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Amiodarone

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MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Amiodarone may be confused with aMILoride, amrinone
Cordarone® may be confused with Cardura®, Cordran®

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

MEDICATION GUIDE — An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication for each new outpatient prescription and refill.
Cordarone®: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM152841.pdf
Pacerone®: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088668.pdf

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 when adequate arrhythmia control is achieved, decrease to 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: 2.2 g)

I.V. to oral therapy conversion: Use the following as a guide:
<1 week I.V. infusion: 800-1600 mg/day
1- to 3-week I.V. infusion: 600-800 mg/day
>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 weeks, since any changes in serum amiodarone concentrations during this period may not be clinically significant. Unlabeled uses:
Atrial fibrillation prophylaxis following open heart surgery (unlabeled use):Note: A variety of regimens have been used in clinical trials, including oral and intravenous regimens:
Oral: Starting in postop recovery, 400 mg twice daily for up to 7 days. Alternative regimen of amiodarone: 600 mg/day for 7 days prior to surgery, followed by 200 mg/day until hospital discharge, has also been shown to decrease the risk of postoperative atrial fibrillation. Note: A variety of regimens have been used in clinical trials.
I.V.: Starting at postop recovery, 1000 mg infused over 24 hours for 2 days has been shown to reduce the risk of postoperative atrial fibrillation. Note: A variety of regimens have been used in clinical trials.
Atrial fibrillation pharmacologic cardioversion (ACC/AHA/ESC Practice Guidelines) (unlabeled use):
Oral: Inpatient: 1.2-1.8 g/day in divided doses until 10 g total, then 200-400 mg/day maintenance. Note: Other regimens have been described and may be used clinically (Roy, 2000):
400 mg 3 times/day for 5-7 days, then 400 mg/day for 1 month, then 200 mg/day
or
10 mg/kg/day for 14 days, followed by 300 mg/day for 4 weeks, followed by maintenance dosage of 100-200 mg/day
I.V.: 5-7 mg/kg over 30-60 minutes, then 1.2-1.8 g/day continuous infusion or in divided oral doses until 10 g total. Maintenance: See oral dosing.
Recurrent atrial fibrillation (unlabeled use): No standard regimen defined; examples of regimens include: Oral: Initial: 10 mg/kg/day for 14 days; followed by 300 mg/day for 4 weeks, followed by maintenance dosage of 100-200 mg/day (Roy D, 2000). Other regimens have been described and are used clinically (ie, 400 mg 3 times/day for 5-7 days, then 400 mg/day for 1 month, then 200 mg/day).
Stable VT or SVT (unlabeled use): I.V.: First 24 hours: 1050 mg according to following regimen
Step 1: 150 mg (100 mL) over first 10 minutes (mix 3 mL in 100 mL D5W)
Step 2: 360 mg (200 mL) over next 6 hours (mix 18 mL in 500 mL D5W): 1 mg/minute
Step 3: 540 mg (300 mL) over next 18 hours: 0.5 mg/minute
Note: After the first 24 hours: 0.5 mg/minute utilizing concentration of 1-6 mg/mL

DOSING: PEDIATRIC

(For additional information see “Amiodarone: Pediatric drug information”)
Arrhythmias (unlabeled use):
Loading dose: Oral: 10-20 mg/kg/day in 1-2 doses for 4-14 days or until adequate control of arrhythmia or prominent adverse effects occur; alternative loading dose in children <1 year: 600-800 mg/1.73 m2/day in 1-2 divided doses/day.
Maintenance dose: Oral: Dose may be reduced to 5 mg/kg/day for several weeks (or 200-400 mg/1.73 m2/day given once daily); if no recurrence of arrhythmia, dose may be further reduced to 2.5 mg/kg/day; maintenance doses may be given 5-7 days/week.

Arrhythmias (unlabeled use, dosing based on limited data):
Loading dose: I.V.: 5 mg/kg over 30 minutes; may repeat up to 3 times if no response.
Maintenance dose: I.V.: 2-20 mg/kg/day (5-15 mcg/kg/minute) by continuous infusion.
Note: I.V. administration at low flow rates (potentially associated with use in pediatrics) 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.

Pulseless VF or VT (PALS dosing): I.V.: 5 mg/kg (maximum: 300 mg/dose) rapid I.V. bolus or I.O.; repeat up to a maximum daily dose of 15 mg/kg. (Note: Maximum recommended daily dose in adolescents is 2.2 g.)

Perfusing tachycardias (PALS dosing): I.V.: Loading dose: 5 mg/kg (maximum: 300 mg/dose) I.V. over 20-60 minutes or I.O.; may repeat up to maximum dose of 15 mg/kg/day. (Note: Maximum recommended daily dose in adolescents is 2.2 g.)

