ATRACURIUM BESYLATE
DESCRIPTION:
This drug should be used only by adequately trained individuals familiar with
its actions, characteristics, and hazards.
TRACRIUM (atracurium besylate) is an intermediate-duration, nondepolarizing,
skeletal muscle relaxant for intravenous administration. Atracurium besylate is
designated as 2,2'-(1,5-pentanediylbis(oxy(3-oxo- 3,1-propanediyl)))bis (1-
((3,4-dimethoxyphenyl)methyl)-1,2,3,4-tetrahyd ro-6,7-dimethoxy- 2-
methylisoquinolinium)dibenzenesulfonate. It has a molecular weight of 1243.51,
and its molecular formula is C65H82N2O18S2.
Atracurium besylate is a complex molecule containing four sites at which
different stereochemical configurations can occur. The symmetry of the molecule,
however, results in only ten, instead of sixteen, possible different isomers.
The manufacture of atracurium besylate results in these isomers being produced
in unequal amounts but with a consistent ratio. Those molecules in which the
methyl group attached to the quaternary nitrogen projects on the opposite side
to the adjacent substituted- benzyl moiety predominate by approximately 3:1.
TRACRIUM Injection is a sterile, non-pyrogenic aqueous solution. Each mL
contains 10 mg atracurium besylate. The pH is adjusted to 3.25 to 3.65 with
benzenesulfonic acid. The multiple- dose vial contains 0.9% benzyl alcohol added
as a preservative. TRACRIUM slowly loses potency with time at the rate of
approximately 6% per Year under refrigeration (5 deg C). TRACRIUM Injection
should be refrigerated at 2 deg to 8 deg C (36 deg to 46 deg F) to preserve
potency. Rate of loss in potency increases to approximately 5% per Month at 25
deg C (77 deg F). Upon removal from refrigeration to room temperature storage
conditions (25 deg C/77 deg F), use TRACRIUM Injection within 14 days even if
rerefrigerated.
ACTIONS/CLINICAL PHARMACOLOGY:
TRACRIUM is a nondepolarizing skeletal muscle relaxant. Nondepolarizing agents
antagonize the neurotransmitter action of acetylcholine by binding competitively
with cholinergic receptor sites on the motor end-plate. This antagonism is
inhibited, and neuromuscular block reversed, by acetylcholinesterase inhibitors
such as neostigmine, edrophonium, and pyridostigmine.
TRACRIUM can be used most advantageously if muscle twitch response to peripheral
nerve stimulation is monitored to assess degree of muscle relaxation.
The duration of neuromuscular block produced by TRACRIUM is approximately one-
third to one-half the duration of block by d-tubocurarine, metocurine, and
pancuronium at initially equipotent doses. As with other nondepolarizing
neuromuscular blockers, the time to onset of paralysis decreases and the
duration of maximum effect increases with increasing doses of TRACRIUM.
The ED95 (dose required to produce 95% suppression of the muscle twitch response
with balanced anesthesia) has averaged 0.23 mg/kg (0.11 to 0.26 mg/kg in various
studies). An initial dose of TRACRIUM 0.4 to 0.5 mg/kg generally produces
maximum neuromuscular block within 3 to 5 minutes of injection, with good or
excellent intubation conditions within 2 to 2.5 minutes in most patients.
Recovery from neuromuscular block (under balanced anesthesia) can be expected to
begin approximately 20 to 35 minutes after injection. Under balanced anesthesia,
recovery to 25% of control is achieved approximately 35 to 45 minutes after
injection, and recovery is usually 95% complete approximately 60 to 70 minutes
after injection. The neuromuscular blocking action of TRACRIUM is enhanced in
the presence of potent inhalation anesthetics. Isoflurane and enflurane increase
the potency of TRACRIUM and prolong neuromuscular block by approximately 35%;
however, halothane's potentiating effect (approximately 20%) is marginal (see
DOSAGE AND ADMINISTRATION).
