Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4252
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Amiodarone Hydrochloride (Injection, Solution)
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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
Amiodarone Hydrochloride Injection 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
(Amiodarone Hydrochloride Injection 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 Amiodarone Hydrochloride Injection mixed in
100 mL of D5W 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 Amiodarone
Hydrochloride Injection, 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 Amiodarone
Hydrochloride Injection 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. Amiodarone
Hydrochloride Injection must be delivered by a volumetric
infusion pump. Amiodarone Hydrochloride Injection should, whenever possible, be
administered through a central venous catheter dedicated to that
purpose. An in-line filter should be used during administration. Amiodarone Hydrochloride Injection concentrations greater than 3
mg/mL in D5W 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,
Amiodarone Hydrochloride Injection concentrations should not exceed 2
mg/mL unless a central venous catheter is used (see ADVERSE
REACTIONS, Postmarketing
Reports). Amiodarone Hydrochloride Injection infusions exceeding 2 hours
must be administered in glass or polyolefin bottles containing D5W. Use
of evacuated glass containers for admixing Amiodarone Hydrochloride Injection 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 ADMINISTRATIONreflect doses identified in these studies. Amiodarone
Hydrochloride Injection 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
Amiodarone Hydrochloride Injection at higher concentrations and lower
flow rates than provided in DOSAGE
AND ADMINISTRATION. In addition, polysorbate 80, a component of Amiodarone
Hydrochloride Injection, is also known to leach DEHP from PVC (see
DESCRIPTION). Therefore, it is important that the recommendations
in DOSAGE
AND ADMINISTRATION be followed closely. Amiodarone Hydrochloride Injection does not need to be protected
from light during administration.<br/>Admixture Incompatibility: Amiodarone Hydrochloride Injection in DW is
incompatible with the drugs shown below.<br/>Intravenous to Oral Transition: Patients whose arrhythmias have been suppressed by
Amiodarone Hydrochloride Injection may be switched to oral
amiodarone HCl. The optimal dose for changing from intravenous
to oral administration of amiodarone HCl will depend on the dose
of Amiodarone Hydrochloride Injection already administered, as
well as the bioavailability of oral amiodaroneHCl. When
changing to oral amiodarone HCl 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 (see PRECAUTIONS, Drug
Interactions). The following table provides suggested doses of oral
amiodarone HCl to be initiated after varying durations of
Amiodarone Hydrochloride Injection 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.
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Amiodarone Hydrochloride Injection 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. Amiodarone
Hydrochloride Injection is a sterile clear, pale-yellow micellar
solution visually free from particulates. Each milliliter of the
Amiodarone Hydrochloride Injection formulation contains 50 mg of
amiodarone HCl, 20.2 mg of benzyl alcohol, 100 mg of polysorbate 80, and
water for injection. Amiodarone Hydrochloride Injection contains
polysorbate 80, which is known to leach di-(2-ethylhexyl)phthalate
(DEHP) from polyvinylchloride (PVC) (see DOSAGE
AND ADMINISTRATION).
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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. Amiodarone Hydrochloride Injection 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 Amiodarone Hydrochloride Injection
and oral amiodarone HCl is shown in the table below. ���No Change At higher doses (>10 mg/kg) of Amiodarone
Hydrochloride Injection, 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 Amiodarone Hydrochloride Injection 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 Amiodarone Hydrochloride Injection
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 serum concentrations 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
amiodarone HCI administration in humans correlates more closely
with DEA accumulation over time than with amiodarone
accumulation. On the other hand (see CLINICAL
TRIALS), after Amiodarone Hydrochloride Injection
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. Notes: Vc and Vss denote the central and steady-state
volumes of distribution from i.v. studies. "-" denotes not available. 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 single dose of Amiodarone Hydrochloride
Injection 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 amiodarone HCl, 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 amiodarone HCl therapy.<br/>Pharmacodynamics: Amiodarone Hydrochloride Injection 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 occured in 288 of 1836 patients (16%)
treated with Amiodarone Hydrochloride Injection. No correlations
were seen between the baseline injection fraction and the
occurence of clinically significant hypotension during infusion
of Amiodarone Hydrochloride Injection.<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 Amiodarone Hydrochloride
Injection 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 thepreceding 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 Amiodarone
HydrochlorideInjection 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 Amiodarone Hydrochloride Injection) was
deemed necessary.
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Amiodarone Hydrochloride Injection is contraindicated in patients
with known hypersensitivity to any of the components of Amiodarone
Hydrochloride Injection, including iodine, or in patients with
cardiogenic shock, marked sinus bradycardia, and second- or third-degree
AV block unless a functioning pacemaker is available.
