Professional Drug Information > Cisatracurium

Cisatracurium (Systemic)

INN:
Cisatracurium Besilate

VA CLASSIFICATION
Primary: MS300

Commonly used brand name(s): Nimbex.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Neuromuscular blocking (paralyzing) agent—

Indications

Accepted

Skeletal muscle paralysis—Cisatracurium is indicated as an adjunct to general anesthesia to facilitate endotracheal intubation and to induce skeletal muscle relaxation in surgical patients ^{{01} {02} {03} {04} {05} {06} {07} {08} {09} {10}}. It is also indicated to facilitate endotracheal intubation and to induce skeletal muscle relaxation in patients who require mechanical ventilation in the intensive care unit^{1 {01} {02} {11} {13} {14}}. However, cisatracurium has an intermediate onset of action and is therefore not recommended for use in rapid-sequence endotracheal intubation ^{{01} {02}}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Synthetic; one of the 10 isomers of atracurium besylate ^{{01} {02}}.
Molecular weight—
    Cisatracurium: 929.2 ^{{01} {02}}
    Cisatracurium besylate: 1243.51 ^{12}


pH
    Cisatracurium injection: 3.25 to 3.65 ^{{01} {02}}.

Mechanism of action/Effect:

Cisatracurium is a nondepolarizing neuromuscular blocking agent ^{01}. Nondepolarizing neuromuscular blocking agents inhibit neuromuscular transmission by competing with acetylcholine for the cholinergic receptors at the motor end plate, thereby antagonizing the action of acetylcholine ^{01}. This type of competitive neuromuscular blockade is usually antagonized by anticholinesterase agents ^{01}.

Neuromuscular blocking agents have no effect on consciousness or pain threshold ^{{01} {13}}.

Distribution:

Volume of distribution (Vol _D)—Steady-state: 0.145 liter per kg of body weight (L/kg) in patients receiving opioid anesthesia; approximately 21% greater in patients receiving inhalation anesthesia and slightly greater in geriatric patients than in younger adults ^{01}.

Note: A value of 0.28 ± 0.103 L/kg was calculated during the terminal elimination phase in intensive care patients receiving cisatracurium infusions for 24 to 48 hours ^{01}. However, this value is an underestimate because elimination from the peripheral compartment was not included in the calculation ^{{01} {14} {15}}.


Biotransformation:

Eighty percent of a dose is metabolized via Hofmann elimination, a pH- and temperature-dependent process that is independent of renal or hepatic function ^{{01} {14} {16}}. Some hepatic biotransformation also occurs ^{{01} {14}}. The primary metabolites are a monoquaternary acrylate derivative, which is further metabolized via Hofmann elimination (but more slowly than the parent compound) and via hydrolysis by nonspecific plasma esterases, and laudanosine, which is further metabolized to desmethyl metabolites that are subsequently conjugated with glucuronic acid ^{01}. Neither metabolite has neuromuscular blocking activity, although laudanosine causes transient hypotension and, in higher doses, cerebral excitatory effects in animals ^{{01} {17}}. Whether laudanosine may contribute to the development of seizures during long-term cisatracurium administration has not been established ^{01}.

Half-life:


Elimination:


Cisatracurium—

Approximately 22 to 29 minutes, following administration of a single intravenous dose to surgical patients ^{01}. The half-life is not substantially affected by the duration of administration (approximately 26 ± 11 minutes in intensive care patients receiving cisatracurium via intravenous infusion for 24 to 48 hours), type of anesthesia, or hepatic or renal function impairment, but is slightly longer in geriatric patients than in younger adults ^{01}.

In individuals undergoing coronary artery bypass surgery with induced hypothermia (body temperature of 25 to 28 °C [77 to 82.4 °F]), the half-life during hypothermia is prolonged as compared with the half-life during normothermia ^{01}.



Laudanosine—

6.6 ± 4.1 hours, in intensive care patients receiving long-term therapy via intravenous infusion ^{01}; increased in patients with hepatic or renal function impairment ^{01}.



Onset of action:

Time to achieve intubating conditions in adults—Dose-dependent; 2 minutes following administration of 0.15 mg per kg of body weight (mg/kg) and 1.5 minutes following administration of 0.2 mg/kg ^{{01} {06} {09}}. The dose of 0.2 mg/kg is four times the ED ₉₅ (the dose required to produce 95% suppression of the twitch response to peripheral nerve stimulation).