Repeated administration of maintenance doses of TRACRIUM has no cumulative
effect on the duration of neuromuscular block if recovery is allowed to begin
prior to repeat dosing. Moreover, the time needed to recover from repeat doses
does not change with additional doses. Repeat doses can therefore be
administered at relatively regular intervals with predictable results. After an
initial dose of 0.4 to 0.5 mg/kg under balanced anesthesia, the first
maintenance dose (suggested maintenance dose is 0.08 to 0.10 mg/kg) is generally
required within 20 to 45 minutes, and subsequent maintenance doses are usually
required at approximately 15- to 25-minute intervals.
Once recovery from the neuromuscular blocking effects of TRACRIUM begins, it
proceeds more rapidly than recovery from d-tubocurarine, metocurine, and
pancuronium. Regardless of the dose of TRACRIUM, the time from start of recovery
(from complete block) to complete (95%) recovery is approximately 30 minutes
under balanced anesthesia, and approximately 40 minutes under halothane,
enflurane, or isoflurane. Repeated doses have no cumulative effect on recovery
rate.
Reversal of neuromuscular block produced by TRACRIUM can be achieved with an
anticholinesterase agent such as neostigmine, edrophonium or pyridostigmine, in
conjunction with an anticholinergic agent such as atropine or glycopyrrolate.
Under balanced anesthesia, reversal can usually be attempted approximately 20 to
35 minutes after an initial TRACRIUM dose of 0.4 to 0.5 mg/kg, or approximately
10 to 30 minutes after a 0.08- to 0.10-mg/kg maintenance dose, when recovery of
muscle twitch has started. Complete reversal is usually attained within 8 to 10
minutes of the administration of reversing agents. Rare instances of breathing
difficulties, possibly related to incomplete reversal, have been reported
following attempted pharmacologic antagonism of neuromuscular block induced by
TRACRIUM. As with other agents in this class, the tendency for residual
neuromuscular block is increased if reversal is attempted at deep levels of
block or if inadequate doses of reversal agents are employed.
The pharmacokinetics of TRACRIUM in humans are essentially linear within the
0.3- to 0.6-mg/kg dose range. The elimination half-life is approximately 20
minutes. THE DURATION OF NEUROMUSCULAR BLOCK PRODUCED BY TRACRIUM DOES NOT
CORRELATE WITH PLASMA PSEUDOCHOLINESTERASE LEVELS AND IS NOT ALTERED BY THE
ABSENCE OF RENAL FUNCTION. This is consistent with the results of in vitro
studies which have shown that TRACRIUM is inactivated in plasma via two
nonoxidative pathways: ester hydrolysis, catalyzed by nonspecific esterases; and
Hofmann elimination, a nonenzymatic chemical process which occurs at
physiological pH. Some placental transfer occurs in humans.
Radiolabel studies demonstrated that TRACRIUM undergoes extensive degradation in
cats, and that neither kidney nor liver plays a major role in its elimination.
Biliary and urinary excretion were the major routes of excretion of
radioactivity (totaling > 90% of the labeled dose within 7 hours of dosing), of
which TRACRIUM represented only a minor fraction. The metabolites in bile and
urine were similar, including products of Hofmann elimination and ester
hydrolysis.
Elderly patients may have slightly altered pharmacokinetic parameters compared
to younger patients, with a slightly decreased total plasma clearance which is
offset by a corresponding increase in volume of distribution. The net effect is
that there has been no significant difference in clinical duration and recovery
from neuromuscular block observed between elderly and younger patients receiving
TRACRIUM.
TRACRIUM is a less potent histamine releaser than d-tubocurarine or metocurine.
Histamine release is minimal with initial TRACRIUM doses up to 0.5 mg/kg, and
hemodynamic changes are minimal within the recommended dose range. A moderate
histamine release and significant falls in blood pressure have been seen
following 0.6 mg/kg of TRACRIUM. The histamine and hemodynamic responses were
poorly correlated. The effects were generally short-lived and manageable, but
the possibility of substantial histamine release in sensitive individuals or in
patients in whom substantial histamine release would be especially hazardous
(e.g., patients with significant cardiovascular disease) must be considered.
