American Journal of Cardiovascular Drugs

https://doi.org/10.1007/s40256-020-00401-5

REVIEW ARTICLE

Amiodarone: A Comprehensive Guide for Clinicians

David Hamilton Sr.1 · Shuktika Nandkeolyar2 · Howard Lan2 · Pooja Desai3 · Jonathan Evans4 ·
Christopher Hauschild5 · Dimpa Choksi6 · Islam Abudayyeh2 · Tahmeed Contractor2 · Anthony Hilliard2

© Springer Nature Switzerland AG 2020

Abstract
Amiodarone is an effective antiarrhythmic medication frequently used in practice for both ventricular and atrial arrhythmias.
Though classified as a class III antiarrhythmic, it affects all phases of the cardiac action potential. However, the drug has
several side effects, including thyroid abnormalities, pulmonary fibrosis, and transaminitis, for which routine monitoring
is recommended. It also interacts with several medications, such as warfarin, simvastatin, and atorvastatin, and many HIV
antiretroviral medications. Given the common use of this medication in medical practice, it is vital that clinicians understand
the indications, contraindications, dosing, side effects, and interactions of this medication. A thorough understanding of
these topics is essential for clinicians to ensure safe and effective use of amiodarone.

Key Points
1 Introduction

Amiodarone is a class III antiarrhythmic medication that is

Though classified as a class III antiarrhythmic, amiodar-
commonly used for the treatment of atrial arrhythmias and
one affects all phases of the cardiac action potential.
ventricular arrhythmias (VAs) [1]. It is an effective antiar-
Amiodarone has several side effects, including thyroid rhythmic medication, but long-term therapy can result in a
abnormalities, pulmonary fibrosis, and transaminitis, for wide variety of side effects affecting several organ systems,
which routine monitoring is recommended. some of which can be life threatening [2]. Some of these can
Amiodarone interacts with several commonly used medi- be avoided with judicious use of this agent, adjustment to
cations, such as warfarin, simvastatin, and atorvastatin, an appropriate dose, and monitoring for adverse side effects.
and many HIV antiretroviral medications. The purpose of this article is to provide a comprehensive
review of this commonly used medication, the mechanisms
of action, appropriate dosing, common medication interac-
tions, and necessary monitoring or surveillance. The man-
David Hamilton and Shuktika Nandkeolyar Contributed equally to
the writing and editing of the manuscript.
agement of adverse effects is also discussed.

* Shuktika Nandkeolyar
[email protected] 2 Mechanism of Action
1
Division of Cardiology, University of Arizona Sarver Heart
Center, Tucson, USA Amiodarone has several mechanisms of action (Fig. 1). The
2
Division of Cardiology, Department of Medicine, Loma
Vaughan Williams classification system imperfectly classi-
Linda University Medical Center, 112345 Anderson fies the medication as a class III antiarrhythmic because of its
St. SP1637, Loma Linda, CA 92354, USA predominant potassium channel blockade that increases the
3
Department of Internal Medicine, University of California cardiac action potential duration [3]. Amiodarone inhibits
Los Angeles Medical Center, Los Angeles, USA potassium efflux through ­IKr, or rapid delayed rectifier chan-
4
Department of Internal Medicine, University of California, nel, during phase III of the action potential. The medication
Irvine Medical Center, Orange, USA also has class I antiarrhythmic properties via inhibition of
5
Department of Pharmacy, Loma Linda University Medical sodium channels during phase 0 of the cardiac action poten-
Center, Loma Linda, USA tial [4, 5]. In addition, it results in noncompetitive β-receptor
6
Department of Pharmacy, Medical City McKinney, blockade (class II antiarrhythmic activity) and L-type (slow)
Mckinney, USA calcium channel blockade (class IV antiarrhythmic activity)

Vol.:(0123456789)
 D. Hamilton et al.

[4, 5]. During loading, the acute effects of intravenous ami- half-life [8, 9]. Therefore, it is reasonable to withhold ami-
odarone are predominantly sodium-channel, β-receptor, and odarone if severe toxicity is suspected and confirmatory test-
calcium channel blockade [4, 5]. The class III effect is seen ing is performed; however, clinicians should be aware that it
after completion of the loading dose because of increased may take months for amiodarone to clear the body.
levels of the active metabolite, desethylamiodarone [4, 5].

4 Indications and Data Supporting Use

3 Pharmacokinetic Properties
4.1 Ventricular Arrhythmias
Amiodarone has an oral bioavailability of 30–50%, and
the rate and extent of amiodarone absorption are increased 4.1.1 Ventricular Fibrillation, Ventricular Tachycardia,
when taken with food. When taken with a diet rich in fat, the and Cardiac Arrest
absorption is enhanced by 2.4- to 3.8-fold compared with the
fasting state [6, 7]. Therefore, we recommend that amiodar- The ARREST trial showed that, among patients with out-of-
one should be taken with meals. Amiodarone is metabolized hospital cardiac arrest due to ventricular fibrillation (VF),
in the liver to desethylamiodarone [5]. During loading, it goes those receiving amiodarone (n = 246) had a higher rate of
through three phases of distribution: (1) central or vascular survival to admission than those receiving placebo (n = 258)
distribution occurs over approximately 24 h, (2) peripheral (44 vs. 34%; p = 0.03) [10]. Subsequently, the ALIVE trial
or solid organ distribution occurs over the next 7 days, and showed amiodarone (n = 180) increased survival as com-
(3) deep or fat tissue distribution occurs over the subsequent pared with lidocaine (n = 167) in out-of-hospital cardiac
4 weeks. The full antiarrhythmic effect of amiodarone for VA arrest due to shock-resistant VF (22.8 vs. 12.0%; p = 0.009)
plateaus after 10 weeks of therapy [5]. The amount of time [11]. A major limitation of this trial was the small number of
the medication persists in the body is dependent on the fat participants and the lack of a placebo group. However, more
content and prior concentration. Amiodarone leaves the body recently, a large randomized, double-blinded study assessed
in the reverse order of distribution, which can take several the efficacy of amiodarone (n = 974), lidocaine (n = 993),
weeks, with a half-life of 50–60 days [8]. or placebo (n = 1059) in out-of-hospital cardiac arrest from
The long half-life of amiodarone means that if it is with- VF or ventricular tachycardia (VT) that was refractory to
held for a short period of time (up to 1 month) during long- shock therapy. While there was no difference in outcomes
term maintenance therapy, replacement therapy is not neces- between the groups in the overall population, amiodarone
sary. After amiodarone is discontinued, it may continue to demonstrated a survival benefit compared with placebo in
have an effect for up to 3 months because of the prolonged the witnessed arrest subgroup [12]. Amiodarone remains a
commonly used first-line agent for VF (whether refractory to
shock therapy or not) and is the only antiarrhythmic medica-
tion recommended by the American Heart Association for
the Advanced Cardiovascular Life Support algorithm (class
IA recommendation) [13]. Though the survival benefits
of amiodarone were limited in the more recent study from
Kudenchuk et al. [12], we recommend administering intra-
venous amiodarone to all patients with VF and cardiac arrest
given the signals of benefit seen in witnessed arrest cases.
Information as to whether the arrest was witnessed may not
be immediately available, and amiodarone administration in
this situation did not have major signals of harm.