Peak serum concentration:

For laudanosine, in intensive care patients receiving cisatracurium via intravenous infusion for 24 to 48 hours—707 ± 360 nanograms per mL (1.98 ± 1 micromoles per L [micromoles/L]); higher in patients with renal or hepatic function impairment ^{01}.

Time to peak effect:


Time to maximum blockade:


Adults—

Dose-dependent; 3.5 (range, 1.6 to 6.8) minutes following administration of 0.15 mg/kg and 2.9 (range, 1.9 to 5.2) minutes following administration of 0.2 mg/kg in young adults with normal renal and hepatic function receiving opioid anesthesia ^{01}.

Note: After administration of 0.1 mg/kg, mean times to achieve maximum blockade are approximately 1 minute longer in geriatric patients and in patients with end-stage renal function impairment, and approximately 1 minute shorter in patients with end-stage hepatic function impairment than in young adults with normal renal and hepatic function ^{{01} {18}}.




Children 2 to 12 years of age—

2.8 (range, 1.8 to 6.7) minutes following administration of 0.1 mg/kg ^{01}.



Duration of action:

Note: Values reported below for adults undergoing surgery were determined in young adults with normal renal and hepatic function receiving opioid-nitrous oxide-oxygen anesthesia ^{01}. No clinically significant differences in recovery parameters were found in geriatric patients or in patients with hepatic or renal function impairment ^{01}. However, greater variability in duration of effect was observed in patients with renal function impairment ^{18}. Values reported below for children 2 to 12 years of age were determined in surgical patients receiving stable halothane or opioid anesthesia ^{01}.
The duration of action of cisatracurium may be prolonged in patients receiving a potent inhalation anesthetic (e.g., enflurane, isoflurane) ^{01}.
The duration of action may be prolonged in patients with acidosis or hypothermia ^{{01} {27}}.
Administration of an anticholinesterase agent such as edrophonium or neostigmine after some spontaneous recovery has occurred will decrease the recovery times reported below ^{01}.



Duration of clinical effect (time for spontaneous recovery of the twitch response to peripheral nerve stimulation to 25% of the control value [T ₂₅]):


Adults undergoing surgery—

Dose-dependent; 55 (range, 44 to 74) minutes following administration of 0.15 mg/kg and 65 (range, 43 to 103) minutes following administration of 0.2 mg/kg ^{01}.



Children 2 to 12 years of age undergoing surgery—

28 (range, 21 to 38) minutes following administration of 0.1 mg/kg ^{01}.




Time for spontaneous recovery of the twitch response to peripheral nerve stimulation to 95% of the control value (T ₉₅):


Adults undergoing surgery—

Dose-dependent; 76 (range, 60 to 103) minutes following administration of 0.15 mg/kg and 81 (range, 53 to 114) minutes following administration of 0.2 mg/kg ^{01}.



Children 2 to 12 years of age undergoing surgery—

46 (range, 37 to 58) minutes following administration of 0.1 mg/kg ^{01}.




Recovery index (time for the twitch response to nerve stimulation to increase spontaneously from 25% to 75% of the control value [T _25–75]):


Adults undergoing surgery—

Dose-dependent; 13 (range, 11 to 16) minutes following administration of 0.15 mg/kg and 12 (range, 2 to 30) minutes following administration of 0.2 mg/kg ^{01}.



Children 2 to 12 years of age undergoing surgery—

10 (range, 7 to 12) minutes following administration of 0.1 mg/kg ^{01}.




Time to spontaneous recovery of the T ₄:T ₁ ratio (train-of-four stimulation) to ³ 70%:


Adults undergoing surgery—

Dose-dependent; 75 (range, 63 to 98) minutes following administration of 0.15 mg/kg and 85 (range, 55 to 114) minutes following administration of 0.2 mg/kg ^{01}.



Adults receiving long-term intravenous infusion (up to 6 days) in intensive care situations—

55 (range, 20 to 270) minutes in one study; 50 (range, 20 to 175) minutes in another ^{01}.



Children 2 to 12 years of age undergoing surgery—

44 (range, 36 to 58) minutes following administration of 0.1 mg/kg ^{01}.



Elimination:
    Renal, 95%, mostly as metabolites ^{01}. Less than 10% of a dose is eliminated as unchanged cisatracurium ^{01}. About 4% of a dose is eliminated in the feces ^{01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to benzylisoquinolinium compounds, such as atracurium, doxacurium, and mivacurium, may be allergic to cisatracurium also ^{01}.