It is not known whether the prior use of other nondepolarizing neuromuscular
blocking agents has any effect on the activity of TRACRIUM. The prior use of
succinylcholine decreases by approximately 2 to 3 minutes the time to maximum
block induced by TRACRIUM, and may increase the depth of block. TRACRIUM should
be administered only after a patient recovers from succinylcholine-induced
neuromuscular block.
INDICATIONS AND USAGE:
TRACRIUM is indicated, as an adjunct to general anesthesia, to facilitate
endotracheal intubation and to provide skeletal muscle relaxation during surgery
or mechanical ventilation.
CONTRAINDICATIONS:
TRACRIUM is contraindicated in patients known to have a hypersensitivity to it.
Use of TRACRIUM from multiple-dose vials containing benzl alcohol as a
preservative is contraindicated in patients with a known hypersensitivity to
benzyl alcohol.
WARNINGS:
TRACRIUM 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 TRACRIUM BY INTRAMUSCULAR ADMINISTRATION.
TRACRIUM has no known effect on consciousness, pain threshold, or cerebration.
It should be used only with adequate anesthesia.
TRACRIUM 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, TRACRIUM may be inactivated and a free acid
may be precipitated.
TRACRIUM 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. TRACRIUM
Injection 5-mL single-use vials do not contain benzyl alcohol (see PRECAUTIONS:
Pediatric Use).
PRECAUTIONS:
GENERAL: Although TRACRIUM 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 TRACRIUM 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 TRACRIUM dose is lower (0.3
to 0.4 mg/kg) than for other patients and should be administered slowly or in
divided doses over 1 minute.
Since TRACRIUM 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 TRACRIUM than with other muscle relaxants.
TRACRIUM 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 TRACRIUM
has been used. In studies of MH-susceptible animals (swine) and in a clinical
study of MH-susceptible patients, TRACRIUM 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 TRACRIUM 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 TRACRIUM during
mechanical ventilation in the ICU has been evaluated in several studies. Average
infusion rates of 11 to 13 mcg/kg/min (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 TRACRIUM 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 min) and spontaneous recovery to a
train-of- four ratio >75% (the ratio of the 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 min).
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 TRACRIUM 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 TRACRIUM 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
TRACRIUM 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
TRACRIUM. TRACRIUM 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 1,000 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 (1,200 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.
TRACRIUM 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. TRACRIUM should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
TRACRIUM was administered subcutaneously on days 6 through 18 of gestation to
non-ventilated 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.
TRACRIUM (0.3 mg/kg) has been administered to 26 pregnant women during delivery
by cesarean section. No harmful effects were attributable to TRACRIUM in any of
the neonates, although small amounts of TRACRIUM 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 TRACRIUM 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
TRACRIUM is administered to a nursing woman.
PEDIATRIC USE: Safety and effectiveness in pediatric patients below the age of 1
month have not been established.
USE IN THE ELDERLY: 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 ACTIONS/CLINICAL PHARMACOLOGY); however, as with other
neuromuscular blocking agents, the use of a peripheral nerve stimulator to
monitor neuromuscular function is suggested (see DOSAGE AND ADMINISTRATION).
DRUG INTERACTIONS:
Drugs which may enhance the neuromuscular blocking action of TRACRIUM 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
TRACRIUM. TRACRIUM should not be administered until a patient has recovered from
succinylcholine-induced neuromuscular block.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
OBSERVED IN CONTROLLED CLINICAL STUDIES: TRACRIUM was well tolerated and
produced few adverse reactions during extensive clinical trials. Most adverse
reactions were suggestive of histamine release. In studies including 875
patients, TRACRIUM was discontinued in only one patient (who required treatment
for bronchial secretions), and six other patients required treatment for adverse
reactions attributable to TRACRIUM (wheezing in one, hypotension in five). Of
the five patients who required treatment for hypotension, three had a history of
significant cardiovascular disease. The overall incidence rate for clinically
important adverse reactions, therefore, was 7/875 or 0.8%. The table below
includes all adverse reactions reported attributable to TRACRIUM during clinical
trials with 875 patients.