4.1.2 Hemodynamically Tolerated Ventricular Tachycardia

Until recently, only small studies had compared the effi-

cacy of the different antiarrhythmics for acute termination
Fig. 1  The mechanism of action of amiodarone. A depiction of a nor- and safety in the setting of hemodynamically tolerated VT
mal (black) and post-amiodarone (green) action potentials. Amiodar- [14, 15]. A recent randomized controlled trial in 62 patients
one inhibits sodium (Na), slightly prolonging phase 0 of the action
potential. It inhibits L-type calcium channels (ICaL) and inhibits recti-
demonstrated the superiority of procainamide over ami-
fier potassium channels (IKr), prolonging phase 2 and 3 of the action odarone in both acute termination of VT and safety [16].
potential, leading to a prolongation of the QTc Nonetheless, given the familiarity of most physicians with
Comprehensive Clinical Guide to Amiodarone

amiodarone, it is still widely used in this clinical setting. syncope, or palpitations) can receive acute cardioversion
Additionally, procainamide cannot be used as a long-term with amiodarone as an adjunct to or in place of electrical
oral medication in the USA. Data on electrical cardiover- cardioversion [21]. Though electrical cardioversion has a
sion for hemodynamically unstable VT are reviewed in reported success rate of 70–90%, some patients may not
Sect. 4.1.1. In patients with hemodynamically stable VT, wish to undergo electrical cardioversion, preferring pharma-
antiarrhythmics are usually tried first, and cardioversion is cologic cardioversion [22]. The efficacy of amiodarone alone
performed if there are signs of poor perfusion or new hemo- in acute cardioversion of atrial fibrillation is 35–65% [22].
dynamic instability [13, 17]. No data have been published on Amiodarone is also efficacious in maintaining sinus rhythm
which antiarrhythmics aid electrical cardioversion of hemo- after electrical cardioversion, though no more so than other
dynamically stable VT. antiarrhythmics [23]. However, unlike propafenone or fle-
cainide, amiodarone may be used in older patients who may
4.1.3 Prevention of Recurrent Ventricular Tachycardia have concomitant ischemic heart disease.
and Implantable Cardioverter Defibrillator Shocks

Amiodarone is also the first-line therapy for patients receiv- 4.2.2 Recurrent Atrial Fibrillation Prophylaxis
ing appropriate implantable cardioverter defibrillator (ICD)
shocks for VA. In a comparison of β-blockers versus sotalol For patients with left ventricular dysfunction and heart fail-
versus amiodarone plus β-blockers in 412 patients with ure who are hemodynamically stable, amiodarone is less
spontaneous or inducible VAs in patients with ICDs, the effective than catheter ablation for cardioversion of atrial
latter combination resulted in the lowest risk of appropriate fibrillation. An open-label, parallel-group, multicenter, ran-
shocks, albeit at a higher risk of drug-related adverse events domized, controlled trial reported that 70% of patients who
[18]. No randomized comparison of amiodarone and mexi- received catheter ablation (n = 102) versus 34% of patients
letine has been undertaken in this clinical setting. receiving amiodarone alone (n = 101) did not have recur-
Recently, catheter ablation of VA has also emerged as rence of atrial fibrillation at 2-year follow-up [24]. Notably,
an important tool in the management of patients receiving patients who were receiving low-dose amiodarone (< 200 mg
ICD shocks. In a comparison of escalation of antiarrhyth- daily) continued amiodarone for 12 weeks after the ablation
mic therapy (n = 127) versus catheter ablation (n = 132) procedure, whereas patients receiving amiodarone ≥ 200 mg
in patients with ischemic cardiomyopathy and VA, cath- daily were not included in the trial. Maintenance dosing is
eter ablation resulted in a lower rate of recurrent VA and initiated at 400 mg every 8–12 h for 1–2 weeks, followed
ICD shocks [19]. The drug-escalation protocol consisted by 200–400 mg once daily [13]. Dosing can be decreased
of adding amiodarone in naïve patients and increasing for women and those with lower body weights to prevent
the dose in patients receiving lower doses of amiodarone. significant drug toxicity, including preventing the need for
Interestingly, there was no difference in outcomes for pacemaker insertion [25].
patients who were not receiving amiodarone therapy at
baseline. Thus, the benefit of catheter ablation over ami- 4.2.3 Rhythm Control after Cardioversion
odarone in patients with ischemic cardiomyopathy who
are amiodarone naïve or those with nonischemic cardio- For patients with severe left ventricular dysfunction and
myopathy is unclear. This was also demonstrated in the heart failure, or those who are hemodynamically unstable,
SCD-HeFT trial (n = 2521), in which amiodarone showed amiodarone may be used to slow a rapid ventricular response
no difference when compared with placebo in reducing [21]. For patients with symptomatic atrial fibrillation who
mortality in symptomatic patients with a left ventricular are not candidates for atrial fibrillation catheter ablation,
ejection fraction < 35% [20]. medical management with amiodarone may be considered.
Patients with cardiomyopathy who have met criteria for A pooled meta-analysis of the AFFIRM and AF-CHF trials
an ICD but have not had a prior episode of VT gain no added (n = 3307) showed freedom from atrial fibrillation was 84%
benefit from “prophylactic” amiodarone. and 45% at 1 and 5 years, respectively [26]. Interestingly, a
2009 meta-analysis (n = 673) showed that amiodarone was
more effective than placebo or β-blockers at achieving sinus
4.2 Atrial Fibrillation rhythm (21.3 vs. 9.2 per 100 patient-years in sinus rhythm)
and that it did not increase long-term mortality (4.7 vs. 3.9
4.2.1 Acute Cardioversion per 100 patient-years) [27]. Given the possibility of cardio-
version to sinus rhythm, amiodarone should be used when
Patients who are hemodynamically stable but symptomatic cardioversion and the associated risk of thromboembolism
from atrial fibrillation (i.e., left ventricular dysfunction, would be acceptable or has been minimized by therapeutic
 D. Hamilton et al.

