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NIMBEX binds competitively to cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in block of neuromuscular transmission. This action is antagonized by acetylcholinesterase inhibitors such as neostigmine.
The neuromuscular blocking potency of NIMBEX is approximately threefold that of atracurium besylate. The time to maximum block is up to 2 minutes longer for equipotent doses of NIMBEX compared to atracurium besylate. The clinically effective duration of action and rate of spontaneous recovery from equipotent doses of NIMBEX and atracurium besylate are similar.
The average ED95 (dose required to produce 95% suppression of the adductor pollicis muscle twitch response to ulnar nerve stimulation) of cisatracurium is 0.05 mg/kg (range: 0.048 to 0.053) in adults receiving opioid/nitrous oxide/oxygen anesthesia. For comparison, the average ED95 for atracurium when also expressed as the parent bis-cation is 0.17 mg/kg under similar anesthetic conditions.
The pharmacodynamics of 2 ◊ ED95 to 8 ◊ ED95 doses of cisatracurium administered over 5 to 10 seconds during opioid/nitrous oxide/oxygen anesthesia are summarized in Table 1. When the dose is doubled, the clinically effective duration of block increases by approximately 25 minutes. Once recovery begins, the rate of recovery is independent of dose.
Isoflurane or enflurane administered with nitrous oxide/oxygen to achieve 1.25 MAC [Minimum Alveolar Concentration] may prolong the clinically effective duration of action of initial and maintenance doses, and decrease the average infusion rate requirement of NIMBEX. The magnitude of these effects may depend on the duration of administration of the volatile agents. Fifteen to 30 minutes of exposure to 1.25 MAC isoflurane or enflurane had minimal effects on the duration of action of initial doses of NIMBEX and therefore, no adjustment to the initial dose should be necessary when NIMBEX is administered shortly after initiation of volatile agents. In long surgical procedures during enflurane or isoflurane anesthesia, less frequent maintenance dosing, lower maintenance doses, or reduced infusion rates of NIMBEX may be necessary. The average infusion rate requirement may be decreased by as much as 30% to 40%.
The onset, duration of action, and recovery profiles of NIMBEX during propofol/oxygen or propofol/nitrous oxide/oxygen anesthesia are similar to those during opioid/nitrous oxide/oxygen anesthesia.
Table 1: Pharmacodynamic Dose Response* of NIMBEX
During Opioid/Nitrous Oxide/Oxygen Anesthesia
|Initial Dose of NIMBEX
|Time to 90% Block
|Time to Maximum Block
|Time to Spontaneous Recovery||25%-75% Recovery Index
|T 4:T 1
Ratio‡ ≥ 70%
(2 x ED95)
(3 x ED95)
(n = 39)
(4 x ED95)
(n = 30)
(5 x ED95)
(n = 15)
(8 x ED95)
(n = 15)
|Infants (1-23 mos.)|
(n = 18-26)
|Children (2-12 yr)|
(2 x ED95)
(n = 60)
(n = 16)
(n = 23-24)
|* Values shown are medians of means from individual
studies. Values in parentheses are ranges of individual patient values.
† Clinically effective duration of block.
‡ Train-of-four ratio.
§ n=the number of patients with Time to Maximum Block data.
|| Propofol anesthesia.
¶ Halothane anesthesia.
** Thiopentone, alfentanil, N2O/O2 anesthesia
When administered during the induction of adequate anesthesia using propofol, nitrous oxide/oxygen, and co-induction agents (e.g., fentanyl and midazolam), GOOD or EXCELLENT conditions for tracheal intubation occurred in 96/102 (94%) patients in 1.5 to 2.0 minutes following 0.15 mg/kg cisatracurium and in 97/110 (88%) patients in 1.5 minutes following 0.2 mg/kg cisatracurium.
In one intubation study during thiopental anesthesia in which fentanyl and midazolam were administered two minutes prior to induction, intubation conditions were assessed at 120 seconds. Table 2 displays these results in this study of 51 patients.