----------------------------------------------------------------------
TABLE 1: PERCENT OF PATIENTS REPORTING ADVERSE REACTIONS
ADVERSE REACTION INITIAL TRACRIUM DOSE (MG/KG)
-----------------------------------------------------------------------------------------------------------------
0.00-0.30 0.31-0.50* >/= 0.60 Total
(n = 485) (n = 366) (n = 24) (n = 875)
---------------------------------------------------------------------------------------------------------------------------------
Skin Flush 1.0% 8.7% 29.2% 5.0%
Erythema 0.6% 0.5% 0% 0.6%
Itching 0.4% 0% 0% 0.2%
Wheezing/
Bronchial
Secretions 0.2% 0.3% 0% 0.2%
Hives 0.2% 0% 0% 0.1%
----------------------------------------------------------------------------------------------------------------------------------
*Includes the recommended initial dosage range for most patients.
Most adverse reactions were of little clinical significance unless they were
associated with significant hemodynamic changes. Table 2 summarizes the
incidences of substantial vital sign changes noted during clinical trials of
TRACRIUM with 530 patients, without cardiovascular disease, in whom these
parameters were assessed.
TABLE 2: PERCENT OF PATIENTS SHOWING > 30% VITAL SIGN
CHANGES FOLLOWING ADMINISTRATION OF TRACRIUM
VITAL SIGN CHANGE INITIAL TRACRIUM DOSE (MG/KG)
-------------------------------------------------------------------------------------------------------------
0.00-0.30 0.31-0.50* >/= 0.60 Total
(n = 365) (n = 144) (n = 21) (n = 530)
-------------------------------------------------------------------------------------------------------------------------------
Mean Arterial Pressure
Increase 1.9% 2.8% 0% 2.1%
Decrease 1.1% 2.1% 14.3% 1.9%
Heart Rate
Increase 1.6% 2.8% 4.8% 2.1%
Decrease 0.8% 0% 0% 0.6%
-------------------------------------------------------------------------------------------------------------------------------
*Includes the recommended initial dosage range for most patients.
OBSERVED IN CLINICAL PRACTICE: Based on initial clinical practice experience in
approximately 3 million patients who received TRACRIUM in the U.S. and in the
United Kingdom, spontaneously reported adverse reactions were uncommon
(approximately 0.01% to 0.02%). The following adverse reactions are among the
most frequently reported, but there are insufficient data to support an estimate
of their incidence:
GENERAL: Allergic reactions (anaphylactic or anaphylactoid responses) which, in
rare instances, were severe (e.g., cardiac arrest)
MUSCULOSKELETAL: Inadequate block, prolonged block
CARDIOVASCULAR: Hypotension, vasodilatation (flushing), tachycardia, bradycardia
RESPIRATORY: Dyspnea, bronchospasm, laryngospasm
INTEGUMENTARY: Rash, urticaria, reaction at injection site
There have been rare spontaneous reports of seizures in ICU patients following
long-term infusion of atracurium to support mechanical ventilation. There are
insufficient data to define the contribution, if any, of atracurium and/or its
metabolite laudanosine. (See PRECAUTIONS: Long-Term Use in Intensive Care Unit
(ICU)).
OVERDOSAGE:
There has been limited experience with overdosage of TRACRIUM. The possibility
of iatrogenic overdosage can be minimized by carefully monitoring muscle twitch
response to peripheral nerve stimulation. Excessive doses of TRACRIUM can be
expected to produce enhanced pharmacological effects. Overdosage may increase
the risk of histamine release and cardiovascular effects, especially
hypotension. If cardiovascular support is necessary, this should include proper
positioning, fluid administration, and the use of vasopressor agents if
necessary. The patient's airway should be assured, with manual or mechanical
ventilation maintained as necessary. A longer duration of neuromuscular block
may result from overdosage and a peripheral nerve stimulator should be used to
monitor recovery. Recovery may be facilitated by administration of an
anticholinesterase reversing agent such as neostigmine, edrophonium, or
pyridostigmine, in conjunction with an anticholinergic agent such as atropine or
glycopyrrolate. The appropriate package inserts should be consulted for
prescribing information.