anticoagulation for 3 weeks or the patient has been in atrial 5.2 Atrial Arrhythmias
fibrillation for < 48 h [21].
Similar loading strategies and dosages can be used for both
4.3 Other Supraventricular Tachyarrhythmias atrial arrhythmias and VAs. When amiodarone is used for
rhythm control in atrial fibrillation, typical dosing is 200 mg
Stable patients with rate-controlled atrial flutter or cardio- daily, but 100 mg daily could be considered for elderly
verted atrioventricular nodal re-entrant tachycardia, atrial patients [32].
tachycardia, or atrioventricular re-entrant tachycardia should
be referred for catheter ablation rather than placed on long-
term amiodarone because of the high cure rates with cath- 6 Drug Interactions
eter ablation [28]. However, amiodarone has been found to
be efficacious in critically ill or severely comorbid patients 6.1 Cardiac Medications
(n = 33) with atrial tachyarrhythmias who are otherwise pre-
cluded from catheter ablation candidacy [29]. Amiodarone use with class 1a antiarrhythmic medica-
tions (quinidine, procainamide, and disopyramide) is
contraindicated because of dose-independent QTc pro-
5 Dosing longation [33]. Amiodarone should also not be used with
other Vaughan William class III agents because of the
5.1 Ventricular Arrhythmias risk of significant QTc prolongation. When prescribed in
combination with β-blockers or calcium channel block-
For patients experiencing VF or hemodynamically unsta- ers, amiodarone may further increase the risk of brady-
ble VT, a loading is initiated with intravenous or intraos- cardia because of sinus nodal or atrioventricular nodal
seous amiodarone for faster onset of action than with oral blockade [34]. Therefore, amiodarone and β-blocker dual
amiodarone (150–300 mg intravenous or intraosseous bolus therapy should be used cautiously. The combined use of
per American Heart Association guidelines for Advanced digoxin and amiodarone can increase serum concentra-
Cardiovascular Life Support), followed by a continuous infu- tions of digoxin because of inhibition of gastrointesti-
sion of 1 mg/min for 6 h; then 0.5 mg/min for at least 18 h nal p-glycoprotein, putting patients at risk for digoxin
[13, 21]. For hemodynamically stable patients, the loading toxicity [35–37]. Though flecainide and amiodarone are
for VA is initiated with intravenous amiodarone for bet- clinically rarely used together, dosing of flecainide should
ter bioavailability: 150 mg intravenous bolus, followed by be adjusted when concurrently using amiodarone. Given
1 mg/min for 6 h; followed by 0.5 mg/min for 18 h or until the hepatic metabolism of flecainide via cytochrome
switched to oral therapy (as described above) [13]. No dose P450 (CYP)-2D6 inhibition, flecainide dosing should be
adjustment is required for renal impairment. No specific decreased by 50% when used in combination with ami-
guidelines exist for hepatic impairment; however, given the odarone, though one study found that flecainide levels
intermediate first-pass extraction through the liver, treatment were increased by 30% in patients receiving amiodar-
may be initiated at a low-normal dose, with low maintenance one [38]. Because of amiodarone-mediated inhibition of
dosing [30]. CYP3A4, both simvastatin and atorvastatin concentra-
Converting patients from intravenous amiodarone to oral tions can be increased when used in combination with
amiodarone depends on the period of time for which the amiodarone [39]. This interaction could potentiate the
patient received the intravenous infusion. If the intravenous risk of myopathy, including rhabdomyolysis. The cur-
infusion was continued for < 1 week, the initial oral dose rently recommended dose of simvastatin is 20 mg if used
should be 800–1600 mg per day. If the intravenous infusion concomitantly with amiodarone [40]. Pravastatin may be
was continued for 1–3 weeks, the initial oral dose should considered in lieu of simvastatin or atorvastatin as its
be 600–800 mg per day. Finally, if the intravenous infusion blood concentration has not been shown to be altered by
was continued for > 3 weeks, then the initial oral dose should concurrent amiodarone use [39]. Amiodarone potentiates
be 400 mg daily. Dosing adjustments should be considered the anticoagulation effect and plasma concentration of
in patients with hepatic dysfunction but is not necessary in warfarin via inhibition of the S-isomer of warfarin (the
patients with renal dysfunction. Overlapping intravenous and more potent enantiomer) and CYP2C9 and CYP3A4,
oral amiodarone does not decrease the rate of early tachyar- requiring closer monitoring of the international normal-
rhythmia recurrence [31]. ized ratio [41]. If amiodarone is started while a patient
is receiving warfarin, a dose reduction of warfarin by
approximately 30–50% is usually required [42].
Comprehensive Clinical Guide to Amiodarone

