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Practical Guidelines for Clinicians Who Treat Patients with Amiodarone

Practical Guidelines for Clinicians Who Treat Patients with Amiodarone

SPECIAL ARTICLE Practical Guidelines for Clinicians Who Treat Patients With Amiodarone

Nora Goldschlager, MD; Andrew E. Epstein, MD; Gerald Naccarelli, MD; Brian Olshansky, MD; Braman Singh, MD; for the Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology

miodarone has become an important for the treatment of supraventricular and ventricular , in short-term inpatient and outpatient settings. It may also have a role in affecting outcome in patients at high risk for arrhythmic events and sudden death; its place among available therapies is being established in clinical trials. A Arch Intern Med. 2000;160:1741-1748

Patterns of use of amiodarone are not uni- fibrillation (VF) or ventricular tachycar- form, either in academic or in community dia (VT) with hemodynamic instability. settings; overuse and underuse are likely This indication includes the stipula- real phenomena, although data are sparse tion that the arrhythmias are not respon- and largely anecdotal. Guidelines for phy- sive to other available antiarrhythmic sicians who use amiodarone are unavail- agents or that the patients are intolerant able. Because of the potential for serious of them. with its use, knowledge of drug dos- It is the consensus of this committee ing, beneficial effects, and adverse effects that amiodarone should be used as the an- is essential for proper patient manage- tiarrhythmic agent of choice, in connec- ment. This guideline was created as an ap- tion with other therapies (eg, ␤ block- proach to the use of amiodarone in clini- ers), in patients with sustained ventricular cal practice. The guideline reviews the tachyarrhythmias who have structural indications for use of amiodarone and meth- disease, especially left ventricular ods of initiation of therapy, suggests strat- dysfunction, and who are not candidates egies for the follow-up of patients receiv- for an implantable cardioverter-defibrilla- ing amiodarone, and outlines the adverse tor (ICD). This recommendation is based effects of therapy. on the following: (1) 2-year rates The recommendations contained in reducing arrhythmic events by more herein are based on the best available data than 60%; (2) minimal negative inotro- or, where these are lacking, the collective pic effects and a low incidence of associ- experience of the members of the writing ated proarrhythmia; (3) long-term safety committee. in patients after experiencing a myocar- dial infarction (as demonstrated in the Eu- INDICATIONS FOR USE ropean Myocardial Infarct Amiodarone Trial [EMIAT]1 and the Canadian Amio- Oral Amiodarone darone Myocardial Infarction Arrhyth- mia Trial [CAMIAT]2) and in patients with Oral amiodarone is approved by the Food significant left ventricular dysfunction and Drug Administration for the treat- (as shown in the Grupo de Estudio de la ment of life-threatening recurrent ven- Sobrevida en la Insuficiencia Cardiaca en tricular arrhythmias, such as ventricular trial [GESICA]3 and the Sur- vival Trial of Antiarrhythmic Therapy in Congestive Heart Failure [CHF-STAT]4); From the Cardiology Division, University of California, San Francisco, San Francisco and (4) efficacy rates for empirical use of General Hospital. A list of all members of the Practice Guidelines Subcommittee, North amiodarone, which are superior to elec- American Society of Pacing and Electrophysiology, appears on page 1747. trophysiologically guided therapy with

