Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3222
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NUROMAX (Injection)
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NUROMAX SHOULD ONLY
BE ADMINISTERED INTRAVENOUSLY. NUROMAX,
like other long-acting neuromuscular blocking agents, displays variability
in the duration of its effect. The potential for a prolonged clinical duration
of neuromuscular block must be considered when NUROMAX is selected for administration.
The dosage information provided below is intended as a guide only. Doses
should be individualized (see CLINICAL PHARMACOLOGY
-Individualization of Dosages).
Factors that may warrant dosage adjustment include: advancing age, the presence
of kidney or liver disease, or obesity (patients weighing���30%
more than ideal body weight for height). The use of a peripheral nerve stimulator
will permit the most advantageous use of NUROMAX, minimize 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.<br/>Adults:<br/>Initial Doses: When administered as a component of a thiopental/narcotic
induction-intubation paradigm as well as for production of long-duration neuromuscular
block during surgery, 0.05 mg/kg (2��ED) NUROMAX produces
good-to-excellent conditions for tracheal intubation in 5 minutes in approximately
90% of patients. Lower doses of NUROMAX may result in a longer time for development
of satisfactory intubation conditions. Clinically effective neuromuscular
block may be expected to last approximately 100 minutes on average (range:
39 to 232) following 0.05 mg/kg NUROMAX administered to patients receiving
balanced anesthesia. An initial NUROMAX dose
of 0.08 mg/kg (3��ED) should be reserved for instances
in which a need for very prolonged neuromuscular block is anticipated. In
approximately 90% of patients, good-to-excellent intubation conditions may
be expected in 4 minutes after this dose; however, clinically effective block
may be expected to persist for as long as 160 minutes or more (range: 110
to 338) (see CLINICAL PHARMACOLOGY). If NUROMAX is administered during steady-state isoflurane,
enflurane, or halothane anesthesia, reduction of the dose of NUROMAX by one
third should be considered. When succinylcholine
is administered to facilitate tracheal intubation in patients receiving balanced
anesthesia, an initial dose of 0.025 mg/kg (ED) NUROMAX provides
about 60 minutes (range: 9 to 145) of clinically effective neuromuscular
block for surgery. For a longer duration of action, a larger initial dose
may be administered.<br/>Maintenance Doses: Maintenance dosing will generally be required
about 60 minutes after an initial dose of 0.025 mg/kg NUROMAX or 100 minutes
after an initial dose of 0.05 mg/kg NUROMAX during balanced anesthesia. Repeated
maintenance doses administered at 25% Trecovery may be expected
to be required at relatively regular intervals in each patient. The interval
may vary considerably between patients. Maintenance doses of 0.005 and 0.01
mg/kg NUROMAX each provide an average 30 minutes (range: 9 to 57) and
45 minutes (range: 14 to 108), respectively, of additional clinically
effective neuromuscular block. For shorter or longer desired durations, smaller
or larger maintenance doses may be administered.<br/>Children: When administered during halothane anesthesia, an
initial dose of 0.03 mg/kg (ED) produces maximum neuromuscular
block in about 7 minutes (range: 5 to 11) and clinically effective block
for an average of 30 minutes (range: 12 to 54). Under halothane anesthesia,
0.05 mg/kg produces maximum block in about 4 minutes (range: 2 to
10) and clinically effective block for 45 minutes (range: 30 to
80). Maintenance doses are generally required more frequently in children
than in adults. Because of the potentiating effect of halothane seen in adults,
a higher dose of NUROMAX may be required in children receiving balanced anesthesia
than in children receiving halothane anesthesia to achieve a comparable onset
and duration of neuromuscular block. NUROMAX has not been studied in pediatric
patients below the age of 2 years.<br/>Compatibility:<br/>Y-site Administration: NUROMAX Injection may not be compatible with alkaline
solutions with a pH greater than 8.5 (e.g., barbiturate solutions). NUROMAX is compatible with:<br/>Dilution Stability: NUROMAX diluted up to 1:10 in 5% Dextrose Injection,
USP or 0.9% Sodium Chloride Injection, USP has been shown to be physically
and chemically stable when stored in polypropylene syringes at 5��to
25��C (41��to 77��F), for up to 24 hours. Since dilution
diminishes the preservative effectiveness of benzyl alcohol, aseptic techniques
should be used to prepare the diluted product. Immediate use of the diluted
product is preferred, and any unused portion of diluted NUROMAX should be
discarded after 8 hours.
