Cordarone is a member of a new class of antiarrhythmic drugs with predominantly Class III (Vaughan
Williams� classification) effects, available for oral administration as pink, scored tablets containing
200 mg of amiodarone hydrochloride. The inactive ingredients present are colloidal silicon dioxide,
lactose, magnesium stearate, povidone, starch, and FD&C Red 40. Cordarone is a benzofuran
derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone
hydrochloride. It is not chemically related to any other available antiarrhythmic drug.
The structural formula is as follows:
Amiodarone HCl is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble
in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight.
Electrophysiology/Mechanisms of Action
In animals, Cordarone is effective in the prevention or suppression of experimentally induced
arrhythmias. The antiarrhythmic effect of Cordarone may be due to at least two major properties: 1) a
prolongation of the myocardial cell-action potential duration and refractory period and
2) noncompetitive �- and �-adrenergic inhibition.
Cordarone prolongs the duration of the action potential of all cardiac fibers while causing minimal
reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged
in all cardiac tissues. Cordarone increases the cardiac refractory period without influencing resting
membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally
reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to
20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave
contour. These changes should not require discontinuation of Cordarone as they are evidence of its
pharmacological action, although Cordarone can cause marked sinus bradycardia or sinus arrest and
heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see
In animal studies and after intravenous administration in man, Cordarone relaxes vascular smooth
muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After
oral dosing, however, Cordarone produces no significant change in left ventricular ejection fraction
(LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, Cordarone
may have a mild negative inotropic effect.
Following oral administration in man, Cordarone is slowly and variably absorbed. The bioavailability
of Cordarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum
plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may
occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma
concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a
mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual
variability. Food increases the rate and extent of absorption of Cordarone. The effects of food upon the
bioavailability of Cordarone have been studied in 30 healthy subjects who received a single 600-mg
dose immediately after consuming a high-fat meal and following an overnight fast. The area under the
plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone
increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of
food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma
concentration (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55%
(range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tmax in the
presence of food.
Cordarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of
extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as
the liver, lung, and spleen. One major metabolite of Cordarone, desethylamiodarone (DEA), has been
identified in man; it accumulates to an even greater extent in almost all tissues. No data are available
on the activity of DEA in humans, but in animals, it has significant electrophysiologic and
antiarrhythmic effects generally similar to amiodarone itself. DEA�s precise role and contribution to
the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular
Class III effects after oral Cordarone administration in humans correlates more closely with DEA
accumulation over time than with amiodarone accumulation.
Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible
excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable.
In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients
with VT and VF ranged between 220 and 440 ml/hr/kg. Age, sex, renal disease, and hepatic disease
(cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment
does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone
in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but
mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances
(about 100 ml/hr/kg) than younger subjects (about 150 ml/hr/kg) and an increase in t� from about 20 to
47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are
not significantly altered but the terminal disposition t� of DEA is prolonged. Although no dosage
adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic
treatment with Cordarone, close clinical monitoring is prudent for elderly patients and those with
severe left ventricular dysfunction.
Following single dose administration in 12 healthy subjects, Cordarone exhibited multi-compartmental
pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to
142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In
patients, following discontinuation of chronic oral therapy, Cordarone has been shown to have a
biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much
slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to
107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the
absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would
therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the
mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial
elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a
terminal phase representing extremely slow elimination from poorly perfused tissue compartments
such as fat.
The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what
compartment is critical to drug effect, requires attention to individual responses once arrhythmia
control is achieved with loading doses because the correct maintenance dose is determined, in part, by
the elimination rates. Daily maintenance doses of Cordarone should be based on individual patient
requirements (see �DOSAGE AND ADMINISTRATION�).
Cordarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The
parent drug and its metabolite have been detected in breast milk.
Cordarone is highly protein-bound (approximately 96%).
Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a
parenteral dose of Cordarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually
require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for
longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is
Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after
Cordarone is discontinued, but the time of recurrence is variable and unpredictable. In general, when
the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly
compared to the initial response, presumably because tissue stores were not wholly depleted at the time
There is no well-established relationship of plasma concentration to effectiveness, but it does appear
that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are
generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations
can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify
patients whose levels are unusually low, and who might benefit from a dose increase, or unusually
high, and who might have dosage reduction in the hope of minimizing side effects. Some observations
have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as
pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral
neuropathy, gastrointestinal and central nervous system effects.
Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent
ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified
investigators recommending use of ambulatory monitoring, programmed electrical stimulation with
various stimulation regimens, or a combination of these, to assess response. There is no present
consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on
1. If a patient with a history of cardiac arrest does not manifest a hemodynamically unstable
arrhythmia during electrocardiographic monitoring prior to treatment, assessment of the effectiveness
of Cordarone requires some provocative approach, either exercise or programmed electrical
2. Whether provocation is also needed in patients who do manifest their life-threatening arrhythmia
spontaneously is not settled, but there are reasons to consider PES or other provocation in such
patients. In the fraction of patients whose PES-inducible arrhythmia can be made noninducible by
Cordarone (a fraction that has varied widely in various series from less than 10% to almost 40%,
perhaps due to different stimulation criteria), the prognosis has been almost uniformly excellent, with
very low recurrence (ventricular tachycardia or sudden death) rates. More controversial is the meaning
of continued inducibility. There has been an impression that continued inducibility in Cordarone
patients may not foretell a poor prognosis but, in fact, many observers have found greater recurrence
rates in patients who remain inducible than in those who do not. A number of criteria have been
proposed, however, for identifying patients who remain inducible but who seem likely nonetheless to
do well on Cordarone. These criteria include increased difficulty of induction (more stimuli or more
rapid stimuli), which has been reported to predict a lower rate of recurrence, and ability to tolerate the
induced ventricular tachycardia without severe symptoms, a finding that has been reported to correlate
with better survival but not with lower recurrence rates. While these criteria require confirmation and
further study in general, easier inducibility or poorer tolerance of the induced arrhythmia should
suggest consideration of a need to revise treatment.
Several predictors of success not based on PES have also been suggested, including complete
elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low
premature ventricular-beat rates (less than 1 VPB/1,000 normal beats).
While these issues remain unsettled for Cordarone, as for other agents, the prescriber of Cordarone
should have access to (direct or through referral), and familiarity with, the full range of evaluatory
procedures used in the care of patients with life-threatening arrhythmias.
It is difficult to describe the effectiveness rates of Cordarone, as these depend on the specific
arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number
of drugs tried before resorting to Cordarone, the duration of follow-up, the dose of Cordarone, the use
of additional antiarrhythmic agents, and many other factors. As Cordarone has been studied principally
in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be
selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with
other agents or placebo have not been possible. Reports of series of treated patients with a history of
cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates
that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10
to 15%. Overall arrhythmia-recurrence rates (fatal and nonfatal) also were highly variable (and, as
noted above, depended on response to PES and other measures), and depend on whether patients who
do not seem to respond initially are included. In most cases, considering only patients who seemed to
respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to
40% in series with a mean follow-up of a year or more.
INDICATIONS AND USAGE
Because of its life-threatening side effects and the substantial management difficulties associated with
its use (see �WARNINGS� below), Cordarone is indicated only for the treatment of the following
documented, life-threatening recurrent ventricular arrhythmias when these have not responded to
documented adequate doses of other available antiarrhythmics or when alternative agents could not be
As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of
Cordarone (amiodarone HCl) Tablets favorably affects survival.
Cordarone should be used only by physicians familiar with and with access to (directly or through
referral) the use of all available modalities for treating recurrent life-threatening ventricular
arrhythmias, and who have access to appropriate monitoring facilities, including in-hospital and
ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of
the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and
potential exacerbation of the arrhythmia, initiation of therapy with Cordarone should be carried out in
Cordarone is contraindicated in severe sinus-node dysfunction, causing marked sinus bradycardia;
second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope
(except when used in conjunction with a pacemaker).