(REPRINTED) ARCH INTERN MED/ VOL 160, JUNE 26, 2000 WWW.ARCHINTERNMED.COM 1741 Downloaded from www.archinternmed.com , on January 24, 2006 ©2000 American Medical Association. All rights reserved. class 1 antiarrhythmic agents (shown 60% of patients during a 2- to 3-year for this use. However, since acutely in the in Seattle: Con- period. Given its safety profile, administered IV amiodarone has ventional vs Amiodarone Drug especially in patients after a myo- little effect on atrial refractory peri- Evaluation [CASCADE] trial5). cardial infarction and in patients ods, placebo-controlled trials12 have Several prospective trials (An- with heart failure, amiodarone demonstrated no increase in effi- tiarrhythmics Versus Implantable should be considered to be one of cacy in converting atrial fibrilla- Defibrillators [AVID],6 Cardiac Ar- the of choice in maintaining tion to sinus rhythm. One recent rest Study Hamburg [CASH],7 and sinus rhythm in patients with par- study suggests that IV amiodarone Canadian Implantable Defibrillator oxysmal . In pa- may minimize the occurrence of Study [CIDS]8) have demonstrated tients without structural heart dis- atrial fibrillation in patients who that an ICD is superior to empirical ease, amiodarone should be used if have undergone an aortocoronary amiodarone therapy in preventing their atrial fibrillation is refractory bypass.13 Further trials should verify sudden cardiac death. Moreover, the to other agents or if the patient is these findings before routine pro- AVID trial6 showed improvement in intolerant of them. phylactic use of amiodarone can be overall survival. Of patients who have Although preoperative oral recommended. ICDs, 30% to 70% require concomi- amiodarone loading has been re- tant antiarrhythmic treatment. Amio- ported to significantly reduce the in- DRUG DOSING darone is effective in slowing the rate cidence of atrial fibrillation after aor- of VT, as tested in the electrophysi- tocoronary bypass surgery,9 this Amiodarone appears to have an un- ology laboratory; this effect appears management strategy has not been paralleled efficacy, a broad spec- to be predictive of a better outcome. widely accepted because of the wide- trum of antiarrhythmic action, and Although amiodarone can increase spread use of ␤ blockers, logistical a complex array of adverse effects the threshold, necessi- preoperative loading issues, and when used as an antiarrhythmic and tating ICD retesting once the drug has cost. antifibrillatory compound. Some been initiated, it may be useful for pa- knowledge of its pharmacodynam- tients refractory to, or who are not Intravenous (IV) Amiodarone ics, electropharmacologic features, candidates for, hydrochlo- and is essential as ride or other ␤-blocker therapy. In Intravenous amiodarone has been a basis for initiating therapy in the cases of extremely elderly or criti- approved by the Food and Drug Ad- hospital or in the outpatient setting cally ill patients in whom an ICD ministration for the treatment and and for its safe and effective use might not be appropriate, amioda- prophylaxis of recurrent VF and he- during long-term therapy. rone should be used as first-line modynamically unstable VT in pa- The complexity of the electro- therapy in hemodynamically un- tients refractory to other therapy. pharmacologic profile of amioda- stable sustained VT. The role of elec- This indication is supported by 2 rone is striking.14 The drug length- trophysiologic testing in patients re- prospective, randomized, parallel, ens repolarization, but it is not just ceiving amiodarone is controversial, dose-response studies10,11 that dem- another class 3 ; and remains to be clarified. onstrated a favorable trend toward it exhibits all 4 electrophysiologic Although patients with non- a decrease in VT or VF events per classes of action. Its sodium chan- sustained VT and left ventricular hour and time to the first VT or VF nel–blocking action is seen largely dysfunction are recognized to be at event. Significantly fewer supple- at rapid heart rates but is not asso- increased risk for sudden cardiac mental infusions were required in ciated with the proarrhythmic ef- death, treatment of these arrhyth- patients receiving IV amiodarone, fect typical of class 1 agents. Unlike mias is controversial. In the CHF- 1000 mg/d, compared with those re- the class 1 drugs, it neither in- STAT4 and the GESICA trial,3 use ceiving smaller doses. creases mortality nor depresses ven- of amiodarone had neutral overall Intravenous amiodarone was tricular function; in fact, it in- effects on mortality in patients reported to have comparable effi- creases left ventricular ejection with ischemic cardiomyopathy and cacy to IV tosylate in one fraction in patients with heart fail- improved survival in those with study11; the mortality rate was not ure. Its class 2 or antiadrenergic ac- nonischemic cardiomyopathy. Based affected. Intravenous amiodarone is tions resemble those of ␤ blockers on these studies, the consensus of also approved to treat patients with but without their adverse effects, in this committee is that it is reason- VT or VF who are candidates for oral part because its ␤-blocking activity able to use amiodarone in patients amiodarone but are transiently un- is relatively weak. It differs from all with significant left ventricular dys- able to take the oral preparation. other class 3 agents in (1) rarely function and nonsustained VT that In critically ill patients who de- producing torsade de pointes is symptomatic or concerning velop atrial fibrillation with rapid despite markedly lengthening the enough to warrant treatment. ventricular response, IV amioda- QT interval and (2) maintaining its Although not Food and Drug rone has been found to be effective efficacy at rapid heart rates. The Administration–approved for use in in controlling the ventricular rate compound can be administered atrial fibrillation, oral amiodarone is through its short-term calcium chan- “empirically,” without electrophysi- effective in controlling ventricular nel-blocking and sympatholytic ef- ologic testing or Holter-guided rate in atrial fibrillation and in main- fects, although it is not approved by evaluation, which simplifies its use taining sinus rhythm in more than the Food and Drug Administration in clinical practice.15

