WARNINGS
ATRACURIUM SHOULD BE USED ONLY BY THOSE
SKILLED IN AIRWAY MANAGEMENT AND RESPIRATORY
SUPPORT. EQUIPMENT AND PERSONNEL MUST BE
IMMEDIATELY AVAILABLE FOR ENDOTRACHEAL INTUBATION
AND SUPPORT OF VENTILATION, INCLUDING
ADMINISTRATION OF POSITIVE PRESSURE OXYGEN.
ADEQUACY OF RESPIRATION MUST BE ASSURED THROUGH
ASSISTED OR CONTROLLED VENTILATION.
ANTICHOLINESTERASE REVERSAL AGENTS SHOULD BE
IMMEDIATELY AVAILABLE.
DO NOT GIVE ATRACURIUM BESYLATE BY
INTRAMUSCULAR ADMINISTRATION.
Atracurium has no known effect on
consciousness, pain threshold, or cerebration. It
should be used only with adequate
anesthesia.
Atracurium besylate injection, which
has an acid pH, should not be mixed with alkaline
solutions (e.g., barbiturate solutions) in the
same syringe or administered simultaneously during
intravenous infusion through the same needle.
Depending on the resultant pH of such mixtures,
atracurium may be inactivated and a free acid may
be precipitated.
Atracurium besylate injection 10 mL
multiple dose vials contain benzyl alcohol. In
neonates, benzyl alcohol has been associated with
an increased incidence of neurological and other
complications which are sometimes fatal.
Atracurium besylate 5 mL single use vials do not
contain benzyl alcohol (see
PRECAUTIONS: Pediatric
Use
).
Anaphylaxis:
Severe anaphylactic reactions
to neuromuscular blocking agents, including
atracurium besylate, have been reported. These
reactions have in some cases been life-threatening
and fatal. Due to the potential severity of these
reactions, the necessary precautions, such as the
immediate availability of appropriate emergency
treatment, should be taken. Precautions should
also be taken in those individuals who have had
previous anaphylactic reactions to other
neuromuscular blocking agents since
cross-reactivity between neuromuscular blocking
agents, both depolarizing and non-depolarizing,
has been reported in this class of
drugs.
PRECAUTIONS
Since allergic cross-reactivity has
been reported in this class, request information
from your patients about previous anaphylactic
reactions to other neuromuscular blocking agents.
In addition, inform your patients that severe
anaphylactic reactions to neuromuscular blocking
agents, including atracurium besylate have been
reported.
General:
Although atracurium is a less
potent histamine releaser than d-tubocurarine or
metocurine, the possibility of substantial
histamine release in sensitive individuals must be
considered. Special caution should be exercised in
administering atracurium to patients in whom
substantial histamine release would be especially
hazardous (e.g., patients with clinically
significant cardiovascular disease) and in
patients with any history (e.g., severe
anaphylactoid reactions or asthma) suggesting a
greater risk of histamine release. In these
patients, the recommended initial atracurium
besylate dose is lower (0.3 to 0.4 mg/kg) than for
other patients and should be administered slowly
or in divided doses over one minute.
Since atracurium has no clinically
significant effects on heart rate in the
recommended dosage range, it will not counteract
the bradycardia produced by many anesthetic agents
or vagal stimulation. As a result, bradycardia
during anesthesia may be more common with
atracurium than with other muscle
relaxants.
Atracurium may have profound effects in
patients with myasthenia gravis, Eaton-Lambert
syndrome, or other neuromuscular diseases in which
potentiation of nondepolarizing agents has been
noted. The use of a peripheral nerve stimulator is
especially important for assessing neuromuscular
block in these patients. Similar precautions
should be taken in patients with severe
electrolyte disorders or
carcinomatosis.
