Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3627
Predicate | Object |
---|---|
rdf:type | |
rdfs:label |
Cordarone (Injection, Solution)
|
dailymed-instance:dosage |
Amiodarone shows considerable interindividual variation
in response. Thus, although a starting dose adequate to suppress life-threatening
arrhythmias is needed, close monitoring with adjustment of dose as needed
is essential. The recommended starting dose of Cordarone I.V. is about 1000 mg
over the first 24 hours of therapy, delivered by the following infusion regimen: After the first
24 hours, the maintenance infusion rate of 0.5 mg/min (720 mg/24
hours) should be continued utilizing a concentration of 1 to 6 mg/mL
(Cordarone I.V. concentrations greater than 2 mg/mL should be administered
via a central venous catheter). In the event of breakthrough episodes of VF
or hemodynamically unstable VT, 150-mg supplemental infusions of Cordarone
I.V. mixed in 100 mL of DW may be administered. Such infusions
should be administered over 10 minutes to minimize the potential for hypotension.
The rate of the maintenance infusion may be increased to achieve effective
arrhythmia suppression. The first 24-hour dose
may be individualized for each patient; however, in controlled clinical trials,
mean daily doses above 2100 mg were associated with an increased risk
of hypotension. The initial infusion rate should not exceed 30 mg/min. Based on the experience from clinical studies of Cordarone
I.V., a maintenance infusion of up to 0.5 mg/min can be cautiously continued
for 2 to 3 weeks regardless of the patient's age, renal function, or
left ventricular function. There has been limited experience in patients receiving
Cordarone I.V. for longer than 3 weeks. The surface properties of solutions containing
injectable amiodarone are altered such that the drop size may be reduced.
This reduction may lead to underdosage of the patient by up to 30% if drop
counter infusion sets are used. Cordarone I.V. must be delivered by a volumetric
infusion pump. Cordarone I.V.
should, whenever possible, be administered through a central venous catheter
dedicated to that purpose. An in-line filter should be used during administration. Cordarone I.V. loading infusions at much higher concentrations
and rates of infusion much faster than recommended have resulted in hepatocellular
necrosis and acute renal failure, leading to death . Cordarone I.V. concentrations greater than 3 mg/mL in
DW have been associated with a high incidence of peripheral vein
phlebitis; however, concentrations of 2.5 mg/mL or less appear to be
less irritating. Therefore, for infusions longer than 1 hour, Cordarone I.V.
concentrations should not exceed 2 mg/mL unless a central venous catheter
is used (see ADVERSE REACTIONS,
Postmarketing Reports). Cordarone
I.V. infusions exceeding 2 hours must be administered in glass or polyolefin
bottles containing DW. Use of evacuated
glass containers for admixing Cordarone I.V. is not recommended
as incompatibility with a buffer in the container may cause precipitation. It is well known that amiodarone adsorbs to polyvinyl chloride
(PVC) tubing and the clinical trial dose administration schedule was designed
to account for this adsorption. All of the clinical trials were conducted
using PVC tubing and its use is therefore recommended. The concentrations
and rates of infusion provided in DOSAGE
AND ADMINISTRATION reflect doses identified in these
studies. Cordarone I.V. has been found to leach out plasticizers, including
DEHP [di-(2-ethylhexyl)phthalate] from intravenous tubing (including PVC tubing).
The degree of leaching increases when infusing Cordarone I.V. at higher concentrations
and lower flow rates than provided in DOSAGE AND ADMINISTRATION. In addition, polysorbate
80, a component of Cordarone I.V., is also known to leach DEHP from PVC . Therefore,
it is important that the recommendations in DOSAGE AND ADMINISTRATION be followed closely. Cordarone I.V. does not need to be protected from light during
administration.<br/>Admixture Incompatibility: Cordarone I.V. in DW is incompatible
with the drugs shown below.<br/>Intravenous to Oral Transition: Patients whose arrhythmias have been suppressed
by Cordarone I.V. may be switched to oral Cordarone. The optimal dose for
changing from intravenous to oral administration of Cordarone will depend
on the dose of Cordarone I.V. already administered, as well as the bioavailability
of oral Cordarone. When changing to oral Cordarone therapy, clinical monitoring
is recommended, particularly for elderly patients. Since
there are some differences between the safety and efficacy profiles of the
intravenous and oral formulations, the prescriber is advised to review the
package insert for oral amiodarone when switching from intravenous to oral
amiodarone therapy. 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 . The following table provides suggested doses of oral Cordarone
to be initiated after varying durations of Cordarone I.V. administration.