Three pediatric patients (3 weeks, 4 and 5 months of age) unintentionally
received doses of 0.8 mg/kg to 1.0 mg/kg of TRACRIUM. The time to 25% recovery
(50 to 55 minutes) following these doses, which were 5 to 6 times the ED95 dose,
was moderately longer than the corresponding time observed following doses 2.0
to 2.5 times the TRACRIUM ED95 dose in infants (22 to 36 minutes).
Cardiovascular changes were minimal. Nonetheless the possibility of
cardiovascular changes must be considered in the case of overdose.
An adult patient (17 years of age) unintentionally received an initial dose of
1.3 mg/kg of TRACRIUM. The time from injection to 25% recovery (83 minutes) was
approximately twice that observed following maximum recommended doses in adults
(35 to 45 minutes). The patient experienced moderate hemodynamic changes (13%
increase in mean arterial pressure and 27% increase in heart rate) which
persisted for 40 minutes and did not require treatment.
The intravenous LD50s determined in non- ventilated male and female albino mice
and male Wistar rats were 1.9, 2.01, and 1.31 mg/kg, respectively. Deaths
occurred within 2 minutes and were caused by respiratory paralysis. The
subcutaneous LD50 determined in non-ventilated male Wistar rats was 282.8 mg/kg.
Tremors, ptosis, loss of reflexes, and respiratory failure preceded death which
occurred 45 to 120 minutes after injection.
DOSAGE AND ADMINISTRATION:
To avoid distress to the patient, TRACRIUM should not be administered before
unconsciousness has been induced. TRACRIUM should not be mixed in the same
syringe, or administered simultaneously through the same needle, with alkaline
solutions (e.g., barbiturate solutions).
TRACRIUM should be administered intravenously. DO NOT GIVE TRACRIUM BY
INTRAMUSCULAR ADMINISTRATION. Intramuscular administration of TRACRIUM may
result in tissue irritation and there are no clinical data to support this route
of administration.
As with other neuromuscular blocking agents, the use of a peripheral nerve
stimulator will permit the most advantageous use of TRACRIUM, minimizing the
possibility of overdosage or underdosage, and assist in the evaluation of
recovery.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
BOLUS DOSES FOR INTUBATION AND MAINTENANCE OF NEUROMUSCULAR BLOCK: ADULTS: A
dose of TRACRIUM of 0.4 to 0.5 mg/kg (1.7 to 2.2 times the ED95), given as an
intravenous bolus injection, is the recommended initial dose for most patients.
With this dose, good or excellent conditions for nonemergency intubation can be
expected in 2 to 2.5 minutes in most patients, with maximum neuromuscular block
achieved approximately 3 to 5 minutes after injection. Clinically required
neuromuscular block generally lasts 20 to 35 minutes under balanced anesthesia.
Under balanced anesthesia, recovery to 25% of control is achieved approximately
35 to 45 minutes after injection, and recovery is usually 95% complete
approximately 60 minutes after injection.
TRACRIUM is potentiated by isoflurane or enflurane anesthesia. The same initial
dose of TRACRIUM of 0.4 to 0.5 mg/kg may be used for intubation prior to
administration of these inhalation agents; however, if TRACRIUM is first
administered under steady state of isoflurane or enflurane, the initial dose of
TRACRIUM should be reduced by approximately one-third, i.e., to 0.25 to 0.35
mg/kg, to adjust for the potentiating effects of these anesthetic agents. With
halothane, which has only a marginal (approximately 20%) potentiating effect on
TRACRIUM, smaller dosage reductions may be considered.
Doses of TRACRIUM of 0.08 to 0.10 mg/kg are recommended for maintenance of
neuromuscular block during prolonged surgical procedures. The first maintenance
dose will generally be required 20 to 45 minutes after the initial TRACRIUM
Injection, but the need for maintenance doses should be determined by clinical
criteria. Because TRACRIUM lacks cumulative effects, maintenance doses may be
administered at relatively regular intervals for each patient, ranging
approximately from 15 to 25 minutes under balanced anesthesia, slightly longer
under isoflurane or enflurane. Higher doses of TRACRIUM (up to 0.2 mg/kg) permit
maintenance dosing at longer intervals.