Table 2: Study of Tracheal Intubation Comparing Two
Doses of Cisatracurium (Thiopental Anesthesia)
|Intubating Conditions at 120 seconds||3 x ED95 0.15 mg/kg
n = 26
|4 x ED95 0.20 mg/kg
n = 25
|Excellent and Good|
While GOOD or EXCELLENT intubation conditions were achieved in the majority of patients in this setting, EXCELLENT intubation conditions were more frequently achieved with the 0.2 mg/kg dose (60%) than the 0.15 mg/kg dose (31%) when intubation was attempted 2.0 minutes following cisatracurium.
A second study evaluated intubation conditions after 3 and 4 ◊ ED95 (0.15 mg/kg and 0.20 mg/kg) following induction with fentanyl and midazolam and either thiopental or propofolanesthesia. This study compared intubation conditions produced by these doses of cisatracurium after 1.5 minutes. Table 3 displays these results.
Table 3: Study of Tracheal Intubation Comparing Three
Doses of Cisatracurium (Thiopental or Propofol Anesthesia)
|Intubating Conditions at 90 seconds||3 x ED95 0.15 mg/kg Propofol
n = 31
|3 x ED95 0.15 mg/kg Thiopental
n = 31
|4 x ED95 0.20 mg/kg Propofol
n = 30
|4 x ED95 0.20 mg/kg Thiopental
n = 28
|Excellent and Good|
EXCELLENT intubation conditions were more frequently observed with the 0.2 mg/kg dose when intubation was attempted 1.5 minutes following cisatracurium.
A third study in pediatric patients (ages 1 month to 12 years) evaluated intubation conditions at 120 seconds after 0.15 mg/kg NIMBEX following induction with either halothane (with halothane/nitrous oxide/oxygen maintenance) or thiopentone and fentanyl (with thiopentone/fentanyl nitrous oxide/oxygen maintenance). The results are summarized in Table 4.
Table 4: Study of Tracheal Intubation for Pediatrics
Stratified by Age Group (0.15 mg/kg NIMBEX with Halothane or Thiopentone/
|Intubating Conditions at 120 seconds**||NIMBEX 0.15 mg/kg 1-11 mo.
n = 30
|NIMBEX 0.15 mg/kg 1- 4 years
n = 31
|NIMBEX 0.15 mg/kg 5-12 years
n = 30
|Halothane Anesthesia||Thiopentone/ Fentanyl Anesthesia||Halothane Anesthesia||Thiopentone/ Fentanyl Anesthesia||Halothane Anesthesia||Thiopentone/ Fentanyl Anesthesia|
|Excellent and Good|
|** Excellent: Easy passage of the tube without
coughing. Vocal cords relaxed and abducted.
Good: Passage of tube with slight coughing and/or bucking. Vocal cords relaxed and abducted.
Poor: Passage of tube with moderate coughing and/or bucking. Vocal cords moderately adducted. Response of patient requires adjustment of ventilation pressure and/or rate.
EXCELLENT or GOOD intubating conditions were produced 120 seconds following 0.15 mg/kg NIMBEX in 88/90 (98%) of patients induced with halothane and in 85/90 (94%) of patients induced with thiopentone and fentanyl. There were no patients for whom intubation was not possible, but there were 7/120 patients ages 1-12 years for whom intubating conditions were described as poor.
Repeated administration of maintenance doses or a continuous infusion of NIMBEX for up to 3 hours is not associated with development of tachyphylaxis or cumulative neuromuscular blocking effects. The time needed to recover from successive maintenance doses does not change with the number of doses administered as long as partial recovery is allowed to occur between doses. Maintenance doses can therefore be administered at relatively regular intervals with predictable results. The rate of spontaneous recovery of neuromuscular function after infusion is independent of the duration of infusion and comparable to the rate of recovery following initial doses (Table 1).