These recommendations are made on the basis of a comparable total body amount
of amiodarone delivered by the intravenous and oral routes, based on 50% bioavailability
of oral amiodarone.
|
dailymed-instance:descripti... |
Cordarone Intravenous (Cordarone I.V.) contains amiodarone
HCl (CHINO���HCl),
a class III antiarrhythmic drug. Amiodarone HCl is (2-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone
hydrochloride. Amiodarone HCl has the following structural formula: Amiodarone
HCl is a white to slightly yellow crystalline powder, and is very slightly
soluble in water. It has a molecular weight of 681.78 and contains 37.3% iodine
by weight. Cordarone I.V. is a sterile clear, pale-yellow micellar solution
visually free from particulates. Each milliliter of the Cordarone I.V. formulation
contains 50 mg of amiodarone HCl, 20.2 mg of benzyl alcohol, 100 mg of
polysorbate 80, and water for injection. Cordarone
I.V. contains polysorbate 80, which is known to leach di-(2-ethylhexyl)phthalate
(DEHP) from polyvinylchloride (PVC) .
|
dailymed-instance:clinicalP... |
Mechanisms of Action: Amiodarone is generally considered a class III antiarrhythmic
drug, but it possesses electrophysiologic characteristics of all four Vaughan
Williams classes. Like class I drugs, amiodarone blocks sodium channels at
rapid pacing frequencies, and like class II drugs, it exerts a noncompetitive
antisympathetic action. One of its main effects, with prolonged administration,
is to lengthen the cardiac action potential, a class III effect. The negative
chronotropic effect of amiodarone in nodal tissues is similar to the effect
of class IV drugs. In addition to blocking sodium channels, amiodarone blocks
myocardial potassium channels, which contributes to slowing of conduction
and prolongation of refractoriness. The antisympathetic action and the block
of calcium and potassium channels are responsible for the negative dromotropic
effects on the sinus node and for the slowing of conduction and prolongation
of refractoriness in the atrioventricular (AV) node. Its vasodilatory action
can decrease cardiac workload and consequently myocardial oxygen consumption. Cordarone I.V. administration prolongs intranodal conduction
(Atrial-His, AH) and refractoriness of the atrioventricular node (ERP AVN),
but has little or no effect on sinus cycle length (SCL), refractoriness of
the right atrium and right ventricle (ERP RA and ERP RV), repolarization (QTc),
intraventricular conduction (QRS), and infranodal conduction (His-ventricular,
HV). A comparison of the electrophysiologic effects of Cordarone I.V. and
oral Cordarone is shown in the table below. At higher doses (>10 mg/kg) of Cordarone
I.V., prolongation of the ERP RV and modest prolongation of the QRS have been
seen. These differences between oral and intravenous administration suggest
that the initial acute effects of Cordarone I.V. may be predominantly focused
on the AV node, causing an intranodal conduction delay and increased nodal
refractoriness due to slow channel blockade (class IV activity) and noncompetitive
adrenergic antagonism (class II activity).<br/>Pharmacokinetics and Metabolism: Amiodarone exhibits complex disposition characteristics
after intravenous administration. Peak serum concentrations after single 5 mg/kg
15-minute intravenous infusions in healthy subjects range between 5 and 41 mg/L.
