E. Kevin Heist, MD PhD and Jeremy Ruskin, MD

Cardiac Arrhythmia Service, Massachusetts General Hospital

2

Outline of Patient Screening 3

Introduction 4-5

Pulmonary Toxicity 6-7

Ocular (Eye) Toxicity 8

Thyroid Toxicity 9-10

Cardiovascular Toxicity 11-12

Liver Toxicity 13

Skin Toxicity 14

Neurologic Toxicity 15

Drug-Drug Interactions 16

Use in Pregnant/Lactating Women and Children 17

References 18-19

3

Pre-Amiodarone Treatment Evaluation

Thorough review of indications, potential benefits, risks and alternatives to amiodarone

therapy.

Assessment of potential/relative contraindications to amiodarone including preexisting

pulmonary, thyroid, liver and eye disease.

Pre-treatment laboratory evaluation:

CBC with differential

Standard metabolic panel including liver, renal and thyroid function

tests and electrolytes

Urinalysis

Pulmonary function tests with diffusion capacity

Chest X-ray

Comprehensive eye evaluation including slit lamp and retinal examinations

EKG

Comprehensive discussion with patient and family (if available) about the risks of

amiodarone and the need for close medical follow up as detailed below.

Follow up Schedule for Patients Receiving Amiodarone

Every Six Months:

Clinic Visit with complete history and physical examination with Nurse Practitioner and

M.D.

Full metabolic panel including liver and renal function tests, thyroid screen (TSH) and

electrolytes

Complete blood count

EKG

Every Twelve Months:

Chest X-ray

Pulmonary function testing with diffusion capacity (DLCO)

Eye examination for corneal opacities and optic neuritis

Patients are also instructed to contact us if they experience any new symptoms including

but not limited to: visual changes, skin rash, pain, tingling or weakness in the arms or

legs, cough, wheezing, shortness of breath, fever, rapid heart beat, fatigue, lethargy,

unusual weight gain, edema, hair loss, cold or heat intolerance, lightheadedness or

fainting.

4

Amiodarone (Cordarone: Wyeth) is a commonly used antiarrhythmic agent

available in both oral and IV formulations. According to the approved Cordarone label,

the agent is indicated “only for the treatment of the following documented, lifethreatening

recurrent ventricular arrhythmias when these have not responded to

documented adequate doses of other available antiarrhythmics or when alternative

agents could not be tolerated. 1. Recurrent ventricular fibrillation. 2. Recurrent

labeling acknowledges the substantial and potentially disabling or even fatal toxicities to

multiple organs of amiodarone, and states “Patients…must be hospitalized while the

loading dose of Cordarone is given”. Based on this labeling, the expectation would be

that amiodarone would be used only rarely, only for arrhythmias which are immediately

life threatening and refractory to other agents, only with inpatient initiation, and only with

careful monitoring for potential toxicities.

Licensed physicians are not restricted to prescription of medications for labeled

indications only, however, and amiodarone is frequently used in a manner which differs

substantially from its labeling. Supporting this statement are the following (*note that this

is a description rather than an endorsement by the authors of current clinical practice

with amiodarone):

-Amiodarone is used relatively frequently in clinical practice, often as a first line agent for

-Amiodarone is often used for symptomatic but generally non-life-threatening

arrhythmias, including a variety of supraventricular arrhythmias (especially atrial

fibrillation) and non-lethal ventricular arrhythmias. Although amiodarone is not labeled

for these indications, its use for these arrhythmias is supported both by published

written by major cardiology organizations such as the American College of Cardiology

clinicians.

-Amiodarone is often initiated in outpatient settings such as medical clinics, and by

physicians with highly variable understanding of and experience with the potential side

effects and toxicities of amiodarone. Largely for this reason, monitoring for amiodarone

5

toxicity is highly variable and ranges from nonexistent monitoring to frequent, scrupulous

monitoring of multiple organ systems.