Cordarone is contraindicated in patients with a known hypersensitivity to the drug or to any of its
components, including iodine.
WARNINGS AND PRECAUTIONS
Cordarone is intended for use only in patients with the indicated life-threatening arrhythmias
because its use is accompanied by substantial toxicity.
Cordarone has several potentially fatal toxicities, the most important of which is pulmonary
toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in
clinically manifest disease at rates as high as 10 to 17% in some series of patients with
ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity
without symptoms in a much higher percentage of patients. Pulmonary toxicity has been fatal
about 10% of the time. Liver injury is common with Cordarone, but is usually mild and
evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been
fatal in a few cases. Like other antiarrhythmics, Cordarone can exacerbate the arrhythmia, e.g.,
by making the arrhythmia less well tolerated or more difficult to reverse. This has occurred in 2
to 5% of patients in various series, and significant heart block or sinus bradycardia has been
seen in 2 to 5%. All of these events should be manageable in the proper clinical setting in most
cases. Although the frequency of such proarrhythmic events does not appear greater with
Cordarone than with many other agents used in this population, the effects are prolonged when
Even in patients at high risk of arrhythmic death, in whom the toxicity of Cordarone is an
acceptable risk, Cordarone poses major management problems that could be life-threatening in
a population at risk of sudden death, so that every effort should be made to utilize alternative
The difficulty of using Cordarone effectively and safely itself poses a significant risk to patients.
Patients with the indicated arrhythmias must be hospitalized while the loading dose of Cordarone
is given, and a response generally requires at least one week, usually two or more. Because
absorption and elimination are variable, maintenance-dose selection is difficult, and it is not
unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of
192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at
least temporary discontinuation because of adverse effects, and several series have reported 15 to
20% overall frequencies of discontinuation due to adverse reactions. The time at which a
previously controlled life-threatening arrhythmia will recur after discontinuation or dose
adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk
during this time and may need prolonged hospitalization. Attempts to substitute other
antiarrhythmic agents when Cordarone must be stopped will be made difficult by the gradually,
but unpredictably, changing amiodarone body burden. A similar problem exists when Cordarone
is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.
In the National Heart, Lung and Blood Institute�s Cardiac Arrhythmia Suppression Trial
(CAST), a long-term, multi-centered, randomized, double-blind study in patients with
asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions
more than six days but less than two years previously, an excessive mortality or non-fatal cardiac
arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that
seen in patients assigned to matched placebo-treated groups (22/725). The average duration of
treatment with encainide or flecainide in this study was ten months.
Cordarone therapy was evaluated in two multi-centered, randomized, double-blind, placebocontrolled
trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia
Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-
MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular
arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses
of 200 to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those
randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long
loading dose schedules. Intent-to-treat all-cause mortality results were as follows:
These data are consistent with the results of a pooled analysis of smaller, controlled studies
involving patients with structural heart disease (including myocardial infarction).
There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients
treated with oral Cordarone with or without initial I.V. therapy. Findings have included pulmonary
infiltrates on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some
cases have progressed to respiratory failure and/or death.
Cordarone (amiodarone HCl) Tablets may cause a clinical syndrome of cough and progressive dyspnea
accompanied by functional, radiographic, gallium-scan, and pathological data consistent with
pulmonary toxicity, the frequency of which varies from 2 to 7% in most published reports, but is as
high as 10 to 17% in some reports. Therefore, when Cordarone therapy is initiated, a baseline chest Xray
and pulmonary-function tests, including diffusion capacity, should be performed. The patient
should return for a history, physical exam, and chest X-ray every 3 to 6 months.
Pulmonary toxicity secondary to Cordarone seems to result from either indirect or direct toxicity as
represented by hypersensitivity pneumonitis or interstitial/alveolar pneumonitis, respectively.
Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops.
Hypersensitivity pneumonitis usually appears earlier in the course of therapy, and rechallenging these
patients with Cordarone results in a more rapid recurrence of greater severity.
Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when
a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted
and Cordarone therapy discontinued in these patients.
Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or
phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis
or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to
inhibition of phospholipase, will be present in most cases of Cordarone-induced pulmonary toxicity;
however, these changes also are present in approximately 50% of all patients on Cordarone therapy.
These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of
Cordarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or,
preferably, to withdrawal of the Cordarone to establish reversibility, especially if other acceptable
antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in
symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a
clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve
within two to four months. According to some experts, steroids may prove beneficial. Prednisone in
doses of 40 to 60 mg/day or equivalent doses of other steroids have been given and tapered over the
course of several weeks depending upon the condition of the patient. In some cases rechallenge with
Cordarone at a lower dose has not resulted in return of toxicity. Reports suggest that the use of lower
loading and maintenance doses of Cordarone are associated with a decreased incidence of Cordaroneinduced
In a patient receiving Cordarone, any new respiratory symptoms should suggest the possibility of
pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with
diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high
sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity
approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be
performed as part of the diagnostic workup.
Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in
patients with life-threatening arrhythmias, discontinuation of Cordarone therapy due to suspected druginduced
pulmonary toxicity should be undertaken with caution, as the most common cause of death in
these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes
of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary,
respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing Cordarone in these
patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may
be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy
If a diagnosis of Cordarone-induced hypersensitivity pneumonitis is made, Cordarone should be
discontinued, and treatment with steroids should be instituted. If a diagnosis of Cordarone-induced
interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably,
Cordarone discontinued or, at a minimum, reduced in dosage. Some cases of Cordarone-induced
interstitial/alveolar pneumonitis may resolve following a reduction in Cordarone dosage in conjunction
with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in
return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe
alveolar damage) the pulmonary lesions have not been reversible.
Cordarone, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia, a
risk that may be enhanced by the presence of concomitant antiarrhythmics. Exacerbation has been
reported in about 2 to 5% in most series, and has included new ventricular fibrillation, incessant
ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia
associated with QTc prolongation (torsades de pointes [TdP]). In addition, Cordarone has caused
symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients.
Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have
been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when
fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See �Drug
Interactions, Other reported interactions with amiodarone�.)
The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be
based on a careful assessment of the potential risks and benefits of doing so for each patient.
A careful assessment of the potential risks and benefits of administering Cordarone must be made in
patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of
arrhythmia in these patients.
Elevations of hepatic enzyme levels are seen frequently in patients exposed to Cordarone and in most
cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an
elevated baseline, discontinuation of Cordarone or dosage reduction should be considered. In a few
cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or
cirrhosis. Hepatic failure has been a rare cause of death in patients treated with Cordarone.
Loss of Vision
Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been
reported in patients treated with amiodarone. In some cases, visual impairment has progressed to
permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of
therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual
impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt
ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for reevaluation
of Cordarone therapy. The risks and complications of antiarrhythmic therapy with
Cordarone must be weighed against its benefits in patients whose lives are threatened by cardiac
arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is
recommended during administration of Cordarone. (See �ADVERSE REACTIONS�).
Neonatal Hypo- or Hyperthyroidism
Cordarone can cause fetal harm when administered to a pregnant woman. Although Cordarone use
during pregnancy is uncommon, there have been a small number of published reports of congenital
goiter/hypothyroidism and hyperthyroidism. If Cordarone is used during pregnancy, or if the patient
becomes pregnant while taking Cordarone, the patient should be apprised of the potential hazard to the
In general, Cordarone (amiodarone HCl) Tablets should be used during pregnancy only if the potential
benefit to the mother justifies the unknown risk to the fetus.
In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9
times, respectively, the maximum recommended human maintenance dose*) had no adverse effects on
the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human
maintenance dose*) caused abortions in greater than 90% of the animals. In the rat, doses of
50 mg/kg/day or more were associated with slight displacement of the testes and an increased
incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal
body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption.
(These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human
maintenance dose.*) Adverse effects on fetal growth and survival also were noted in one of two strains
of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human
*600 mg in a 50 kg patient (doses compared on a body surface area basis)
Impairment of Vision
Optic Neuropathy and/or Neuritis
Cases of optic neuropathy and optic neuritis have been reported (see �WARNINGS�).
