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CLINICAL PHARMACOLOGY

Amiodarone: Guidelines for Use and Monitoring LYLE A. SIDDOWAY, M.D., York Hospital, York, Pennsylvania

Amiodarone is a potent that is used to treat ventricular arrhyth- mias and . The drug prevents the recurrence of life-threatening ven- tricular and produces a modest reduction of sudden deaths in high-risk patients. Amiodarone is more effective than or in preventing recurrent atrial fibrillation in patients for whom a rhythm-control strategy is chosen. When long-term amiodarone therapy is used, potential drug toxicity and interactions must be considered. The dosage of amiodarone should be kept at the lowest effective level. In patients who also are taking and , physicians must pay close attention to digoxin levels and , keeping in mind that the effects of interaction with amiodarone do not peak until seven weeks after the initiation of con- comitant therapy. Laboratory studies to assess and function should be performed at least every six months. (Am Fam Physician 2003;68:2189-96. Copyright 2003© American Academy of Family Physicians.)

Richard W. Sloan, miodarone (Cordarone) is a tions in fat and muscle, as well as in the liver, M.D., R.Ph., coordina- complex antiarrhythmic agent , and skin. Amiodarone crosses the pla- tor of this series, is chairman and residency with multiple electrophysio- centa and reaches measurable levels in breast program director of logic effects, unusual pharma- milk. the Department of cokinetics, and numerous po- The major metabolite of amiodarone is Family Medicine at Atentially harmful drug interactions and desethylamiodarone (DEA), which is known York (Pa.) Hospital and adverse effects. Although the U.S. Food and to have antiarrhythmic properties. clinical associate pro- fessor in family and Drug Administration (FDA) has labeled juice can inhibit amiodarone metabolism and 3 community medicine at amiodarone only for the treatment of life- lead to elevated drug levels, but the impact of the Milton S. Hershey threatening ventricular arrhythmias, the drug this interaction on the long-term efficacy and Medical Center, Penn- also is used to treat atrial fibrillation. Because toxicity of amiodarone is not known. sylvania State Univer- of the complexity and widespread use of this The elimination half-life of amiodarone is sity, Hershey, Pa. agent, other treatment decisions often are highly variable and unusually long, averaging affected. This article reviews the pharmacol- about 58 days. The long half-life is thought to ogy, indications, adverse effects, and drug be a result of the drug’s slow release from interactions of amiodarone, and outlines a lipid-rich tissues.2 strategy for surveillance of patients who are taking this drug. ELECTROPHYSIOLOGIC EFFECTS Amiodarone is considered to be a class III Clinical Pharmacology drug (Vaughan Williams classification), which indicates that it prolongs the QT interval. Amiodarone is an -containing com- However, the drug has many other effects: it pound with some structural similarity to thy- slows rate and atrioventricular nodal roxine. The drug’s high iodine content likely is conduction (via and beta- a factor in its effects on the thyroid gland. The blockade), prolongs refractoriness of amiodarone is variable but (via potassium and block- generally poor, ranging from 22 to 95 per- ade), and slows intracardiac conduction (via cent.1 Absorption is enhanced when the drug sodium channel blockade). See page 2113 for 2 definitions of strength- is taken with food. Amiodarone is highly The relationship between plasma amio- of-evidence levels. lipid soluble and is stored in high concentra- darone concentrations and effect, as well as

Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright© 2003 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. tality rate from 24.3 percent to 19.9 percent Amiodarone is approved for use in the secondary prevention (ARR, 4.4 percent; NNT, 23). Because of life-threatening ventricular arrhythmias. implantable cardioverter-defibrillators (ICDs) are more effective than amiodarone in reduc- ing mortality in high-risk patients with previ- ous myocardial infarction, primary treatment the contribution of the metabolite DEA, is not should be an ICD.6-9 [Reference 6—Evidence well established.2 Routine monitoring of the level A, meta-analysis] In these patients, amio- amiodarone plasma level is not recom- darone may be used as an adjunct to reduce mended.4 [Evidence level C, consensus/ expert the frequency of ICD shocks or to control guidelines] atrial fibrillation in selected highly sympto- matic patients. The relative efficacy of amio- Indications darone and ICDs in preventing sudden death LONG-TERM TREATMENT in patients without coronary disease is under Amiodarone is approved for use in the sec- investigation. ondary prevention of life-threatening ven- Amiodarone is used in the treatment of tricular arrhythmias. The North American atrial fibrillation, although the FDA has not Society for Pacing and Electrophysiology approved this indication. Various practice (NASPE) recommends amiodarone as the guidelines recommend amiodarone as a sec- antiarrhythmic agent of choice in patients ond-line drug in the long-term treatment of who have survived sustained ventricular tachy- atrial fibrillation in patients with structural arrhythmias, particularly those with left ven- heart disease and in highly symptomatic tricular dysfunction.4 patients without heart disease.10 Several Studies on the use of amiodarone for the smaller studies have shown that amiodarone primary prevention of sudden death in high- is similar to and sotalol in the treat- risk patients have had mixed results. One ment of atrial fibrillation in these patients.11,12 meta-analysis of 13 studies of patients with In one randomized controlled trial (RCT),12 congestive heart failure or recent myocardial sinus rhythm was maintained successfully for infarction showed a small reduction in total 16 months in 65 percent of patients treated annual mortality, from 12.3 percent to 10.9 with amiodarone, compared with 37 percent percent (absolute risk reduction [ARR], 2.4 of patients treated with sotalol or propa- percent; number needed to treat [NNT], 42).5 fenone (ARR, 28 percent; NNT, 3.6). However, [Evidence level A, meta-analysis] The benefit recent studies have shown that aggressive of amiodarone therapy was more pronounced attempts to maintain sinus rhythm using in the patients who had congestive heart fail- amiodarone or other drugs do not improve ure, with treatment reducing the annual mor- outcomes in relatively asymptomatic pa- tients.13,14 Therefore, long-term amiodarone therapy, with its potential for toxicity, does not The Author appear to be justified in patients who are tak- ing anticoagulant drugs if rate-control strate- LYLE A. SIDDOWAY, M.D., is director of the cardiac electrophysiology laboratory at York (Pa.) Hospital and assistant clinical professor in the Department of Medicine at gies can provide satisfactory symptomatic Pennsylvania State University College of Medicine, Hershey. After receiving his medical improvement. degree from Johns Hopkins University School of Medicine, Baltimore, Dr. Siddoway completed an internal medicine residency and clinical pharmacology and cardiology ACUTE TREATMENT fellowships at Vanderbilt University Medical Center, Nashville. Intravenously administered amiodarone is Address correspondence to Lyle A. Siddoway, M.D., 25 Monument Rd., Suite 200, York, PA 17403 (e-mail: [email protected]). Reprints are not available from effective for the emergency treatment of ven- the author. tricular tachyarrhythmias. Onset of the antiar-

2190 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 11 / DECEMBER 1, 2003 TABLE 1 Dosage Guidelines for Amiodarone (Cordarone)

Administration Indication route and setting Dosage Potential adverse effects

Life-threatening IV, inpatient 150-mg IV bolus over 10 minutes (if necessary, bolus may Hypotension, , treatment be repeated in 10 to 30 minutes); then 1 mg per minute for 6 hours; then 0.5 mg per minute for 18 hours; then reduce IV dosage or convert to oral dosing when possible.2 Ventricular Oral, inpatient 800 to 1,600 mg per day in divided doses until a total of Bradycardia, QT prolongation, arrhythmia treatment 10 g has been given; then 200 to 400 mg per day.2 GI upset, constipation; rarely, Atrial fibrillation Oral, inpatient 600 to 800 mg per day in divided doses until a total of Bradycardia, QT prolongation, or outpatient 10 g has been given (may use higher initial dosage or IV GI upset, constipation; rarely, treatment dosing in unstable inpatients); then 200 mg per day10 torsades de pointes