Amiodarone has the potential for toxicities to multiple organ systems, including,

but not limited to, the thyroid, eyes, liver, lungs, heart, skin, nerves and fetus/nursing

infant. Amiodarone accumulates very slowly in the body, and many of these toxicities

become apparent only after the drug has been taken for months, years or even decades.

Amiodarone is retained in the body for months after the drug has been stopped, and so

toxicities also may become apparent after the drug has been discontinued for a

considerable period of time, potentially obscuring the association between the toxicity

and the drug. Careful screening of patients before initiation of amiodarone is important,

to determine that amiodarone use is justified, to determine if there are patient factors

which may predispose to amiodarone toxicity and to establish baseline values for organ

systems which could be later affected by amiodarone toxicity. Further evaluation is then

required while amiodarone is being taken, and even for some period of time after it has

been discontinued, to determine if toxicity is developing. Prompt recognition and

treatment of amiodarone toxicity can often make the difference between complete

recovery and severe disability or even lethality.

The purpose of this document is to make suggestions for the monitoring of patients for

whom amiodarone treatment is given. The monitoring suggested here will not eliminate

the potential for severe amiodarone toxicity, but will help to identify patients who are

predisposed to amiodarone toxicity and to identify toxicity early when it is generally most

amenable to treatment.

6

Toxicity

Pulmonary toxicity from amiodarone has been estimated to occur in

doses of amiodarone, but it can occur in any patients and at any doses. Pulmonary

toxicity may occur at any time after the initiation of amiodarone; some forms of the

toxicity (i.e. hypersensitivity pneumonitis) tend to occur early in the course of therapy,

while others (i.e. restrictive lung disease/lung fibrosis) tend to occur later. Common

symptoms include cough and shortness of breath, but these symptoms are often

mistaken for other conditions (i.e. heart failure, allergies) and so the diagnosis of

amiodarone toxicity can be delayed despite the presence of symptoms. Amiodaroneinduced

pulmonary toxicity can be progressive and fatal if not recognized and treated.

Mortality rates up to 10% have been reported with this toxicity, but this is likely to be

substantially less if diagnosed early and treated appropriately.

Screening

Prior to the initiation of amiodarone, proper screening includes a physical

examination, chest X-ray and pulmonary function testing with diffusion capacity

pre-existing pulmonary fibrosis or restrictive disease) prior to the initiation of amiodarone

is not an absolute contra-indication to the use of amiodarone, it should at least prompt

consideration of alternative agents and use of the lowest effective amiodarone doses

and more frequent monitoring. During amiodarone treatment for all patients, pulmonary

new pulmonary symptoms is likely to identify pulmonary toxicity early.

Treatment

Treatment of amiodarone-induced pulmonary toxicity typically involves

discontinuation of the drug, especially when severe toxicity is present. When toxicity is

mild and the indication for amiodarone is very strong, treatment of the toxicity as well as

7

reduction in amiodarone dosage may be reasonable. Steroids are often used as

treatment for the condition. Patients with amiodarone-induced pulmonary toxicity are

typically referred to a pulmonologist. In some cases, pulmonary toxicity is reversible

when diagnosed and treated early. Of note, some forms of amiodarone-induced

pulmonary toxicity (i.e. hypersensitivity pneumonitis) will occur with greater rapidity and

severity if amiodarone is given again in the future to a patient who has experienced this

toxicity. For this reason, re-starting amiodarone in a patient who has previously suffered

from amiodarone pulmonary toxicity should be considered contra-indicated, except in

exceptional circumstances under the direct supervision of both arrhythmia and

pulmonary specialists and when no alternative antiarrhythmic agent can be used.

8

Toxicity

Ocular toxicity from amiodarone ranges from asymptomatic corneal

microdeposits (which occur in the majority of patients who take the drug and appear to

cause no ill effects) to more substantial microdeposits causing minor visual

disturbances, to severe damage/inflammation of the nerve serving the eyes (optic

neuropathy/optic neuritis) which can cause permanent blindness if not promptly

amidoarone therapy, while the more dangerous optic neuritis can develop suddenly and

unpredictably.