DOSING: ELDERLY — 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.

DOSING: RENAL IMPAIRMENT — Hemodialysis effects: Not removed by hemodialysis or peritoneal dialysis (0% to 5%); no supplemental doses required.

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.

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

Injection, solution, as hydrochloride: 50 mg/mL (3 mL, 9 mL, 18 mL) [contains benzyl alcohol and polysorbate 80]

Tablet, as hydrochloride [scored]: 200 mg, 400 mg
Cordarone®: 200 mg
Pacerone®: 100 mg [not scored], 200 mg, 400 mg

DOSAGE FORMS: CONCISE
Injection, solution: 50 mg/mL (3 mL, 9 mL, 18 mL)

Tablet [scored]: 200 mg, 400 mg
Cordarone®: 200 mg
Pacerone®: 100 mg [not scored], 200 mg, 400 mg

GENERIC EQUIVALENT AVAILABLE — Yes

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

I.V.: For infusions >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 slo
wly 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, ceftizoxime, ceftriaxone, cefuroxime, 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.
Visually Compatible (Chalmers, 2001): Amphotericin B, atracurium, atropine, calcium chloride, calcium gluconate, ciprofloxacin, epinephrine, eptifibatide, famotidine, fentanyl citrate, fluconazole, furosemide (1 mg/mL), lepirudin, lorazepam, magnesium sulfate (20 mg/mL), methylprednisolone sodium succinate, milrinone, sodium nitroprusside, tirofiban, vasopressin, vecuronium. Visually Incompatible: Ampicillin-sulbactam, ceftazidime, digoxin, furosemide (10 mg/mL), imipenem-cilastatin, magnesium sulfate (500 mg/mL), piperacillin, piperacillin-tazobactam, potassium phosphate, sodium phosphate.

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Compatibility in syringe: Incompatible: Heparin.

Compatibility when admixed: Compatible: Dobutamine, lidocaine, potassium chloride, procainamide, propafenone, verapamil. 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 baseline 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 associated with 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%) 1% to 10%:
Cardiovascular: CHF (3%), bradycardia (3% to 5%), AV block (5%), conduction abnormalities, SA node dysfunction (1% to 3%), cardiac arrhythmia, flushing, edema. Additional effects associated with I.V. administration include asystole, cardiac arrest, electromechanical dissociation, ventricular tachycardia, and cardiogenic shock.
Dermatologic: Slate blue skin discoloration (<10%)
Endocrine & metabolic: Hyperthyroidism (3% to 10%; more common in iodine-deficient regions of the world), libido decreased
Gastrointestinal: Abdominal pain, abnormal salivation, abnormal taste (oral)
Hematologic: Coagulation abnormalities
Hepatic: Hepatitis and cirrhosis (<3%)
Local: Phlebitis (I.V., with concentrations >3 mg/mL)
Ocular: Visual disturbances (2% to 9%), halo vision (<5% occurring especially at night), optic neuritis (1%)
Respiratory: Pulmonary toxicity has been estimated to occur at a frequency between 2% and 7% of patients (some reports indicate a frequency as high as 17%). Toxicity may present as hypersensitivity pneumonitis; pulmonary fibrosis (cough, fever, malaise); pulmonary inflammation; interstitial pneumonitis; or alveolar pneumonitis. ARDS has been reported in up to 2% of patients receiving amiodarone, and postoperatively in patients receiving oral amiodarone.
Miscellaneous: Abnormal smell (oral)

<1% (Limited to important or life-threatening): Acute intracranial hypertension (I.V.), acute renal failure, agranulocytosis, alopecia, anaphylactic shock, angioedema, aplastic anemia, bone marrow granuloma, bronchiolitis obliterans organizing pneumonia (BOOP), bronchospasm, confusion, disorientation, dyspnea, encephalopathy, epididymitis (noninfectious), erectile dysfunction, erythema multiforme, exfoliative dermatitis, hallucination, hemolytic anemia, hemoptysis, hyperglycemia, hypertriglyceridemia, hypotension (oral), hypoxia, impotence, injection site reactions, leukocytoclastic vasculitis, muscle weakness, myopathy, neutropenia, optic neuropathy, pancreatitis, pancytopenia, parkinsonian symptoms, photophobia, pleuritis, proarrhythmia, pruritus, pseudotumor cerebri, pulmonary alveolar hemorrhage, pulmonary edema, pulmonary mass, QT interval increased, rash, renal impairment, renal insufficiency, respiratory failure, rhabdomyolysis, SIADH, sinus arrest, spontaneous ecchymosis, Stevens-Johnson syndrome, thrombocytopenia, thyroid nodules, thyroid cancer, thyrotoxicosis, torsade de pointes (rare), toxic epidermal necrolysis, urticaria, vasculitis, ventricular fibrillation, wheezing CONTRAINDICATIONS — Hypersensitivity to amiodarone, iodine, or any component of the formulation; severe sinus-node dysfunction; 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; pregnancy WARNINGS / PRECAUTIONS
Boxed warnings: Arrhythmias: Appropriate use: See “Disease-related concerns” below. Hepatotoxicity: See “Concerns related to adverse effects” below. Proarrhythmic effect: See “Concerns related to adverse effects” below. Pulmonary toxicity: See “Concerns related to adverse effects” below.