Carcinogenicity

Studies have not been done ^{01}.

Mutagenicity

Positive results occurred in the mouse lymphoma assay, both in the presence and absence of exogenous metabolic activation (rat liver S-9) ^{01}. In the absence of metabolic activation, cisatracurium was positive at in vitro concentrations of 40 micrograms per mL (mcg/mL) or higher ^{01}. In the presence of S-9, cisatracurium was mutagenic at a concentration of 300 mcg/mL, but not at lower or higher concentrations ^{01}. No mutagenicity was found in the Ames Salmonella mutation test, a rat bone marrow cytogenic assay, or an in vitro human lymphocyte cytogenic assay ^{01}.

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies have not been done in humans ^{01}.

No maternal or fetal toxicity or teratogenicity was found in studies in nonventilated rats receiving maximum subparalyzing doses of 4 mg/kg subcutaneously (equivalent to eight times the intravenous human ED ₉₅ [dose required to produce 95% suppression of the twitch response to peripheral nerve stimulation]) or in ventilated rats receiving paralyzing doses of 0.5 or 1 mg/kg intravenously (equivalent to 10 or 20 times the intravenous human ED ₉₅, respectively) ^{01}.

FDA Pregnancy Category B ^{01}.


Labor and delivery—

Use of cisatracurium during labor, vaginal delivery, or cesarean section has not been studied in humans ^{01}. Whether administration to the mother may affect the fetus has not been determined ^{01}. However, potentiation of neuromuscular blockade may occur if magnesium salts are used for management of toxemia of pregnancy ^{01}.

Administration of 0.2 or 0.4 mg/kg of cisatracurium to female beagles undergoing cesarean section produced negligible quantities of the medication in umbilical vessel blood and no adverse effects on the offspring ^{01}.

Breast-feeding

It is not known whether cisatracurium is distributed into breast milk ^{01}.

Pediatrics

Neonates—Multiple-dose vials of cisatracurium injection contain benzyl alcohol. Administration of excessive doses of benzyl alcohol to neonates has been associated with neurologic and other complications ^{01}.

Infants and children up to 2 years of age—Appropriate studies on the relationship of age to the effects of cisatracurium have not been performed in infants and children up to 2 years of age ^{01}.

Children 2 to 12 years of age—Appropriate studies on the relationship of age to the effects of cisatracurium have shown that the ED ₉₅ of cisatracurium is lower, the onset of action is faster, the duration of action is shorter, and recovery time after administration of a reversal agent is more rapid than in adults ^{{01} {21}}. However, pediatrics-specific adverse effects or other problems that would limit the use of cisatracurium in children have not been documented ^{01}.


Geriatrics


Clinical trials that included 145 patients 65 years of age or older, some of whom had cardiovascular disease, did not demonstrate geriatrics-specific problems that would limit the usefulness of cisatracurium in the elderly ^{{01} {28} {29}}. These studies showed the time to achieve maximum neuromuscular blockade to be approximately 1 minute longer in elderly patients than in younger adults ^{{01} {28} {29}}. However, despite some minor differences in pharmacokinetic parameters between elderly patients and younger adults, there were no clinically significant differences in recovery following a single dose of 0.1 mg/kg ^{{01} {29}}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Aminoglycosides or
» Anesthetics, parenteral-local or
Bacitracin or
» Clindamycin or
Colistimethate sodium or
Colistin or
» Lincomycin or
Lithium or
» Magnesium salts, large doses (e.g., for management of toxemia of pregnancy) or
» Polymyxins or
» Procainamide or
» Quinidine or
Tetracyclines    (these agents may enhance the effects of nondepolarizing neuromuscular blocking agents ^{{01} {02}})


Aminophylline or
Theophylline    (resistance to neuromuscular blockade may occur; higher doses of cisatracurium may be needed ^{{30} {31}})


Anesthetics, hydrocarbon inhalation, especially:
Enflurane
Isoflurane    (these agents may prolong the clinically effective duration of initial and maintenance doses of cisatracurium; although adjustment of the initial dose of cisatracurium should not be necessary when it is administered shortly after the start of inhalation anesthesia, during long surgical procedures, less frequent maintenance dosing and/or lower maintenance doses may be necessary; average infusion rate requirements during enflurane or isoflurane administration may be decreased by 30 to 40% or more ^{01})