(REPRINTED) ARCH INTERN MED/ VOL 160, JUNE 26, 2000 WWW.ARCHINTERNMED.COM 1742 Downloaded from www.archinternmed.com , on January 24, 2006 ©2000 American Medical Association. All rights reserved. Amiodarone is highly lipo- fects due to previous exposure to the an ICD can minimize the risks of ar- philic, with a long elimination half- drug. rhythmia recurrence and adverse life that is highly variable among pa- drug effects, while the ICD offers tients (35-110 days). It may require Oral Drug Initiation protection against arrhythmic death. months for blood levels to reach For the initial control of VT and fi- steady state, and levels are not cor- Clinical experience with amioda- brillation, therapy is always initi- related with clinical effects. Thus, rone has led to various drug-dosing ated in the hospital except in pa- caution must be used in assessing ge- considerations that are of practical tients who already have an ICD, in neric versions of the compound ex- importance, whether the drug is be- whom amiodarone therapy can be clusively based on drug bioequiva- ing used to maintain sinus rhythm in initiated on an outpatient basis. lence. The oral of paroxysmal atrial flutter and fibril- In the management of patients amiodarone averages 30% to 50%, lation, to treat ventricular arrhyth- with atrial fibrillation, loading and and via the kidneys is mias as a principal mode of therapy, maintenance doses can be much minimal; it can, therefore, be ad- or as adjunctive therapy in patients lower than those for life-threaten- ministered safely in anephric pa- with ICDs. The most significant prin- ing ventricular arrhythmias and tients. The amiodarone dose does ciple of therapy is to use the lowest therapy can be initiated safely in the not need to be reduced in patients dose of the drug that will produce outpatient clinic. Caution must be with renal disease; the drug and its the desired therapeutic effects to re- exercised in patients in whom there metabolite are not dialyzable. Amio- duce the risk of intolerable or po- is a suspicion of sinus or AV node darone is metabolized in the , tentially serious adverse effects. Al- dysfunction, in whom drug- its major metabolite being deseth- though high-dose loading regimens induced may develop. ylamiodarone, which is pharmaco- have been used, advantages over Various regimens have been recom- logically active and has a longer lower-dose loading regimens have mended. A reasonable loading dos- elimination half-life than that of the not been demonstrated,16 although age is 600 to 800 mg/d (in 2 di- parent compound. Because they are they may be well tolerated.17 The vided doses) for 2 to 4 weeks; lipophilic, amiodarone and its me- relative merits of IV loading in place thereafter, the dose can be reduced tabolites are extensively accumu- of these high-dose oral regimens is to 400 mg/d, and further reduced to lated in the liver, , fat, skin, and unknown. 100 to 300 mg/d at 3 to 6 months, other tissues. The onset of action af- An initial loading dosage, in pa- depending on clinical efficacy and ter IV drug administration occurs tients with ventricular arrhyth- the development of adverse effects. within several hours, whereas after mias, of 800 to 1600 mg/d (usually The usual for oral administration the onset of ac- in divided doses) for up to 2 to 3 atrial fibrillation is 200 mg/d, al- tion may require 2 to 3 days, de- weeks is reasonable. At this stage, the though in the event of break- pending on the dosing regimen. dose may be reduced to 400 to 600 through arrhythmias, short peri- There is a reasonable linearity be- mg/d, since such a regimen is usu- ods of higher doses may be required; tween plasma drug concentration ally adequate to produce close to a higher maintenance doses may be re- and dose of amiodarone, and the steady state in patients with ven- quired in some patients. In some plasma level of the drug in patients tricular arrhythmias. For many pa- situations, satisfactory clinical effi- successfully treated with amioda- tients, this dose will be sufficient for cacy can be obtained with amioda- rone usually ranges between 1.5 and long-term maintenance during the rone, 200 mg/d, given 5 days a week, 2.5 µg/mL; desethylamiodarone lev- first year. In some patients, the dose especially in women with a low body els also increase as a function of time may be reduced even further (to 200- mass index. During loading and and reach a level either comparable 300 mg/d). Dose reduction may be maintenance dosing, drug interac- to or in excess of that of the parent necessary earlier in the event of ad- tions with and so- compound. However, there is a poor verse effects, especially constipa- dium must be recognized, since correlation between plasma levels tion and central nervous system these drug dosages will have to be and either the therapeutic or toxic symptoms. Lower loading and main- reduced accordingly. effects of the drug. As a result, es- tenance doses are preferable in tablished pharmacokinetic prin- women and in all patients with a low IV Dosing ciples may not provide a reliable ba- body weight.18 Reducing the dose to sis for predicting the attainment of 200 mg/d in patients being treated There appears to be substantial in- steady-state therapeutic effects of the for ventricular arrhythmias may re- dividual variation in response time drug. sult in a high risk of re- during the initiation of IV amioda- There are few absolute contra- currence, especially as a function of rone therapy.19 Consequently, dos- indications to the use of amioda- time. In such situations, the addi- ing recommendations are derived rone. The drug is best avoided in pa- tion of a second antiarrhythmic drug, from experience and tients with active thyrotoxicosis, in particular a ␤ blocker, may be provide guidelines only; close pa- of the liver or other forms helpful. Alternatively, an ICD may tient observation and dose adjust- of advanced , and se- be implanted if an increase in amio- ments are essential for optimum ben- vere pulmonary disease (especially darone dose is deemed undesirable efit without adverse effects. For extensive fibrosis) and in patients or is not well tolerated. Lower doses example, hypotension and other ad- with a history of major adverse ef- of amiodarone in conjunction with verse cardiac effects that may be seen