Peak concentrations after 10-minute infusions of 150 mg Cordarone I.V.
in patients with ventricular fibrillation (VF) or hemodynamically unstable
ventricular tachycardia (VT) range between 7 and 26 mg/L. Due to rapid
distribution, serum concentrations decline to 10% of peak values within 30
to 45 minutes after the end of the infusion. In clinical trials, after 48
hours of continued infusions (125, 500, or 1000 mg/day) plus supplemental
(150 mg) infusions (for recurrent arrhythmias), amiodarone mean serumconcentrations between 0.7 to 1.4 mg/L were observed (n = 260). N-desethylamiodarone (DEA) is the major active metabolite
of amiodarone in humans. DEA serum concentrations above 0.05 mg/L are
not usually seen until after several days of continuous infusion but with
prolonged therapy reach approximately the same concentration as amiodarone.
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. The highly variable
systemic availability of oral amiodarone may be attributed potentially to
large interindividual variability in CYP3A4 activity. 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. Amiodarone and DEA cross the placenta
and both appear in breast milk. No data are
available on the activity of DEA in humans, but in animals, it has significant
electrophysiologic and antiarrhythmic effects generally similar to amiodarone
itself. DEA's precise role and contribution to the antiarrhythmic activity
of oral amiodarone are not certain. The development of maximal ventricular
class III effects after oral Cordarone administration in humans correlates
more closely with DEA accumulation over time than with amiodarone accumulation.
On the other hand (see Clinical
Trials), after Cordarone I.V. administration, there is
evidence of activity well before significant concentrations of DEA are attained. The following table summarizes the mean ranges of pharmacokinetic
parameters of amiodarone reported in single dose i.v. (5 mg/kg over 15 min)
studies of healthy subjects. Desethylamiodarone clearance and volume involve
an unknown biotransformation factor. The systemic
availability of oral amiodarone
in healthy subjects ranges between 33% and 65%. From in
vitro studies, the protein binding of amiodarone is>96%. 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/h/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
singledose of Cordarone I.V. 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 oral Cordarone, close clinical monitoring
is prudent for elderly patients and those with severe left ventricular dysfunction. There is no established relationship between drug concentration
and therapeutic response for short-term intravenous use. Steady-state amiodarone
concentrations of 1 to 2.5 mg/L have been associated with antiarrhythmic
effects and acceptable toxicity following chronic oral Cordarone therapy.<br/>Pharmacodynamics: Cordarone I.V. has been reported to produce negative
inotropic and vasodilatory effects in animals and humans. In clinical studies
of patients with refractory VF or hemodynamically unstable VT, treatment-emergent,
drug-related hypotension occurred in 288 of 1836 patients (16%) treated with
Cordarone I.V. No correlations were seen between the baseline ejection fraction
and the occurrence of clinically significant hypotension during infusion of
Cordarone I.V.<br/>Clinical Trials: Apart from studies in patients with VT or VF, described
below, there are two other studies of amiodarone showing an antiarrhythmic
effect before significant levels of DEA could have accumulated. A placebo-controlled
study of i.v. amiodarone (300 mg over 2 hours followed by 1200 mg/day)
in post-coronary artery bypass graft patients with supraventricular and 2- to 3-consecutive-beat
ventricular arrhythmias showed a reduction in arrhythmias from 12 hours
on. A baseline-controlled study using a similar i.v. regimen in patients with
recurrent, refractory VT/VF also showed rapid onset of antiarrhythmic activity;
amiodarone therapy reduced episodes of VT by 85% compared to baseline. The acute effectiveness of Cordarone I.V. in suppressing
recurrent VF or hemodynamically unstable VT is supported by two randomized,
parallel, dose-response studies of approximately 300 patients each. In these
studies, patients with at least two episodes of VF or hemodynamically unstable
VT in the preceding 24 hours were randomly assigned to receive doses of approximately
125 or 1000 mg over the first 24 hours, an 8-fold difference. In one
study, a middle dose of approximately 500 mg was evaluated. The dose
regimen consisted of an initial rapid loading infusion, followed by a slower
6-hour loading infusion, and then an 18-hour maintenance infusion. The maintenance
infusion was continued up to hour 48. Additional 10-minute infusions of 150 mg
Cordarone I.V. were given for���breakthrough���VT/VF more frequently
to the 125-mg dose group, thereby considerably reducing the planned 8-fold
differences in total dose to 1.8- and 2.6- fold, respectively, in the two
studies. The prospectively defined primary
efficacy end point was the rate of VT/VF episodes per hour. For both studies,
the median rate was 0.02 episodes per hour in patients receiving the high
dose and 0.07 episodes per hour in patients receiving the low dose, or approximately
0.5 versus 1.7 episodes per day (p = 0.07, 2-sided, in both
studies). In one study, the time to first episode of VT/VF was significantly
prolonged (approximately 10 hours in patients receiving the low dose and 14
hours in patients receiving the high dose). In both studies, significantly
fewer supplemental infusions were given to patients in the high-dose group.