PEDIATRIC PATIENTS: No TRACRIUM dosage adjustments are required for pediatric
patients two years of age or older. A dose of TRACRIUM 0.3 to 0.4 mg/kg is
recommended as the initial dose for infants (1 month to 2 years of age) under
halothane anesthesia. Maintenance doses may be required with slightly greater
frequency in infants and children than in adults.
SPECIAL CONSIDERATIONS: An initial dose of TRACRIUM of 0.3 to 0.4 mg/kg, given
slowly or in divided doses over 1 minute, is recommended for adults,
adolescents, children, or infants with significant cardiovascular disease and
for adults, adolescents, children, or infants with any history (e.g., severe
anaphylactoid reactions or asthma) suggesting a greater risk of histamine
release.
Dosage reductions must be considered also in patients with neuromuscular
disease, severe electrolyte disorders, or carcinomatosis in which potentiation
of neuromuscular block or difficulties with reversal have been demonstrated.
There has been no clinical experience with TRACRIUM in these patients, and no
specific dosage adjustments can be recommended. No TRACRIUM dosage adjustments
are required for patients with renal disease.
An initial dose of TRACRIUM of 0.3 to 0.4 mg/kg is recommended for adults
following the use of succinylcholine for intubation under balanced anesthesia.
Further reductions may be desirable with the use of potent inhalation
anesthetics. The patient should be permitted to recover from the effects of
succinylcholine prior to administration of TRACRIUM. Insufficient data are
available for recommendation of a specific initial dose of TRACRIUM for
administration following the use of succinylcholine in children and infants.
USE BY CONTINUOUS INFUSION: INFUSION IN THE OPERATING ROOM (OR): After
administration of a recommended initial bolus dose of TRACRIUM (0.3 to 0.5
mg/kg), a diluted solution of TRACRIUM can be administered by continuous
infusion to adults and pediatric patients aged 2 or more years for maintenance
of neuromuscular block during extended surgical procedures.
Infusion of TRACRIUM should be individualized for each patient. The rate of
administration should be adjusted according to the patient's response as
determined by peripheral nerve stimulation. Accurate dosing is best achieved
using a precision infusion device.
Infusion of TRACRIUM should be initiated only after early evidence of
spontaneous recovery from the bolus dose. An initial infusion rate of 9 to 10
mcg/kg/min may be required to rapidly counteract the spontaneous recovery of
neuromuscular function. Thereafter, a rate of 5 to 9 mcg/kg/min should be
adequate to maintain continuous neuromuscular block in the range of 89% to 99%
in most pediatric and adult patients under balanced anesthesia. Occasional
patients may require infusion rates as low as 2 mcgm/kg/min or as high as 15
mcg/kg/min.
The neuromuscular blocking effect of TRACRIUM administered by infusion is
potentiated by enflurane or isoflurane and, to a lesser extent, by halothane.
Reduction in the infusion rate of TRACRIUM should, therefore, be considered for
patients receiving inhalation anesthesia. The infusion rate of TRACRIUM should
be reduced by approximately one-third in the presence of steady-state enflurane
or isoflurane anesthesia; smaller reductions should be considered in the
presence of halothane.
In patients undergoing cardiopulmonary bypass with induced hypothermia, the rate
of infusion of TRACRIUM required to maintain adequate surgical relaxation during
hypothermia (25 deg to 28 deg C) has been shown to be approximately half the
rate required during normothermia.
Spontaneous recovery from neuromuscular block following discontinuation of
infusion of TRACRIUM may be expected to proceed at a rate comparable to that
following administration of a single bolus dose.
INFUSION IN THE INTENSIVE CARE UNIT(ICU): The principles for infusion of
TRACRIUM in the OR are also applicable to use in the ICU.
An infusion rate of 11 to 13 mcg/kg/min (range: 4.5 to 29.5) should provide
adequate neuromuscular block in adult patients in an ICU. Limited information
suggests that infusion rates required for pediatric patients in the ICU may be
higher than in adult patients. There may be wide interpatient variability in
dosage requirements and these requirements may increase or decrease with time
(see PRECAUTIONS: Long-Term Use in Intensive Care Unit (ICU)). Following
recovery from neuromuscular block, readministration of a bolus dose may be
necessary to quickly re- establish neuromuscular block prior to reinstitution of
the infusion.