Screening and Treatment

Pre-drug screening for amiodarone ocular toxicity typically involves a complete

eye examination by an ophthalmologist, including a slit-lamp examination. This should

be considered mandatory for any patient with baseline visual abnormalities. A

conservative approach is to require this examination of all patients prior to starting

amiodarone, although some argue that it may not be necessary for patients with normal

intervals, and immediately if any visual changes develop. If asymptomatic or minimally

symptomatic, corneal microdeposits may be treated conservatively and do not

necessarily mandate discontinuation of amiodarone. Any suggestion of optic neuropathy

or especially optic neuritis should prompt immediate discontinuation of amiodarone and

emergent referral to an ophthalmologist, as these disorders can result in permanent

blindness. Patients taking amiodarone should be told to report any visual changes

immediately to their physician, as these could represent an early sign of potentially

dangerous ocular toxicity.

9

Toxicity

Amiodarone-induced thyroid gland dysfunction is common, and has been

taking the drug. A decrease in thyroid function (hypothyroidism) with symptoms such as

decreased energy, cold intolerance and weight gain, is among the most common

toxicities of amiodarone. The development of amiodarone-induced hypothyroidism is

often gradual and insidious, and symptoms may be mistakenly attributed to such factors

as “simply getting older” or “gaining too much weight”. Elevated thyroid function

(hyperthyroidism), with symptoms such as atrial rhythm disturbances, elevated heart

rate, heat intolerance and weight loss, is a less common, but more difficult to manage,

toxicity of amiodarone. It can occur anytime, even quite suddenly and/or quickly, after

the initiation of the drug.

Screening

Screening for amiodarone-induced thyroid dysfunction typically involves a

thorough history and physical exam as well as the measurement of blood levels of TSH

(thyroid stimulating hormone), as well as the thyroid hormones free T4 and total T3,

before initiation of drug therapy. Identification of pre-existing thyroid dysfunction may

warrant treatment of the thyroid disorder, and consultation with an endocrinologist

should be obtained before a patient with pre-existing thyroid disease is given

amiodarone. Assuming that there is no pre-existing thyroid disease, follow up history,

physical exam and blood tests for thyroid function should be performed approximately

every 6 months during amiodarone therapy, acutely if any symptoms suggesting thyroid

dysfunction develop, and even for the next year if amiodarone is stopped. Of note,

alterations in the blood levels of TSH, T4 and T3 are seen in most patients during the

first 3 months after the initiation of amiodarone, and these changes reflect the normal

10

Treatment

Treatment of amiodarone-induced hypothyroidism often simply involves daily

thyroid replacement hormone (Synthroid, L-Thyroxine) therapy. This may, but does not

necessarily, require consultation with an endocrinologist. This hypothyroidism often (but

not always) will eventually resolve if amiodarone is discontinued. The decision of

whether or not to discontinue amiodarone in the setting of drug-induced hypothyroidism

will depend on weighing the benefits of amiodarone in the patient and the presence of

alternative agents. Treatment of amiodarone-induced hyperthyroidism is more complex,

will often require the discontinuation of amiodarone in addition to treatment of the

hyperthyroidism, and should always involve consultation with an endocrinologist.

11

Toxicity

Amiodarone can reduce the heart’s pumping function (as a negative inotrope)

and can also cause a drop in blood pressure (hypotension). While potentially

dangerous, these toxicities are seen to a clinically relevant degree primarily with large

doses of IV formulations of amiodarone (while a patient is generally under close

monitoring) and rarely result from typical oral outpatient doses of amiodarone. More

commonly encountered, however, are heart rhythm disorders resulting from amiodarone.