Mortality was not affected in these studies; at the end of double-blind therapy
or after 48 hours, all patients were given open access to whatever treatment
(including Cordarone I.V.) was deemed necessary.
|
dailymed-instance:activeIng... | |
dailymed-instance:contraind... |
Cordarone I.V. is contraindicated in patients with
known hypersensitivity to any of the components of Cordarone I.V., including
iodine, or in patients with cardiogenic shock, marked sinus bradycardia, and
second- or third-degree AV block unless a functioning pacemaker is available.
|
dailymed-instance:supply |
Cordarone I.V. (amiodarone HCl) is
available in packages of 10 ampuls (2 cartons each containing 5 ampuls), 3 mL
each, as follows: 50 mg per mL, NDC 0008-0814-01. Store at room temperature,
15��to 25��C (59��to 77��F). Protect from light and excessive heat. Use carton
to protect contents from light until used. Wyeth Wyeth
Pharmaceuticals Inc. Philadelphia, PA 19101 by arrangement with Sanofi S.A. W10422C009 ET01 Rev 02/06
|
dailymed-instance:activeMoi... | |
dailymed-instance:inactiveI... | |
dailymed-instance:precautio... |
Cordarone I.V. 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 facilities adequate for monitoring the effectiveness
and side effects of treatment.<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. Cordaroneinduced
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 of Cordarone. The institution of antithyroid
drugs,��-adrenergic blockers and/or temporary corticosteroid therapy
may be necessary. The action of antithyroid drugs may be especially delayed
in amiodarone-induced thyrotoxicosis because of substantial quantities of
preformed thyroid hormones stored in the gland. There have been reports of
death associated with amiodarone induced thyrotoxicosis. Radioactive iodine
therapy is contraindicated because of the low radioiodine uptake associated
with amiodarone-induced hyperthyroidism. Cordarone-induced hyperthyroidism
may be followed 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 anestheticmanagement 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: 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 defects
of halogenated inhalational anesthetics.<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/>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 (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism). 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
a limited number of in vivo drug-drug
interactions with amiodarone have been reported, chiefly with the oral formulation,
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 shouldbe reassessed and, where appropriate,
plasma concentration measured. In view of the long and variable half-life
of amiodarone, potential for drug interactions exists not only with concomitant
medication but also with drugs administered after discontinuation of amiodarone. Since amiodarone is
a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit these isoenzymes
may decrease the metabolism and increase serum concentration 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%, resulting in increased plasma levels of amiodarone.
Grapefruit juice should not be taken during treatment with oral amiodarone.