6.2 Noncardiac Medications of placebo-controlled trials of amiodarone, the relative risk

of thyroid toxic events was about 4.4 [55]. Amiodarone-
Amiodarone in combination with other QTc-prolonging induced hypothyroidism (AIH) is thought to occur because
medications can result in the R-on-T phenomenon and of the large amount of iodine released from amiodarone,
is therefore a risk category X (avoid combination) [43]. which inhibits thyroid hormone synthesis, termed the
Cholestyramine and other bile acid sequestrants can Wolff–Chaikoff effect. This is usually a temporary effect
decrease the bioavailability of amiodarone so therapy until the thyroid “escapes” and usual synthesis of T4 occurs.
modification should be considered [44]. Amiodarone can However, AIH occurs when the body does not “escape” or
increase the concentration of doxorubicin by inhibiting is more susceptible to the inhibitory effect of iodine on hor-
CYP2D6, CYP3A4, and p-glycoprotein, which requires monal synthesis. AIH is expected to resolve 2–4 months
closer monitoring of these patients [45]. Fosphenytoin, after drug cessation, which correlates with the half-life of
lopinavir/ritonavir, and ivabradine are other medications amiodarone. Patients with persistent hypothyroidism usu-
that can prolong the QTc in combination with amiodar- ally have underlying autoimmune thyroid disease [54].
one and should therefore be used with caution [46–48]. Hypothyroidism may develop as rapidly as 2 weeks and
Both indinavir and ritonavir can increase the concentra- as late as 39 months, and complications can be as serious
tion of amiodarone and are combination class X [46, 49]. as myxedema coma. On the opposite end of the spectrum,
Similarly, amiodarone should also not be combined with there are two types of amiodarone-induced thyrotoxicosis
ledipasvir/sofosbuvir because of the risk of severe and (AIT): type I (excessive iodine-induced hormone synthesis
rare but fatal bradycardia [50]. and release in patients with abnormal thyroid glands) and
type II (destructive thyroiditis usually in patients without
underlying thyroid disease) [54, 56].
7 Toxicities/Side Effects

The adverse reactions of amiodarone include both life- 7.2 Lung

threatening effects leading to black box warnings and com-
mon side effects (Table 1). Common intolerances include Pulmonary toxicity from amiodarone most commonly pre-
nausea, vomiting, and taste disturbances, which can be mini- sents as interstitial lung disease or hypersensitivity syn-
mized by dividing into twice-daily doses [51–53]. Serious drome (relative risk 1.77 compared with placebo), although
black box warnings include hepatotoxicity and pulmonary acute respiratory distress syndrome, pulmonary nodules/
dysfunction. masses, or pleural effusions have also been reported [55,
57–61]. Pulmonary complications, including fibrosis and
7.1 Thyroid hypersensitivity, have been reported in studies as occur-
ring in about 1–2% of patients receiving amiodarone [62,
Amiodarone can cause mild alterations in thyroid hor- 63]. This pulmonary toxicity is fatal approximately 10% of
mones, including decreased serum T2, increased serum the time [57]. High-resolution computerized tomography
T4, and reversed T3 levels, and either normal or slight scans of the lungs can be performed at that time to check
elevations in thyroid-stimulating hormone, likely because for evidence of hypersensitivity pneumonitis but is not rec-
of interference with the iodothyronine deiodinases, which ommended for routine monitoring [64]. Amiodarone should
metabolize thyroid hormones [54]. In a large meta-analysis be used cautiously in patients with preexisting pulmonary

Table 1  Toxicities and monitoring [54–71]

Organ Toxicity Monitoring

Thyroid Hyperthyroid, hypothyroid TSH, free T4 every 6 months

Lung Interstitial lung disease, hypersensitivity PFT (including DLCO) on initiation, repeated if concern for pulmonary
syndrome toxicity; annual chest X-ray
Liver Transaminitis Liver function panel every 6 months
Heart Bradycardia, QTc prolongation ECG monitoring before and after initiation of therapy and annually thereafter
Eye Corneal microdeposits, light sensitivity, Baseline and annual ophthalmologic exam including slit-lamp evaluation
optic neuropathy
Skin Phototoxic, photoallergic Annual physical exam, sunscreen use

DLCO lung diffusing capacity of carbon monoxide, ECG electrocardiogram, PFT pulmonary function test, TSH thyroid-stimulating hormone
 D. Hamilton et al.

disease (e.g., severe asthma, chronic obstructive pulmonary In patients with VT and hypothyroidism as the only toxicity,
disease) or those requiring oxygen therapy, as they are at amiodarone should not be discontinued because amiodarone
higher risk of pulmonary toxicity [57, 65]. has increased efficacy compared with many other antiar-
rhythmics, and levothyroxine is a generally well-tolerated
drug. Rather, hypothyroidism should be treated while ami-
7.3 Liver odarone is continued. In patients with atrial fibrillation or
other supraventricular tachyarrhythmias, amiodarone should
Hepatotoxicity typically manifests as mild transaminitis in be withheld if the patient is a candidate for other antiarrhyth-
approximately 0.5–1% of cases, but fatal hepatic failure has mics such as propafenone, sotalol, dofetilide, or flecainide
occurred in a few cases [63, 66]. The relative risk of devel- to prevent polypharmacy.
oping hepatotoxicity compared with placebo is approxi- In the setting of hyperthyroidism due to type I AIT,
mately 2.3 according to a recent meta-analysis [55]. another agent should be started in lieu of amiodarone, methi-
mazole 40–80 mg daily or propylthiouracil 400–800 mg
daily should be initiated, amiodarone should be stopped, and
7.4 Heart alternative therapy should be initiated. In type II AIT, ami-
odarone can be continued initially and prednisone 40–60 mg
Significant heart block or sinus bradycardia is seen in 2–5% daily should be prescribed [56]. If there is no improvement
of patients (relative risk 1.9), along with QTc prolongation, in thyroid function within 1–2 months, then amiodarone
although this is generally not associated with arrhythmias should be withheld and alternative therapy initiated. Fre-
[55, 63]. quently, type II AIT subsequently results in hypothyroidism,
which can be treated with levothyroxine [56].
Patients who develop thyroid toxicities should be referred
7.5 Eye
to an endocrinologist [64]. Whether hypo- or hyperthyroid-
ism, decisions about continuing or withholding amiodarone
Epithelial keratopathy, or corneal microdeposits, can occur
require discussion with the patient about the risks and ben-
in up to 90% of the cases according to the literature. Light
efits of the treatment options and effects on quality of life
sensitivity and optic neuropathy are less common [67].
and subsequent shared decision making.