Carbamazepine or
Phenytoin    (resistance to the effects of other nondepolarizing neuromuscular blocking agents has been reported in patients receiving long-term anticonvulsant therapy; although the effects of such treatment on the efficacy of cisatracurium have not been established, a slightly shorter duration of neuromuscular blockade and increased infusion rate requirements should be anticipated ^{01})


Corticosteroids    (a syndrome of prolonged paralysis and/or skeletal muscle weakness has occurred in intensive care patients receiving neuromuscular blocking agents to assist mechanical ventilation; the use of corticosteroids has been associated with the development of this syndrome ^{{02} {30}})


Succinylcholine    (the time to onset of maximum neuromuscular blockade is decreased by approximately 2 minutes when cisatracurium is administered following either 10% recovery or 95% recovery from a 1 mg/kg intubating dose of succinylcholine, but the duration of action of initial or maintenance doses of cisatracurium is not altered ^{{01} {20}})

    (cisatracurium infusion requirements following prior administration of succinylcholine are similar to or slightly higher than are needed without initial use of succinylcholine ^{01})

    (administration of cisatracurium prior to succinylcholine, to attenuate some of succinylcholine's adverse effects, has not been studied ^{01})


Note: No interactions occurred when atracurium, pancuronium, or vecuronium was administered after varying degrees of recovery from single doses or infusions of cisatracurium ^{01}.


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Acid-base or electrolyte imbalance    (action of nondepolarizing neuromuscular blocking agents may be antagonized or potentiated ^{01})


Burns    (resistance to neuromuscular blockade may occur, resulting in an increase in the dosage requirement and a shorter duration of action of cisatracurium; the extent to which the response is altered may depend on the size of the burn and the time elapsed since the burn injury ^{01})


Carcinomatosis or
Neuromuscular disease, such as myasthenia gravis or myasthenic syndrome or
Other conditions in which prolonged neuromuscular blockade is a possibility    (effect of neuromuscular blocking agents may be enhanced and/or prolonged; it is recommended that the patient be carefully monitored with a peripheral nerve stimulator, and that the initial cisatracurium dose be limited to 0.02 mg/kg ^{01})


Hemiparesis or
Paraparesis    (affected limb or limbs may be resistant to neuromuscular blockade; a nonparetic limb should be used to monitor effect and recovery ^{01})


Sensitivity to cisatracurium or related compounds^{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Muscle function    (onset, degree, and recovery from neuromuscular blockade should be assessed periodically using a peripheral nerve stimulator ^{{01} {25}}; grip strength and/or ability to maintain a 5-second head lift may also be used to assess recovery ^{{01} {25}})




Side/Adverse Effects

Note: Cisatracurium does not increase plasma histamine concentrations in doses up to eight times the ED ₉₅ (dose required to produce 95% suppression of the twitch response to peripheral nerve stimulation) ^{{01} {22} {26}}. Also, cisatracurium has no clinically significant effect on blood pressure or heart rate in children 2 to 12 years of age receiving doses of up to two times the pediatric ED ₉₅ ^{21}, in healthy adult surgical patients, or in adult patients with cardiovascular disease undergoing coronary artery bypass surgery receiving doses as high as eight times the adult ED ₉₅, administered over 5 to 10 seconds ^{22}. However, anaphylactic and anaphylactoid reactions have been reported with the use of cisatracurium ^{{01} {33}}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare—less than 0.5%
    
Bradycardia^{01}
    
bronchospasm^{01}
    
flushing, cutaneous^{33}
    
hypotension^{01}{08}{22}
    
skin rash^{01}

Note: The above side/adverse effects were reported in surgical patients ^{01}. Bronchospasm also was reported in one intensive care patient receiving a long-term cisatracurium infusion ^{01}. Also, in clinical trials in intensive care patients, prolonged recovery following discontinuation of long-term infusion therapy occurred in 2 of 28 patients receiving cisatracurium (in comparison, prolonged recovery occurred in 13 of 30 patients receiving vecuronium) ^{{01} {11}}.






Overdose
For specific information on the agents used in the management of cisatracurium overdose, see:    • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Edrophonium (Systemic) monograph;
   • Glycopyrrolate in Anticholinergics/Antispasmodics (Systemic) monograph; and/or
   • Neostigmine in Antimyasthenics (Systemic) monograph.

For more information on the management of an overdose contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effect has been selected on the basis of its potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Paralysis, prolonged


Treatment of overdose
Recommended treatment includes maintaining a patent airway and assisting ventilation until adequate recovery has occurred ^{01}.