Long-term infusion (up to 6 days) of NIMBEX during mechanical ventilation in the ICU has been evaluated in two studies. In a randomized, double-blind study using presence of a single twitch during train-of-four (TOF) monitoring to regulate dosage, patients treated with NIMBEX (n = 19) recovered neuromuscular function (T4:T1 ratio ≥ 70%) following termination of infusion in approximately 55 minutes (range: 20 to 270) whereas those treated with vecuronium (n = 12) recovered in 178 minutes (range: 40 minutes to 33 hours). In another study comparing NIMBEX and atracurium, patients recovered neuromuscular function in approximately 50 minutes for both NIMBEX (range: 20 to 175; n = 34) and atracurium (range: 35 to 85; n = 15).
The neuromuscular block produced by NIMBEX is readily antagonized by anticholinesterase agents once recovery has started. As with other nondepolarizing neuromuscular blocking agents, the more profound the neuromuscular block at the time of reversal, the longer the time required for recovery of neuromuscular function.
In children (2 to 12 years) cisatracurium has a lower ED95 than in adults (0.04 mg/kg, halothane/nitrous oxide/oxygen anesthesia). At 0.1 mg/kg during opioid anesthesia, cisatracurium had a faster onset and shorter duration of action in children than in adults (Table 1). Recovery following reversal is faster in children than in adults.
At 0.15 mg/kg during opioid anesthesia, cisatracurium had a faster onset and longer clinically effective duration of action in infants aged 1-23 months compared to children aged 2-12 years (Table 1).
Studies were conducted during both opioid-based and halothane-based anesthesia in children aged 1-11 months, 1-4 years, and 5-12 years. Cisatracurium had a faster onset and longer duration of action in infants 1-11 months compared to children 1-4 years, who in turn have a faster onset and longer duration of action for cisatracurium compared to children 5-12 years.
The mean time to onset of maximum T1 suppression was generally faster for pediatric patients induced with halothane compared to thiopentone/fentanyl and the clinically effective duration (time to 25% recovery) was longer (by up to 15%) for pediatric patients under halothane anesthesia.
The cardiovascular profile of NIMBEX allows it to be administered by rapid bolus at highermultiples of the ED95 than atracurium. NIMBEX has no dose-related effects on mean arterial blood pressure (MAP) or heart rate (HR) following doses ranging from 2 to 8 ◊ ED95 ( > 0.1 to > 0.4 mg/kg), administered over 5 to 10 seconds, in healthy adult patients (Figure 1) or in patients with serious cardiovascular disease (Figure 2).
A total of 141 patients undergoing coronary artery bypass grafting (CABG) have been administered NIMBEX in three active controlled clinical trials and have received doses ranging from 2 to 8 ◊ ED95. While the hemodynamic profile was comparable in both the NIMBEX and active control groups, data for doses above 0.3 mg/kg in this population are limited.
Unlike atracurium, NIMBEX, at therapeutic doses of 2 ◊ ED95 to 8 ◊ ED95 (0.1 to 0.4 mg/kg), administered over 5 to 10 seconds, does not cause dose-related elevations in mean plasma histamine concentration.
Figure 1: Maximum Percent Change from Preinjection in
Heart Rate (HR) and Mean Arterial Pressure (MAP) During First 5 Minutes after
Initial 4 ◊ ED95 to 8 ◊ ED95 Doses of NIMBEX in Healthy Adult Patients
Receiving Opioid/Nitrous Oxide/Oxygen Anesthesia (n = 44)
Figure 2: Percent Change from Preinjection in Heart
Rate (HR) and Mean Arterial Pressure (MAP) 10 Minutes After an Initial 4 ◊ ED95
to 8 ◊ ED95 Dose of NIMBEX in Patients Undergoing CABG Surgery Receiving Oxygen/Fentanyl/Midazolam/Anesthesia
(n = 54)
No clinically significant changes in MAP or HR were observed following administration of doses up to 0.1 mg/kg NIMBEX over 5 to 10 seconds in 2- to 12-year-old children receiving either halothane/nitrous oxide/oxygen or opioid/nitrous oxide/oxygen anesthesia. Doses of 0.15 mg/kg NIMBEX administered over 5 seconds were not consistently associated with changes inHR and MAP in pediatric patients aged 1 month to 12 years receiving opioid/nitrous oxide/oxygen or halothane/nitrous oxide/oxygen anesthesia.