IV = intravenous; GI = gastrointestinal. Information from references 2 and 10.

rhythmic effect of intravenous amiodarone similar to other antiarrhythmic drugs in its occurs in less than 30 minutes.15 ability to convert patients to normal sinus In the Advanced Cardiac Life Support rhythm (72.1 percent for amiodarone com- (ACLS) guidelines published in 2000, amio- pared with 71.9 percent for other antiarrhyth- darone and are recommended mic drugs).18 [Evidence level A, meta-analy- for the initial treatment of hemodynamically sis] The meta-analysis did not address the stable wide-complex .16 However, effect of antiarrhythmic drugs on mortality these guidelines list amiodarone as being only and other clinical outcomes. Use of these “possibly effective” for the treatment of refrac- drugs would be most appropriate in patients tory pulseless or ven- with recurrent hemodynamically unstable tricular fibrillation. In contrast, a recent study atrial fibrillation.10 Amiodarone may be par- comparing the use of amiodarone and lido- ticularly beneficial in patients with rapid ven- caine in patients with shock-resistant, out-of- tricular rates or impaired renal function. hospital showed that amiodarone therapy substantially improves Adverse Effects survival and hospital admission rates.17 [Evi- Amiodarone has been associated with toxic- dence level A, RCT] ity involving the lungs, thyroid gland, liver, Typical amiodarone dosages in the ACLS eyes, skin, and nerves (Table 2).2,5,11,19 The fre- setting are provided in Table 1.2,10 In patients quency of most adverse effects is related to the who require long-term treatment, intravenous total amiodarone exposure (i.e., dosage and dosing should be switched to oral dosing. duration of treatment). Therefore, physicians Patients who received intravenous amio- must use the lowest possible dosage of amio- darone for less than one week should take 800 darone and, if possible, discontinue treatment to 1,600 mg oral amiodarone per day.2 if adverse effects occur. Patients who received intravenous amio- darone for one to three weeks should take 600 to 800 oral amiodarone per day, and patients The most serious potential adverse effect of who received intravenous amiodarone for amiodarone therapy is pulmonary toxicity, more than three weeks should take 400 mg which may result from direct drug-induced oral amiodarone per day. phospholipidosis or immune-mediated Intravenously administered amiodarone is hypersensitivity.19 The most common clinical being used with increasing frequency in the presentation is subacute cough and progres- acute treatment of atrial fibrillation. In a sive dyspnea, with associated patchy intersti- meta-analysis of 18 RCTs, amiodarone was tial infiltrates on chest radiographs and

DECEMBER 1, 2003 / VOLUME 68, NUMBER 11 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2191 pulmonary toxicity can develop rapidly with Recent studies have shown that aggressive attempts to main- no antecedent abnormalities on chest radio- tain sinus rhythm using amiodarone or other drugs do not graphs or pulmonary function tests. Any improve outcomes in relatively asymptomatic patients. report from the patient of worsening dyspnea or cough should elicit a prompt assessment for pulmonary toxicity. Congestive heart fail- ure can mimic amiodarone pneumonitis and, reduced diffusing capacity on pulmonary thus, must be ruled out early in the evaluation. function tests. A much less common presenta- High-resolution computed tomographic tion is adult respiratory distress syndrome. scanning can be helpful in making a diagnosis. In early studies, the frequency of pul- The primary treatment for pulmonary tox- monary toxicity in amiodarone therapy was icity is withdrawal of amiodarone and provi- 2 to 17 percent.2 More recent studies have sion of supportive care and, in some cases, shown a lower incidence in patients receiving corticosteroids. In most instances, the toxicity dosages of 300 mg per day or less. A meta- is reversible. analysis11 of double-blind trials found the fre- quency of adult respiratory distress syndrome THYROID TOXICITY to be 1 percent annually. Thyroid toxicity is the most common com- Routine screening for adult respiratory dis- plication that requires intervention. Thyroid tress syndrome is of limited value, because abnormalities have been described in up to 10

TABLE 2 Adverse Effects of Amiodarone (Cordarone)

