increased serum alkaline phosphatase, increased serum creatinine, jaundice, leukocytoclastic vasculitis, malignant neoplasm of skin, mass (pulmonary), myopathy, optic neuropathy, pancytopenia, pleural effusion, pleurisy, pseudotumor cerebri, pulmonary alveolar hemorrhage, pulmonary infiltrates, pulmonary phospholipidosis, prolonged Q-T interval on ECG (associated with worsening of arrhythmia), renal insufficiency, respiratory arrest, respiratory failure, rhabdomyolysis, SIADH, sinoatrial arrest, skin carcinoma, skin granuloma, skin sclerosis, spontaneous ecchymosis, Stevens-Johnson syndrome, superior vena cava syndrome, thrombocytopenia, thyroid cancer, thyroid nodule, thyrotoxicosis, tissue necrosis at injection site, toxic epidermal necrolysis, vasculitis, vortex keratopathy (Chan 2015)

ALERT: U.S. Boxed Warning

Life-threatening arrhythmias (tablet):

Amiodarone is intended for use only in patients with indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.

Potentially fatal toxicities (tablet):

Amiodarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10% to 17% in some series of patients with ventricular arrhythmias given doses of approximately 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal approximately 10% of the time. Liver injury is common with amiodarone, but is usually mild and evidenced only by abnormal liver enzymes. However, overt liver disease can occur and has been fatal in a few cases. Like other antiarrhythmics, amiodarone can exacerbate the arrhythmia (eg, by making the arrhythmia less well tolerated or more difficult to reverse). This has occurred in 2% to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2% to 5%. In most cases, all of these events should be manageable in the proper clinical setting. Although the frequency of such proarrhythmic events does not appear greater with amiodarone than with many other agents used in this population, the effects are prolonged when they occur.

High-risk patients (tablet):

Even in patients at high risk of arrhythmic death in whom the toxicity of amiodarone is an acceptable risk, amiodarone poses major management problems that could be life-threatening in a population at risk of sudden death; therefore, make every effort to utilize alternative agents first.

The difficulty of using amiodarone effectively and safely poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of amiodarone is given, and a response generally requires at least 1 week, usually 2 weeks or more. Because absorption and elimination are variable, maintenance dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 patients required dose reduction and 18 required at least temporary discontinuation because of adverse reactions, and several series have reported 15% to 20% overall frequencies of discontinuation because of adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when amiodarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when amiodarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.

Warnings/Precautions

Concerns related to adverse effects:

• Bradycardia/hypotension: May cause hypotension and bradycardia (infusion-rate related). Hypotension with rapid administration has been attributed to the emulsifier polysorbate 80. Commercially-prepared premixed solutions do not contain polysorbate 80 and may have a lower incidence of hypotension.

• Dermatologic toxicity: May cause life-threatening or fatal cutaneous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). If symptoms or signs (eg, progressive skin rash often with blisters or mucosal lesions) occur, immediately discontinue.

• Hepatotoxicity: [US Boxed Warning (tablet)]: Liver toxicity is common, but usually mild with evidence of only increased liver enzymes; severe liver toxicity can occur and has been fatal in a few cases. Hepatic enzyme levels are frequently elevated in patients exposed to amiodarone; most cases are asymptomatic. If increases >3x ULN (or ≥2x baseline in patients with preexisting elevations), consider dose reduction or discontinuation. Monitor hepatic enzymes regularly in patients on relatively high maintenance doses. Elevated bilirubin levels have been reported have been reported in patients administered IV amiodarone. Note: Although the US Boxed Warning pertains to the tablet prescribing information, these effects may also be seen with intravenous administration depending on duration of use.

• Neurotoxicity: Peripheral neuropathy has been reported rarely with chronic administration; may resolve when amiodarone is discontinued, but resolution may be slow and incomplete.

• Ocular effects: Regular ophthalmic examination (including slit lamp and fundoscopy) is recommended. May cause optic neuropathy and/or optic neuritis resulting in visual impairment (peripheral vision loss, changes in acuity) at any time during therapy; permanent blindness has occurred. If symptoms of optic neuropathy and/or optic neuritis occur, prompt ophthalmic evaluation is recommended. If diagnosis of optic neuropathy and/or optic neuritis is confirmed, reevaluate amiodarone therapy. Corneal microdeposits occur in a majority of adults and may cause visual disturbances in up to 10% of patients (blurred vision, halos); asymptomatic microdeposits may be reversible and are not generally considered a reason to discontinue treatment. Corneal refractive laser surgery is generally contraindicated in amiodarone users (from manufacturers of surgical devices).