Specific treatment—With the onset of spontaneous recovery, further recovery may be facilitated by administering an anticholinesterase agent (e.g., edrophonium or neostigmine) ^{01}. The reversal agent should be given in conjunction with a suitable anticholinergic agent (e.g., atropine or glycopyrrolate) ^{01}.

Monitoring—Recovery may be assessed by monitoring functions such as grip strength and/or ability to maintain a 5-second head lift, as well as by peripheral nerve stimulation ^{01}.


General Dosing Information
Neuromuscular blocking agents have no clinically significant effect on consciousness or pain threshold and should therefore always be used in conjunction with adequate anesthesia ^{{01} {13}} (surgical patients) or sedation and, if necessary, analgesia (intensive care patients).

Neuromuscular blocking agents should be administered only by personnel experienced in the techniques of resuscitation and life support (e.g., tracheal intubation, artificial respiration, oxygen administration) ^{01}. Facilities for these procedures and an antagonist (e.g., edrophonium, neostigmine) should be immediately available ^{01}.

Cisatracurium is given intravenously; there are no data to support administration by intramuscular injection ^{01}.

The ED ₉₅ of cisatracurium (dose required to produce 95% suppression of the twitch response to peripheral nerve stimulation) is approximately 0.05 (range, 0.048 to 0.053) mg per kg of body weight (mg/kg) in adults ^{{01} {03} {10} {23}} and approximately 0.04 mg/kg in children 2 to 12 years of age ^{{01} {21} {24}}. However, higher doses are used clinically to reduce the time to achieve adequate intubating conditions and maximum blockade and to prolong the duration of effective muscle relaxation ^{{01} {03} {05} {21}}. The stated initial doses for adults and children are equivalent to three and four times the adult ED ₉₅ and 1.5 times the pediatric ED ₉₅, respectively ^{{01} {21}}.

The stated doses are given only as guidelines ^{01}. Actual dosage must be individualized ^{01}. It is recommended that a peripheral nerve stimulator be used to monitor response, need for additional doses, and recovery ^{{01} {25}}.

For use in surgical patients
It has been established that the duration of action of initial and subsequent doses of cisatracurium may be prolonged when the medication is given after anesthesia with a potent inhalation anesthetic (e.g., enflurane, isoflurane) ^{01}. Less frequent maintenance dosing and/or lower maintenance doses of cisatracurium may be required; infusion rate requirements may be decreased by 30 to 40% or more ^{01}. However, alteration of initial dosage should not be necessary if cisatracurium is administered shortly after the start of anesthesia ^{01}.

Repeated administration of maintenance doses of cisatracurium, or administration by continuous intravenous infusion for up to 3 hours, does not result in cumulative effects or tachyphylaxis ^{01}.

The time needed for recovery from a maintenance dose is not affected by the number of doses given, if partial recovery is allowed to occur between doses ^{01}. Maintenance doses therefore may be given at regular intervals ^{01}.

For use in intensive care patients
Use of cisatracurium for longer than 6 days has not been studied ^{01}.

Dosage requirements may increase or decrease with time ^{01}. It is recommended that cisatracurium use be monitored via peripheral nerve stimulation ^{01}. Cisatracurium infusion therapy should be discontinued temporarily if there is no response to stimulation, and treatment resumed, if necessary, only after a definite response is obtained ^{01}.

The effects of procedures such as hemodialysis, hemoperfusion, or hemofiltration on the plasma concentrations of cisatracurium or its metabolites have not been determined ^{01}.

Multiple-dose vials of cisatracurium for injection contain benzyl alcohol. Administration of excessive doses of benzyl alcohol to neonates has been associated with a fatal toxic syndrome consisting of metabolic acidosis, CNS depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhage ^{01}. Administration of excessive doses of benzyl alcohol is more likely during prolonged use of cisatracurium, which may occur in intensive care patients ^{32}.

For reversal of neuromuscular blockade
The effect of cisatracurium may be reversed by an anticholinesterase agent (e.g., 1 mg per kg of body weight [mg/kg] of edrophonium or 0.04 to 0.07 mg/kg of neostigmine), which should be administered concurrently with a suitable anticholinergic agent (e.g., atropine or glycopyrrolate) ^{01}. However, the antagonist should not be given until some spontaneous recovery has begun ^{01}. The time required for recovery increases with the depth of neuromuscular blockade at the time the reversal agent is administered. ^{01} Also, recovery may be delayed if certain medical conditions (e.g., carcinomatosis, debilitation, cachexia) are present, or if medications that enhance neuromuscular blockade (e.g., anesthetic agents, various antibiotics) and/or independently cause respiratory depression have been given ^{01}.