This information should be considered when changing from intravenous amiodarone
to oral amiodarone (see DOSAGE
AND ADMINISTRATION, Intravenous to Oral Transition). 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:: Simvastatin (CYP3A4 substrate) in combination
with amiodarone has been associated with reports of myopathy/rhabdomyolysis.<br/>Cardiovasculars:: Cardiac
glycosides: In patients receiving digoxin therapy, administration of oral amiodarone regularly results in
an increase in serum digoxin concentration that may reach toxic levels with
resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases
the serum digoxin concentration by 70% after one day. On
administration of oral amiodarone, the need for digitalis therapy should be
reviewed and the dose reduced by approximately 50% or discontinued. If
digitalis treatment is continued, serum levels should be closely monitored
and patients observed for clinical evidence of toxicity. These precautions
probably should apply to digitoxin administration as well. Antiarrhythmics: Other antiarrhythmic drugs, such as quinidine,
procainamide, disopyramide, and phenytoin, have been used concurrently with amiodarone. There have been case
reports of increased steady-state levels of quinidine, procainamide, and phenytoin
during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone
levels. Amiodarone taken concomitantly with quinidine increases quinidine
serum concentration by 33% after two days. Amiodarone taken concomitantly
with procainamide for less than seven days increases plasma concentrations
of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine
and procainamide doses should be reduced by one-third when either is administered
with amiodarone. Plasma levels of flecainide have
been reported to increase in the presence of oral amiodarone; because of this,
the dosage of flecainide should be adjusted when these drugs are administered
concomitantly. In general, any added antiarrhythmic drug should be initiated
at a lower than usual dose with careful monitoring. Combination of amiodarone
with other antiarrhythmictherapy should be reserved for patients with life-threatening
ventricular arrhythmias who are incompletely responsive to a single agent
or incompletely responsive to amiodarone. During transfer to oral amiodarone,
the dose levels of previously administered agents should be reduced by 30
to 50% several days after the addition of oral amiodarone . The continued need for the other antiarrhythmic agent should
be reviewed after the effects of amiodarone have been established, and discontinuation
ordinarily should be attempted. If the treatment is continued, these patients
should be particularly carefully monitored for adverse effects, especially
conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone
is continued. In amiodarone-treated patients who require additional antiarrhythmic
therapy, the initial dose of such agents should be approximately half of the
usual recommended dose. Antihypertensives: Amiodarone should be used
with caution in patients receiving��-receptor blocking
agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor)
because of the possible potentiation of bradycardia, sinus arrest, and AV block;
if necessary, amiodarone can continue to be used after insertion of a pacemaker
in patients with severe bradycardia or sinus arrest. Anticoagulants: Potentiation
of warfarin-type (CYP2C9 and CYP3A4 substrate)
anticoagulant response is almost always seen in patients receiving amiodarone
and can result in serious or fatal bleeding. Since the concomitant administration
of warfarin with amiodarone increases the prothrombin time by 100% after 3
to 4 days, the dose of the anticoagulant should
be reduced by one-third to one-half, and prothrombin times should be monitored
closely. A similar effect has been reported with fluindione , an oral vitamin K antagonist, when administered concomitantly
with Cordarone. Clopidogrel , an inactive thienopyridine prodrug, is metabolized in the liver
by CYP3A4 to an active metabolite. A potential interaction between clopidogrel
and Cordarone resulting in ineffective inhibition of platelet aggregation
has been reported. Some drugs/substances are known to accelerate the metabolism
of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This
may lead to low amiodarone serum levels and potential decrease in efficacy.
Reported examples of this interaction include the following:<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. 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: Patients with hypokalemia or hypomagnesemia should
have the condition corrected whenever possible before being treated with Cordarone
I.V., as these disorders can exaggerate the degree of QTc prolongation and
increase the potential for TdP. Special attention should be given to electrolyte
and acid-base balance in patients experiencing severe or prolonged diarrhea
or in patients receiving concomitant diuretics.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity studies were conducted with Cordarone
I.V. However, oral 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 in rats was greater than the incidence in controls even at the lowest
dose level tested, i.e., 5 mg/kg/day (approximately 0.08times the maximum
recommended human maintenance dose). Mutagenicity studies
conducted with amiodarone HCl (Ames, micronucleus, and lysogenic induction
tests) were negative. No fertility studies
were conducted with Cordarone I.V. However, in a study in which amiodarone
HCl was orally 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).<br/>Pregnancy: Category
D. See WARNINGS,
Neonatal Hypo- or Hyperthyroidism. In addition to causing
infrequent congenital goiter/hypothyroidism and hyperthyroidism, amiodarone
has caused a variety of adverse effects in animals. In a reproductive study in which amiodarone was given intravenouslyto rabbits at dosages of 5, 10, or 25 mg/kg per day (about
0.1, 0.3, and 0.7 times the maximum recommended human dose [MRHD] on a body
surface area basis), maternal deaths occurred in all groups, including controls.