Adverse effect Frequency (%) Method of diagnosis Treatment

Serious effects Pulmonary toxicity 2 to 172 Chest radiograph; pulmonary Stop amiodarone; initiate corticosteroid therapy. function tests, including DLCO 2 2 Free T4 level, TSH level Initiate antithyroid drug therapy; consider stopping amiodarone. 5 6 Free T4 level, TSH level Administer thyroid hormone supplementation. Liver toxicity 15 Liver enzyme levels three times Consider stopping amiodarone. higher than normal Optic neuropathy Unknown19 Ophthalmologic examination Consider stopping amiodarone; causal relationship is uncertain. Proarrhythmia <111 ECG Stop amiodarone. Bradycardia 2 to 42 Physical examination, ECG If severe, stop amiodarone or insert pacemaker. Minor effects Nausea, anorexia 302 History, physical examination Reduce dosage. Corneal microdeposits > 902,19 Slit-lamp examination None Photosensitivity 4 to 92 History, physical examination Use sunblock. Blue discoloration of skin <92 Physical examination Reduce dosage.

DLCO = diffusing capacity of for carbon monoxide; T4 = thyroxine; TSH = thyroid-stimulating hormone; ECG = electrocardiogram. Information from references 2, 5, 11, and 19.

2192 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 11 / DECEMBER 1, 2003 Amiodarone

percent of patients receiving long-term amio- darone therapy.2 Hyperthyroidism may result The most serious potential adverse effect of amiodarone from an excess of iodine or acute thyroiditis.20 therapy is pulmonary toxicity. The most common clinical Hypothyroidism is two to four times more presentation is subacute cough and progressive dyspnea, common than hyperthyroidism.2 with associated patchy interstitial infiltrates on chest In hypothyroid patients with a strong clinical indication for amiodarone, the drug may be radiographs and reduced diffusing capacity on pulmonary continued with appropriate thyroid hormone function tests. supplementation. Treatments of amiodarone- induced hyperthyroidism include the with- drawal of amiodarone (if this can be done DERMATOLOGIC ADVERSE EFFECTS safely), the addition of antithyroid Photosensitivity is common in patients or prednisone, and surgical thyroidectomy.20 receiving amiodarone therapy. Therefore, all patients should be cautioned to use sunblock LIVER TOXICITY and, whenever possible, to cover exposed skin Liver toxicity, manifested by elevation of when they are outdoors. liver transaminase levels, is common in In patients with extended and recurrent sun patients who are receiving long-term amio- exposure, bluish skin discoloration may darone therapy. This adverse effect occurs at a develop in exposed areas. The discoloration rate of 0.6 percent annually.11 resolves over several months after amiodarone Patients with liver toxicity are rarely symp- is discontinued. tomatic. If liver enzyme levels are three times higher than normal, amiodarone should be discontinued unless a patient is at high risk for TABLE 3 2 recurrence of life-threatening arrhythmia. Important Amiodarone (Cordarone) Drug Interactions

GASTROINTESTINAL ADVERSE EFFECTS Drug Result of interaction Gastrointestinal side effects of amiodarone include nausea, anorexia, and constipation. Digoxin22 Elevated digoxin plasma concentration These symptoms often are dosage related Warfarin Elevated prothrombin time and usually improve when the dosage is (Coumadin)21 reduced. Increased incidence of myopathy when simvastatin (Zocor)24 dosage is higher than 20 mg per day OCULAR ADVERSE EFFECTS Increased sildenafil plasma concentration 25 Corneal microdeposits are visible on slit- (Viagra) lamp examination in nearly all patients Cyclosporine Increased cyclosporine plasma concentration (Sandimmune)4 treated with amiodarone.19 These deposits sel- dom affect vision and rarely necessitate dis- Antiarrhythmic Additive effects: possible elevated plasma concentrations drugs4 of quinidine, (Norpace), continuation of the drug. (Tambocor), propafenone (Rythmol), and Optic neuropathy and optic neuritis, some- (Tikosyn) times progressing to total blindness, have been Quinolones23 Additive QT effect: possible increased risk of described in a small number of patients proarrhythmia treated with amiodarone. A causal relation- Antidepressants23 Increased plasma concentration of hepatically metabolized ship is not well established. Any patient who drugs: possible increased risk of proarrhythmia notes changes in visual acuity or peripheral vision should be referred for ophthalmologic Information from references 4 and 21 through 25. evaluation.