(REPRINTED) ARCH INTERN MED/ VOL 160, JUNE 26, 2000 WWW.ARCHINTERNMED.COM 1743 Downloaded from www.archinternmed.com , on January 24, 2006 ©2000 American Medical Association. All rights reserved. during initial rapid infusion may im- More than 90% of the patients loading and maintenance doses of prove significantly with a decrease who received IV amiodarone in the IV formulation until the arrhyth- in the .20-22 In con- controlled clinical trials eventually mia is suppressed, and then to pre- trast, supplemental IV boluses are underwent oral therapy, principally scribe oral therapy. frequently needed for patients with because they had significant arrhyth- recurrent arrhythmias during the mias that were not due to an easily Assessment of Efficacy early phases of dosing. The recom- reversible cause. When the drug is mended initial IV loading dose10,22 is used in clinical situations in which After a patient has received loading 150 mg administered for 10 min- the underlying condition can be rem- doses of either oral or IV amioda- utes, followed by an intermediate in- edied, such as in patients with an rone, the question may arise as to the fusion of 1 mg/min for 6 hours and acute myocardial infarction who have need for an evaluation to confirm 0.5 mg/min thereafter. Supplemen- undergone successful revasculariza- clinical efficacy before hospital dis- tal boluses of 150 mg may be given tion, the rate of conversion to oral charge. Arrhythmia suppression for 10 to 30 minutes for recurrent ar- therapy will probably decline. Pa- with an IV antiarrhythmic drug does rhythmias, but because hypotension tients who have been receiving IV not necessarily predict the efficacy occurs more frequently at daily doses therapy for more than 2 to 3 weeks of its oral formulation. Moreover, the greater than 2000 mg, no more than can be started safely on mainte- sporadic nature of recurrent VT or 6 to 8 supplemental boluses in any 24- nance doses of oral amiodarone (300- VF and paroxysmal atrial arrhyth- hour period may be possible. Plasma 400 mg/d). Those treated for 1 week mias can make short-term suppres- drug levels are not routinely used be- or less should probably receive the sion of arrhythmia difficult to inter- cause they are high and uninterpret- usual oral loading regimen of 800 to pret vis-a`-vis long-term suppression. able in the early phases of therapy and 1200 mg/d, whereas an intermedi- Options include either monitoring because there is a wide variation in ate dose of 400 to 800 mg/d might be to determine whether, for ex- “effective concentrations” of parent suitable for patients who fall in be- ample, repetitive forms, especially compound and metabolite. When tween these time frames. If there is nonsustained VT, have been sup- given intravenously, amiodarone concern about gastrointestinal tract pressed or performing electrophysi- should be mixed in a 5% dextrose so- function, both oral and IV therapy ologic testing. There are no defini- lution and should be infused with a should be maintained for a few days. tive data to prove the value of either volumetric pump. If used in high con- These recommendations are empiri- method. Patients with paroxysmal centrations (Ͼ2 mg/mL), it must be cal, based on the usual target total atrial arrhythmias need not un- delivered through a central vein drug dose for in-hospital drug load- dergo such testing. because it can cause peripheral ing, and are not based on careful phlebitis (in Ͻ3% of patients). pharmacological trials. FOLLOW-UP Amiodarone does not need light Occasionally, a patient who is re- protection but is physically incom- ceiving long-term therapy tempo- Appropriate long-term manage- patible with several drugs, such as rarily cannot take oral . Be- ment of patients taking amioda- heparin, with which it is frequently cause amiodarone is slowly eliminated rone is essential. Without proper as- used. In multicenter trials, the me- from the body, cessation of therapy sessment of the patient by the dian duration of IV amiodarone for a few days is of little conse- physician, the risk-benefit ratio of therapy was 4 days, but there was quence, but patients should have elec- using amiodarone may weigh in fa- wide variation. Patients who could trocardiographic monitoring within vor of risk rather than benefit. Ad- not take oral medication were treated 5 to 7 days because of the drug’s bi- verse effects are common, with a for 3 to 6 weeks without difficulty. phasic elimination profile. If oral prevalence as high as 15% in the first therapy cannot be started after that year of use and up to 50% during Transition to Oral Therapy time, or if there is doubt about ad- long-term use (Table 1),20-22 indi- equate gastrointestinal tract absorp- cating a cumulative The bioavailability of oral vs IV tion, IV therapy can be substituted. profile. Fortunately, many of these amiodarone varies from 30% to 70%. A is not necessary; based adverse effects are manageable and Bioavailability appears to be lower on the known range of its bioavail- the need to stop amiodarone therapy in elderly patients and in those with ability, infusion of 30% to 70% of the due to serious adverse reactions is cardiopulmonary disease. Recom- daily oral dose will suffice. relatively low, occurring in less than mendations regarding the transi- Intravenous amiodarone has 20% of patients. Specific evalua- tion from IV to oral therapy take into been used for the treatment of pa- tion for adverse effects appears account these properties, in addi- tients who have received long-term to identify the development and tion to the fact that there may be a oral therapy but who have recur- prevent the progression of serious delay of 4 to 5 hours between inges- rent arrhythmias. Under these cir- adverse effects. Accelerated fol- tion of the oral drug and an in- cumstances, it should be assumed low-up is required when there is crease in the plasma level. Gener- that the patient has insufficient myo- development of an adverse effect. ally, the longer the patient has been cardial tissue drug concentrations, Optimizing therapy with amio- receiving IV therapy, the less the especially if the QT interval is not darone entails using the lowest need for the customary large oral prolonged. It is customary in these effective dose to minimize adverse loading doses. situations to use the recommended effects.

