AMIODARONE
DESCRIPTION:
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.
C25H29I2NO3.HCl : Molecular Weight: 681.8
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.
ACTIONS/CLINICAL PHARMACOLOGY:
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
alpha- and beta- 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
"WARNINGS").
HEMODYNAMICS
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.
PHARMACOKINETICS
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.
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, has been identified in man;
it accumulates to an even greater extent in almost all tissues. The
pharmacological activity of this metabolite, however, is not known. During
chronic treatment, the plasma ratio of metabolite to parent compound is
approximately one.
The main route of elimination is via hepatic excretion into bile, and some
enterohepatic recirculation may occur. However, its kinetics in patients with
hepatic insufficiency have not been elucidated. Cordarone has a very low plasma
clearance with negligible renal excretion, so that it does not appear necessary
to modify the dose in patients with renal failure. In patients with renal
impairment, the plasma concentration of Cordarone is not elevated. Neither
Cordarone nor its metabolite is dialyzable.
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 the 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 used.
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 of recurrence.
PHARMACODYNAMICS
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.
MONITORING EFFECTIVENESS
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 some aspects:
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 stimulation
(PES).
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 tolerated.
1. Recurrent ventricular fibrillation.
2. Recurrent hemodynamically unstable ventricular tachycardia.
As is the case for other antiarrhythmic agents, there is no evidence from
controlled trials that the use of Cordarone 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 the hospital.
CONTRAINDICATIONS:
Cordarone is contraindicated in severe sinus-node dysfunction, causing marked
sinus bradycardia; second- and 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.
WARNINGS:
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 THEY OCCUR.
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 AGENTS
FIRST.
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.
MORTALITY
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.
The applicability of these results to other populations (e.g., those without
recent myocardial infarctions) or to Cordarone-treated patients is uncertain.
While definitive controlled trials with Cordarone are in progress, pooled
analysis of small controlled studies in patients with structural heart disease
(including post-myocardial infarction) have not shown excess mortality in the
Cordarone-treated population.
PULMONARY TOXICITY
Cordarone 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 Xray every 3 to 6
months.
Preexisting pulmonary disease does not appear to increase the risk of developing
pulmonary toxicity; however, these patients have a poorer prognosis if pulmonary
toxicity does develop.
Pulmonary toxicity secondary to Cordarone seems to result from either indirect
or direct toxicity as represented by hypersensitivity pneumonitis or
interstitial/alveolar pneumonitis, respectively.
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 Xray
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. Recent reports suggest that the use of lower loading and maintenance
doses of Cordarone are associated with a decreased incidence of Cordarone-
induced pulmonary toxicity.
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 drug-induced 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 is available.
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.
WORSENED ARRHYTHMIA
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 QT prolongation (Torsade de Pointes). In
addition, Cordarone has caused symptomatic bradycardia or sinus arrest with
suppression of escape foci in 2 to 4% of patients.
LIVER INJURY
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 re-evaluation 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.") PREGNANCY: PREGNANCY CATEGORY D
Cordarone has been shown to be embryotoxic (increased fetal resorption and
growth retardation) in the rat when given orally at a dose of 200 mg/kg/day (18
times the maximum recommended maintenance dose). Similar findings have been
noted in one strain of mice at a dose of 5 mg/kg/day (approximately 1/2 the
maximum recommended maintenance dose) and higher, but not in a second strain nor
in the rabbit at doses up to 100 mg/kg/day (9 times the maximum recommended
maintenance dose).
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
fetus.
In general, Cordarone should be used during pregnancy only if the potential
benefit to the mother justifies the unknown risk to the fetus.
PRECAUTIONS:
IMPAIRMENT OF VISION
Optic Neuropathy And/Or Neuritis
Cases of optic neuropathy and optic neuritis have been reported (see
"WARNINGS").
Corneal Microdeposits
Corneal microdeposits appear in the majority of adults treated with
Cordarone(R).
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").
PHOTOSENSITIVITY
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.
THYROID ABNORMALITIES
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 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. 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, beta-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.
SURGERY
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, rare 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 Cordarone.
LABORATORY TESTS
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.