Concer
ns related to adverse effects: Bradycardia/hypotension: May cause hypotension and bradycardia (infusion-rate related). Hepatotoxicity: [U.S. Boxed Warning]: Liver toxicity is common, but usually mild with evidence of increased liver enzymes; severe liver toxicity can occur and has been fatal in a few cases. Optic neuritis/neuropathy: May cause optic neuropathy and/or optic neuritis, usually resulting in visual impairment. Corneal microdeposits occur in a majority of patients, and may cause visual disturbances in some patients (blurred vision, halos); these 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. Proarrhythmic effect: [U.S. Boxed Warning]: 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 (torsade 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. Pulmonary toxicity: [U.S. Boxed Warning]: Lung damage (abnormal diffusion capacity) may occur without symptoms; monitor for pulmonary toxicity (eg, chronic interstitial pneumonitis, organizing pneumonia, acute respiratory distress syndrome, solitary pulmonary mass). Educate patients about monitoring for symptoms (eg, nonproductive cough, dyspnea, pleuritic pain, weight loss, fever, malaise). Evaluate new respiratory symptoms; pre-existing 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.

Disease-related concerns: Arrhythmias: Appropriate use: [U.S. Boxed Warnings]: Only indicated for patients with life-threatening arrhythmias because of risk of toxicity. Alternative therapies should be tried first before using amiodarone. Patients should be hospitalized when amiodarone is initiated. Currently, the 2005 ACLS guidelines recommend I.V. amiodarone as the preferred antiarrhythmic for the treatment of pulseless VT/VF, both life-threatening arrhythmias. 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. 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 or hypomagnesemia, prior to use and throughout therapy. Hepatic impairment: Use with caution in patients with hepatic impairment. Thyroid disease: Use very cautiously and with close monitoring in patients with thyroid disease; may cause hyper- or hypothyroidism. Hyperthyroidism may result in thyrotoxicosis and may aggravate or cause breakthrough arrhythmias. If any new signs of arrhythmia appear, hyperthyroidism should be considered. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in the elderly and in patients with underlying thyroid dysfunction.

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Concurrent drug therapy issues: 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.

Special populations: Elderly: Monitor thyroid function prior to treatment and periodically thereafter. Pediatrics: Safety and efficacy have not been fully established in children. Surgical patients: Caution in surgical patients; may enhance hemodynamic effect of anesthetics; associated with increased risk of adult respiratory distress syndrome (ARDS) postoperatively.

Dosage form specific issues: Benzyl alcohol: Injection contains benzyl alcohol which has been associated with “gasping syndrome” in neonates.

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 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. METABOLISM / TRANSPORT EFFECTS — Substrate of CYP1A2 (minor), 2C8 (major at low concentration), 2C19 (minor), 2D6 (minor), 3A4 (major); Inhibits CYP1A2 (weak), 2A6 (moderate), 2B6 (weak), 2C9 (moderate), 2C19 (weak), 2D6 (moderate), 3A4 (moderate) DRUG INTERACTIONS
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Antiarrhythmic Agents (Class Ia): May enhance the QTc-prolonging effect of Amiodarone. Amiodarone may increase the metabolism of Antiarrhythmic Agents (Class Ia). Risk D: Consider therapy modification

Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Azithromycin: May enhance the QTc-prolonging effect of Amiodarone. Risk D: Consider therapy modification

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. Risk C: Monitor therapy

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

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

Cardiac Glycosides: Amiodarone may increase the serum concentration of Cardiac Glycosides. Risk D: Consider therapy modification

Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Amiodarone. Consider using an alternative H2 antagonist. Risk D: Consider therapy modification

Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: 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. Risk C: Monitor therapy

Colchicine: P-Glycoprotein Inhibitors may increase the se
rum 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. Risk D: Consider therapy modification

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: Consider therapy modification

CycloSPORINE: Amiodarone may decrease the metabolism of CycloSPORINE. Risk D: Consider therapy modification