Even after administration of a reversal agent, ventilatory assistance should be continued until the patient is able to maintain an adequate respiratory exchange unassisted ^{01}.

Evidence of adequate recovery, such as grip strength and/or ability to maintain a 5-second head lift, should be evaluated after administration of a reversal agent ^{01}.


Parenteral Dosage Forms

Note: Cisatracurium injection contains cisatracurium besylate ^{01}. However, the dosage and strengths of the injection are stated in terms of cisatracurium base (not the besylate salt) ^{01}.


CISATRACURIUM INJECTION

Usual adult and adolescent dose
Skeletal muscle paralysis


Initial (intubating dose), for surgical or intensive care patients:
Intravenous, 150 mcg (0.15 mg) (base) per kg of body weight, to produce intubating conditions in approximately two minutes and approximately fifty-five minutes of relaxation ^{{01} {02} {03} {06} {09}}, or

Intravenous, 200 mcg (0.2 mg) (base) per kg of body weight, to produce intubating conditions in approximately one and one-half minutes and approximately sixty-one minutes of relaxation ^{{01} {02} {03} {06} {09}}.



Maintenance:


Surgical patients—
Intravenous, 30 mcg (0.03 mg) (base) per kg of body weight, administered after the effects of the intubating dose begin to subside and at approximately twenty-minute intervals thereafter, although dosage may be adjusted as necessary to provide shorter or longer durations of action ^{{01} {02}}, or

Intravenous infusion, 3 mcg (0.003 mg) (base) per kg of body weight per minute, initially, then decreased to 1 to 2 mcg (0.001 to 0.002 mg) per kg of body weight per minute ^{{01} {02} {03} {14}}.
Note: In individuals undergoing coronary artery bypass surgery with induced hypothermia (body temperature of 25 to 28 °C [77 to 82.4 °F]), maintenance infusion rate requirements during hypothermia may be reduced to approximately 50% of those needed during normothermia ^{01}.
Less frequent maintenance dosing or lower maintenance doses may be required in patients who have been exposed to potent inhalation anesthetics (e.g., enflurane, isoflurane) ^{{01} {11}}. Infusion rate requirements may be decreased by 30 to 40% or more ^{01}.





Intensive care patients—
Intravenous infusion, 3 mcg (0.003 mg) (base) per kg of body weight per minute, initially, then adjusted as needed^{01}{11} .¹ Dosage requirements are subject to wide interpatient variability; doses ranging from 0.5 to 10.2 mcg (0.0005 to 0.0102 mg) per kg of body weight per minute have been used ^{{01} {11}}. Also, dosage requirements may increase or decrease over time ^{01}.

Note: If significant recovery from neuromuscular blockade occurs when an infusion is stopped temporarily, administration of an intubating dose may be needed to re-establish neuromuscular blockade quickly before the infusion is resumed ^{01}.





Usual pediatric dose
Skeletal muscle paralysis


Infants and children up to 2 years of age:
Dosage has not been established ^{01}.



Children 2 years of age and older:


Initial—
Intravenous, 100 mcg (0.1 mg) (base) per kg of body weight, administered over five to ten seconds, to produce maximum blockade in approximately two minutes, forty-eight seconds and approximately twenty-eight minutes of relaxation ^{{01} {02}}.



Maintenance—


Surgical patients—
Intravenous infusion, 3 mcg (0.003 mg) (base) per kg of body weight per minute, initially, then decreased to 1 to 2 mcg (0.001 to 0.002 mg) per kg of body weight per minute ^{{01} {02}}.

Note: In individuals undergoing coronary artery bypass surgery with induced hypothermia (body temperature of 25 to 28 °C [77 to 82.4 °F]), maintenance infusion rate requirements during hypothermia may be reduced to approximately 50% of those needed during normothermia ^{01}.
Less frequent maintenance dosing or lower maintenance doses may be required in patients who have been exposed to potent inhalation anesthetics (e.g., enflurane, isoflurane) ^{01}. Infusion rate requirements may be decreased by 30 to 40% or more ^{01}.