DRUG INTERACTIONS
Although only a small number of drug-drug interactions with Cordarone have been
explored formally, most of these have shown such an interaction. The potential
for other interactions should be anticipated, particularly for drugs with
potentially 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 Cordarone, potential for drug
interactions exists not only with concomitant medication but also with drugs
administered after discontinuation of Cordarone.
Cyclosporine
Concomitant use of amiodarone and cyclosporine has been reported to produce
persistently elevated plasma concentrations of cyclosporine resulting in
elevated creatinine, despite reduction in dose of cyclosporine.
Digitalis
Administration of Cordarone to patients receiving digoxin therapy regularly
results in an increase in the serum digoxin concentration that may reach toxic
levels with resultant clinical toxicity. ON INITIATION OF CORDARONE, 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 well.
Anticoagulants
Potentiation of warfarin-type anticoagulant response is almost always seen in
patients receiving Cordarone and can result in serious or fatal bleeding. THE
DOSE OF THE ANTICOAGULANT SHOULD BE REDUCED BY ONE-THIRD TO ONE-HALF, AND
PROTHROMBIN TIMES SHOULD BE MONITORED CLOSELY.
Antiarrhythmic Agents
Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and
phenytoin, have been used concurrently with Cordarone.
There have been case reports of increased steady- state levels of quinidine,
procainamide, and phenytoin during concomitant therapy with Cordarone. In
general, any added antiarrhythmic drug should be initiated at a lower than usual
dose with careful monitoring.
In general, combination of Cordarone 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
Cordarone. During transfer to Cordarone the dose levels of previously
administered agents should be reduced by 30 to 50% several days after the
addition of Cordarone, when arrhythmia suppression should be beginning. The
continued need for the other antiarrhythmic agent should be reviewed after the
effects of Cordarone 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 Cordarone is continued. In
Cordarone-treated patients who require additional antiarrhythmic therapy, the
initial dose of such agents should be approximately half of the usual
recommended dose.
Cordarone should be used with caution in patients receiving beta-blocking agents
or calcium antagonists because of the possible potentiation of bradycardia,
sinus arrest, and AV block; if necessary, Cordarone can continue to be used
after insertion of a pacemaker in patients with severe bradycardia or sinus
arrest.
SUMMARY OF DRUG INTERACTIONS WITH CORDARONE
Interaction
-------------------------------------------------------------------------------------------------
Recommended
Concomitant Onset Dose Reduction
of Concomitant
Drug (days) Magnitude Drug
------------------------------------------------------------------------------------------------------------------
down arrow
Warfarin 3 to 4 Increases prothrombin time by 100% 1/3 to 1/2
down arrow
Digoxin 1 Increases serum concentration by 70% 1/2
down arrow
Quinidine 2 Increases serum concentration by 33% 1/3 to 1/2
(or discontinue)
down arrow
Procainamide <7 Increases plasma concentration by 1/3
55%, NAPA* concentration by 33% (or discontinue)
-----------------------------------------------------------------------------------------------------------------------
*NAPA = n-acetyl procainamide.
----------------------------------------------------------------------------
ELECTROLYTE DISTURBANCES
Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in
patients with hypokalemia, any potassium or magnesium deficiency should be
corrected before instituting Cordarone therapy.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Cordarone reduced fertility of male and female rats at a dose level of 90
mg/kg/day (8 X highest recommended human maintenance dose).
Cordarone caused 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 of Cordarone tested, i.e., 5 mg/kg/day or approximately equal to 1/2 the
highest recommended human maintenance dose. Mutagenicity studies (Ames,
micronucleus, and lysogenic tests) with Cordarone were negative.
PREGNANCY: PREGNANCY CATEGORY D
See "WARNINGS."
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.
NURSING MOTHERS
Cordarone is 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.
PEDIATRIC USE
The safety and effectiveness of Cordarone in pediatric patients have not been
established.
DRUG INTERACTIONS:
Although only a small number of drug-drug interactions with Cordarone have been
explored formally, most of these have shown such an interaction. The potential
for other interactions should be anticipated, particularly for drugs with
potentially 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 Cordarone, potential for drug
interactions exists not only with concomitant medication but also with drugs
administered after discontinuation of Cordarone.