• Photosensitivity: Avoid excessive exposure to sunlight; may cause photosensitivity. During long-term treatment, a blue-gray discoloration of exposed skin may occur; risk increased in patients with fair complexion or excessive sun exposure; may be related to cumulative dose and duration of therapy.

• Proarrhythmic effects: [US Boxed Warning (tablet)]: Amiodarone can exacerbate arrhythmias, by making them more difficult to tolerate or reverse; other types of arrhythmias have occurred, including significant heart block, sinus bradycardia, new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (torsades de pointes [TdP]). Risk may be increased with concomitant use of other antiarrhythmic agents or drugs that prolong the QTc interval. Proarrhythmic effects may be prolonged. Note: Although the US Boxed Warning pertains to the tablet prescribing information, these effects may also be seen with intravenous administration depending on duration of use.

• Pulmonary toxicity: [US Boxed Warning (tablet)]: Pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis and abnormal diffusion capacity without symptoms) may occur. Reports of acute-onset pulmonary injury (pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, pleural effusion, pulmonary fibrosis, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, hypoxia) have occurred; some cases have progressed to respiratory failure and/or death. Fatalities due to pulmonary toxicity occur in ~10% of cases; most fatalities due to sudden cardiac death occurred when amiodarone was discontinued; rule out other causes of respiratory impairment before discontinuing amiodarone in patients with life-threatening arrhythmias; use extreme caution if dose is decreased or discontinued. If hypersensitivity pneumonitis occurs, discontinue amiodarone and institute steroid therapy; if interstitial/alveolar pneumonitis occurs, institute steroid therapy and reduce amiodarone dose or preferably, discontinue. Some cases of interstitial/alveolar pneumonitis may resolve following dosage reduction and steroid therapy; rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis in some patients; however, in some patients the pulmonary lesions have not been reversible. Educate patients about monitoring for symptoms (eg, nonproductive cough, dyspnea, pleuritic pain, hemoptysis, wheezing, weight loss, fever, malaise). Evaluate new respiratory symptoms; preexisting pulmonary disease does not increase risk of developing pulmonary toxicity, but if pulmonary toxicity develops then the prognosis is worse. Use of lower doses may be associated with a decreased incidence, but pulmonary toxicity has been reported in patients treated with low doses. The lowest effective dose should be used as appropriate for the acuity/severity of the arrhythmia being treated. Note: Although the US Boxed Warning pertains to the tablet prescribing information, these effects may also be seen with intravenous administration depending on duration of use.

• Thyroid effects: May cause hyper- or hypothyroidism; hyperthyroidism may result in thyrotoxicosis (including fatalities) and/or the possibility of arrhythmia breakthrough or aggravation. If any new signs of arrhythmia appear, consider the possibility of hyperthyroidism. Hypothyroidism (sometimes severe) may be primary or subsequent to resolution of preceding amiodarone-induced hyperthyroidism; myxedema (may be fatal) has been reported. If hyper- or hypothyroidism occurs, reduce dose or discontinue amiodarone. Thyroid nodules and/or thyroid cancer have also been reported. Use caution in patients with thyroid disease; thyroid function should be monitored prior to treatment and periodically thereafter, particularly in the elderly and in patients with underlying thyroid dysfunction.

Disease-related concerns:

• Arrhythmias: Appropriate use: [US Boxed Warnings (tablet)]: Only indicated for patients with life-threatening arrhythmias because of risk of substantial toxicity. Alternative therapies should be tried first before using amiodarone. Patients should be hospitalized when amiodarone is initiated. Currently, the 2015 ACLS guidelines recommend the consideration of IV amiodarone as the preferred antiarrhythmic for the treatment of pulseless VT/VF unresponsive to CPR, defibrillation, and vasopressor therapy (AHA [Link 2015]). In patients with non-life-threatening arrhythmias (eg, atrial fibrillation), amiodarone should be used only if the use of other antiarrhythmics has proven ineffective or are contraindicated. Note: Although the US Boxed Warning pertains to the tablet prescribing information, these effects may also be seen with intravenous administration depending on duration of use.

• Cardiac devices (eg, implanted defibrillators, pacemakers): Chronic administration of antiarrhythmic drugs may affect defibrillation or pacing thresholds. Assess when initiating amiodarone and during therapy.

• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia, hypomagnesemia, or hypocalcemia, prior to use and throughout therapy.

• Myocardial infarction: In the setting of acute myocardial infarction, beta-blocker therapy should still be initiated even though concomitant amiodarone therapy provides beta-blockade.