(REPRINTED) ARCH INTERN MED/ VOL 160, JUNE 26, 2000 WWW.ARCHINTERNMED.COM 1744 Downloaded from www.archinternmed.com , on January 24, 2006 ©2000 American Medical Association. All rights reserved. Table 1. Adverse Reactions to Amiodarone

Reaction Incidence, % Diagnosis* Management Pulmonary 1-20 Cough, especially with local or diffuse infiltrates Usually discontinue drug; corticosteroids may be considered; on chest x-ray film, suggesting interstitial occasionally, can continue drug if levels high and

pneumonitis; and decrease in DLCO abnormalities resolve; rarely, continue amiodarone from baseline with corticosteroid if no other option Gastrointestinal tract 30 Nausea, anorexia, and constipation Symptoms may decrease with decrease in dose 15-50 AST or ALT level greater than 2 times normal If considered, exclude other causes Ͻ3 Hepatitis and cirrhosis Consider discontinuation, biopsy, or both to determine whether cirrhosis is present 1-22 Thyroxine Ͻ3 Corticosteroids, propylthiouracil or methimazole, and may need thyroidectomy Skin Ͻ10 Blue discoloration Reassurance and sunblock 25-75 Photosensitivity Sunblock Central nervous system 3-30 Ataxia, paresthesias, peripheral polyneuropathy, Often dose dependent, and improve or resolve with dose sleep disturbance, impaired memory, adjustment and tremor Ocular Ͻ5 Halo vision, especially at night Corneal deposits the norm; if optic neuritis occurs, discontinue 1 Optic neuritis Ͼ90 Photophobia, visual blurring, and microdeposits Heart 5 Bradycardia and AV block May need permanent cardiac pacing Ͻ1 Proarrhythmia May need to discontinue the drug Genitourinary Ͻ1 Epididymitis and erectile dysfunction Pain may resolve spontaneously

*DLCO indicates diffusion capacity of carbon monoxide; AST, aspartate aminotransferase; and ALT, alanine aminotransferase.