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| dailymed-instance:descripti... |
NUROMAX (doxacurium chloride) is a long-acting, nondepolarizing
skeletal muscle relaxant for intravenous administration. Doxacurium chloride
is [1��,2��(1'S*,2'R*)]-2,2'-[(1,4-dioxo-1,4-butanediyl)bis(oxy-3,1-propanediyl)]bis[1,2,3,4-tetrahydro-6,7,8-trimethoxy-2-
methyl-1-[(3,4,5-trimethoxyphenyl)methyl]isoquinolinium] dichloride (meso
form). The molecular formula is CHCINOand
the molecular weight is 1106.14. The compound does not partition into the
1-octanol phase of a distilled water/ 1-octanol system, i.e., the n-octanol:water
partition coefficient is 0. Doxacurium chloride
is a mixture of three trans, trans stereoisomers, a dl pair [(1R,1'R,2S,2'S) and (1S,1'S,2R,2'R)] and a meso form (1R,1'S,2S,2'R). The meso form is illustrated below: NUROMAX Injection is a sterile, nonpyrogenic aqueous solution
(pH 3.9 to 5.0) containing doxacurium chloride equivalent to 1 mg/mL doxacurium
in Water for Injection. Hydrochloric acid may have been added to adjust pH.
NUROMAX Injection contains 0.9% w/v benzyl alcohol.
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NUROMAX binds competitively to cholinergic receptors
on the motor end-plate to antagonize the action of acetylcholine, resulting
in a block of neuromuscular transmission. This action is antagonized by acetylcholinesterase
inhibitors, such as neostigmine.<br/>Pharmacodynamics: NUROMAX is approximately 2.5 to 3 times more potent
than pancuronium and 10 to 12 times more potent than metocurine. NUROMAX
in doses of 1.5 to 2��EDhas a clinical duration of action
(range and variability) similar to that of equipotent doses of pancuronium
and metocurine (historic data and limited comparison). The average ED(dose
required to produce 95% suppression of the adductor pollicis muscle twitch
response to ulnar nerve stimulation) of NUROMAX is 0.025 mg/kg (range: 0.020
to 0.033) in adults receiving balanced anesthesia. The
onset and clinically effective duration (time from injection to 25% recovery)
of NUROMAX administered alone or after succinylcholine during stable balanced
anesthesia are shown in Table 1. Initial doses of 0.05 mg/kg (2��ED)
and 0.08 mg/kg (3��ED) NUROMAX administered during the
induction of thiopental-narcotic anesthesia produced good-to-excellent conditions
for tracheal intubation in 5 minutes (13 of 15 cases studied) and 4 minutes
(eight of nine cases studied) (which are before maximum block), respectively. As with other long-acting agents, the clinical duration
of neuromuscular block associated with NUROMAX shows considerable interpatient
variability. An analysis of 390 cases in US clinical trials utilizing a variety
of premedications, varying lengths of surgery, and various anesthetic agents,
indicates that approximately two thirds of the patients had clinical durations
within 30 minutes of the duration predicted by dose (based on mg/kg actual
body weight). Patients���60 years old are approximately twice as likely
to experience prolonged clinical duration (30 minutes longer than predicted)
than patients<60 years old; thus, care should be used in older patients
when prolonged recovery is undesirable (see PRECAUTIONS
-Geriatric Use and CLINICAL PHARMACOLOGY - Individualization of Dosages subsection).
In addition, obese patients (patients weighing���30% more than ideal
body weight for height) were almost twice as likely to experience prolonged
clinical duration than non-obese patients; therefore, dosing should be based
on ideal body weight (IBW) for obese patients (see CLINICAL
PHARMACOLOGY - Individualization of Dosages subsection). The mean time for spontaneous Trecovery from
25% to 50% of control following initial doses of NUROMAX is approximately
26 minutes (range: 7 to 104, n = 253) during balanced anesthesia. The mean
time for spontaneous Trecovery from 25% to 75% is 54 minutes
(range: 14 to 184, n = 184). Most patients
receiving NUROMAX in clinical trials required pharmacologic reversal prior
to full spontaneous recovery from neuromuscular block (see OVERDOSAGE
- Antagonism of Neuromuscular Block); therefore, relatively few
data are available on the time from injection to 95% spontaneous recovery
of the twitch response. As with other long-acting neuromuscular blocking
agents, NUROMAX may be associated with prolonged times to full spontaneous
recovery. Following an initial dose of 0.025 mg/kg NUROMAX, some patients
may require as long as 4 hours to exhibit full spontaneous recovery. Cumulative neuromuscular blocking effects are not associated
with repeated administration of maintenance doses of NUROMAX at 25% Trecovery.
