Included as part of the PRECAUTIONS section.
NEXTERONE 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 therapy, and who have access to facilities adequate for monitoring
the effectiveness and side effects of treatment.
Because of the long half-life
of amiodarone and its metabolite desethylamiodarone, the potential for adverse
reactions or interactions, as well as observed adverse effects, can persist
following amiodarone withdrawal.
Hypotension is the most common
adverse reaction seen with intravenous amiodarone. In clinical trials,
treatment-emergent, drug-related hypotension was reported as an adverse effect
in 288 (16%) of 1836 patients treated with intravenous amiodarone. 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 intravenous
amiodarone therapy was reported in 3% of patients, with permanent
discontinuation required in less than 2% of patients.
Treat hypotension initially by
slowing the infusion; additional standard therapy may be needed, including the
following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor
the initial rate of infusion closely and do not exceed the recommended rate [see
DOSAGE AND ADMINISTRATION].
In some cases, hypotension may
be refractory and result in a fatal outcome [see ADVERSE REACTIONS].
Bradycardia And Atrio-ventricular
In 90 (4.9%) of 1836 patients
in clinical trials, drug-related bradycardia that was not dose-related occurred
while they were receiving intravenous amiodarone for life-threatening VT/VF.
Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In
some patients, inserting a pacemaker is required. Despite such measures,
bradycardia was progressive and terminal in 1 patient during the controlled
trials. Treat patients with a known predisposition to bradycardia or AV block
with NEXTERONE in a setting where a temporary pacemaker is available.
Elevations of blood hepatic
enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase
(AST), and gamma-glutamyl transferase (GGT)] are commonly seen 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 intravenous amiodarone
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. Elevated bilirubin levels have
been reported in patients administered intravenous amiodarone.
Acute, centrolobular confluent
hepatocellular necrosis leading to hepatic coma, acute renal failure, and death
has been associated with the administration of intravenous amiodarone (see DOSAGE
In patients with
life-threatening arrhythmias, the potential risk of hepatic injury should be
weighed against the potential benefit of NEXTERONE therapy. Carefully monitor
patients receiving NEXTERONE for evidence of progressive hepatic injury. In
such cases, consider reducing the rate of administration or withdrawing
Like all antiarrhythmic agents,
NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new
arrhythmia, sometimes leading to fatal outcomes [see ADVERSE REACTIONS].
Proarrhythmia, primarily torsade de pointes (TdP), has been associated with
prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or
greater. Although QTc prolongation occurred frequently in patients receiving
intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than
2%). Monitor patients for QTc prolongation during infusion with NEXTERONE.
Reserve the combination of amiodarone with other antiarrhythmic therapies that
prolong the QTc to patients with life-threatening ventricular arrhythmias who
are incompletely responsive to a single agent.
hypomagnesemia or hypocalcemia whenever possible before initiating treatment
with NEXTERONE, as these disorders can exaggerate the degree of QTc
prolongation and increase the potential for TdP. Give special attention to
electrolyte and acid-base balance in patients experiencing severe or prolonged
diarrhea or in patients receiving concomitant diuretics and laxatives.
Amiodarone causes thyroid
dysfunction in some patients, which may lead to potentially fatal breakthrough
or exacerbated arrhythmias.
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 and
masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and
hypoxia. Some cases have progressed to respiratory failure or death.
Two percent (2%) of patients
were reported to have adult respiratory distress syndrome (ARDS) during
clinical studies involving 48 hours of therapy.
There have been reports of
early development of pulmonary fibrosis (within 1 to 3 months) following
initiation of amiodarone treatment. Only 1 of more than 1000 patients treated
with intravenous amiodarone in clinical studies developed pulmonary fibrosis.
In that patient, the condition was diagnosed 3 months after treatment with
intravenous amiodarone, during which time the patient received oral amiodarone.
Pulmonary toxicity is a well-recognized complication of long-term amiodarone
use (see package insert for oral amiodarone).