INFUSION RATE TABLES: The amount of infusion solution required per minute will
depend upon the concentration of TRACRIUM in the infusion solution, the desired
dose of TRACRIUM, and the patient's weight. The following tables provide
guidelines for delivery, in mL/hr (equivalent to microdrops/min when 60
microdrops = 1 mL), of solutions of TRACRIUM in concentrations of 0.2 mg/mL (20
mg in 100 mL) or 0.5 mg/mL (50 mg in 100 mL) with an infusion pump or a gravity
flow device.
TABLE 3: TRACRIUM (ATRACURIUM BESYLATE) INFUSION RATES
FOR A CONCENTRATION OF 0.2 MG/ML
---------------------------------------------------------------------------------------------------------------------------------
Drug Delivery Rate (mcg/kg/min)
Patient
Weight 5 6 7 8 9 10 11 12 13
(Kg) ------------------------------------------------------------------------------------
Infusion Delivery Rate (mL/hr)
------------------------------------------------------------------------------------------------------------------
30 45 54 63 72 81 90 99 108 117
35 53 63 74 84 95 105 116 126 137
40 60 72 84 96 108 120 132 144 156
45 68 81 95 108 122 135 149 162 176
50 75 90 105 120 135 150 165 180 195
55 83 99 116 132 149 165 182 198 215
60 90 108 126 144 162 180 198 216 234
65 98 117 137 156 176 195 215 234 254
70 105 126 147 168 189 210 231 252 273
75 113 135 158 180 203 225 248 270 293
80 120 144 168 192 216 240 264 288 312
90 135 162 189 216 243 270 297 324 351
100 150 180 210 240 270 300 330 360 390
------------------------------------------------------------------------------------------------------------------
TABLE 4: TRACRIUM (ATRACURIUM BESYLATE) INFUSION RATES
FOR A CONCENTRATION OF 0.5 MG/ML
-------------------------------------------------------------------------------------------------------------------------------------
Drug Delivery Rate (mcg/kg/min)
Patient
Weight 5 6 7 8 9 10 11 12 13
(Kg) ---------------------------------------------------------------------------------------------
Infusion Delivery Rate (mL/hr)
--------------------------------------------------------------------------------------------------------
30 18 22 25 29 32 36 40 43 47
35 21 25 29 34 38 42 46 50 55
40 24 29 34 38 43 48 53 58 62
45 27 32 38 43 49 54 59 65 70
50 30 36 42 48 54 60 66 72 78
55 33 40 46 53 59 66 73 79 86
60 36 43 50 58 65 72 79 86 94
65 39 47 55 62 70 78 86 94 101
70 42 50 59 67 76 84 92 101 109
75 45 54 63 72 81 90 99 108 117
80 48 58 67 77 86 96 106 115 125
90 54 65 76 86 97 108 119 130 140
100 60 72 84 96 108 120 132 144 156
------------------------------------------------------------------------------------------------------------
COMPATIBILITY AND ADMIXTURES: Infusion solutions of TRACRIUM may be prepared by
admixing TRACRIUM Injection with an appropriate diluent such as 5% Dextrose
Injection, USP; 0.9% Sodium Chloride Injection, USP; or 5% Dextrose and 0.9%
Sodium Chloride Injection, USP. Infusion solutions should be used within 24
hours of preparation. Unused solutions should be discarded. Solutions containing
0.2 mg/mL or 0.5 mg/mL TRACRIUM in the above diluents may be stored either under
refrigeration or at room temperature for 24 hours without significant loss of
potency. Care should be taken during admixture to prevent inadvertent
contamination. Visually inspect prior to administration.
Spontaneous degradation of TRACRIUM has been demonstrated to occur more rapidly
in Lactated Ringer's solution than in 0.9% sodium chloride solution. Therefore,
it is recommended that Lactated Ringer's Injection USP not be used as a diluent
in preparing solutions of TRACRIUM for infusion.
************************************************************************