Amiodarone

U.S. BRAND NAMES — Cordarone®; Pacerone®

PHARMACOLOGIC CATEGORY
Antiarrhythmic Agent, Class III

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

Ventricular arrhythmias: Oral: 800-1600 mg/day in 1-2 doses for 1-3 weeks, then 600-800 mg/day in 1-2 doses for 1 month; maintenance: 400 mg/day; lower doses are recommended for supraventricular arrhythmias.

Breakthrough VF or VT: I.V.: 150 mg supplemental doses in 100 mL D5W over 10 minutes

Pulseless VF or VT: I.V. push: Initial: 300 mg in 20-30 mL NS or D5W; if VF or VT recurs, supplemental dose of 150 mg followed by infusion of 1 mg/minute for 6 hours, then 0.5 mg/minute (maximum daily dose: 2.1 g)

I.V. to oral therapy conversion: Use the following as a guide:
<1>3 week I.V. infusion: 400 mg

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>1 hour, use concentrations 2 mg/mL unless a central venous catheter is used. Use only volumetric infusion pump; use of drop counting may lead to underdosing. Administer through I.V. line with in-line filter.

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 glass or polyolefin bottles. Note: I.V. 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.

COMPATIBILITY — Variable stability (consult detailed reference): D5W, NS.

Y-site administration: Compatible: Amikacin, bretylium, clarithromycin, clindamycin, dobutamine, dopamine, doxycycline, erythromycin lactobionate, esmolol, gentamicin, insulin (regular), isoproterenol, labetalol, lidocaine, metaraminol, metronidazole, midazolam, morphine, nitroglycerin, norepinephrine, penicillin G potassium, phentolamine, phenylephrine, potassium chloride, procainamide, tobramycin, vancomycin. Incompatible: Aminophylline, cefamandole, heparin, sodium bicarbonate. Variable (consult detailed reference): Cefazolin.

Compatibility in syringe: Incompatible: Heparin.

Compatibility when admixed: Compatible: Dobutamine, lidocaine, potassium chloride, procainamide, propafenone, verapamil. Incompatible: Floxacillin. Variable (consult detailed reference): Furosemide, quinidine.

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

USE - UNLABELED/INVESTIGATIONAL
Cardiac arrest with persistent ventricular tachycardia (VT) or ventricular fibrillation (VF) if defibrillation, CPR, and vasopressor administration have failed (ACLS/PALS guidelines)

Control of hemodynamically-stable VT, polymorphic VT with a normal QT interval, or wide-complex tachycardia of uncertain origin (ACLS/PALS guidelines)

Control of rapid ventricular rate due to accessory pathway conduction in pre-excited atrial arrhythmias (ACLS guidelines)

Heart rate control in patients with atrial fibrillation and heart failure [no accessory pathway] (ACC/AHA/ESC Practice Guidelines)

Paroxysmal supraventricular tachycardia (SVT)

Prevention of postoperative atrial fibrillation during cardiothoracic surgery

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

Pharmacologic conversion of atrial fibrillation to normal sinus rhythm; maintenance of normal sinus rhythm

ADVERSE REACTIONS SIGNIFICANT — In a recent meta-analysis, patients taking lower doses of amiodarone (152-330 mg daily for at least 12 months) were more likely to develop thyroid, neurologic, skin, ocular, and bradycardic abnormalities than those taking placebo (Vorperian, 1997). Pulmonary toxicity was similar in both the low dose amiodarone group and in the placebo group but there was a trend towards increased toxicity in the amiodarone group. Gastrointestinal and hepatic events were seen to a similar extent in both the low dose amiodarone group and placebo group. As the frequency of adverse events varies considerably across studies as a function of route and dose, a consolidation of adverse event rates is provided by Goldschlager, 2000.
Cardiovascular: Hypotension (I.V. 16%, refractory in rare cases)
Central nervous system (3% to 40%): Abnormal gait/ataxia, dizziness, fatigue, headache, malaise, impaired memory, involuntary movement, insomnia, poor coordination, peripheral neuropathy, sleep disturbances, tremor
Dermatologic: Photosensitivity (10% to 75%)
Endocrine & Metabolic: Hypothyroidism (1% to 22%)
Gastrointestinal: Nausea, vomiting, anorexia, and constipation (10% to 33%)
Hepatic: AST or ALT level >2x normal (15% to 50%)
Ocular: Corneal microdeposits (>90%; causes visual disturbance in <10%)>3 mg/mL)
Ocular: Visual disturbances (2% to 9%), halo vision (<5%>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. Antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias. Discontinuation of therapy: Due to complex pharmacokinetics, when discontinued there is still an increased risk of drug interactions and it may be difficult to predict when an arrhythmia may occur.

RESTRICTIONS — An FDA-approved medication guide must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.

DRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2C8 (major at low concentrations), 2C19 (minor), 2D6 (minor), 3A4 (major); Inhibits CYP1A2 (weak), 2A6 (moderate), 2B6 (weak), 2C9 (moderate), 2C19 (weak), 2D6 (moderate), 3A4 (moderate)

Anesthetics (halogenated, inhaled): Amiodarone enhances the myocardial depressant and conduction effects of inhalation anesthetics; monitor.

Azole antifungals: May prolong QTc, potentially leading to malignant arrhythmias; use caution.

Beta-blockers may cause excessive AV block; monitor response.

Calcium channel blockers (diltiazem, verapamil): May cause excessive AV block; monitor.

Cimetidine: May increase amiodarone blood levels.

Cholestyramine: May decrease amiodarone blood levels.

Cisapride: May prolong QTc interval potentially leading to malignant arrhythmias.

Cyclosporine: Serum levels may be increased by amiodarone; monitor.

CYP2A6 substrates: Amiodarone may increase the levels/effects of CYP2A6 substrates. Example substrates include dexmedetomidine and ifosfamide.

CYP2C8 inducers: May decrease the levels/effects of amiodarone. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8 inhibitors: May increase the levels/effects of amiodarone. Example inhibitors include atazanavir, gemfibrozil, and ritonavir.

CYP2C9 substrates: Amiodarone may increase the levels/effects of CYP2C9 substrates. Example substrates include bosentan, dapsone, fluoxetine, glimepiride, glipizide, losartan, montelukast, nateglinide, paclitaxel, phenytoin, warfarin, and zafirlukast.

CYP2D6 substrates: Amiodarone may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Amiodarone may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of amiodarone. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of amiodarone. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.

CYP3A4 substrates: Amiodarone may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, ergot derivatives, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine.

Digoxin levels may be increased by amiodarone; consider reducing digoxin dose by 50% and monitor digoxin blood levels closely.

Fentanyl: Concurrent use may lead to bradycardia, sinus arrest, and hypotension.

Flecainide blood levels may be increased; consider reducing flecainide dose by 25% to 33% with concurrent use.

Fluoroquinolones (sparfloxacin, gatifloxacin, moxifloxacin): May result in additional prolongation of the QT interval; concurrent use of sparfloxacin is contraindicated.

HMG-CoA reductase inhibitors (lovastatin, simvastatin, and others dependent on CYP3A4 metabolism): Amiodarone inhibits metabolism of lovastatin and/or simvastatin and may increase the risk of myopathy and rhabdomyolysis. Concurrent use of lovastatin or simvastatin is not recommended, but if unavoidable, dose of lovastatin should not exceed 40 mg/day. The dose of simvastatin should not exceed 20 mg/day; consider alternative HMG-CoA reductase inhibitor.

Lidocaine: Amiodarone may increase serum levels/toxicity of lidocaine. Sinus bradycardia may occur with concurrent use.

Macrolide antibiotics: May prolong QTc, potentially leading to malignant arrhythmias. Use caution and evaluate risk:benefit.

Metoprolol blood levels may be increased; monitor response.

Phenytoin blood levels may be increased by amiodarone; amiodarone blood levels may be decreased by phenytoin.

Procainamide and NAPA plasma levels may be increased; consider reducing procainamide dosage by 25% with concurrent use.

Propranolol blood levels may be increased.

Protease inhibitors (amprenavir, indinavir, ritonavir): May increase amiodarone blood levels and toxicity; concurrent use is contraindicated.

QTc interval prolonging agents (including but may not be limited to amitriptyline, bepridil, disopyramide, erythromycin, haloperidol, imipramine, quinidine, pimozide, procainamide, sotalol, and thioridazine): Effect/toxicity increased; use with caution.

Quinidine blood levels may be increased; monitor quinidine trough concentration.

Rifampin may decrease amiodarone blood levels.

Theophylline blood levels may be increased.

Thioridazine: Amiodarone may enhance the QTc-prolonging effect of thioridazine.

Thyroid supplements: Amiodarone may alter thyroid function; monitor closely.

Trazodone: Amiodarone may increase levels/effects of trazodone. QTC prolongation and torsade de pointes have been reported with concurrent use.

Warfarin: Hypoprothrombinemic response increased. Monitor INR closely when amiodarone is initiated or discontinued. Reduce warfarin's dose by 1/3 to 1/2 when amiodarone is started.

ETHANOL/NUTRITION/HERB INTERACTIONS
Food: Increases the rate and extent of absorption of amiodarone. Grapefruit juice increases bioavailability of oral amiodarone by 50% and decreases the conversion of amiodarone to N-DEA (active metabolite); altered effects are possible; use should be avoided during therapy.

Herb/Nutraceutical: St John's wort may decrease amiodarone levels or enhance photosensitization. Avoid ephedra (may worsen arrhythmia). Avoid dong quai.