As with initial doses, however, the duration of action following maintenance
doses of NUROMAX may vary considerably among patients. The NUROMAX EDfor children 2 to 12 years of age
receiving halothane anesthesia is approximately 0.03 mg/kg. Children require
higher doses of NUROMAX on a mg/kg basis than adults to achieve comparable
levels of block. The onset time and duration of block are shorter in children
than adults. During halothane anesthesia, doses of 0.03 mg/kg and 0.05
mg/kg NUROMAX produce maximum block in approximately 7 and 4 minutes,
respectively. The duration of clinically effective block is approximately
30 minutes after an initial dose of 0.03 mg/kg and approximately 45 minutes
after 0.05 mg/kg. NUROMAX has not been studied in pediatric patients
below the age of 2 years. The neuromuscular
block produced by NUROMAX may be antagonized by anticholinesterase agents.
As with other nondepolarizing neuromuscular blocking agents, the more profound
the neuromuscular block at reversal, the longer the time and the greater the
dose of anticholinesterase required for recovery of neuromuscular function.<br/>Hemodynamics: Administration of doses of NUROMAX up to and including
0.08 mg/kg (~3��ED) over 5 to 15 seconds to healthy adult
patients during stable-state balanced anesthesia and to patients with serious
cardiovascular disease undergoing coronary artery bypass grafting, cardiac
valvular repair, or vascular repair produced no dose-related effects on mean
arterial blood pressure (MAP) or heart rate (HR). No
dose-related changes in MAP and HR were observed following administration
of up to 0.05 mg/kg NUROMAX over 5 to 15 seconds in 2- to 12-year-old children
receiving halothane anesthesia. Doses of 0.03
to 0.08 mg/kg (1.2 to 3��ED) were not associated with dose-dependent
changes in mean plasma histamine concentration. Clinical experience with
more than 1000 patients indicates that adverse experiences typically associated
with histamine release (e.g., bronchospasm, hypotension, tachycardia, cutaneous
flushing, urticaria, etc.) are very rare following the administration of NUROMAX
(see ADVERSE REACTIONS).<br/>Pharmacokinetics: Pharmacokinetic and pharmacodynamic results from
a study of 24 healthy young adult patients and eight healthy elderly patients
are summarized in Table 2. The pharmacokinetics are linear over the dosage
range tested (i.e., plasma concentrations are approximately proportional to
dose). This study showed that the pharmacokinetics of
NUROMAX were similar in healthy young adult and elderly patients. Some healthy
elderly patients tended to be more sensitive to the neuromuscular blocking
effects of NUROMAX than healthy young adult patients receiving the same dose.
The time to maximum block was longer in elderly patients than in young adult
patients (11.2 minutes versus 7.7 minutes at 0.025 mg/kg NUROMAX). In addition,
the clinically effective duration of block was more variable and tended to
be longer in healthy elderly patients than in healthy young adult patients
receiving the same dose. In contrast, a second study evaluated the pharmacokinetics
and pharmacodynamics of doxacurium and showed that the plasma clearance was
lower (1.75��0.16 vs. 2.54��0.24, respectively) and the half-life
was longer (120��10 vs. 75.9��4.4 minutes, respectively)
in 9 elderly patients (70 to 83 years of age) than in 9 younger patients
(19 to 39 years of age) receiving a single intravenous dose of NUROMAX 0.03
mg/kg. In addition, the time to maximum block was slower (12.9 versus
8.9 minutes, respectively) and the time to 25% Trecovery was
longer (113.4��17.0 vs. 48.1��5.2 minutes, respectively)
in elderly patients than in younger patients. Overall, these studies showed
that there may be differences in the pharmacokinetics of doxacurium in individual
elderly patients and that the onset is slower and the duration of action is
likely to be more variable and may be longer in elderly patients. Table 3 summarizes the pharmacokinetic and pharmacodynamic
results from a study of nine healthy young adult patients, eight patients
with end-stage kidney disease undergoing kidney transplantation, and seven
patients with end-stage liver disease undergoing liver transplantation. The
results suggest that a longer tcan be expected in patients
with end-stage kidney disease; in addition, these patients may be more sensitive
to the neuromuscular blocking effects of NUROMAX. The time to maximum block
was slightly longer and the clinically effective duration of block was prolonged
in patients with end-stage kidney disease. No data are available from patients with liver
disease not requiring transplantation. There are no significant alterations
in the pharmacokinetics of NUROMAX in liver transplant patients. Sensitivity
to the neuromuscular blocking effects of NUROMAX was highly variable in patients
undergoing liver transplantation. Three of seven patients developed���50%
block, indicating that a reduced sensitivity to NUROMAX may occur in such
patients. In those patients who developed>50% neuromuscular block,
the time to maximum block and the clinically effective duration tended to
be longer than in healthy young adult patients (see CLINICAL
PHARMACOLOGY - Individualization of Dosages subsection). Consecutively administered maintenance doses of 0.005 mg/kg
NUROMAX, each given at 25% Trecovery following the preceding
dose, do not result in a progressive increase in the plasma concentration
of doxacurium or a progressive increase in the depth or duration of block
produced by each dose. NUROMAX is not metabolized in vitro in fresh human plasma. Plasma protein
binding of NUROMAX is approximately 30% in human plasma. In vivo data from humans
suggest that NUROMAX is not metabolized and that the major elimination pathway
is excretion of unchanged drug in urine and bile. In studies of healthy adult
patients, 24% to 38% of an administered dose was recovered as parent drug
in urine over 6 to 12 hours after dosing. High bile concentrations of NUROMAX
(relative to plasma) have been found 35 to 90 minutes after administration.