Cyclosporine
Concomitant use of amiodarone and cyclosporine has been reported to produce
persistently elevated plasma concentrations of cyclosporine resulting in
elevated creatinine, despite reduction in dose of cyclosporine.
Digitalis
Administration of Cordarone to patients receiving digoxin therapy regularly
results in an increase in the serum digoxin concentration that may reach toxic
levels with resultant clinical toxicity. ON INITIATION OF CORDARONE, 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 well.
Anticoagulants
Potentiation of warfarin-type anticoagulant response is almost always seen in
patients receiving Cordarone and can result in serious or fatal bleeding. THE
DOSE OF THE ANTICOAGULANT SHOULD BE REDUCED BY ONE-THIRD TO ONE-HALF, AND
PROTHROMBIN TIMES SHOULD BE MONITORED CLOSELY.
Antiarrhythmic Agents
Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and
phenytoin, have been used concurrently with Cordarone.
There have been case reports of increased steady- state levels of quinidine,
procainamide, and phenytoin during concomitant therapy with Cordarone. In
general, any added antiarrhythmic drug should be initiated at a lower than usual
dose with careful monitoring.
In general, combination of Cordarone 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
Cordarone. During transfer to Cordarone the dose levels of previously
administered agents should be reduced by 30 to 50% several days after the
addition of Cordarone, when arrhythmia suppression should be beginning. The
continued need for the other antiarrhythmic agent should be reviewed after the
effects of Cordarone 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 Cordarone is continued. In
Cordarone-treated patients who require additional antiarrhythmic therapy, the
initial dose of such agents should be approximately half of the usual
recommended dose.
Cordarone should be used with caution in patients receiving beta-blocking agents
or calcium antagonists because of the possible potentiation of bradycardia,
sinus arrest, and AV block; if necessary, Cordarone can continue to be used
after insertion of a pacemaker in patients with severe bradycardia or sinus
arrest.
SUMMARY OF DRUG INTERACTIONS WITH CORDARONE
Interaction Recommended
---------------------------------------------------Dose
Reduction
Concomitant Onset of
Concomitant
Drug (days) Magnitude Drug
-------------------------------------------------------------------------------------------------------------------------
Warfarin 3 to 4 Increases prothrombin time by 100% 1/3 to 1/2
Digoxin 1 Increases serum concentration by 70% 1/2
Quinidine 2 Increases serum concentration by 33% 1/3 to 1/2
(or
discontinue)
Procainamide <7 Increases plasma concentration by 1/3
55%, NAPA* concentration by 33% (or
discontinue)
*NAPA = n-acetyl procainamide.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
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.
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 high-dose 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.
Hepatitis, cholestatic hepatitis, cirrhosis, epididymitis, vasculitis,
pseudotumor cerebri, thrombocytopenia, and angioedema also have been reported in
patients receiving Cordarone.
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).
THE FOLLOWING SIDE EFFECTS WERE 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:
Thyroid: Hypothyroidism, hyperthyroidism.
Neurologic: Decreased libido, insomnia, headache, sleep disturbances.
Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node
dysfunction.
Gastrointestinal: Abdominal pain.
Hepatic: Nonspecific hepatic disorders.
Other: Flushing, abnormal taste and smell, edema, abnormal salivation,
coagulation abnormalities.
THE FOLLOWING SIDE EFFECTS WERE EACH REPORTED IN LESS THAN 1% OF PATIENTS:
Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension,
and cardiac conduction abnormalities.
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.
OVERDOSAGE:
There have been a few reported cases of Cordarone overdose in which 3 to 8 grams
were taken. There were no deaths or permanent sequelae. Animal studies indicate
that Cordarone has a high oral LD80 (>3,000 mg/kg).
In addition to general supportive measures, the patient's cardiac rhythm and
blood pressure should be monitored, and if bradycardia ensues, a beta-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.
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. 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.
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 "ACTIONS/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
ACTIONS/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 TO THERAPY.
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:
Loading Dose (Daily) Adjustment and Maintenance
Dose (Daily)
---------------------------------------------------------------------------------------------------------------
Ventricular Arrhythmias 1 to 3 weeks approx. 1 month usual maintenance
---------------------------------------------------------------------------------------------------------------
800 to 1,600 mg 600 to 800 mg 400 mg