The time to steady state on a provide the follow-up support of pa- sion of this underlying disease, how- given dose of a drug may exceed 6 tients taking amiodarone. ever, from the additive effects of months. Likewise, it may take more Routine evaluation requires an amiodarone. Nevertheless, in pa- than 6 months before an adverse office visit to assess new symptoms tients who have underlying pulmo- drug effect is reversed. possibly related to the drug (Table nary disease, more careful fol- Issues of importance in fol- 1), recurrence of arrhythmias, the low-up is required, even if the patient low-up are the continued assess- need for upward or downward drug is taking a low dose (mean dose, ment of drug efficacy, titration of titration, laboratory testing, and Ͻ300 mg).23,24 drug dose after achieving a steady changes in drug therapy. Fol- To our knowledge, there are few state, evaluation of adverse and toxic low-up should be most intensive ini- data to document a better outcome effects, appropriate management of tially, especially if dose titration is with more careful and frequent fol- toxic effects, and attention to im- expected to be necessary or if out- low-up, despite the intuitive pru- portant drug-drug and drug-device patient oral dose loading is under dence of this approach. However, interactions. way. Initial assessment should oc- early recognition of organ toxicity will When amiodarone first be- cur every 3 months for the first year expedite early corrective manage- came available in the , to assess arrhythmia stability and ad- ment. The treating physician should because of its potential toxicity, elec- verse effects, after which follow-up educate the patient regarding drug in- trophysiologists were the only phy- visits should occur every 6 months. teractions and potential , and sicians who prescribed the drug. As Adverse effects are partly dose re- document these discussions in the the drug gained popularity, its use by lated, increasing with time of expo- medical record. physicians who do not specialize in sure. Some adverse effects (neuro- arrhythmia management increased. logic and gastrointestinal tract Specific Information An electrophysiologist is not re- toxicity) are clearly dose related, and to Be Acquired During quired for routine long-term fol- often occur in the first phases of Follow-up Visits low-up if the treating physician has amiodarone loading. Visual changes knowledge of drug doses and ad- (“haloes” around lights) are gener- History. Complaints of fatigue (sug- verse effects of amiodarone and has ally, but not always, dose related. Se- gesting bradycardia, AV block, or hy- demonstrated expertise in the fol- rious long-term toxicity (the most pothyroidism), dyspnea or cough low-up of patients taking amioda- worrisome of which is pulmonary (suggesting ), rone. Whereas such physicians have toxicity) appears related in part to palpitations (suggesting hyperthy- generally been cardiologists, some in- drug dosing. It is arguable whether roidism or recurrence of arrhyth- ternists and family practitioners may pulmonary toxicity occurs to a greater mias), syncope, visual changes (in- have enough experience with, and degree in patients who have under- cluding loss of vision), skin changes comfort using, the drug to provide lying pulmonary disease, such as ob- (including photosensitivity), weight follow-up evaluation. We believe that structive pulmonary disease. It can be change (suggesting hypothyroid- nonphysician personnel should not difficult to distinguish the progres- ism or hyperthyroidism), paresthe-

(REPRINTED) ARCH INTERN MED/ VOL 160, JUNE 26, 2000 WWW.ARCHINTERNMED.COM 1745 Downloaded from www.archinternmed.com , on January 24, 2006 ©2000 American Medical Association. All rights reserved. of little use. Drug interactions with Table 2. Routine Laboratory Testing in Patients Receiving Amiodarone* amiodarone, especially digoxin and warfarin, must be recognized and Type of Test† Time When Test Is Performed monitored as necessary (Table 3),26 Baseline and every 6 mo since dose adjustments of these (T4 and TSH) Baseline and every 6 mo agents will be required. Serum creatinine and electrolytes Baseline and as indicated Chest x-ray film Baseline and then yearly Ophthalmologic evaluation At baseline if visual impairment or for symptoms Nonroutine Laboratory Evalua- Pulmonary function tests Baseline and for unexplained dyspnea, especially tion. Laboratory tests should be or-