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

CYP2C8 Inducers (Highly Effective): May increase the metabolism of CYP2C8 Substrates (High risk). Risk C: Monitor therapy

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates (High risk). Risk C: Monitor therapy

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

CYP2C9 Substrates (High risk): CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy

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

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

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

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

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

CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

Dabigatran Etexilate: Amiodarone may increase the serum concentration of Dabigatran Etexilate. Risk D: Consider therapy modification

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

Deferasirox: May increase the serum concentration of CYP2C8 Substrates (High risk). Risk C: Monitor therapy

Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: A lower starting dose of eplerenone (25 mg once daily) is recommended in patients with hypertension who are also taking drugs that are moderate inhibitors of CYP3A4. Risk D: Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Risk X: Avoid combination

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Risk D: Consider therapy modification

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

Flecainide: Amiodarone may decrease the metabolism of Flecainide. Risk D: Consider therapy modification

Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification

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

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

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 (e.g., simvastatin prescribing information recommends not exceeding 20 mg/day during concurrent therapy). Exceptions: Pravastatin. Risk D: Consider therapy modification

Lidocaine: Amiodarone may decrease the metabolism of Lidocaine. Risk C: Monitor therapy

Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Orlistat: May decrease the absorption of Amiodarone. Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein 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.). Risk C: Monitor therapy

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P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein 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.). Risk C: Monitor therapy

P-Glycoprotein Substrates: P-Glycoprotein Inhibitors may increase the serum concentration of P-Glycoprotein 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.). Risk C: Monitor therapy

Phenytoin: May increase the metabolism of Amiodarone. Amiodarone may decrease the metabolism of Phenytoin. Risk C: Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy

Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination

Protease Inhibitors: May decrease the metabolism of Amiodarone. Risk X: Avoid combination

QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification

QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Rifamycin Derivatives: May increase the metabolism of Amiodarone. Risk C: Monitor therapy

Rivaroxaban: P-Glycoprotein Inhibitors may increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Risk C: Monitor therapy

Saxagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Saxagliptin. Risk C: Monitor therapy

Silodosin: P-Glycoprotein Inhibitors may increase the serum concentration of Silodosin. Risk X: Avoid combination

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

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the formation of highly potent active metabolites. Risk D: Consider therapy modification

Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination

Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination

Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: 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. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Amiodarone may enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination

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): $272.01

Tablets (Pacerone)
100 mg (30): $147.29

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.

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

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

CANADIAN BRAND NAMES — Alti-Amiodarone; Amiodarone Hydrochloride for Injection®; Apo-Amiodarone®; Cordarone®; Dom-Amiodarone; Gen-Amiodarone; Mylan-Amiodarone; Novo-Amiodarone; PHL-Amiodarone; PMS-Amiodarone; PRO-Amiodarone; ratio-Amiodarone; ratio-Amiodarone I.V.; Riva-Amiodarone; Sandoz-Amiodarone

INTERNATIONAL BRAND NAMES — Aldarin (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Aldarone (TH); Amicordin (PL); Amiocar (AR); Amiodacore (IL); Amiodarex (DE); Amiodarona (CN); Amiohexal (DE); Amiokordin (PL); Ancaron (JP); Angiodarona (BR); Angoron (GR); Anoion (PH); Aratac (AU, MY, SG, TH, TW); Arycor (CO); Atlansil (AR, BR, CN, EC, PE, UY); Braxan (MX); Cardilor (MY, TH); Cardinorm (AU); Coedarone (MX); Corbionax (FR); Cordarex (DE); Cordarone (AE, BB, BE, BF, BG, BH, BJ, BM, BS, BZ, CH, CI, CL, CR, CY, CZ, DO, EC, EE, EG, ET, FI, FR, GH, GM, GN, GT, GY, HK, HN, ID, IL, IQ, IR, IT, JM, JO, KE, KP, KW, LB, LR, LY, MA, ML, MR, MU, MW, MY, NE, NG, NI, NL, NO, OM, PA, PE, PH, PK, PL, PT, PY, QA, SA, SC, SD, SE, SL, SN, SR, SV, SY, TH, TN, TT, TW, TZ, UG, YE, ZA, ZM, ZW); Cordarone X (AU, GB, IE, IN, ZA); Coronovo (AR); Diarona (UY); Escodaron (CH); Eurythmic (IN); Forken (MX); Hexarone (ZA); Kendaron (ID); Keritmon (MX); Miodar (DO); Opacorden (PL); Procor (IL); Rithmik (AU); 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
Absorption: Slow and variable

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)

Protein binding: 96%

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

Bioavailability: Oral: 35% to 65%

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

Time to peak, serum: 3-7 hours

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

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