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dailymed-instance:supply |
Amiodarone Hydrochloride Injection, 50 mg per mL, is available
in: NDC 67457-153-03 3 mL vial, packages of 10. NDC 67457-153-09 9 mL vial, packages of 10. NDC 67457-153-18 18 mL single use vial. Store at 20��C to
25��C (68��F to 77��F). (See USP
Controlled Room Temperature). Protect from light and excessive
heat. Retain in carton until time of use. Manufactured for: Bioniche Pharma USA LLC, Lake Forest, IL 60045 Manufactured by: Bioniche Teo., Inverin, Co. Galway, Ireland.
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Amiodarone Hydrochloride Injection 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
amiodarone HCl therapy, and who have access to facilities adequate for
monitoring the effectiveness and side effects of treatment.<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
Amiodarone Hydrochloride Injection 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 Amiodarone Hydrochloride
Injection 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 Amiodarone Hydrochloride Injection therapy,
but patients receiving Amiodarone Hydrochloride Injection should
be monitored carefully for evidence of progressive hepatic
injury. Consideration should be given to reducing the rate of
administration or withdrawing Amiodarone Hydrochloride Injection
in such cases.<br/>Proarrhythmia: Like all antiarrhythmic agents, Amiodarone Hydrochloride
Injection may cause a worsening of existing arrhythmias or
precipitate a new arrhythmia. Proarrhythmia, primarily torsades
de pointes, has been associated with prolongation by Amiodarone
Hydrochloride Injection of the QTc interval to 500 ms or
greater. Although QTc prolongation occurred frequently in
patients receiving Amiodarone Hydrochloride Injection, torsades
de pointes or new-onset VF occurred infrequently (less than
2%). Patients should be monitored for QTc prolongation
during infusion with Amiodarone Hydrochloride Injection.
Combination of amiodarone with other antiarrhythmic therapy that
prolongs the QTc should be reserved for patients with
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 coadminister 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 Amiodarone Hydrochloride Injection 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 intravenous amiodarone. Findings have
included pulmonary infiltrates on X-ray, bronchospasm,
wheezing, fever, dyspnea, cough, hemoptysis, and
hypoxia. Some cases have progressed to respiratory
failure and/or death.<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
intravenous amiodarone patients.
Intravenous amiodarone may play a role in
causing or exacerbating pulmonary disorders in those
patients. Postoperatively, occurrences of ARDS have been
reported in patients receiving oral amiodarone HCl 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
amiodarone HCl.<br/>Pulmonary fibrosis: Only 1 of more than 1000 patients treated with
Amiodarone Hydrochloride Injection in clinical studies
developed pulmonary fibrosis. In that patient, the
condition was diagnosed 3 months after treatment with
Amiodarone Hydrochloride Injection, during which time
she received oral amiodarone HCl. Pulmonary toxicity is a
well-recognized complication of long-term amiodarone use
(seelabeling for oral amiodarone HCl).<br/>Thyroid Abnormalities: Amiodarone 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 euthroid 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, amiodarone can cause either hypothyroidism or
hyperthyroidism. Thyroid function should be monitored prior to
treatment and periodically thereafter, particularly in elderly
patients, and in any patients with a history of thyroid nodules,
goiter, or other thyroid dysfunction. Because of the slow
elimination of amiodarone and its metabolites, high plasma
iodide levels, altered thyroid function, and abnormal
thyroid-function tests may persist for several weeks or even
months following amiodarone 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 Amiodarone dose reduction and/or thyroid hormone
supplement. However, therapy must be individualized, and it may
be necessary to discontinue Amiodarone Tablets in some patients. Hyperthyroidism occurs in about 2% of patients
receiving amiodarone, but the incidence may be higher among
patients with prior inadequate dietary iodine intake.