Embryotoxicity (as manifested by fewer full-term fetuses and increased resorptions
with concomitantly lower litter weights) occurred at dosages of 10 mg/kg
and above. No evidence of embryotoxicity was observed at 5 mg/kg and
no teratogenicity was observed at any dosages. In
a teratology study in which amiodarone was administered by continuous i.v.
infusion to rats at dosages of 25, 50, or 100 mg/kg per day (about 0.4,
0.7, and 1.4 times the MRHD when compared on a body surface area basis), maternal
toxicity (as evidenced by reduced weight gain and food consumption) and embryotoxicity
(as evidenced by increased resorptions, decreased live litter size, reduced
body weights, and retarded sternum and metacarpal ossification) were observed
in the 100 mg/kg group. Cordarone I.V.
should be used during pregnancy only if the potential benefit to the mother
justifies the risk to the fetus.<br/>Nursing Mothers: Amiodarone 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 amiodarone have demonstrated reduced viability
and reduced body weight gains. The risk of exposing the infant to amiodarone
should be weighed against the potential benefit of arrhythmia suppression
in the mother. The mother should be advised to discontinue nursing.<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 on the duration of gestation
or on parturition.<br/>Pediatric Use: The safety and efficacy of Cordarone in the pediatric
population have not been established; therefore, its use in pediatric patients
is not recommended. In a pediatric trial of 61 patients, aged 30 days to 15
years, hypotension (36%), bradycardia (20%), and atrio-ventricular block (15%)
were common dose-related adverse events and were severe or life-threatening
in some cases. Injection site reactions were seen in 5 (25%) of the 20 patients
receiving Cordarone I.V. through a peripheral vein irrespective of dose regimen. Cordarone I.V. contains the preservative benzyl alcohol
. There have been reports of fatal���gasping syndrome���in neonates (children less than one month of age) following the administration
of intravenous solutions containing the preservative benzyl alcohol. Symptoms
include a striking onset of gasping respiration, hypotension, bradycardia,
and cardiovascular collapse.<br/>Geriatric Use: Clinical studies of Cordarone I.V. 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.
|
dailymed-instance:overdosag... |
There have been cases, some fatal, of amiodarone overdose.
Effects of an inadvertent overdose of Cordarone I.V. include hypotension,
cardiogenic shock, bradycardia, AV block, and hepatotoxicity. Hypotension
and cardiogenic shock should be treated by slowing the infusion rate or with
standard therapy: vasopressor drugs, positive inotropic agents, and volume
expansion. Bradycardia and AV block may require temporary pacing. Hepatic
enzyme concentrations should be monitored closely. Amiodarone is not dialyzable.
|
dailymed-instance:genericMe... |
Amiodarone Hydrochloride
|
dailymed-instance:fullName |
Cordarone (Injection, Solution)
|
dailymed-instance:adverseRe... |
In a total of 1836 patients in controlled and uncontrolled
clinical trials, 14% of patients received Cordarone I.V. for at least 1 week,
5% received it for at least 2 weeks, 2% received it for at least 3 weeks,
and 1% received it for more than 3 weeks, without an increased incidence of
severe adverse reactions. The mean duration of therapy in these studies was
5.6 days; median exposure was 3.7 days. The
most important treatment-emergent adverse effects were hypotension, asystole/cardiac
arrest/electromechanical dissociation (EMD), cardiogenic shock, congestive
heart failure, bradycardia, liver function test abnormalities, VT, and AV
block. Overall, treatment was discontinued for about 9% of the patients because
of adverse effects. The most common adverse effects leading to discontinuation
of Cordarone I.V. therapy were hypotension (1.6%), asystole/cardiac arrest/EMD
(1.2%), VT (1.1%), and cardiogenic shock (1%). The
following table lists the most common (incidence���2%) treatment-emergent
adverse events during Cordarone I.V. therapy considered at least possibly
drug-related. These data were collected in clinical trials involving 1836
patients with life-threatening VT/VF. Data from all assigned treatment groups
are pooled because none of the adverse events appeared to be dose-related. Other treatment-emergent possibly drug-related adverse
events reported in less than 2% of patients receiving Cordarone I.V. in Wyeth-Ayerst
controlled and uncontrolled studies included the following: abnormal kidney
function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung
edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock,
sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting.<br/>Postmarketing Reports: In postmarketing surveillance, hypotension (sometimes
fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock),
angioedema, 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, pleuritis,
pseudotumor cerebri, syndrome of inappropriate antidiuretic hormone secretion
(SIADH), thyroid nodules/thyroid cancer, toxic epidermal 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. Also, in patients receiving recommended
dosages of Cordarone I.V., there have been postmarketing reports of the following
injection site reactions: pain, erythema, edema, pigment changes, venous thrombosis,
phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing .
|
dailymed-instance:warning |
Hypotension: Hypotension is the most common adverse effect seen
with Cordarone I.V. In clinical trials, treatment-emergent, drug-related hypotension
was reported as an adverse effect in 288 (16%) of 1836 patients treated with
Cordarone I.V. Clinically significant hypotension during infusions was seen
most often in the first several hours of treatment and was not dose related,
but appeared to be related to the rate of infusion. Hypotension necessitating
alterations in Cordarone I.V. therapy was reported in 3% of patients, with
permanent discontinuation required in less than 2% of patients. Hypotension should be treated initially by slowing the infusion;
additional standard therapy may be needed, including the following: vasopressor
drugs, positive inotropic agents, and volume expansion. The
initial rate of infusion should be monitored closely and should not exceed
that prescribed in DOSAGE AND ADMINISTRATION. In some cases, hypotension may be refractory resulting in
fatal outcome (see ADVERSE
REACTIONS, Postmarketing Reports).<br/>Bradycardia and AV Block: Drug-related bradycardia occurred in 90 (4.9%) of
1836 patients in clinical trials while they were receiving Cordarone I.V.
for life-threatening VT/VF; it was not dose-related. Bradycardia should be
treated by slowing the infusion rate or discontinuing Cordarone I.V. In some
patients, inserting a pacemaker is required. Despite such measures, bradycardia
was progressive and terminal in 1 patient during the controlled trials. Patients
with a known predisposition to bradycardia or AV block should be treated with
Cordarone I.V. in a setting where a temporary pacemaker is available.<br/>Liver Enzyme Elevations: Elevations of blood hepatic enzyme values���alanine
aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl
transferase (GGT)���are seen commonly in patients with immediately life-threatening
VT/VF. Interpreting elevated AST activity can be difficult because the values
may be elevated in patients who have had recent myocardial infarction, congestive
heart failure, or multiple electrical defibrillations. Approximately 54% of
patients receiving Cordarone I.V. in clinical studies had baseline liver enzyme
elevations, and 13% had clinically significant elevations. In 81% of patients
with both baseline and on-therapy data available, the liver enzyme elevations
either improved during therapy or remained at baseline levels. Baseline abnormalities
in hepatic enzymes are not a contraindication to treatment. Acute, centrolobular confluent hepatocellular necrosis leading
to hepatic coma, acute renal failure, and death has been associated with the
administration of Cordarone I.V. at a much higher loading dose concentration
and much faster rate of infusion than recommended in DOSAGE AND ADMINISTRATION. Therefore, the initial concentration and rate of infusion should
be monitored closely and should not exceed that prescribed in DOSAGE AND ADMINISTRATION (see DOSAGE AND
ADMINISTRATION). In patients
with life-threatening arrhythmias, the potential risk of hepatic injury should
be weighed against the potential benefit of Cordarone I.V. therapy, but patients
receiving Cordarone I.V. should be monitored carefully for evidence of progressive
hepatic injury. Consideration should be given to reducing the rate of administration
or withdrawing Cordarone I.V. in such cases.<br/>Proarrhythmia: Like all antiarrhythmic agents, Cordarone I.V. may
cause a worsening of existing arrhythmias or precipitate a new arrhythmia.
Proarrhythmia, primarily torsade de pointes (TdP), has been associated with
prolongation by Cordarone I.V. of the QTc interval to 500 ms or greater.