DECEMBER 1, 2003 / VOLUME 68, NUMBER 11 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2193 NEUROLOGIC TOXICITY CARDIOVASCULAR ADVERSE EFFECTS Neurologic toxicity associated with amio- Bradycardia and heart block occur in 1 to darone therapy can include ataxia, paresthe- 3 percent of patients receiving amiodarone.2 sias, and tremor. These conditions often are Amiodarone-induced proarrhythmia occurs dosage related and improve when the dosage at an annual rate of less than 1 percent.11 is reduced. has been Although almost all patients treated with the reported to occur at a rate of 0.3 percent drug have prolongation of the QT interval, annually.11 polymorphic ventricular tachycardia (i.e., torsades de pointes) is rare. Amiodarone therapy is contraindicated in patients with second- or third-degree heart block who do TABLE 4 Follow-up of Patients Treated with Amiodarone (Cordarone) not have a pacemaker. Intravenously administered amiodarone causes heart block or bradycardia in 4.9 per- Baseline assessment cent of patients and hypotension in 16 per- Complete history and physical examination, with special 2 attention to congestive heart failure, arrhythmia symptoms, and concomitant cent. If these conditions occur, infusion of the medications drug should be discontinued, or the rate of Chest radiograph infusion should be reduced. Thyroid studies and liver transaminase levels Intravenous amiodarone therapy should not Digoxin level, prothrombin time, and INR, when appropriate be used in patients with bradycardia or heart Pulmonary function tests, including DLCO block who do not have a pacemaker. Because Ophthalmologic examination (if preexisting visual impairment) phlebitis may occur, the drug should be given During outpatient loading through a central venous line when possible. Close surveillance of heart rate, especially during first week of treatment Drug Interactions History and physical examination directed at detecting anticipated adverse effects Amiodarone is a potent inhibitor of the Every six months hepatic and renal metabolism of several drugs 4,21-25 Thyroid studies and liver transaminase levels (Table 3). Amiodarone inhibits metabo- Digoxin level as appropriate lism through several path- History and physical examination directed at detecting anticipated adverse ways, including CYP 2C9 (which metabolizes effects warfarin [Coumadin]), CYP 2D6 (which Suspected pulmonary toxicity metabolizes several beta blockers and nar- Chest radiograph cotics), and CYP 3A4 (which metabolizes Pulmonary function tests cyclosporine [Sandimmune] and calcium Visual symptoms channel blockers). Interactions with warfarin Ophthalmologic examination and digoxin are the most clinically important. During warfarin (Coumadin) therapy Amiodarone reduces warfarin clearance Close monitoring of prothrombin time and INR (at least once a week during and can lead to sudden and pronounced first six weeks of treatment) increases in the prothrombin time and Inter- Suspected digoxin toxicity national Normalized Ratio.21 The peak effects Digoxin level of interaction occur approximately seven weeks after initiation of therapy. INR = International Normalized Ratio; DLCO = diffusing capacity of lung for car- Digoxin levels predictably double after bon monoxide. coadministration with amiodarone.22 This Information from reference 4. increase occurs because of the inhibition of digoxin secretion from renal tubules and

2194 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 11 / DECEMBER 1, 2003 Checklist for Adult Patients Taking Amiodarone (Cordarone)

Shaded areas indicate procedures that should be performed at a specific visit.