Multiple factors in anesthesia practice
are suspected of triggering malignant hyperthermia
(MH), a potentially fatal hypermetabolic state of
skeletal muscle. Halogenated anesthetic agents and
succinylcholine are recognized as the principal
pharmacologic triggering agents in MH-susceptible
patients; however, since MH can develop in the
absence of established triggering agents, the
clinician should be prepared to recognize and
treat MH in any patient scheduled for general
anesthesia. Reports of MH have been rare in cases
in which atracurium has been used. In studies of
MH-susceptible animals (swine) and in a clinical
study of MH-susceptible patients, atracurium did
not trigger this syndrome.
Resistance to nondepolarizing
neuromuscular blocking agents may develop in burn
patients. Increased doses of nondepolarizing
muscle relaxants may be required in burn patients
and are dependent on the time elapsed since the
burn injury and the size of the burn.
The safety of atracurium has not been
established in patients with bronchial
asthma.
Long-Term Use in Intensive
Care Unit (ICU):
When there is
a need for long-term mechanical ventilation, the
benefits-to-risk ratio of neuromuscular block must
be considered. The long-term (1 to 10 days)
infusion of atracurium besylate during mechanical
ventilation in the ICU has been evaluated in
several studies. Average infusion rates of 11 to
13 mcg/kg per minute (range: 4.5 to 29.5) were
required to achieve adequate neuromuscular block.
These data suggest that there is wide interpatient
variability in dosage requirements. In addition,
these studies have shown that dosage requirements
may decrease or increase with time. Following
discontinuation of infusion of atracurium besylate
in these ICU studies, spontaneous recovery of four
twitches in a train-of- four occurred in an
average of approximately 30 minutes (range: 15 to
75 minutes) and spontaneous recovery to a
train-of-four ratio >75% (the ratio of
height of the fourth to the first twitch in a
train-of-four) occurred in an average of
approximately 60 minutes (range: 32 to 108
minutes).
Little information is available on the
plasma levels and clinical consequences of
atracurium metabolites that may accumulate during
days to weeks of atracurium administration in ICU
patients. Laudanosine, a major biologically active
metabolite of atracurium without neuromuscular
blocking activity, produces transient hypotension
and, in higher doses, cerebral excitatory effects
(generalized muscle twitching and seizures) when
administered to several species of animals. There
have been rare spontaneous reports of seizures in
ICU patients who have received atracurium or other
agents. These patients usually had predisposing
causes (such as head trauma, cerebral edema,
hypoxic encephalopathy, viral encephalitis,
uremia). There are insufficient data to determine
whether or not laudanosine contributes to seizures
in ICU patients.
WHENEVER THE USE OF ATRACURIUM OR ANY
NEUROMUSCULAR BLOCKING AGENT IS CONTEMPLATED IN
THE ICU, IT IS RECOMMENDED THAT NEUROMUSCULAR
TRANSMISSION BE MONITORED CONTINUOUSLY DURING
ADMINISTRATION WITH THE HELP OF A NERVE
STIMULATOR. ADDITIONAL DOSES OF ATRACURIUM OR ANY
OTHER NEUROMUSCULAR BLOCKING AGENT SHOULD NOT BE
GIVEN BEFORE THERE IS A DEFINITE RESPONSE TO
T1 OR TO THE FIRST TWITCH. IF NO
RESPONSE IS ELICITED, INFUSION ADMINISTRATION
SHOULD BE DISCONTINUED UNTIL A RESPONSE
RETURNS.
Hemofiltration has a minimal effect on
plasma levels of atracurium and its metabolites,
including laudanosine. The effects of hemodialysis
and hemoperfusion on plasma levels of atracurium
and its metabolites are unknown.
Drug Interactions:
Drugs which may enhance the
neuromuscular blocking action of atracurium
include: enflurane; isoflurane; halothane; certain
antibiotics, especially the aminoglycosides and
polymyxins; lithium; magnesium salts;
procainamide; and quinidine.
If other muscle relaxants are used
during the same procedure, the possibility of a
synergistic or antagonist effect should be
considered.
The prior administration of
succinylcholine does not enhance the duration, but
quickens the onset and may increase the depth, of
neuromuscular block induced by atracurium
besylate. Atracurium should not be administered
until a patient has recovered from
succinylcholine-induced neuromuscular
block.