• Wolff-Parkinson-White (WPW) syndrome: Amiodarone should not be used in patients with WPW syndrome and preexcited atrial fibrillation/flutter since ventricular fibrillation may result (AHA/ACC/HRS [January 2014]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Drugs metabolized by CYP enzymes: Amiodarone is a potent inhibitor of CYP enzymes and transport proteins (including p-glycoprotein), which may lead to increased serum concentrations/toxicity of a number of medications.

• Drugs with QT prolongation potential: Particular caution must be used when a drug with QTc-prolonging potential relies on metabolism via enzymes amiodarone inhibits, since the effect of elevated concentrations may be additive with the effect of amiodarone. Carefully assess risk:benefit of coadministration of other drugs which may prolong QTc interval.

• Warfarin: Use caution when initiating amiodarone in patients on warfarin. Cases of increased INR with or without bleeding have occurred in patients treated with warfarin; monitor INR closely after initiating amiodarone in these patients.

Special populations:

• Surgical patients: Use caution and close perioperative monitoring in surgical patients; may enhance myocardial depressant and conduction effects of halogenated inhalational anesthetics; adult respiratory distress syndrome (ARDS) has been reported postoperatively (fatal in rare cases). Hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery have been reported (rare); relationship to amiodarone is unknown.

Dosage form specific issues:

• Commercially-prepared premixed infusion: Contains the excipient cyclodextrin (sulfobutyl ether beta-cyclodextrin), which may accumulate in patients with renal insufficiency, although the clinical significance of this finding is uncertain (Luke, 2010).

• Long-term use: There has been limited experience in patients receiving IV amiodarone for >3 weeks.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente, 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer's labeling.

Other warnings/precautions:

• CAST trial: In the Cardiac Arrhythmia Suppression Trial (CAST), recent (>6 days but <2 years ago) myocardial infarction patients with asymptomatic, nonlife-threatening ventricular arrhythmias did not benefit and may have been harmed by attempts to suppress the arrhythmia with flecainide or encainide. An increased mortality or nonfatal cardiac arrest rate (7.7%) was seen in the active treatment group compared with patients in the placebo group (3%). The applicability of the CAST results to other populations is unknown. Use of amiodarone post-MI was not associated with an increase in mortality in two post-MI trials. Antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.

• Discontinuation of therapy: Patients may still be at risk for amiodarone–related adverse reactions or drug interactions after the drug has been discontinued. The pharmacokinetics are complex (due to prolonged duration of action and half-life) and difficult to predict.

Monitoring Parameters

Blood pressure, heart rate (ECG) and rhythm throughout therapy; assess patient for signs of lethargy, edema of the hands or feet, weight loss, and pulmonary toxicity (baseline pulmonary function tests and chest X-ray; continue monitoring chest X-ray annually during therapy); liver function tests (semiannually); monitor serum electrolytes, especially potassium and magnesium. Assess thyroid function tests before initiation of treatment and then periodically thereafter (some experts suggest every 3-6 months). If signs or symptoms of thyroid disease or arrhythmia breakthrough/exacerbation occur then immediate re-evaluation is necessary. Amiodarone partially inhibits the peripheral conversion of thyroxine (T4) to triiodothyronine (T3); serum T4 and reverse triiodothyronine (rT3) concentrations may be increased and serum T3 may be decreased; most patients remain clinically euthyroid, however, clinical hypothyroidism or hyperthyroidism may occur.

Perform regular ophthalmic exams.

Patients with implantable cardiac devices: Monitor pacing or defibrillation thresholds with initiation of amiodarone and during treatment.

Consult individual institutional policies and procedures.

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Amiodarone crosses the placenta (~10% to 50%) and may cause fetal harm when administered to a pregnant woman, leading to congenital goiter, hypo- or hyperthyroidism, neurodevelopmental, or neurological effects in the neonate. Growth retardation and premature birth have also been noted (ESG 2011). Amiodarone should be used in pregnant women only to treat arrhythmias that are life-threatening or refractory to other treatments (Blomström-Lundqvist 2003; ESG 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, nausea, vomiting, loss of strength and energy, or lack of appetite. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), signs of thyroid problems (change in weight without trying, feeling nervous and excitable, feeling restless, feeling very weak, hair thinning, low mood [depression], neck swelling, not able to focus, not able to handle heat or cold, period [menstrual] changes, shakiness, or sweating), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), change in balance, tremors, difficulty moving, rigidity, skin discoloration, coughing up blood, angina, burning or numbness feeling, tachycardia, bradycardia, abnormal heartbeat, vision changes, eye pain, severe eye irritation, sensitivity to light, urinary retention, change in amount of urine passed, severe dizziness, passing out, abnormal movements, joint pain, muscle pain, dyspnea, excessive weight gain, swelling of arm or leg, bruising, or bleeding (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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