Patient name: ——————————————————————————————————————————— Date of birth: —————————— Chart no.: ————————

Baseline Loading 6 months 6 months 6 months 6 months 6 months 6 months Date →

Amiodarone monitoring

Complete H&P with special attention to HF, arrhythmia, and concomitant medications

H&P directed at anticipated adverse effects

Heart rate surveillance

Thyroid studies

Liver transaminase levels

Digoxin level (if taking digoxin)

PT/INR (if taking warfarin [Coumadin]): at least once a week during first 6 weeks

Chest radiograph Also if any suspected pulmonary toxicity

PFT, including DLCO Also if any suspected pulmonary toxicity

Eye examination (if preexisting Also if any visual symptoms visual impairment)

FIGURE 1. Checklist for the monitoring of adult patients taking amiodarone. (H&P = history and physical examination; HF = heart failure; PT = prothrombin time; INR = International Normalized Ratio; PFT = pulmonary function test; DLCO = dif- fusing capacity of lung for carbon monoxide). A downloadable checklist is available online at: http://www.aafp.org/afp.

the inhibition of the P-glycoprotein mem- Table 1.10 Because dosages below 300 mg per brane transporter system.23 The digoxin day are associated with a reduced incidence of dosage should be reduced by 50 percent pulmonary adverse effects, physicians should when amiodarone is started, and plasma aim for a long-term maintenance dosage of digoxin levels should be monitored closely. 200 mg per day or less.18 Patients taking amiodarone should not eat grapefruit or drink grapefruit juice because it Monitoring can inhibit the conversion of amiodarone to Patients treated with amiodarone should be an active metabolite. followed regularly to assess ongoing need for amiodarone, efficacy of the drug, appropriate- Dosage and Administration ness of dosage, adverse effects, and potential In patients receiving oral amiodarone ther- drug interactions. Consensus follow-up rec- apy, there may be a delay of two weeks or ommendations from the NASPE are summa- more before antiarrhythmic effects are noted. rized in Table 4.4 A form to guide patient mon- A loading regimen (i.e., use of a relatively high itoring is provided in Figure 1. dosage at the beginning of therapy) can shorten the delay. The author indicates that he does not have any con- Typical dosing regimens are provided in flicts of interest. Sources of funding: none reported.

DECEMBER 1, 2003 / VOLUME 68, NUMBER 11 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 2195 Amiodarone

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Br J Clin Pharmacol 2000;49:373-8. diographic effects of a new aqueous formulation 4. Goldschlager N, Epstein AE, Naccarelli G, Olshan- of intravenous amiodarone. Am J Cardiol 2002; sky B, Singh B. Practical guidelines for clinicians 90:964-8. who treat patients with amiodarone. Practice 16. Guidelines 2000 for cardiopulmonary Guidelines Subcommittee, North American Society and emergency cardiovascular care. Part 6: of Pacing and Electrophysiology. Arch Intern Med advanced cardiovascular life support: section 1: 2000;160:1741-8. introduction to ACLS 2000: overview of recom- 5. Effect of prophylactic amiodarone on mortality mended changes in ACLS from the guidelines after acute myocardial infarction and in congestive 2000 conference. The American Heart Association heart failure: meta-analysis of individual data from in collaboration with the International Liaison 6500 patients in randomised trials. Amiodarone Committee on Resuscitation. Circulation 2000;102 Trials Meta-Analysis Investigators. Lancet 1997; (8 suppl):I86-9. 350:1417-24. 17. Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas 6. Lee DS, Green LD, Liu PP, Dorian P, Newman DM, R, Barr A. Amiodarone as compared with Grant FC, et al. Effectiveness of implantable defib- for shock-resistant ventricular fibrillation [Published rillators for preventing arrhythmic events and erratum appears in N Engl J Med 2002;347:955]. N death: a meta-analysis. J Am Coll Cardiol 2003;41: Engl J Med 2002;346:884-90 . 1573-82. 18. Hilleman DE, Spinler SA. Conversion of recent- 7. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, onset atrial fibrillation with intravenous amio- Cannom DS, et al. Prophylactic implantation of a darone: a meta-analysis of randomized controlled defibrillator in patients with myocardial infarction trials. Pharmacotherapy 2002;22:66-74. and reduced ejection fraction. N Engl J Med 19. Pollak PT. 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