Corneal microdeposits appear in the majority of adults treated with Cordarone. They are usually
discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred
vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or
termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or
discontinue treatment (see �ADVERSE REACTIONS�).
Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral
neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and
Cordarone has induced photosensitization in about 10% of patients; some protection may be afforded
by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray
discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion
or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy.
Cordarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause
increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in
clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because
of its release of inorganic iodine, or perhaps for other reasons, Cordarone can cause either
hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and
periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid
nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of Cordarone and its
metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests
may persist for several weeks or even months following Cordarone withdrawal.
Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series.
This condition may be identified by relevant clinical symptoms and particularly by elevated serum
TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values
may be normal. Hypothyroidism is best managed by Cordarone dose reduction and/or thyroid hormone
supplement. However, therapy must be individualized, and it may be necessary to discontinue
Cordarone (amiodarone HCl) Tablets in some patients.
Hyperthyroidism occurs in about 2% of patients receiving Cordarone, but the incidence may be higher
among patients with prior inadequate dietary iodine intake. Cordarone-induced hyperthyroidism
usually poses a greater hazard to the patient than hypothyroidism because of the possibility of
arrhythmia breakthrough or aggravation, which may result in death. In fact, IF ANY NEW SIGNS OF
ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE
CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs,
accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum
T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat
TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since
arrhythmia breakthroughs may accompany Cordarone-induced hyperthyroidism, aggressive medical
treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone. The
institution of antithyroid drugs, �-adrenergic blockers and/or temporary corticosteroid therapy may be
necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced
thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland.
Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with
amiodarone-induced hyperthyroidism. Experience with thyroid surgery in this setting is extremely
limited, and this form of therapy runs the theoretical risk of inducing thyroid storm. Cordarone-induced
hyperthyroidism may be followed by a transient period of hypothyroidism.
Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing
general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial
depressant and conduction effects of halogenated inhalational anesthetics.
Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary
bypass during open-heart surgery in patients receiving Cordarone have been reported. The relationship
of this event to Cordarone therapy is unknown.
Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been
reported in patients receiving Cordarone therapy who have undergone either cardiac or noncardiac
surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the
outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the
determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on
Information for Patients
Patients should be instructed to read the accompanying Medication Guide each time they refill their
prescription. The complete text of the Medication Guide is reprinted at the end of this document.
Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high
maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver
enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of
Cordarone or discontinuing therapy.
Cordarone alters the results of thyroid-function tests, causing an increase in serum T4 and
serum reverse T3, and a decline in serum T3 levels. Despite these biochemical changes, most patients
remain clinically euthyroid.
Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group,
specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in
both the liver and intestines (see �CLINICAL PHARMACOLOGY, Pharmacokinetics�).
Amiodarone is also known to be an inhibitor of CYP3A4. Therefore, amiodarone has the potential for
interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4. While
only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the
potential for other interactions should be anticipated. This is especially important for drugs associated
with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be
reassessed and, where appropriate, plasma concentration measured. In view of the long and variable
half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication,
but also with drugs administered after discontinuation of amiodarone.
Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit
CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone.
Reported examples include the following:
Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient
taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone
concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no
evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum
concentration during concomitant protease inhibitor therapy should be considered.
Histamine H2 antagonists:
Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels.
Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%,
and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated
metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of
amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone.
This information should be considered when changing from intravenous amiodarone to oral
amiodarone (see �DOSAGE AND ADMINISTRATION�).
Amiodarone may suppress certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6,
and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which
are metabolized by those CYP450 enzymes. Reported examples of this interaction include the
Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been
reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated
creatinine, despite reduction in dose of cyclosporine.
HMG-CoA reductase inhibitors:
Simvastatin (CYP3A4 substrate) in combination with amiodarone has been associated with reports of
Cardiac glycosides: In patients receiving digoxin therapy, administration of oral amiodarone
regularly results in an increase in the serum digoxin concentration that may reach toxic levels with
resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin
concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis
therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If
digitalis treatment is continued, serum levels should be closely monitored and patients observed for
clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as
Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have
been used concurrently with oral amiodarone.