7.6 Skin 8.2 Lung

Phototoxic and photoallergic reactions have been reported Baseline testing should include pulmonary function tests
in 25–75% of patients, as has hyperpigmentation, affecting (PFTs), including lung diffusing capacity of carbon monox-
4–9% of patients (overall relative risk 1.99) [55, 68]. ide (DLCO) and a chest radiograph [70]. PFTs with DLCO
can be repeated if there is clinical suspicion for pulmonary
7.7 Pregnancy toxicity, as serial monitoring has not shown clear benefit
[64]. However, it is recommended to repeat chest X-ray films
Amiodarone, listed as a class D drug during pregnancy, annually [64]. If there is evidence of pulmonary toxicity,
is associated with cardiac, endocrine, and neurodevelop- then amiodarone should be promptly discontinued and the
mental anomalies and should only be used as a drug of last patient referred to a pulmonologist; initiation of prednisone
resort [69]. In breastfeeding mothers, amiodarone should be 40–60 mg daily is recommended [64].
avoided or breastfeeding should be stopped to decrease the
risk of newborn hypothyroidism [69]. 8.3 Liver

Clinicians should order baseline and repeat testing of liver

8 Monitoring and Treatment of Side Effects function every 6 months because of the potential for hepatic
dysfunction. Screening liver function tests should include
8.1 Thyroid aspartate aminotransferase (AST) and alanine aminotrans-
ferase (ALT). AST or ALT elevation greater than two times
Thyroid function should be monitored via TSH and free T4 the upper limit of normal should prompt either dose reduc-
every 6 months [54, 64]. If hypothyroidism occurs, levo- tion of amiodarone or a change in agent [64].
thyroxine should be administered [56]. Hypothyroidism can
persist for 8 months after amiodarone is discontinued [54].
Comprehensive Clinical Guide to Amiodarone

8.4 Heart discontinuation of amiodarone if optical nerve neuropathy

is diagnosed.
The cardiac system should be monitored for QTc prolonga-
tion and bradycardia with an electrocardiogram before start- 8.6 Skin
ing the medication and annually thereafter [64]. In asymp-
tomatic bradycardia, we recommend maintaining the dose The integumentary system should be monitored via annual
if the heart rate remains above 40 beats per minute (bpm). physical exam. If photosensitivity occurs, the patient should
However, if heart rates drop below 40 bpm, a dose reduction be encouraged to avoid sunlight (particularly immediately
of 50% followed by monitoring for breakthrough tachyar- after the dose is taken) and use sunscreen [68]. Photosensi-
rhythmias and improved sinus heart rate (via 14- or 30-day tivity alone does not necessitate a change in dose or cessa-
event monitor) is recommended. If the patient develops tion of amiodarone if these precautions are taken.
symptomatic bradycardia, amiodarone should be decreased
by 50% or withheld completely. If intolerable tachyarrhyth-
mias occur, placement of a pacemaker should be considered 8.7 Alternatives to Amiodarone
for patients with supraventricular tachycardias or an ICD
considered in patients with VT. In situations where amiodarone needs to be stopped, or
the reduced dose is ineffective, alternative antiarrhythmics
8.5 Eye should be considered [13]. For VA, mexiletine or sotalol
are options [13]. Rarely, quinidine and procainamide can be
A baseline and annual ophthalmologic exam, including slit- used, though these have a very high risk of Torsades [13].
lamp evaluation, should be performed to evaluate for corneal For atrial arrhythmias, in the absence of coronary artery
deposits and optical nerve neuropathies [64, 67]. Corneal disease or heart failure, class 1c agents can be used [21].
microdeposits rarely impact on vision and therefore do not Dronedarone can also be used in patients with structurally
necessitate a decreased dose or cessation of amiodarone. normal hearts [21]. The next line of agents includes sotalol
Prescribers should promptly refer the patient to an ophthal- or dofetilide if renal function is satisfactory and QTc is not
mologist for any changes in visual acuity while patients prolonged at baseline [21].
are receiving amiodarone [64]. We recommend immediate

Fig. 2  Sample amiodarone

safety monitoring protocol.
ALT alanine aminotransferase,
AST aspartate aminotransferase,
CMP comprehensive metabolic
panel, CXR chest X-ray, DLCO
lung diffusing capacity of
carbon monoxide, ECG electro-
cardiogram, GI gastrointestinal,
INR international normaliza-
tion ratio, Mg magnesium, PT
prothrombin time, SCr serum
creatinine, TSH thyroid-stimu-
lating hormone
 D. Hamilton et al.