Intensive care patients—
Intravenous infusion, 3 mcg (0.003 mg) (base) per kg of body weight per minute, initially, then adjusted as needed^{01} .¹ Dosage requirements are subject to wide interpatient variability; doses ranging from 0.5 to 10.2 mcg (0.0005 to 0.0102 mg) per kg of body weight per minute have been used in adults ^{01}. Also, dosage requirements may increase or decrease with time ^{01}.

Note: If significant recovery from neuromuscular blockade occurs when an infusion is stopped temporarily, administration of an intubating dose may be needed to re-establish neuromuscular blockade quickly before the infusion is resumed ^{01}.






Strength(s) usually available
U.S.—


2 mg (base) per mL (Rx) [Nimbex^{01} (benzenesulfonic acid) (benzyl alcohol 0.9% [10-mL multiple-dose vial only])]


10 mg (base) per mL (Rx) [Nimbex^{01} (benzenesulfonic acid)]

Canada—


2 mg (base) per mL (Rx) [Nimbex^{02} (benzenesulfonic acid) (benzyl alcohol 0.9% [10-mL multiple-dose vial only])]


10 mg (base) per mL (Rx) [Nimbex^{02} (benzenesulfonic acid)]

Note: The 10-mg-per-mL strength is intended only for preparing intravenous infusions for adults to be used in the intensive care unit ^{01}. The 10-mg-per-mL vials contain benzyl alcohol and should not be used to prepare infusions for neonates.


Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) in the original carton. Protect from light and freezing ^{01}.

Preparation of dosage form:
For preparation of intravenous infusions, cisatracurium injection may be diluted with a suitable quantity of 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose and 0.9% sodium chloride injection ^{01}. The quantity of infusion required will depend on the concentration of cisatracurium, desired dose, and patient's body weight ^{01}. The patient's fluid requirement also should be considered when determining an appropriate infusion volume ^{01}. Cisatracurium injection may be infused through intravenous lines (i.e., by Y-site) administering solutions of droperidol, fentanyl citrate, midazolam hydrochloride, or sufentanil citrate, prepared according to the manufacturers' specifications ^{01}.

Stability:
Undiluted cisatracurium injection, when kept under refrigeration at 5 °C (41 °F), loses potency at a rate of approximately 5% per year ^{01}. The rate of potency loss increases to 5% per month at room temperature (25 °C [77 °F]) ^{01}. The injection should be used within 21 days after it is brought to room temperature, even if it is subsequently re-refrigerated ^{01}.

Cisatracurium infusions prepared by dilution to a concentration of 0.1 mg per mL with 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose and 0.9% sodium chloride injection may be stored under refrigeration or at room temperature for up to 24 hours without significant loss of potency ^{01}. Cisatracurium infusions prepared by dilution to a concentration of 0.1 or 0.2 mg per mL with 5% dextrose and lactated Ringer's injection are stable for up to 24 hours at 5 °C (41 °F) ^{01}.

Incompatibilities:
Cisatracurium injection is incompatible with lactated Ringer's injection ^{01}.

Cisatracurium injection is acidic and may not be compatible with injections having a pH greater than 8.5 (e.g., barbiturate injections) ^{01}.

Cisatracurium injection is incompatible with propofol injection or ketorolac injection for Y-site administration ^{01}.

Revised: 10/05/1998

References

1. Nimbex package insert (Glaxo Wellcome—US), Rev 06/98, Rec 08/98.
   

2. Nimbex package insert (Glaxo Wellcome—Canada), Rev 12/96, Rec 3/97.
   

3. Belmont M, Lien C, Quessy S, et al. The clinical neuromuscular pharmacology of 51W89 in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1995; 82: 1139-45.
   

4. Mellinghoff H, Radbruch L, Diefenbach C, et al. A comparison of cisatracurium and atracurium: onset of neuromuscular block after bolus injection and recovery after subsequent infusion. Anesth Analg 1996; 83: 1072-5.
   

5. Bluestein L, Stinson L, Wilson R, et al. Evaluation of 51W89 for endotracheal intubation in patients anesthetized with propofol and nitrous oxide [abstract]. Anesthesiology 1993; 79(3A): A920.
   

6. Schmautz E, Deriaz H, Vrillon M, et al. Evaluation of 51W89 for endotracheal intubation in surgical patients during N ₂O/O ₂/propofol anesthesia [abstract]. Anesthesiology 1994; 81(3A): A1081.
   

7. Lien C, Schmith V, Belmont M, et al. Pharmacokinetics/dynamics of 51W89 in healthy patients during opioid anesthesia [abstract]. Anesthesiology 1994; 81(3A): A1082.
   