Amiodarone-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. Hyperthroidism 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 amiodarone-induced hyperthyroidism, aggressive medical
treatment is indicated, including, if possible, dose reduction
or withdrawal of Amiodarone. 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. Amiodarone-induced
hyperthyroidism may be followed by transient period of
hypothyroidism (see WARNINGS, Thyrotoxicosis). 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, andthis 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 Amiodarone. In
some instances hyperthyroidism was also present .<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 Amiodarone
Hydrochloride.<br/>Drug Interactions: Amiodarone is metabolized to desethylamiodarone by the
cytochrome P450 (CYP450) enzyme group, specifically cytochrome
P450 3A4 (CYP3A4). 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
should be reassessed and, where appropriate, plasma
concentration measured. In view of the long and variable
half-life of amiodarone, potential for drug interactions exists
not only with concomitant medication but also with drugs
administered after discontinuation of amiodarone. Since amiodarone is a
substrate for CYP3A4 and CYP2C8, drug/substances that
inhibit these isoenzymes may decrease the metabolism and
increase serum concentrations of amiodarone. Reported
examples of this interaction 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 concentrations 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 coadminstration 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
pintes 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 Cmax by 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:: HMG-CoA reductase inhibitors that are CYP3A4 substrates (including simvastatin and atorvastatin) in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis.<br/>Cardiovasculars:: Cardiac glycosides: Inpatients 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, has 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 concurrently
with quinidineincreases quinidine serum concentrations
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 whenthese drugs are administered
concomitantly. In general, any added antiarrhythmic drug
should be initiated at a lower than usual dose with
careful monitoring. Combination of amiodarone with other
antiarrhythmic therapy should be reserved for patients
with life-threatening ventricular arrhythmias who are
incompletely responsive to 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 (see DOSAGE AND
ADMINISTRATION, Intravenous to Oral
Transition). 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. Cllopidogrel,
an inactive thienopyridine prodrug, is
metabolized in the liver by CYP3A4 to an active
metabolite. Apotential interaction between clopidogrel
and Amiodarone resulting in ineffective inhibition of
platelet aggregation hasbeen 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 the
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, decreased
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 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, orazoles were
administered concomitantly. (See PRECAUTIONS, Proarrhythmia.) Hemodynamic and electrophysiologic interactions
have also been observed after concomitant administration
with propranolol,
diltiazem, and verapamil. Volatile Anesthetic
Agents: (see PRECAUTIONS, Surgery).<br/>Electrolyte Disturbances: Patients with hypokalemia or hypomagnesemia should have
the condition corrected whenever possible before being treated
with Amiodarone Hydrochloride Injection, as these disorders can
exaggerate the degree of QTc prolongation and increase the
potential for torsades de pointes. 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 Amiodarone
Hydrochloride Injection. However, oral amiodarone HCl 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 0.08 times 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 Amiodarone Hydrochloride
Injection. 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 and
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
intravenously to 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. Amiodarone Hydrochloride Injection 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 breastfeeding 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 amiodarone HCl 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 amiodarone HCl 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 atrioventricular
block (15%) were common dose-related adverse events and
were severe or lifethreatening in some cases. Injection site
reactions were seen in 5 (25%) of the 20 patients
receiving intravenous amiodarone through a peripheral vein
irrespective of dose regimen. Amiodarone Hydrochloride Injection contains the
preservative benzyl alcohol (see
DESCRIPTION). 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 Amiodarone Hydrochloride Injection
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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There have been cases, some fatal, of amiodarone overdose.
Effects of an inadvertent overdose of intravenous amiodarone 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.
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Amiodarone Hydrochloride
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dailymed-instance:fullName |
Amiodarone Hydrochloride (Injection, Solution)
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In a total of 1836 patients in controlled and uncontrolled
clinical trials, 14% of patients received Amiodarone
Hydrochloride Injection 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
Amiodarone Hydrochloride Injection 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
Amiodarone Hydrochloride Injection therapy considered at least possibly
drug-related. These data were collected from the 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 Amiodarone
Hydrochloride Injection in 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, 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 (see
DOSAGE AND ADMINISTRATION).
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Hypotension: Hypotension is the most common adverse effect seen with
Amiodarone Hydrochloride Injection. In clinical trials,
treatment-emergent, drug-related hypotension was reported as an
adverse effect in 288 (16%) of 1836 patients treated
with Amiodarone Hydrochloride Injection. 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 Amiodarone Hydrochloride Injection
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
Amiodarone Hydrochloride Injection for life-threatening VT/VF;
it was not dose-related. Bradycardia should be treated by
slowing the infusion rate or discontinuing Amiodarone
Hydrochloride Injection. 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 Amiodarone Hydrochloride Injection in a setting
where a temporary pacemaker is available.<br/>Long-Term Use: See labeling for oral amiodarone HCl. There has been
limited experience in patients receiving Amiodarone
Hydrochloride Injection for longer than 3 weeks.<br/>Thyrotoxicosis: Amiodarone-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 amiodarone 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 Amiodarone Hydrochloride
Injection is administered during pregnancy, the patient should
be apprised of the potential hazard to the fetus.
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Amiodarone Hydrochloride Injection is indicated for initiation of
treatment and prophylaxis of frequently recurring ventricular
fibrillation and hemodynamically unstable ventricular tachycardia in
patients refractory to other therapy. Amiodarone Hydrochloride Injection
also can be used to treat patients with VT/VF for whom oral amiodarone
HCl is indicated, but who are unable to take oral medication. During or
after treatment with Amiodarone Hydrochloride Injection, patients may be
transferred to oral amiodarone HCl therapy (see DOSAGE
AND ADMINISTRATION ).Amiodarone Hydrochloride Injection 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 Amiodarone Hydrochloride Injection may be safely administered for
longer periods if necessary.
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dailymed-instance:name |
Amiodarone Hydrochloride
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