The overall extent of biliary excretion is unknown. The data derived from
analysis of human urine and bile are consistent with data from in
vivo studies in the rat, cat, and dog, which indicate that all of
an administered dose of NUROMAX is recovered as parent drug in the urine and
bile of these species.<br/>Individualization of Dosages: In elderly patients or patients who have impaired
renal function, the potential for a prolongation of block may be reduced by
decreasing the initial dose of NUROMAX and by titrating the dose to achieve
the desired depth of block. In obese patients (patients weighing���30%
more than ideal body weight for height), the dose of NUROMAX should be determined
using the patient's ideal body weight (IBW), according to the following
formulae: Men: IBW in kg = [106 + (6��inches in height above 5 feet)]/2.2 Women:
IBW in kg = [100 + (5��inches in height above 5 feet)]/2.2 Dosage requirements for patients with severe liver disease
are variable; some patients may require a higher than normal initial dose
of NUROMAX to achieve clinically effective block. Once adequate block is
established, the clinical duration of block may be prolonged in such patients
relative to patients with normal liver function. As
with pancuronium, metocurine, and vecuronium, resistance to NUROMAX, manifested
by a reduced intensity and/or shortened duration of block, must be considered
when NUROMAX is selected for use in patients receiving phenytoin or carbamazepine
(see PRECAUTIONS - Drug Interactions). As with other nondepolarizing neuromuscular blocking agents,
a reduction in dosage of NUROMAX must be considered in cachectic or debilitated
patients; in patients with neuromuscular diseases, severe electrolyte abnormalities,
or carcinomatosis; and in other patients in whom potentiation of neuromuscular
block or difficulty with reversal is anticipated. Increased doses of NUROMAX
may be required in burn patients (see PRECAUTIONS).
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NUROMAX is contraindicated in patients known to have
hypersensitivity to it. Use of NUROMAX from multiple-dose vials containing
benzyl alcohol as a preservative is contraindicated in patients with a known
hypersensitivity to benzyl alcohol.
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NUROMAX Injection, 1 mg doxacurium in each mL. 5-mL Multiple-dose vials containing 0.9% w/v benzyl alcohol
as a preservative (see WARNINGS). Tray of 10 (List No. 4437).
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| dailymed-instance:overdosag... |
Overdosage with neuromuscular blocking agents may
result in neuromuscular block beyond the time needed for surgery and anesthesia.