(including DLCO) in patients with underlying lung disease; and if dered sooner than scheduled if there there are suggestive x-ray film abnormalities are symptoms suggestive of amioda- ECG Baseline and every year rone toxicity in a specific organ sys- tem.27 Other testing may be re- If clinical circumstances warrant, more frequent follow-up will be necessary. * quired, depending on changes in drug †T4 indicates thyroxine; TSH, thyrotropin; DLCO, diffusion capacity of carbon monoxide; and ECG, electrocardiogram. dose or changes in (or development of) new symptoms. Event monitor- ing or Holter monitoring may be re- Table 3. Major Amiodarone Drug Interactions quired if new arrhythmia symptoms occur. Testing of ICDs and pacemak- Drug Interaction ers for threshold changes should be performed if changes in clinical sta- Digoxin Increased concentration and effect with sinus and AV node depression and gastrointestinal tus occur, such as the development tract and neurologic toxicity of heart failure or intercurrent myo- Warfarin sodium Increased concentration and effect cardial infarction. , hydrochloride, Increased concentration and effect and torsade or de pointes ventricular Referral to an Electrophysiologist or Bradycardia and AV block ␤ Blockers Bradycardia and AV block acetate Increased concentration and effect Worsening arrhythmia symptoms is Increased concentration and effect the primary indication to refer the Anesthetic drugs Hypotension and bradycardia patient to an electrophysiologist. Evi- Cyclosporine Increased concentration and effect dence of amiodarone toxicity requir- ing changes in drug dosing or drug discontinuation is another impor- sias or weakness (suggesting periph- function tests; pulmonary function tant reason to refer to an electro- eral neuropathy), changes in drug tests (including the diffusion capac- physiologist. Until the arrhythmia therapy (especially additional anti- ity of carbon monoxide); and thy- problem stabilizes, the patient may arrhythmic drugs, warfarin, ␤ block- roid function tests (Table 2).18,25 require intensified monitoring, elec- ers, and digoxin) that require dose Baseline pulmonary function tests trophysiologic testing, ablative adjustment, newly implanted de- are especially recommended in pa- therapy, or pacemaker or ICD im- vices (pacemakers, cardioverter- tients with underlying lung dis- plantation or reprogramming. defibrillators, or both), and sleep ease; in otherwise well persons, these disturbances should be noted. tests can be omitted unless new pul- ADVERSE REACTIONS monary complaints arise. A base- Physical Examination. Documen- line ophthalmologic evaluation Adverse reactions due to amioda- tation of vital signs; skin color; should be obtained in any patient rone should not be unexpected given regularity of pulse; skin color who has significant visual abnor- the drug’s complicated pharmaco- changes; thyromegaly; dry pulmo- malities; it is not required for all pa- logical features, structure, and di- nary rales; evidence of pulmonary tients. The follow-up evaluation verse effects (Table 1). Because of its hypertension, left ventricular dys- should include, at a minimum, a long half-life (averaging Ϸ100 days), function, or both; ; yearly electrocardiogram and a chest amiodarone organ toxicity is poten- and evidence of neurologic effects x-ray film and semiannually a thy- tially more severe and difficult to (tremor, difficulty with writing, or roid profile (thyrotropin and thy- manage than toxic reactions to gait disturbance) should be made. roxine levels) and a profile of liver other drugs with shorter half-lives. If visual changes are reported, a enzymes. Amiodarone levels should Many reactions to amiodarone can thorough evaluation by an ophthal- be obtained if arrhythmias occur or be managed with reassurance and mologist, including a slitlamp recur or if new symptoms develop, observation. Major organ toxicities, examination, is required. especially after dose titration or a however, may be life threatening change in drug formulation (to or and may require a more aggressive Routine Laboratory Evaluation. from generic preparations); amio- intervention. Baseline tests can include tests mea- darone levels may help determine if The most common early symp- suring serum electrolyte, serum urea the drug can be titrated downward. tom of pulmonary toxicity is cough, nitrogen, and creatinine levels; liver Surveillance amiodarone levels are but fever and dyspnea can occur if