8. Lepage J, Malinovsky J. Comparison of equipotent doses of 51W89 and atracurium. Anesthesiology 1994; 81(3A): A1090.
   

9. Stout R, Belmont M. Evaluation and intubation at 90 and 120 seconds following 51W89 administration. Anesthesiology 1994; 81(3A): A1078.
   

10. Lepage J, Malinovsky J, Malinge M, et al. 51W89: dose-response, neuromuscular blocking profile and cardiovascular effects. Anesthesiology 1993; 79(3A): A945.
    

11. Prielipp R, Coursin D, Scuderi P, et al. Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients. Anesth Analg 1995; 81: 3-12.
    

12. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1997. p. 172.
    

13. Miller RD, editor. Anesthesia. 4th ed. New York, NY: Churchill Livingstone, Inc.; 1994. p. 475.
    

14. Kisor D, Schmith V, Wargin W, et al. Importance of the organ-independent elimination of cisatracurium. Anesth Analg 1996; 83: 1065-71.
    

15. Fisher D. (Almost) everything you learned about pharmacokinetics was (somewhat) wrong! Anesth Analg 1996; 83: 901-3.
    

16. Welch R, Brown A, Ravitch J, et al. The in vitro degradation of cisatracurium, the R, cis-R'-isomer of atracurium in human and rat plasma. Clin Pharmacol Ther 1995; 58: 132-42.
    

17. Miller RD, editor. Anesthesia. 4th ed. New York, NY: Churchill Livingstone, Inc.; 1994. p. 439.
    

18. Boyd A, Eastwood N, Parker C, et al. Pharmacodynamics of the 1R cis-1'R cis isomer of atracurium (51W89) in health and chronic renal failure. Br J Anaesth 1995; 74: 400-4.
    

19. Konstadt S, Reich D, Stanley T, et al. A two-center comparison of the cardiovascular effects of cisatracurium (Nimbex™) and vecuronium in patients with coronary artery disease. Anesth Analg 1995; 81: 1010-4.
    

20. Pavlin E, Forrest A, Howard M, et al. Prior administration of succinylcholine (Sch) does not affect the duration of Nimbex (51W89) neuromuscular blockade [abstract]. Anesth Analg 1995; 80: S374.
    

21. Meretoja O, Taivainen T, Wirtavuori K. Pharmacodynamic effects of 51W89, an isomer of atracurium, in children during halothane anaesthesia. Br J Anaesth 1995; 74: 6-11.
    

22. Lien C, Belmont M, Abalos A, et al. The cardiovascular effects and histamine-releasing properties of 51W89 in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1995; 82: 1131-8.
    

23. Lien C, Belmont M, Abalos A, et al. Dose-response relations of 51W89 under nitrous oxide-opioid-barbiturate anesthesia. Anesthesiology 1993; 79: A948.
    

24. Meretoja O, Taivainen T, Wirtavuori K. 51W89 in children under halothane anesthesia. Anesthesiology 1993; 79: A1126.
    

25. Miller RD, editor. Anesthesia. 4th ed. New York, NY: Churchill Livingstone, Inc.; 1994. p. 419-20.
    

26. Donenicke A, Soukup J, Hoernecke R, et al. The lack of histamine release with cisatracurium: a double-blind comparison with vecuronium. Anesth Analg 1997; 84: 623-8.
    

27. Miller RD, editor. Anesthesia. 4th ed. New York, NY: Churchill Livingstone, Inc.; 1994. p. 452.
    

28. Sorooshian S, Stafford M, Eastwood N, et al. Pharmacokinetics and pharmacodynamics of cisatracurium in young and elderly adult patients. Anesthesiology 1996; 84: 1083-91.
    

29. Ornstein E, Lien C, Matteo R, et al. Pharmacodynamics and pharmacokinetics of cisatracurium in geriatric surgical patients. Anesthesiology 1996; 84: 520-5.
    

30. Panel comment, 5/97.
    

31. Daller JA, Erstad B, Rosado E, et al. Aminophylline antagonizes the neuromuscular blockade of pancuronium but not vecuronium. Crit Care Med 1991; 19: 983-5.
    

32. Panel comment, 5/97.
    

33. Clendenen S, Harper J, Wharen R, et al. Anaphylactic reaction after cisatracurium. Anesthesiology 1997; 87: 690-2.
    

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