Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1256
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Cordarone (Tablet)
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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 . 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 . 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:
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Cordarone (amiodarone HCl) 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.
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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: 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 .<br/>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.<br/>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. 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 (C) 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
(T) by 37%. The mean AUC and mean Cof
desethylamiodarone increased by 55% (range 58 to 101%) and 32% (range
4 to 84%), respectively, but there was no change in the Tin 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 dataare 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 correlatesmore closely with DEA accumulation over time than with amiodarone
accumulation. 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. 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 Cand 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 tfrom about 20 to 47 days. In patients with severe
left ventricular dysfunction, the pharmacokinetics of amiodarone are
not significantly altered but the terminal disposition tof 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 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.<br/>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.<br/>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: 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 enoughto 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.
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Cordarone is contraindicated in patients with cardiogenic
shock; 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.
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Cordarone (amiodarone HCl) Tablets
are available in bottles of 60 tablets as follows: 200 mg, NDC 0008-4188-04, round, convex-faced, pink tablets
with a raised���C���and marked���200���on
one side, with reverse side scored and marked���WYETH���and���4188.��� Keep tightly closed. Store at Controlled Room Temperature, 20��to 25��C (68��to
77��F). Protect from light. Dispense in a light-resistant,
tight container.
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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.
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Impairment of Vision:<br/>Optic Neuropathy and/or Neuritis: Cases of optic neuropathy and optic neuritis have
been reported .<br/>Corneal Microdeposits: 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 .<br/>Neurologic: 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 incomplete.<br/>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 thosewith excessive sun exposure,
and may be related to cumulative dose and duration of therapy.<br/>Thyroid Abnormalities: Cordarone inhibits peripheral conversion of thyroxine
(T) to triiodothyronine (T) and may cause
increased thyroxine levels, decreased Tlevels, and increased
levels of inactive reverse T(rT) 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 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 thyrotoxicosis and/or arrhythmia breakthrough
or aggravation, all of which may result in death. There have been
reports of death associated with amiodarone-induced thyrotoxicosis.
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 TRIA, and further
elevations of serum T, 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 ofCordarone. 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. Cordarone-induced hyperthyroidism
may befollowed by a transient period of hypothyroidism . When aggressive treatment of amiodarone-induced
thyrotoxicosis has failed or amiodarone cannot be discontinued because
it is the only drug effective against the resistant arrhythmia, surgical
management may be an option. Experience with thyroidectomy as a treatment
for amiodarone-induced thyrotoxicosis is limited, and this form of
therapy could induce thyroid storm. Therefore, surgical and anesthetic
management require careful planning. There have
been postmarketing reports of thyroid nodules/thyroid cancer in patients
treated with Cordarone. In some instances hyperthyroidism was also
present (see���WARNINGS���and���ADVERSE
REACTIONS���).<br/>Surgery: 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 FiOand the determinants of oxygen delivery to the
tissues (e.g., SaO, PaO) be closely monitored
in patients on Cordarone.<br/>Corneal Refractive Laser Surgery: Patients should be advised that most manufacturers
of corneal refractive laser surgery devices contraindicate that procedure
in patients taking Cordarone.<br/>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.<br/>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 Tand serum reverse
T, and a decline in serum Tlevels. Despite
these biochemical changes, most patients remain clinically euthyroid.<br/>Drug Interactions: 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 . Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein.