(REPRINTED) ARCH INTERN MED/ VOL 160, JUNE 26, 2000 WWW.ARCHINTERNMED.COM 1746 Downloaded from www.archinternmed.com , on January 24, 2006 ©2000 American Medical Association. All rights reserved. Practice Guidelines Subcommittee amiodarone use is usually most prominent on the face and around the eyes and simply indicates ab- North American Society of Pacing and Electrophysiology sorption. It can be worsened by sun University of California, San Francisco General Hospital: Nora Goldschlager, MD. exposure. Photosensitivity, even if The University of Alabama–Birmingham: Andrew E. Epstein, MD. Syncope Clinic, not severe, can be managed by in- The Cleveland Clinic Foundation, Cleveland, Ohio: Fetnat M. Fouad-Tarazi, MD, structing patients to avoid the sun PhD. Mayo Clinic, Rochester, Minn: Paul A. Friedman, MD. Cardiovascular Medi- and to use sunblock. cal Group of Southern CA, Beverly Hills, Calif: Eli S. Gang, MD. Medical College Neurologic complaints in- of Ohio, Toledo: Blair P. Grubb, MD. New Jersey Medical School, Millburn: Ryszard clude cerebellar ataxia, peripheral Krol, MD, PhD. Loyola University Medical Center, Maywood, Ill: Brian Olshan- neuropathy with paresthesia, sleep sky, MD. disturbance, and, occasionally, im- paired memory. These effects are of- ten dose dependent and improve or the condition progresses. The inci- sidered to determine whether hepa- resolve with minor downward dos- dence is reported to be as high as titis or cirrhosis with necrosis is age adjustment. 10% to 15% in some series,20,24 but present. Mallory bodies (as with Ocular changes are common. as low as 1% to 2% in others.22,24,25 foamy macrophages, previously dis- Corneal deposits are the norm, and The chest x-ray film com- cussed) are a sign of amiodarone ab- simply reflect drug absorption. Halo monly shows focal or diffuse infil- sorption and do not necessarily indi- vision is common. Reassurance trates. A decrease in the diffusing cate toxicity. If amiodarone liver should be provided. The most seri- capacity of carbon monoxide from toxicity is diagnosed, the drug should ous, albeit rare, complication is op- baseline pulmonary function test- bediscontinued; amiodarone-induced tic neuritis. Discontinuation of amio- ing supports the diagnosis. Bron- hepatitis can be fatal.27 darone is required if it occurs. choscopy is useful to exclude other Thyroid abnormalities occur in Adverse cardiac reactions are diseases such as tuberculosis and up to 22% of patients.25 Chemical ab- uncommon. Bradycardia is an ex- disseminated carcinoma. Foamy normalities of thyroid function can pected drug effect, and permanent macrophages are a manifestation of be seen in clinically euthyroid pa- cardiac pacing is occasionally re- drug absorption and do not neces- tients and do not require treatment quired to support slow heart rates. sarily indicate toxicity. Although other than monitoring of thyrotro- Similarly, although QT prolonga- amiodarone pulmonary toxicity pin levels. Hypothyroidism may de- tion is to be expected, torsade de often responds to corticosteroid ad- velop insidiously, with signs and pointes VT is rare. Ventricular sys- ministration, the drug usually must symptoms mistakenly attributed to tolic function is not worsened. be discontinued. Since pulmonary other causes. For example, bradycar- Other drug reactions are rare, toxicity in its early stages can mimic dia may be attributed to amioda- eg, epididymitis and erectile dys- congestive heart failure, a high in- rone or another drug rather than to function. Although the drug may dex of suspicion for this drug effect hypothyroidism. Conversely, hyper- need to be discontinued, the pain of is necessary. Failure to diagnose pul- thyroidism may manifest as a wors- the former often resolves indepen- monary toxicity in its early stages can ening of arrhythmias or as weight dently. lead to a fatal outcome. loss; resting tachycardia is often ab- Finally, amiodarone is fre- Gastrointestinal tract distur- sent due to the negative chrono- quently used with pacemakers and bances such as nausea, anorexia, and tropic effect of amiodarone. Al- implantable defibrillators. It does not constipation are common, espe- though hypothyroidism is easily alter the pacing threshold; how- cially during the initial loading phase treated with sodium, ever, there are important interac- of amiodarone therapy. These symp- hyperthyroidism is difficult to man- tions with implantable defibrilla- toms usually abate when the dose is age. Radioactive ablation with io- tors. Amiodarone may not only decreased for long-term mainte- dine 131 is usually not possible, since decrease the rate of VTs to below the nance. The most feared gastrointes- the sodium iodide uptake is sup- device detection rate, but long- tinal tract complications are hepa- pressed by the iodide contained in the term use can also increase the defi- titis and cirrhosis (incidence, Ͻ3%). amiodarone molecule. Since hyper- brillation threshold. Whenever Hepatitis should be considered when thyroidism due to amiodarone is usu- amiodarone therapy is initiated in a there is an increase in the aspartate ally inflammatory thyroiditis, corti- patient who has an implantable de- aminotransferase or alanine amino- costeroid therapy may be effective. fibrillator, electrophysiologic study transferase(serumglutamate-pyruvate Propylthiouracil and methimazole should be performed to test ad- transaminase, present almost exclu- can be used as stopgap measures. verse drug-device interactions after sively in the liver) level to at least Thyroidectomy is often the best man- loading is complete. twice normal levels. In the diagnosis agement option since it reverses the of amiodarone hepatic toxicity, other hyperthyroidism and allows continu- CONCLUSIONS causes of liver function abnormali- ation of the drug, and the iatrogenic ties should be considered (other drug hypothyroidism is easily treated. Although clinical judgment takes reactions and viral and alcoholic The slate blue skin discolora- precedence over guidelines for clini- hepatitis). A liver biopsy can be con- tion that characterizes long-term cal practice, it is nevertheless use-

(REPRINTED) ARCH INTERN MED/ VOL 160, JUNE 26, 2000 WWW.ARCHINTERNMED.COM 1747 Downloaded from www.archinternmed.com , on January 24, 2006 ©2000 American Medical Association. All rights reserved. ful to attempt to provide a consen- low-dose amiodarone in severe congestive heart of atrial fibrillation after open heart surgery: the sus approach to the management of failure. Lancet. 1994;344:493-498. Amiodarone Reduction in Coronary Heart (ARCH) 4. Singh SN, Fletcher RD, Fisher SG, et al. Amioda- trial. J Am Coll Cardiol. 1999;34:343-347. patients with specific clinical con- rone in patients with congestive heart failure and 14. Kodama I, Kamiya K, Toyama J. Cellular electro- ditions. The goal of this guideline is asymptomatic ventricular arrhythmia: Survival Trial of amiodarone. Cardiovasc Res. to provide such an approach. The of Antiarrhythmic Therapy in Congestive Heart Fail- 1997;35:13-29. physician who prescribes amioda- ure (CHF-STAT). N Engl J Med. 1995;333:77-82. 15. Singh BN. 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