9 Need for an Outpatient Monitoring Tool 4. Kodama I, Kamiya K, Toyama J. Cellular electropharmacology
of amiodarone. Cardiovasc Res. 1997;35:13–29.
5. Mitchell LB, Wyse DG, Gillis AM, Duff HJ. Electropharma-
Several studies have demonstrated that adherence to appro- cology of amiodarone therapy initiation. Time courses of onset
priate monitoring of amiodarone is poor [71–73]. One pro- of electrophysiologic and antiarrhythmic effects. Circulation.
posed solution for improved surveillance while receiving 1989;80:34–42.
6. Shayeganpour A, Jun AS, Brocks DR. Pharmacokinetics of Ami-
amiodarone is pharmacist-led amiodarone monitoring ser- odarone in hyperlipidemic and simulated high fat-meal rat models.
vices, which have been beneficial in increasing screening Biopharm Drug Dispos. 2005;26:249–57.
compliance in retrospective cohort and longitudinal studies 7. Meng X, Mojaverian P, Doedée M, Lin E, Weinryb I, Chiang ST,
[74]. Figure 2 shows the protocol used at Loma Linda Uni- et al. Bioavailability of amiodarone tablets administered with and
without food in healthy subjects. Am J Cardiol. 2001;87:432–5.
versity Medical Center as an example. 8. Holt DW, Tucker GT, Jackson PR, Storey GCA. Amiodarone phar-
macokinetics. Am Heart J. 1983;106:840–7.
9. Freedman MD, Somberg JC. Pharmacology and Pharmacokinetics
of Amiodarone. J Clin Pharmacol. 1991;31:1061–9.
10 Need for Informed Consent 10. Kudenchuk PJ, Doherty AM, Murray WA. Amiodarone for resus-
citation after out-of-hospital cardiac arrest due to ventricular
fibrillation. N Engl J Med. 1999;8.
Given the significant side effects possible with amiodarone, 11. Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas R, Barr
clinicians should explicitly document discussion of all pos- A. Amiodarone as compared with lidocaine for shock-resistant
sible side effects. Shared decision making is essential in ventricular fibrillation. N Engl J Med. 2002;346:884–90.
12. Kudenchuk PJ, Brown SP, Daya M, Rea T, Nichol G, Morrison LJ,
increasing adherence to medications and prompt recogni-
et al. Amiodarone, lidocaine, or placebo in out-of-hospital cardiac
tion of any adverse drug reaction. While formal informed arrest. N Engl J Med. 2016;374:1711–22.
consent is not necessary, it may be considered. 13. Al-Khatib Sana M, Stevenson William G, Ackerman Michael J,
Bryant William J, Callans David J, Curtis Anne B, et al. 2017
AHA/ACC/HRS guideline for management of patients with ven-
tricular arrhythmias and the prevention of sudden cardiac death.
Circulation. 2018;138:e272–391.
11 Conclusion 14. Marill KA, deSouza IS, Nishijima DK, Senecal EL, Setnik GS,
Stair TO, et al. Amiodarone or procainamide for the termination
Although amiodarone has an important role in the arma- of sustained stable ventricular tachycardia: an historical multi-
mentarium of experienced clinicians, it should be used judi- center comparison. Acad Emerg Med. 2010;17:297–306.
15. Tomlinson DR, Cherian P, Betts TR, Bashir Y. Intravenous ami-
ciously and only in patients who are likely to receive proper odarone for the pharmacological termination of haemodynam-
follow-up. The ability to treat life-threatening arrhythmias ically-tolerated sustained ventricular tachycardia: is bolus dose
makes this medication valuable in certain situations. How- amiodarone an appropriate first-line treatment? Emerg Med J.
ever, the potentially fatal toxicities of long-term use of ami- 2008;25:15.
16. Ortiz M, Martín A, Arribas F, Coll-Vinent B, del Arco C, Peinado
odarone require vigilant monitoring and a low threshold for R, et al. Randomized comparison of intravenous procainamide
dose reduction or change in agent whenever appropriate. vs. intravenous amiodarone for the acute treatment of tolerated
wide QRS tachycardia: the PROCAMIO study. Eur Heart J.
Compliance with Ethical Standards 2016;ehw230.
17. Panchal Ashish R, Berg Katherine M, Kudenchuk Peter J,
Marina Del Rios, Hirsch Karen G, Link Mark S, et al. American
Funding No external funding was used in the preparation of this manu- Heart Association Focused Update on advanced cardiovascular
script. life support use of antiarrhythmic drugs during and immediately
after cardiac arrest: an update to the american heart association
Conflicts of interest David Hamilton Sr., Shuktika Nandkeolyar, How- guidelines for cardiopulmonary resuscitation and emergency
ard Lan, Pooja Desai, Jonathan Evans, Christopher Hauschild, Dimpa cardiovascular care. Circulation. 2018;2018(138):e740–9.
Choksi, Islam Abudayyeh, Tahmeed Contractor, and Anthony Hilliard 18. Connolly SJ, Dorian P, Roberts RS, Gent M, Bailin S, Fain ES,
have no potential conflicts of interest that might be relevant to the con- et al. Comparison of β-blockers, amiodarone plus β-Blockers, or
tents of this manuscript. sotalol for prevention of shocks from implantable cardioverter
defibrillators: the OPTIC study: a randomized trial. JAMA.
2006;295:165–71.
19. Sapp JL, Wells GA, Parkash R, Stevenson WG, Blier L, Sarrazin
References J-F, et al. Ventricular tachycardia ablation versus escalation of
antiarrhythmic drugs. N Engl J Med. 2016;375:111–21.
1. Williams EMV. A classification of antiarrhythmic actions 20. Bardy GH, Boineau R, Johnson G, Davidson-Ray LD, Ip JH.
reassessed after a decade of new drugs. J Clin Pharmacol. Amiodarone or an implantable cardioverter–defibrillator for
1984;24:129–47. congestive heart failure. N Engl J Med. 2005;13.
2. Haverkamp W, Israel C, Parwani A. Klinische Besonderheiten der 21. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleve-
Therapie mit Amiodaron. Herzschr Elektrophys. 2017;28:307–16. land JC, et al. AHA/ACC/HRS Focused Update of the 2014
3. Vaughan Williams EM. Classification of antidysrhythmic drugs. AHA/ACC/HRS guideline for the management of patients
Pharmacol Ther B. 1975;1:115–38. with atrial fibrillation: a report of the American college of
Comprehensive Clinical Guide to Amiodarone