Therefore, amiodarone has the potential for interactions with drugs
or substances that may be substrates, inhibitors or inducers of CYP3A4
and substrates of p-glycoprotein. While only alimited 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 withdrugs 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:<br/>Protease inhibitors:: 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.<br/>Histamine Hantagonists:: Loratadine, a
non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT
interval prolongation and torsade de pointes have been reported with
the co-administration of loratadine and amiodarone.<br/>Histamine Hantagonists:: Cimetidine inhibits
CYP3A4 and can increase serum amiodarone levels.<br/>Antidepressants:: Trazodone, an
antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation
and torsade de pointes have been reported with the co-administration
of trazodone and amiodarone.<br/>Other substances:: Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and
Cby 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 . Amiodarone
inhibits p-glycoprotein and 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 or are substrates of p-glycoprotein. Reported examples of
this interaction include the following:<br/>Immunosuppressives:: 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.<br/>HMG-CoA reductase inhibitors:: HMG-CoA reductase inhibitors that are CYP3A4 substrates
(including simvastatin and atorvastatin) in combination with amiodarone
have been associated with reports of myopathy/rhabdomyolysis. When co-administered with amiodarone, lower starting and
maintenance doses of these agents should be considered.<br/>Cardiovasculars::<br/>Antibiotics:: 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 desethylamiodarone.<br/>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.<br/>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
and t. 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 . In addition to the interactions
noted above, chronic (>2 weeks) oral Cordarone administration impairs metabolism of phenytoin,
dextromethorphan, and methotrexate.<br/>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 and
during Cordarone therapy. Use caution when coadministering Cordarone
with drugs which may induce hypokalemia and/or hypomagnesemia.<br/>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 0.08times 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)<br/>Pregnancy: Pregnancy Category D: See���WARNINGS, Neonatal Hypo- or Hyperthyroidism���.<br/>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.<br/>Nursing Mothers: 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.<br/>Pediatric Use: The safety and effectiveness of Cordarone Tablets
in pediatric patients have not been established.<br/>Geriatric Use: 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.
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| dailymed-instance:overdosag... |
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 LDof
amiodarone HCl in mice and rats is greater than 3,000 mg/kg.
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| dailymed-instance:genericMe... |
Amiodarone Hydrochloride
|
| dailymed-instance:fullName |
Cordarone (Tablet)
|
| dailymed-instance:adverseRe... |
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 pulmonarytoxicity, exacerbation
of arrhythmia, and rare serious liver injury , 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 . 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. 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).<br/>The following side effects were each reported in 10 to 33%
of patients:: Gastrointestinal: Nausea and vomiting.<br/>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.<br/>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.<br/>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.<br/>Postmarketing Reports: In postmarketing surveillance, hypotension (sometimes
fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including
shock), angioedema, urticaria, hepatitis, cholestatic hepatitis, cirrhosis,
pancreatitis, renal impairment, renal insufficiency, acute renal failure,
bronchospasm, possibly fatal respiratory disorders (including distress,
failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia
(possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia,
pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage,
pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia
and bradykinesia (sometimes reversible with discontinuation of therapy),
syndrome of inappropriate antidiuretic hormone secretion (SIADH),
thyroid nodules/thyroid cancer, toxicepidermal necrolysis (sometimes
fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative
dermatitis, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic
anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis,
granuloma, myopathy, muscle weakness, rhabdomyolysis, hallucination,
confusional state, disorientation, delirium, epididymitis, and impotence,
also have been reported with amiodarone therapy.
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| dailymed-instance:warning |
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.<br/>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. Cordarone therapy was evaluated in two
multi-centered, randomized, double-blind, placebo-controlled 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).<br/>Pulmonary Toxicity: There have been post-marketing 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 and/or mass on X-ray, pulmonary alveolar hemorrhage, bronchospasm,
wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases
have progressed to respiratory failure and/or death. Post-marketing
reports describe cases of pulmonary toxicity in patients treated with
low doses of Cordarone; however, reports suggest that the use of lower
loading and maintenance doses of Cordarone are associated with a decreased
incidence of Cordarone-induced pulmonarytoxicity. Cordarone 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 X-ray and pulmonary-function tests,
including diffusion capacity, should be performed. The patient shouldreturn 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. 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.<br/>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 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.<br/>Implantable Cardiac Devices: In patients with implanted defibrillators or pacemakers,
chronic administration of antiarrhythmic drugs may affect pacing or
defibrillating thresholds. Therefore, at the inception of and during
amiodarone treatment, pacing and defibrillation thresholds should
be assessed.<br/>Thyrotoxicosis: Cordarone-induced hyperthyroidism may result in thyrotoxicosis
and/or the possibility of arrhythmia breakthrough or aggravation.
There have been reports of death associated with amiodarone-induced
thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY
OF HYPERTHYROIDISM SHOULD BE CONSIDERED .<br/>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.<br/>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. .<br/>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 apprisedof the potential hazard to the fetus. In general, Cordarone 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 maintenance dose*). *600 mg
in a 50 kg patient (doses compared on a body surface area basis)
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| dailymed-instance:indicatio... |
Because of its life-threatening side effects and
the substantial management difficulties associated with its use , 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. As is the case for other antiarrhythmic agents,
there is no evidence from controlled trials that the use of Cordarone
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 the hospital.
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Cordarone
|