Loss Of Vision
Cases of optic neuropathy and
optic neuritis, usually resulting in visual impairment, have been reported in
patients treated with oral amiodarone or intravenous amiodarone. In some cases,
visual impairment has progressed to permanent blindness. Optic neuropathy and
neuritis may occur at any time following initiation of therapy. A causal
relationship to the drug has not been clearly established. Perform an
ophthalmic examination if symptoms of visual impairment appear, such as changes
in visual acuity and decreases in peripheral vision. Re-evaluate the necessity
of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform
regular ophthalmic examination, including fundoscopy and slit-lamp examination,
during administration of NEXTERONE.
Amiodarone inhibits peripheral
conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased
T4 levels, decreased T3 levels, and increased levels of inactive reverse T3
(rT3) in clinically euthyroid patients. Amiodarone is also a potential source
of large amounts of inorganic iodine and can cause either hypothyroidism or
hyperthyroidism. Evaluate thyroid function 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 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 NEXTERONE withdrawal.
There have been postmarketing
reports of thyroid nodules/thyroid cancer in patients treated with amiodarone.
In some instances hyperthyroidism was also present.
hyperthyroidism in about 2% of patients. Thyrotoxicosis and arrhythmia with
fatal outcome has been reported in the presence of pre-existing hyperthyroidism
even following a single intravenous amiodarone dose. Consider the possibility
of hyperthyroidism if any new signs of arrhythmia appear.
Hyperthyroidism may result from
iodine load (type 1 amiodarone-induced thyrotoxicosis [type 1 AIT]; in
particular in patients with underlying autonomous thyroid nodules or latent
Grave's disease). Hyperthyroidism may also result from direct amiodaroneinduced
destructive thyroiditis that occurs in individuals with no underlying thyroid
disease (type 2 AIT), resulting in the release of preformed thyroid hormone
into the bloodstream from damaged thyroid follicular epithelium. Mixed forms of
hyperthyroidism as a result of both pathogenic mechanisms (excessive thyroid
hormone production and thyroid destruction) can also occur. The risk of
hyperthyroidism may be higher among patients with prior inadequate dietary
Identify hyperthyroidism by
relevant clinical signs and symptoms, subnormal serum levels of thyroid
stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or
normal serum T3. Since arrhythmia breakthroughs may accompany
amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated,
including, if possible, dose reduction or withdrawal of amiodarone. Amiodarone
hyperthyroidism may be followed by a transient period of hypothyroidism.
The institution of antithyroid
drugs, β-adrenergic blockers or temporary corticosteroid therapy may be
necessary. The action of antithyroid drugs may be especially delayed in
amiodarone-induced thyrotoxicosis because of substantial quantities of
preformed thyroid hormones stored in the gland. Radioactive iodine therapy is
not recommended because of the low radioiodine uptake associated with
When aggressive treatment of
amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued
because it is the only drug effective against the resistant arrhythmia,
surgical management may be an option. Experience with thyroidectomy as a
treatment for amiodarone-induced thyrotoxicosis is limited, and this form of
therapy could induce thyroid storm. Therefore, surgical and anesthetic
management require careful planning.
Hypothyroidism has been
reported in 2 to 10% of patients receiving amiodarone and may be primary or
subsequent to resolution of preceding amiodarone-induced hyperthyroidism. This
condition may be identified by clinical symptoms and elevated serum TSH levels.
Cases of severe hypothyroidism and myxedema coma, sometimes fatal, have been
reported in association with amiodarone therapy. In some clinically hypothyroid
amiodarone-treated patients, free thyroxine index values may be normal. Manage
hypothyroidism by reducing the dose of or discontinuing NEXTERONE and
considering the need for thyroid hormone supplement.
Amiodarone can cause fetal harm
when administered to a pregnant woman. Fetal exposure may increase the
potential for adverse experiences including cardiac, thyroid,
neurodevelopmental, neurological and growth effects in neonate. Inform the
patient of the potential hazard to the fetus if NEXTERONE is administered
during pregnancy or if the patient becomes pregnant while taking NEXTERONE [See
Exaggerated Effects Of Perisurgical
Perform close perioperative
monitoring 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.