Although QTc prolongation occurred frequently in patients receiving Cordarone
I.V., torsade de pointes or new-onset VF occurred infrequently (less than
2%). Patients should be monitored for QTc prolongation during infusion with
Cordarone I.V. Combination of amiodarone with other antiarrhythmic therapy
that prolongs the QTc should be reserved for patientswith life-threatening
ventricular arrhythmias who are incompletely responsive to a single agent. 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
I.V. must be made in patients with thyroid dysfunction due to the possibility
of arrhythmia breakthrough or exacerbation of arrhythmia, which may result
in death, in these patients.<br/>Pulmonary Disorders:<br/>Early-onset pulmonary toxicity: There have been postmarketing reports of acute-onset
(days to weeks) pulmonary injury in patients treated with Cordarone I.V. Findings
have included pulmonary infiltrates and/or mass on X-ray, bronchospasm, wheezing,
fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed
to respiratory failure and/or death.<br/>ARDS: Two percent (2%) of patients were reported to
have adult respiratory distress syndrome (ARDS) during clinical studies involving
48 hours of therapy. ARDS is a disorder characterized by bilateral, diffuse
pulmonary infiltrates with pulmonary edema and varying degrees of respiratory
insufficiency. The clinical and radiographic picture can arise after a variety
of lung injuries, such as those resulting from trauma, shock, prolonged cardiopulmonary
resuscitation, and aspiration pneumonia, conditions present in many of the
patients enrolled in the clinical studies. There have been postmarketing reports
of ARDS in Cordarone I.V. patients. Cordarone I.V. may play a role in causing
or exacerbating pulmonary disorders in those patients. Postoperatively, occurrences of ARDS have been reported in
patients receiving oral 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/>Pulmonary fibrosis: Only 1 of more than 1000 patients treated with
Cordarone I.V. in clinical studies developed pulmonary fibrosis. In that patient,
the condition was diagnosed 3 months after treatment with Cordarone I.V.,
during which time she received oral Cordarone.
Pulmonary toxicity is a well-recognized complication of long-term Cordarone
use (see labeling for oral 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 oral amiodarone. In some cases, visual impairment has progressed to permanent
blindness. Amiodarone I.V. is indicated for initiation of treatment and prophylaxis
of frequently recurring ventricular fibrillation (VF) and hemodynamically
unstable ventricular tachycardia (VT) in patients refractory to other therapy
and can also can be used to treat patients with VT/VF for whom oralamiodarone
is indicated, but who are unable to take oral medication. 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 amiodarone
therapy. The risks and complications of antiarrhythmic therapy with amiodarone
must be weighed against its benefits in patients whose lives are threatened
by cardiac arrhythmias. Regular ophthalmic examination, including fundoscopy
and slit-lamp examination, is recommended during administrations of amiodarone.<br/>Long-Term Use: See labeling for oral Cordarone. There has been
limited experience in patients receiving Cordarone I.V. for longer than 3
weeks.<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 (see PRECAUTIONS,
Thyroid Abnormalities).<br/>Neonatal Hypo- or Hyperthyroidism: Although Cordarone use during pregnancy is uncommon,
there have been a small number of published reports of congenital goiter/hypothyroidism
and hyperthyroidism associated with its oral administration. If Cordarone
I.V. is administered during pregnancy, the patient should be apprised of the
potential hazard to the fetus.
|
dailymed-instance:indicatio... |
Cordarone I.V. is indicated for initiation of treatment
and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically
unstable ventricular tachycardia in patients refractory to other therapy.
Cordarone I.V. also can be used to treat patients with VT/VF for whom oral
Cordarone is indicated, but who are unable to take oral medication. During
or after treatment with Cordarone I.V., patients may be transferred to oral
Cordarone therapy (see DOSAGE
AND ADMINISTRATION). Cordarone
I.V. should be used for acute treatment until the patient's ventricular
arrhythmias are stabilized. Most patients will require this therapy for 48
to 96 hours, but Cordarone I.V. may be safely administered for longer periods
if necessary.
|
dailymed-instance:represent... | |
dailymed-instance:routeOfAd... | |
dailymed-instance:name |
Cordarone
|