Cardiology/American heart association task force on clini- 36. Robinson K, Johnston A, Walker S, Mulrow JP, McKenna WJ,
cal practice guidelines and the heart rhythm society in col- Holt DW. The digoxin-amiodarone interaction. Cardiovasc Drug
laboration with the society of thoracic surgeons. Circulation. Ther. 1989;3:25–8.
2019;2019:140. 37. Fenner K, Troutman M, Kempshall S, Cook J, Ware J, Smith D,
22. Chevalier P, Durand-Dubief A, Burri H, Cucherat M, Kirkorian et al. Drug–drug interactions mediated through P-glycoprotein:
G, Touboul P. Amiodarone versus placebo and class ic drugs for clinical relevance and in vitro–in vivo correlation using digoxin
cardioversion of recent-onset atrial fibrillation: a meta-analysis. as a probe drug. Clin Pharmacol Ther. 2009;85:173–81.
J Am Coll Cardiol. 2003;41:255–62. 38. Shea P, Lal R, Kim SS, Schechtman K, Ruffy R. Flecainide and
23. Gwag HB, Chun KJ, Hwang JK, Park S-J, Kim JS, Park K-M, amiodarone interaction. J Am Coll Cardiol. 1986;7:1127–30.
et al. Which antiarrhythmic drug to choose after electrical car- 39. Becquemont L, Neuvonen M, Verstuyft C, Jaillon P, Letierce A,
dioversion: A study on non-valvular atrial fibrillation patients. Neuvonen PJ, et al. Amiodarone interacts with simvastatin but
PLoS One [Internet]. 2018 [cited 2020 Jan 30];13. Available not with pravastatin disposition kinetics. Clin Pharmacol Ther.
from: https​://www.ncbi.nlm.nih.gov/pmc/artic​les/PMC59​63785​ 2007;81:679–84.
/. 40. Research C for DE and. FDA Drug Safety Communication:
24. Di Biase L, Mohanty P, Mohanty S, Santangeli P, Trivedi C, Lak- Revised dose limitation for Zocor (simvastatin) when taken with
kireddy D, et al. Ablation versus amiodarone for treatment of per- amiodarone. FDA [Internet]. 2018 [cited 2019 Jun 7]; Available
sistent atrial fibrillation in patients with congestive heart failure from: http://www.fda.gov/drugs​/drug-safet​y-and-avail​abili​ty/fda-
and an implanted device. Circulation. 2016;133:1637–44. drug-safet​y-commu​nicat​ion-revis​ed-dose-limit​ation​-zocor​-simva​
25. Essebag V, Reynolds MR, Hadjis T, Lemery R, Olshansky B, stati​n-when-taken​-amiod​arone​.
Buxton AE, et al. Sex differences in the relationship between ami- 41. O’Reilly RA, Trager WF, Rettie AE, Goulart DA. Interaction
odarone use and the need for permanent pacing in patients with of amiodarone with racemic warfarin and its separated enantio-
atrial fibrillation. Arch Intern Med. 2007;167:1648–53. morphs in humans. Clin Pharmacol Ther. 1987;42:290–4.
26. Cadrin-Tourigny J, Wyse DG, Roy D, Blondeau L, Levesque S, 42. Holm J, Lindh JD, Andersson ML, Mannheimer B. The effect of
Talajic M, et al. Efficacy of amiodarone in patients with atrial amiodarone on warfarin anticoagulation: a register-based nation-
fibrillation with and without left ventricular dysfunction: a pooled wide cohort study involving the Swedish population. J Thromb
analysis of AFFIRM and AF-CHF trials. J Cardiovasc Electro- Haemost. 2017;15:446–53.
physiol. 2014;25:1306–13. 43. Wei A, Peng J, Gu Z, Li J. QTc prolongation and torsades de
27. Doyle JF, Ho KM. Benefits and risks of long-term amiodarone pointes due to a coadministration of fluoxetine and amiodarone in
therapy for persistent atrial fibrillation: a meta-analysis. Mayo a patient with implantable cardioverter–defibrillator: case report
Clin Proc. 2009;84:234–42. and review of the literature. Medicine. 2017;96:e9071.
28. Brugada J, Katritsis DG, Arbelo E, Arribas F, Bax JJ, Blomström- 44. Nitsch J, Lüderitz B. Beschleunigte elimination von amiodaron
Lundqvist C, et al. 2019 ESC Guidelines for the management of durch Colestyramin*. Dtsch Med Wochenschr. 1986;111:1241–4.
patients with supraventricular tachycardiaThe Task Force for the 45. Chauffert B, Martin M, Hammann A, Michel MF, Martin F. Ami-
management of patients with supraventricular tachycardia of the odarone-induced enhancement of doxorubicin and 4′-Deoxydoxo-
European Society of Cardiology (ESC)Developed in collabora- rubicin cytotoxicity to rat colon cancer cells in vitro and in vivo.
tion with the Association for European Paediatric and Congenital Cancer Res. 1986;46:825–30.
Cardiology (AEPC). Eur Heart J [Internet]. [cited 2020 Jan 30]; 46. Crouch MA, Limon L, Cassano AT. clinical relevance and man-
Available from: https:​ //academ​ ic.oup.com/eurhea​ rtj/advanc​ e-artic​ agement of drug-related QT interval prolongation. Pharmaco-
le/doi/10.1093/eurhe​artj/ehz46​7/55568​21. therapy. 2003;23:881–908.
29. Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Intravenous 47. Rushworth GF, Lambrakis P, Leslie SJ. Ivabradine: a new rate-
amiodarone for acute heart rate control in the critically ill patient limiting therapy for coronary artery disease and heart failure. Ther
with atrial tachyarrhythmias. Am J Cardiol. 1998;81:594–8. Adv Drug Saf. 2011;2:19–28.
30. Lewis JH, Stine JG. Review article: prescribing medications in 48. Nolan PE, Marcus FI, Hoyer GL, Bliss M, Gear K. Pharmacoki-
patients with cirrhosis—a practical guide. Aliment Pharmacol netic interaction between intravenous phenytoin and amiodarone
Ther. 2013;37:1132–56. in healthy volunteers. Clin Pharmacol Ther. 1989;46:43–9.
31. Arnouk S, Aberle C, Altshuler D, Merchan C, Piper GL, Papado- 49. Antiretroviral therapy increases serum concentrations of amiodar-
poulos J. Clinical effects of intravenous to oral amiodarone transi- one. Ann Pharmacother. 1999;33:645–6
tion strategies in critically ill adult patients. J Clin Pharm Ther. 50. Research C for DE and. FDA Drug Safety Communication: FDA
2019;44:693–700. warns of serious slowing of the heart rate when antiarrhythmic
32. Sandler M. Amiodarone dosage in older patients with atrial drug amiodarone is used with hepatitis C treatments containing
fibrillation: an open, multi-centre study. Curr Med Res Opin. sofosbuvir (Harvoni) or Sovaldi in combination with another
1992;13:31–6. Direct Acting Antiviral drug. FDA [Internet]. 2019 [cited 2019
33. Antonelli D, Atar S, Freedberg NA, Rosenfeld T. Torsade de May 24]; Available from: http://www.fda.gov/drugs​/drug-safet​
pointes in patients on chronic amiodarone treatment: contribut- y-and-avail​abili​ty/fda-drug-safet​y-commu​nicat​ion-fda-warns​
ing factors and drug interactions. Isr Med Assoc J. 2005;7:3. -serio​us-slowi​ng-heart​-rate-when-antia​r rhyt​hmic-drug.
34. Hauser TH, Pinto DS, Josephson ME, Zimetbaum P. Safety and 51. CORDARONE® (amiodarone HCl) Dosage and Administration
feasibility of a clinical pathway for the outpatient initiation of | Pfizer Medical Information - US [Internet]. [cited 2019 Jun 8].
antiarrhythmic medications in patients with atrial fibrillation or Available from: https:​ //www.pfizer​ medic​ alinf​ ormat​ ion.com/en-us/
atrial flutter. Am J Cardiol. 2003;91:1437–41. corda​rone/dosag​e-admin​.
35. Nademanee K, Kannan R, Hendrickson J, Ookhtens M, Kay I, 52. Dosing | NEXTERONE (amiodarone HCl) [Internet]. [cited 2019
Singh BN. Amiodarone-digoxin interaction: clinical signifi- Jun 8]. Available from: http://www.nexte​rone.com/dosin​g.html.
cance, time course of development, potential pharmacokinetic 53. NEXTERONE (amiodarone HCI) Premixed Injection [Internet].
mechanisms and therapeutic implications. J Am Coll Cardiol. [cited 2019 Jun 8]. Available from: http://www.nexte​rone.com/
1984;4:111–6. about​_nexte​rone.html.
 D. Hamilton et al.