Amiodarone can cause slow heart rhythms through a variety of mechanisms (including

slowing of the sinus rate, and the development of A-V block), which can result in fatigue,

lethargy, poor exercise tolerance, dizziness and fainting (syncope). Much less common,

but more dangerous, are amiodarone-induced ventricular arrhythmias (particularly

polymorphic ventricular tachycardia—so called “Torsades de Pointes” or TdP, which can

cause sudden cardiac death). Amiodarone-induced TdP typically results from

prolongation of the QTc interval on the EKG. TdP is a recognized toxicity of

amiodarone, but is uncommon and TdP is encountered far more commonly with use of

Screening

Screening for amiodarone-related heart rhythm disorders involves, at a minimum,

a 12 lead EKG prior to initiation of the drug. Baseline bradycardia or PR interval

prolongation/AV block suggests a strong possibility that amiodarone will worsen the

bradycardia, and warrants either avoidance of amiodarone, consideration for pacemaker

placement prior to starting amiodarone or, at least, close patient follow up. Substantial

prolongation of the baseline QTc interval suggests an elevated risk of amiodaroneinduced

TdP, suggesting that amiodarone should either be avoided, or the patient

should be followed very closely after initiation of the drug with serial EKGs. Amiodarone

is felt to be an acceptable anti-arrhythmic agent in the presence of a variety of forms of

cardiac structure and function is performed in most patients prior to starting amiodarone.

Clinical history and EKGs to assess heart rate, rhythm, and intervals (including PR, QRS

12

and QTc) should be performed at a minimum of 6-month intervals to assess for

amiodarone induced pro-arrhythmia. Arrhythmias that appear during amiodarone

treatment should also warrant re-evaluation for amiodarone-induced thyroid dysfunction.

Treatment

Symptomatic amiodarone-induced bradycardia is typically treated with

discontinuation of the drug or with cardiac pacemaker placement, unless the cause is

found to be amiodarone-induced hypothyroidism, in which case treatment of the thyroid

disorder is usually undertaken first. Amiodarone-induced TdP is a life-threatening

emergency and warrants immediate hospitalization and treatment by a cardiac

specialist. Amiodarone should be discontinued after amiodarone-induced TdP, except in

exceptional cases with consultation from a cardiac electrophysiologist. Because

amiodarone is cleared very slowly from the body, the risk of amiodarone-induced

bradycardia and TdP may be present for months after the drug is discontinued.

13

Toxicity

Liver (hepatic) toxicity is commonly encountered with amiodarone, although in

most cases this is manifest only by asymptomatic and relatively mild increases in blood

liver function tests (LFTs—including AST, ALT, and bilirubin). Severe liver dysfunction,

and even fatal liver failure has been reported with amiodarone, however, and so

with asymptomatic elevations of liver function tests, but more severe cases may present

with signs of overt liver failure (including jaundice, abdominal pain and distension).

Screening

Screening for patients includes obtaining a history of prior liver disease or risk

factors (such as a history of heavy alcohol use or hepatitis) and baseline LFTs. A history

of liver disease, or baseline elevation of LFTs suggest a greater risk of amiodaroneinduced

liver dysfunction, and may warrant avoidance of the drug, or use of the drug at

lower doses and with close follow up. Repeat LFTs should be performed approximately

every 6 months to detect early signs of liver dysfunction. Patients should also be told to

contact their clinician if any symptoms of liver dysfunction develop.

Treatment

In many cases, amiodarone can be continued if very mild LFT abnormalities are

detected after initiation of the drug, but LFTs should then be followed very closely and

carefully for signs of worsening toxicity. Substantial LFT abnormalities should prompt

immediate discontinuation of the drug and referral to a hepatic specialist.

14

Photosensitivity (an increase in sensitivity to the sun producing easy burning of

resolves if amiodarone is discontinued, and is treated with sun avoidance and the use of

additional clothing and sunscreens. Amiodarone treatment can also lead to a blue or

gray discoloration of the skin, which is related to cumulative drug dosage (amiodarone

dose and duration of therapy). This discoloration is unsightly but not dangerous and can

persist after amiodarone is discontinued, although it may fade very gradually (often

years) after drug discontinuation. There is no specific skin screening typically performed

prior to initiation of amiodarone other than a complete physical examination, including

skin exam. Fair skinned patients are more likely to suffer from skin toxicity.