The primary treatment is maintenance of a patent airway and controlled ventilation
until recovery of normal neuromuscular function is assured. Once evidence
of recovery from neuromuscular block is observed, further recovery may be
facilitated by administration of an anticholinesterase agent (e.g., neostigmine,
edrophonium) in conjunction with an appropriate anticholinergic agent (see Antagonism of Neuromuscular Block below).<br/>Antagonism of Neuromuscular Block: ANTAGONISTS (SUCH AS NEOSTIGMINE) SHOULD NOT BE
ADMINISTERED PRIOR TO THE DEMONSTRATION OF SOME SPONTANEOUS RECOVERY FROM
NEUROMUSCULAR BLOCK. THE USE OF A NERVE STIMULATOR TO DOCUMENT RECOVERY AND
ANTAGONISM OF NEUROMUSCULAR BLOCK IS RECOMMENDED. T/TSHOULD
BE>ZERO BEFORE ANTAGONISM IS ATTEMPTED. In
an analysis of patients in whom antagonism of neuromuscular block was evaluated
following administration of single doses of neostigmine averaging 0.06 mg/kg
(range: 0.05 to 0.075) administered at approximately 25% Tspontaneous
recovery during balanced anesthesia, 71% of patients exhibited T/T���0.7 before monitoring was discontinued. For these patients, the mean time
to T/T���0.7 was 19 minutes (range: 7 to
55). As with other long-acting nondepolarizing neuromuscular blocking agents,
the time for recovery of neuromuscular function following administration of
neostigmine is dependent upon the level of residual neuromuscular block at
the time of attempted reversal; longer recovery times than those cited above
may be anticipated when neostigmine is administered at more profound levels
of block (i.e., at<25% Trecovery). Patients should be evaluated for adequate clinical evidence
of antagonism, e.g., 5-second head lift, and grip strength. Ventilation must
be supported until no longer required. As with other neuromuscular blocking
agents, physicians should be alert to the possibility that the action of the
drugs used to antagonize neuromuscular block may wear off before the effects
of NUROMAX on the neuromuscular junction have declined sufficiently. Antagonism may be delayed in the presence of debilitation,
carcinomatosis, and the concomitant use of certain broad-spectrum antibiotics
or anesthetic agents and other drugs which enhance neuromuscular block or
separately cause respiratory depression (see PRECAUTIONS
- Drug Interactions). Under such circumstances the management is
the same as that of prolonged neuromuscular block. In
clinical trials, a dose of 1 mg/kg edrophonium was not as effective as a dose
of 0.06 mg/kg neostigmine in antagonizing moderate to deep levels of
neuromuscular block (i.e.,<60% Trecovery). Therefore,
the use of 1 mg/kg edrophonium is not recommended for reversal from moderate
to deep levels of block. The use of pyridostigmine has not been studied.
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doxacurium chloride
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NUROMAX (Injection)
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| dailymed-instance:adverseRe... |
The most frequent adverse effect of nondepolarizing
blocking agents as a class consists of an extension of the pharmacological
action beyond the time needed for surgery and anesthesia. This effect may
vary from skeletal muscle weakness to profound and prolonged skeletal muscle
paralysis resulting in respiratory insufficiency and apnea which requiremanual
or mechanical ventilation until recovery is judged to be clinically adequate
(see OVERDOSAGE). Inadequate reversal
of neuromuscular block from NUROMAX is possible, as with all nondepolarizing
agents. Prolonged neuromuscular block and inadequate reversal may lead to
postoperative complications.<br/>Observed in Clinical Trials: Adverse experiences were uncommon among the 1034
surgical patients and volunteers who received NUROMAX and other drugs in US
clinical studies in the course of a wide variety of procedures conducted during
balanced or inhalational anesthesia. The following adverse experiences were
reported in patients administered NUROMAX (all events judged by investigators
during the clinical trials to have a possible causal relationship):<br/>Incidence Greater than 1%: None<br/>Incidence Less than 1%:
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| dailymed-instance:warning |
NUROMAX SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED
DOSAGE BY OR UNDER THE SUPERVISION OF EXPERIENCED CLINICIANS WHO ARE FAMILIAR
WITH THE DRUG'S ACTIONS AND THE POSSIBLE COMPLICATIONS OF ITS USE. THE
DRUG SHOULD NOT BE ADMINISTERED UNLESS FACILITIES FOR INTUBATION, ARTIFICIAL
RESPIRATION, OXYGEN THERAPY, AND AN ANTAGONIST ARE WITHIN IMMEDIATE REACH.
IT IS RECOMMENDED THAT CLINICIANS ADMINISTERING LONG-ACTING NEUROMUSCULAR
BLOCKING AGENTS SUCH AS NUROMAX EMPLOY A PERIPHERAL NERVE STIMULATOR TO MONITOR
DRUG RESPONSE, NEED FOR ADDITIONAL RELAXANTS, AND ADEQUACY OF SPONTANEOUS
RECOVERY OR ANTAGONISM. NUROMAX HAS NO KNOWN
EFFECT ON CONSCIOUSNESS, PAIN THRESHOLD, OR CEREBRATION. TO AVOID DISTRESS
TO THE PATIENT, NEUROMUSCULAR BLOCK SHOULD NOT BE INDUCED BEFORE UNCONSCIOUSNESS. NUROMAX Injection is acidic (pH 3.9 to 5.0) and may not be
compatible with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate
solutions). NUROMAX Injection contains benzyl
alcohol. In newborn infants, benzyl alcohol has been associated with an increased
incidence of neurological and other complications which are sometimes fatal
(see PRECAUTIONS - Pediatric Use).
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| dailymed-instance:indicatio... |
NUROMAX is a long-acting neuromuscular blocking agent,
indicated to provide skeletal muscle relaxation as an adjunct to general anesthesia,
for endotracheal intubation or to facilitate mechanical ventilation.
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NUROMAX
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