54. Trohman RG, Sharma PS, McAninch EA, Bianco AC. Amiodar- 65. Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. J Thorac
one and thyroid physiology, pathophysiology, diagnosis and man- Dis. 2009;16:6.
agement. Trends Cardiovasc Med. 2019;29:285–95. 66. Gayam V, Khalid M, Dahal S, Garlapati P, Gill A, Alex R, et al.
55. Ruzieh M, Moroi MK, Aboujamous NM, Ghahramani M, Nac- Fatal acute liver failure with intravenous amiodarone: a case
carelli GV, Mandrola J, et al. Meta-analysis comparing the rela- report and literature review. Gastroenterol Res. 2018;11:62–3.
tive risk of adverse events for amiodarone versus placebo. Am J 67. Passman RS, Bennett CL, Purpura JM, Kapur R, Johnson LN,
Cardiol. 2019;124:1889–93. Raisch DW, et al. Amiodarone-associated optic neuropathy: a
56. Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Cardiol. critical review. Am J Med. 2012;125:447–53.
2005;118:706–14. 68. Jaworski K, Walecka I, Rudnicka L, Gnatowski M, Kosior DA.
57. Papiris SA, Triantafillidou C, Kolilekas L, Markoulaki D, Manali Cutaneous adverse reactions of amiodarone. Med Sci Monit.
ED. Amiodarone. Drug Saf. 2010;33:539–58. 2014;20:2369–72.
58. Kumar S, Bangalore S, Kumari R, Grosu H, Jean R. Amiodar- 69. Tan HL, Lie KI. Treatment of tachyarrhythmias during pregnancy
one-induced acute respiratory distress syndrome masquerading and lactation. Eur Heart J. 2001;22:458–64.
as acute heart failure. J Emerg Med. 2012;43:e311–4. 70. Gleadhill IC, Wise RA, Schonfeld SA, Scott PP, Guarnieri T,
59. Azzam I, Tov N, Elias N, Naschitz JE. Amiodarone toxicity pre- Levine JH, et al. Serial lung function testing in patients treated
senting as pulmonary mass and peripheral neuropathy: the con- with amiodarone: a prospective study. Am J Med. 1989;86:4–10.
tinuing diagnostic challenge. Postgrad Med J. 2006;82:73–5. 71. Lavon O, Goldman R. Adherence to monitoring guidelines of ami-
60. Rodrı́guez-Garcı́a JL, Garcı́a-Nieto JC, Ballesta F, Prieto E, odarone adverse reactions. Health Serv Res Manag Epidemiol.
Villanueva MA, Gallardo J. Pulmonary mass and multiple lung 2019;6:233339281984463.
nodules mimicking a lung neoplasm as amiodarone-induced pul- 72. Bickford CL, Spencer AP. Adherence to the NASPE guide-
monary toxicity. Eur J Intern Med. 2001;12:372–6. line for amiodarone monitoring at a medical university. JMCP.
61. Gonzalez-Rothi RJ, Hannan SE, Hood CI, Franzini DA. Amiodar- 2006;12:254–9.
one pulmonary toxicity presenting as bilateral exudative pleural 73. Burgess C, Blaikie A, Ingham T, Robinson G, Narasimhan S.
effusions. Chest. 1987;92:179–82. Monitoring the use of amiodarone: compliance with guidelines.
62. Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deed- Intern Med J. 2006;36:289–93.
wania PC, et al. Amiodarone in patients with congestive heart 74. Dixon DL, Dunn SP, Kelly MS, McLlarky TR, Brown RE. Effec-
failure and asymptomatic ventricular arrhythmia. N Engl J Med. tiveness of pharmacist-led amiodarone monitoring services on
1995;333:77–82. improving adherence to amiodarone monitoring recommenda-
63. Connolly Stuart J. Evidence-based analysis of amiodarone efficacy tions: a systematic review. Pharmacotherapy. 2016;36:230–6.
and safety. Circulation. 1999;100:2025–34.
64. Goldschlager N, Epstein AE, Naccarelli GV, Olshansky B, Singh
B, Collard HR, et al. A practical guide for clinicians who treat
patients with amiodarone: 2007. Heart Rhythm. 2007;4:1250–9.