15

Neurologic toxicity from amiodarone is generally manifest as peripheral

neuropathy. Symptoms may include decreased sensation, pain, and clumsiness or

weakness, especially in the arms, hands, legs and feet. A simple neurologic physical

examination is typically performed prior to initiation of amiodarone, but this seldom

requires referral to a neurologist unless baseline neurologic deficits are encountered.

Patients with baseline neuropathy (i.e. resulting from diabetes) are more likely to suffer

from worsening of neuropathy with amiodarone than patients without baseline deficits,

although it may be difficult to differentiate amiodarone effects from worsening of the preexisting

condition. History and examination for neuropathy should be performed at

follow up visits at approximately 6-month intervals while taking the drug. Neuropathy,

which develops while taking amiodarone, should warrant referral to a neurologist.

Amiodarone-induced neuropathy may improve with discontinuation of the drug, but

16

Important drug-drug interactions are common with amiodarone. These are far

too numerous to list. Examples include amiodarone increasing the levels of other drugs,

such as the blood thinner coumadin or the cardiac drug digitalis, potentially leading to

dangerous coumadin levels and bleeding or to digitalis toxicity. Similarly, some drugs,

such as protease inhibitors used by HIV patients and the antidepressant trazodone, may

increase blood levels of amiodarone, potentially leading to toxicity from high amiodarone

and should be avoided by patients using this drug. Clinicians prescribing amiodarone

should be aware of the common drug-drug interactions relevant to amiodarone.

17

Amiodarone has not been studied in pregnant/lactating women or in children. It

is known to cross the placenta (and thereby enter the fetus) and to be excreted in breast

milk (and thereby enter the nursing child). Use of amiodarone should be avoided if at all

possible in women who are pregnant or likely to become pregnant. Lactating women

who are taking amiodarone should not breastfeed. Given the likelihood of toxicity if

amiodarone is taken for decades, amiodarone use is strongly discouraged in children

unless there are no acceptable alternatives.

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1. Cordarone (Amiodarone HCl) package label, www.wyeth.com

2. Connolly SJ, Dorian P, Roberts RS, et al.

Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for

prevention of shocks from implantable cardioverter defibrillators: the OPTIC

Study: a randomized trial. JAMA 2006 Jan 11; 295(2) :165-71.

3. Singh BN, Singh SN, Reda DJ, et al.

4. Fuster V, Rydén LE, Cannom DS, et al.

ACC/AHA/ESC 2006 guidelines for the management of patients with atrial

fibrillation--executive summary: a report of the American College of

Cardiology/American Heart Association Task Force on Practice Guidelines and

the European Society of Cardiology Committee for Practice Guidelines (Writing

Committee to Revise the 2001 Guidelines for the Management of Patients With

Atrial Fibrillation). J Am Coll Cardiol 2006 Aug 15; 48(4) :854-906.

5. Effect of prophylactic amiodarone on mortality after acute myocardial infarction

and in congestive heart failure: meta-analysis of individual data from 6500

patients in randomised trials. Amiodarone Trials Meta-Analysis Investigators.

6. Goldschlager N, Epstein AE, Naccarelli G, et al.

A Practical Guide for Clinicans who Treat Patients with Amiodarone: 2007. Heart

Rhythm 2007 (in press).

7. Martino E, Bartalena L, Bogazzi F, Braverman LE

The effects of amiodarone on the thyroid. Endocr Rev 2001 Apr; 22(2) :240-54.

19

8. Iervasi G, Clerico A, Bonini R, et al.

Acute effects of amiodarone administration on thyroid function in patients with

cardiac arrhythmia. J Clin Endocrinol Metab 1997 Jan; 82(1) :275-80.

9. Heist EK, Ruskin JN

Drug-induced proarrhythmia and use of QTc-prolonging agents: clues for