Interference With Corneal
Refractive Laser Surgery
Advise patients that most
manufacturers of corneal refractive laser surgery devices contraindicate
corneal refractive laser surgery in patients taking amiodarone.
reactions have been reported with intravenous amiodarone including shock (sometimes
fatal), cardiac arrest, and the following manifestations: hypotension,
tachycardia, hypoxia, cyanosis, rash, flushing, hyperhidrosis and cold sweat.
Since NEXTERONE contains dextrose, patients with allergy to corn or corn
products are at risk for allergic reaction.
Impairment Of Fertility
No carcinogenicity studies were
conducted with intravenous administration of amiodarone. However, oral
amiodarone caused a statistically significant, dose-related increase in the
incidence of thyroid tumors (follicular adenoma and 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 (much less, on a body
surface area basis, than the maximum recommended human maintenance dose of 600
Mutagenicity studies conducted
with amiodarone HCl (Ames, micronucleus, and lysogenic induction tests) were
No fertility studies were
conducted with intravenous administration of amiodarone. 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 of 600 mg/day).
Use In Specific Populations
Pregnancy Category D [see WARNINGS AND PRECAUTIONS].
desethylamiodarone cross the placenta.
Reported risks include
- neonatal bradycardia, QT prolongation, and periodic
- neonatal hypothyroidism (with or without goiter) detected
antenatally or in the newborn and reported even after a few days of exposure
- neonatal hyperthyroxinemia
- neurodevelopmental abnormalities independent of thyroid
function, including speech delay and difficulties with written language and arithmetic,
delayed motor development, and ataxia.
- jerk nystagmus with synchronous head titubation
- fetal growth retardation
- premature birth
Amiodarone has caused a variety
of adverse effects in animals.
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 human intravenous maintenance dose of 0.5mg/min on a body
surface area basis), during gestation days 8 to 16 (organogenesis). The incidence
of maternal deaths increased with increasing dose and occurred in all treated
groups and controls. Mean fetal weights were significantly decreased in the low
and middle dose groups and embryotoxicity (as manifested by fewer full-term
fetuses and increased resorptions) occurred at dosages of 10 mg/kg and above.
There were no significant differences in the number of minor fetal
abnormalities and no major fetal abnormalities were observed.
Amiodarone was administered by
continuous intravenous infusion to rats at dosages of 25, 50, or 100 mg/kg per
day (about 0.3, 0.7 and 1.3 times the human intravenous maintenance dose of 0.5
mg/min on a body surface area basis) during gestation days 8 to 16
(organogenesis). Maternal toxicity (manifest as reduced weight gain and food
consumption) and embryotoxicity (manifest as increased resorptions, decreased
live litter size and fetal body weights, and delayed sternal and metacarpal
ossification) were observed in the 100 mg/kg group. The delayed ossification
was reversible and related to decreased fetal weight. Fetal thyroid tissues
appeared normal in all groups.
Very high concentrations of
amiodarone and desethylamiodarone may be found in testes. An elevated
follicle-stimulating hormone and luteinizing hormone levels, suggestive of
testicular dysfunction, have been reported in men on long-term amiodarone
While planning pregnancy after
discontinuation of amiodarone treatment, consider the long half-life of
amiodarone and its metabolite DEA.
Labor And Delivery
It is not known whether the use
of amiodarone 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.
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 transient reduced body weight gains. The
risk of exposing the infant to amiodarone and DEA must be weighed against the
potential benefit of arrhythmia suppression in the mother. Advise the mother to
The safety and effectiveness of
amiodarone in pediatric patients have not been established; therefore, the use
of amiodarone in pediatric patients is not recommended. In a pediatric trial of
61 patients, aged 30 days to 15 years, hypotension (36%), bradycardia (20%),
and AV block (15%) were common dose-related adverse reactions and were severe
or life-threatening 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.
Clinical studies of amiodarone
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. Carefully consider dose selection in an elderly patient. In
general, start at the low end of the dosing range in the elderly to reflect the
greater frequency of decreased hepatic, renal, or cardiac function, and
concomitant disease or other drug therapy.