PREGNANCY RISK FACTOR — D (show table)

PREGNANCY IMPLICATIONS — May cause fetal harm when administered to a pregnant woman, leading to congenital goiter and hypo- or hyperthyroidism.

LACTATION — Enters breast milk/not recommended (AAP rates "of concern")

BREAST-FEEDING CONSIDERATIONS — Hypothyroidism may occur in nursing infants. Both amiodarone and its active metabolite are excreted in human milk. Breast-feeding may lead to significant infant exposure and potential toxicity.

DIETARY CONSIDERATIONS — Administer 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.

PRICING — (data from drugstore.com)
Tablets (Amiodarone HCl)
200 mg (30): $28.99

Tablets (Cordarone)
200 mg (60): $242.47

Tablets (Pacerone)
100 mg (30): $139.99

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); liver function tests; 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.

REFERENCE RANGE — Therapeutic: 0.5-2.5 mg/L (SI: 1-4 µmol/L) (parent); desethyl metabolite is active and is present in equal concentration to parent drug

TOXICOLOGY/OVERDOSE COMPREHENSIVE — Symptoms include extensions of pharmacologic effect, sinus bradycardia and/or heart block, hypotension and QT prolongation. Patients should be monitored for several days following ingestion. Intoxication with amiodarone necessitates ECG monitoring. Bradycardia may be atropine resistant. Injectable isoproterenol or a temporary pacemaker may be required. Dialysis is not beneficial.

CANADIAN BRAND NAMES — Alti-Amiodarone; Amiodarone Hydrochloride for Injection®; Apo-Amiodarone®; Cordarone®; Gen-Amiodarone; Novo-Amiodarone; Rhoxal-amiodarone; Sandoz-Amiodarone

(For additional information see "Amiodarone: Patient drug information" and see "Amiodarone: Pediatric drug information")

INTERNATIONAL BRAND NAMES — Aldarin (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TZ, UG, ZM, ZW); Alti-Amiodarone (CA); Amdarone (TH); Amicordin (PL); Amiocar (AR); Amiodacore (IL); Amiodarex (DE); Amiodarona (CL); Amiodarone Hydrochloride for Injection (CA); Amiohexal (DE); Amiokordin (PL); Ancaron (JP); Angiodarona (BR); Angoron (GR); Apo-Amiodarone (CA); Aratac (AU, MY, NZ, SG, TH, TW); Arycor (CO); Atlansil (AR, BR, CL, EC, PE, UY); Braxan (MX); Cardinorm (AU); Corbionax (FR); Cordarex (DE); Cordaron (BG); Cordarone (AE, AN, BB, BE, BF, BG, BH, BJ, CA, CH, CI, CN, CO, CR, CY, CZ, DO, EC, EE, EG, ET, FI, FR, GH, GM, GN, GT, HK, HN, HU, ID, IQ, IR, IT, JO, KE, KR, KW, LB, LR, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, NL, NO, OM, PA, PE, PH, PK, PL, PT, PY, QA, SA, SC, SD, SE, SL, SN, SV, SY, TH, TT, TW, TZ, UG, YE, ZA, ZM, ZW); Cordarone X (AU, GB, IE, IN, NZ, ZA); Coronovo (AR); Diarona (UY); Eurythmic (IN); Forken (MX); Gen-Amiodarone (CA); Hexarone (ZA); Kendaron (ID); Miodar (DO); Novo-Amiodarone (CA); Opacorden (PL); Procor (IL); Rhoxal-amiodarone (CA); Rithmik (AU); Sandoz-Amiodarone (CA); Sedacoron (AT, HK, PL, TW); Tachydaron (DE); Tiaryt (ID); Trangorex (ES, VE)

MECHANISM OF ACTION — 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

PHARMACODYNAMICS/KINETICS
Onset of action: Oral: 2 days to 3 weeks; I.V.: May be more rapid
Peak effect: 1 week to 5 months

Duration after discontinuing therapy: 7-50 days
Note: Mean onset of effect and duration after discontinuation may be shorter in children than adults

Distribution: Vd: 66 L/kg (range: 18-148 L/kg); crosses placenta; enters breast milk in concentrations higher than maternal plasma concentrations

Protein binding: 96%

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

Bioavailability: Oral: ~50%

Half-life elimination: Terminal: 40-55 days (range: 26-107 days); shorter in children than adults

Excretion: Feces; urine (<1% as unchanged drug)

PATIENT INFORMATION — Take with food; use sunscreen or stay out of sun to prevent burns; skin discoloration is reversible; photophobia may make sunglasses necessary; do not discontinue abruptly; regular blood work for thyroid functions tests and ophthalmologic exams are necessary; notify prescriber if persistent dry cough or shortness of breath occurs