Carcinogenesis, Mutagenesis,
Impairment of Fertility:
Carcinogenesis and fertility
studies have not been performed. Atracurium was
evaluated in a battery of three short-term
mutagenicity tests. It was non-mutagenic in both
the Ames Salmonella assay at concentrations up to
1000 mcg/plate, and in a rat bone marrow
cytogenicity assay at up to paralyzing doses. A
positive response was observed in the mouse
lymphoma assay under conditions (80 and 100
mcg/mL, in the absence of metabolic activation)
which killed over 80% of the treated cells;
there was no mutagenicity at 60 mcg/mL and lower,
concentrations which killed up to half of the
treated cells. A far weaker response was observed
in the presence of metabolic activation at
concentrations (1200 mcg/mL and higher) which also
killed over 80% of the treated
cells.
Mutagenicity testing is intended to
simulate chronic (years to lifetime) exposure in
an effort to determine potential carcinogenicity.
Thus, a single positive mutagenicity response for
a drug used infrequently and/or briefly is of
questionable clinical relevance.
Pregnancy:
Teratogenic
Effects:
Pregnancy Category C.
Atracurium besylate has been
shown to be potentially teratogenic in rabbits
when given in doses up to approximately one-half
the human dose. There are no adequate and
well-controlled studies in pregnant women.
Atracurium should be used during pregnancy only if
the potential benefit justifies the potential risk
to the fetus.
Atracurium besylate was administered
subcutaneously on days 6 through 18 of gestation
to nonventilated Dutch rabbits. Treatment groups
were given either 0.15 mg/kg once daily or 0.10
mg/kg twice daily. Lethal respiratory distress
occurred in two 0.15 mg/kg animals and in one 0.10
mg/kg animal, with transient respiratory distress
or other evidence of neuromuscular block occurring
in 10 of 19 and in 4 of 20 of the 0.15 mg/kg and
0.10 mg/kg animals, respectively. There was an
increased incidence of certain spontaneously
occurring visceral and skeletal anomalies or
variations in one or both treated groups when
compared to non-treated controls. The percentage
of male fetuses was lower (41% vs. 51%)
and the post-implantation losses were increased
(15% vs. 8%) in the group given 0.15 mg/kg
once daily when compared to the controls; the mean
numbers of implants (6.5 vs. 4.4) and normal live
fetuses (5.4 vs. 3.8) were greater in this group
when compared to the control group.
Labor and Delivery:
It is not known whether muscle
relaxants administered during vaginal delivery
have immediate or delayed adverse effects on the
fetus or increase the likelihood that
resuscitation of the newborn will be necessary.
The possibility that forceps delivery will be
necessary may increase.
Atracurium besylate (0.3 mg/kg) has
been administered to 26 pregnant women during
delivery by cesarean section. No harmful effects
were attributable to atracurium in any of the
neonates, although small amounts of atracurium
were shown to cross the placental barrier. The
possibility of respiratory depression in the
neonate should always be considered following
cesarean section during which a neuromuscular
blocking agent has been administered. In patients
receiving magnesium sulfate, the reversal of
neuromuscular block may be unsatisfactory and the
dose of atracurium besylate should be lowered as
indicated.
Nursing Mothers:
It is not known whether this
drug is excreted in human milk. Because many drugs
are excreted in human milk, caution should be
exercised when atracurium besylate is administered
to a nursing woman.
Pediatric Use:
Safety and effectiveness in
pediatric patients below the age of 1 month have
not been established.
Geriatric Use:
Since marketing in 1983,
uncontrolled clinical experience and limited data
from controlled trials have not identified
differences in effectiveness, safety, or dosage
requirements between healthy elderly and younger
patients (see
CLINICAL
PHARMACOLOGY
);
however, as with other neuromuscular blocking
agents, the use of a peripheral nerve stimulater
to monitor neuromuscular function is suggested
(see
DOSAGE AND
ADMINISTRATION
).
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