There have been case reports of increased steady-state levels of quinidine, procainamide, and
phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone
levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by
33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days
increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%,
respectively. Quinidine and procainamide doses should be reduced by one-third when either is
administered with amiodarone. Plasma levels of flecainide have been reported to increase in the
presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these
drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at
a lower than usual dose with careful monitoring.
Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with
life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or
incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously
administered agents should be reduced by 30 to 50% several days after the addition of amiodarone,
when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic
agent should be reviewed after the effects of amiodarone have been established, and discontinuation
ordinarily should be attempted. If the treatment is continued, these patients should be particularly
carefully monitored for adverse effects, especially conduction disturbances and exacerbation of
tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional
antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual
Amiodarone should be used with caution in patients receiving beta-receptor blocking agents (e.g.,
propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4
substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia,
sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a
pacemaker in patients with severe bradycardia or sinus arrest.
Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost
always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the
concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after
3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and
prothrombin times should be monitored closely.
Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating
the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and
potential decrease in efficacy. Reported examples of this interaction include the following:
Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral
amiodarone has been shown to result in decreases in serum concentrations of amiodarone and
Other substances, including herbal preparations:
St. John�s Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for
CYP3A4, there is the potential that the use of St. John�s Wort in patients receiving amiodarone could
result in reduced amiodarone levels.
Other reported interactions with amiodarone:
Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia,
and decreased cardiac output.
Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4
substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has
been reported with concomitant administration of intravenous amiodarone.
Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6.
Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels
Disopyramide increases QT prolongation which could cause arrhythmia.
Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There
have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when
fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See
�WARNINGS, Worsened Arrhythmia�.)
Hemodynamic and electrophysiologic interactions have also been observed after concomitant
administration with propranolol, diltiazem, and verapamil.
Volatile Anesthetic Agents (See �PRECAUTIONS, Surgery, Volatile Anesthetic Agents.�)
In addition to the interactions noted above, chronic (>2 weeks) oral Cordarone administration impairs
metabolism of phenytoin, dextromethorphan, and methotrexate.
USE IN SPECIFIC POPULATIONS
Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with
hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and
during Cordarone therapy. Use caution when coadministering Cordarone with drugs which may induce
hypokalemia and/or hypomagnesemia.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence
of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was
greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times
the maximum recommended human maintenance dose*).
Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative.
In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks
prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4
times the maximum recommended human maintenance dose*).
*600 mg in a 50 kg patient (dose compared on a body surface area basis)
Pregnancy: Pregnancy Category D
See �WARNINGS, Neonatal Hypo- or Hyperthyroidism.�
Labor and Delivery
It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed
adverse effects. Preclinical studies in rodents have not shown any effect of Cordarone on the duration
of gestation or on parturition.
Cordarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk,
suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug.
Nursing offspring of lactating rats administered Cordarone have been shown to be less viable and have
reduced body-weight gains. Therefore, when Cordarone therapy is indicated, the mother should be
advised to discontinue nursing.
The safety and effectiveness of Cordarone (amiodarone HCl) Tablets in pediatric patients have not
Clinical studies of Cordarone Tablets did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
Adverse reactions have been very common in virtually all series of patients treated with Cordarone for
ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about
three-fourths of all patients and causing discontinuation in 7 to 18%. The most serious reactions are
pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see �WARNINGS�), but
other adverse effects constitute important problems. They are often reversible with dose reduction or
cessation of Cordarone treatment. Most of the adverse effects appear to become more frequent with
continued treatment beyond six months, although rates appear to remain relatively constant beyond one
year. The time and dose relationships of adverse effects are under continued study.
Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise
and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral
neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or
discontinuation (see �PRECAUTIONS�).
Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in
about 25% of patients but rarely require discontinuation of drug. These commonly occur during highdose
administration (i.e., loading dose) and usually respond to dose reduction or divided doses.
Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing
to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma,
lens opacities, and macular degeneration have been reported. (See �WARNINGS.�)
Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug
for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes.
Vision is rarely affected and drug discontinuation is rarely needed.
Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most
common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug
discontinuation is not usually necessary. Prolonged exposure to Cordarone occasionally results in a
blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of
drug but is of cosmetic importance only.
Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon
occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage
reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac
conduction abnormalities occur infrequently and are reversible on discontinuation of drug.
The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515
days (mean 441.3 days).
<>bThe following side effects were each reported in 10 to 33% of patients:
Gastrointestinal: Nausea and vomiting.
The following side effects were each reported in 4 to 9% of patients:
Dermatologic: Solar dermatitis/photosensitivity.
Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination,
abnormal gait/ataxia, dizziness, paresthesias.
Gastrointestinal: Constipation, anorexia.
Ophthalmologic: Visual disturbances.
Hepatic: Abnormal liver-function tests.
Respiratory: Pulmonary inflammation or fibrosis.
The following side effects were each reported in 1 to 3% of patients:
The following side effects were each reported in less than 1% of patients:
Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction
In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment
with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included
pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and
elevation of liver enzymes. Other symptoms causing discontinuations less often included visual
disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism.
There have been cases, some fatal, of Cordarone overdose.
In addition to general supportive measures, the patient�s cardiac rhythm and blood pressure should be
monitored, and if bradycardia ensues, a �-adrenergic agonist or a pacemaker may be used.
Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or
vasopressor agents. Neither Cordarone nor its metabolite is dialyzable.
The acute oral LD50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg.
DOSAGE AND ADMINISTRATION
BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING
SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY
MONITORED, CORDARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO
ARE EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS WHO
ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF CORDARONE
THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF
ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT.
In order to insure that an antiarrhythmic effect will be observed without waiting several months,
loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone has
not been determined. Because of the food effect on absorption, Cordarone should be administered
consistently with regard to meals (see �CLINICAL PHARMACOLOGY�). Individual patient
titration is suggested according to the following guidelines:
For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically
unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading
phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of
the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be
performed in a hospital setting. Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks
(occasionally longer) until initial therapeutic response occurs. (Administration of Cordarone in divided
doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal
intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of
recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with
reduction in complex and total ventricular ectopic beats.
Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the
intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be
taken during treatment with oral amiodarone (see �PRECAUTIONS, Drug Interactions�).
Upon starting Cordarone therapy, an attempt should be made to gradually discontinue prior
antiarrhythmic drugs (see section on �Drug Interactions�). When adequate arrhythmia control is
achieved, or if side effects become prominent, Cordarone dose should be reduced to 600 to 800 mg/day
for one month and then to the maintenance dose, usually 400 mg/day (see �CLINICAL
PHARMACOLOGY�Monitoring Effectiveness�). Some patients may require larger maintenance
doses, up to 600 mg/day, and some can be controlled on lower doses. Cordarone may be administered
as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each
patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as
assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient
tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly
severe toxicity (see �CLINICAL PHARMACOLOGY�).
The lowest effective dose should be used to prevent the occurrence of side effects. In all instances,
the physician must be guided by the severity of the individual patient�s arrhythmia and response
When dosage adjustments are necessary, the patient should be closely monitored for an extended
period of time because of the long and variable half-life of Cordarone and the difficulty in predicting
the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below:
Cordarone (amiodarone HCl) Tablets are available in bottles of 60 tablets and in Redipak cartons
containing 100 tablets (10 blister strips of 10) as follows:
200 mg, NDC 0008-4188, round, convex-faced, pink tablets with a raised �C� and marked �200� on
one side, with reverse side scored and marked �WYETH� and �4188.�
STORAGE AND HANDLING
Keep tightly closed.
Store at room temperature, approximately 25�C (77�F).
Protect from light.
Dispense in a light-resistant, tight container.
Use carton to protect contents from light.
Cordarone is a registered trademark of Sanofi-Synthelabo.
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