Doxacurium Chloride
Adverse Effecte, Treatment, Precautions and Interactions as for competitive neuromuscular blockers in general like Atracurium.
ATRACURIUM
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.
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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)
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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%
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*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)
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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%
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*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)).
Doxacurium has little histamine-releas-
ing activity and causes negligible vagal or sympathetic block-
ade so that significant cardiovascular side-effects are not a
problem.
Renal impairment. Although the duration of neuromuscu-
lar block and speed of recovery following the use of doxacu-
rium were found to be prolonged in patients with renal failure
when compared with patients with normal renal function, the
differences were considered not to be significant.
Pharmacokinetics
Following intravenous administration, doxacurium chloride
is excreted mainly unchanged in the urine and bile. The elim-
ination half-life is reported to be about 2 hours.
Uses and Administration
Doxacurium chloride is a benzylisoquinolinium competitive
neuromuscular blocker (see Atracurium ). It is used
for endotracheal intubation and to provide muscle relaxation
in general anaesthesia for surgical procedures (see Anaesthe-
sia) and to aid controlled ventilation (see below).
Dosages are expressed in terms of the equivalent amount of
doxacurium base. The usual initial dose is 50 ng per kg body-
weight intravenously: maintenance doses of 5 to 10 ng per kg
are employed. At the above dose muscle relaxation occurs
within about 5 minutes and the effect lasts for about 100 min-
utes. For more prolonged procedures an initial dose. of 80 ng
per kg may be used , which produces muscle relaxation in
about 4 minutes and the effects last for about 2 hours.
Administration in the elderly. There are several studies
that have shown that the duration of action of doxacurium is
prolonged in the elderly, although the precise mechanism for
this prolongation is subject to debate. Since both the onset
of action and recovery are delayed some consider that doxa-
curium may not be suitable for use in the elderly for surgical
procedures of less than one hour.
Administration In Infants and children. As for some
other neuromuscular blockers, children over 2 years of age
have been found to require more doxacurium per kg body-
weight than adults to achieve a similar degree of neuromuscu-
lar blockade. and the dosage requirement may be almost
twice as great as that for adults. Children may also recover
more quickly. However, the sensitivity of infants under one
year of age appears to be increased.
Intensive care. Experience of the use of doxacurium to fa-
cilitate mechanical ventilation in patients in intensive care
is relatively limited. It appears to offer prolonged
neuromuscular block without the tachycardia associated with
pancuronium; recovery after prolonged administration may
also be faster than with pancuronium. There has been an an-
ccdotal report of the successful management with doxacuri-
um of 4 patients who had developed tachyphylaxis to long-
term administration to atracurium.