Figure 3: Heart Rate and MAP Change at 1 Minute After
the Initial Dose, By Age GroupTreatment Group: NIMBEX 0:3 ◊ ED95 Opioid
Intubation at 120 Sec.
Figure 4: Heart Rate and MAP Change at 1 Minute After
the Initial Dose, By Age Group Treatment Group: NIMBEX H:3 ◊ ED95 Halothane
Intubation at 120 Sec.
The neuromuscular blocking activity of NIMBEX is due to parent drug. Cisatracurium plasma concentration-time data following IV bolus administration are best described by a twocompartment open model (with elimination from both compartments) with an elimination halflife (t½β) of 22 minutes, a plasma clearance (CL) of 4.57 mL/min/kg, and a volume of distribution at steady state (Vss) of 145 mL/kg. Cisatracurium undergoes organ-independent Hofmann elimination (a chemical process dependent on pH and temperature) to form the monoquaternary acrylate metabolite and laudanosine, neither of which has any neuromuscular blocking activity (see Pharmacokinetics - Metabolism section). Following administration of radiolabeled cisatracurium, 95% of the dose was recovered in the urine; less than 10% of the dose was excreted as unchanged parent drug. Laudanosine, a metabolite of cisatracurium (and atracurium) has been noted to cause transient hypotension and, in higher doses, cerebral excitatory effects when administered to several animal species. The relationship between CNS excitation and laudanosine concentrations in humans has not been established (see PRECAUTIONS - Long-term Use in the Intensive Care Unit). Because cisatracurium is three times more potent than atracurium and lower doses are required, the corresponding laudanosine concentrations following cisatracurium are one third of those that would be expected following an equipotent dose of atracurium (see Pharmacokinetics - Special Populations - Intensive Care Unit Patients).
Results from population pharmacokinetic/pharmacodynamic (PK/PD) analyses from 241 healthy surgical patients are summarized in Table 5.
Table 5: Key Population PK/PD Parameter Estimates for
Cisatracurium in Healthy Surgical Patients* Following 0.1 (2 ◊ ED95) to 0.4 mg/kg
(8 ◊ ED95) NIMBEX
|Parameter||Estimate†||Magnitude of Interpatient Variability (CV)‡|
|* Healthy male non-obese patients 19-64 years of age with
creatinine clearance values greater than 70 mL/min who received cisatracurium
during opioid anesthesia and had venous samples collected.
† The percent standard error of the mean (%SEM) ranged from 3% to 12% indicating good precision for the PK/PD estimates.
‡ Expressed as a coefficient of variation; the %SEM ranged from 20% to 35% indicating adequate precision for the estimates of interpatient variability.
§ Vss is the volume of distribution at steady state estimated using a two-compartment model with elimination from both compartments. Vss is equal to the sum of the volume in the central compartment (Vc) and the volume in the peripheral compartment (Vp); interpatient variability could only be estimated for Vc.
|| Rate constant describing the equilibration between plasma concentrations and neuromuscular block.
¶ Concentration required to produce 50% T1 suppression; an index of patient sensitivity.
The magnitude of interpatient variability in CL was low (16%), as expected based on the importance of Hofmann elimination (see Pharmacokinetics - Elimination). The magnitudes of interpatient variability in CL and volume of distribution were low in comparison to those for keo and EC50. This suggests that any alterations in the time course of cisatracurium-induced block are more likely to be due to variability in the pharmacodynamic parameters than in the pharmacokinetic parameters. Parameter estimates from the population pharmacokinetic analyses were supported by noncompartmental pharmacokinetic analyses on data from healthy patients and from special patient populations.
Conventional pharmacokinetic analyses have shown that the pharmacokinetics of cisatracurium are proportional to dose between 0.1 (2 ◊ ED95) and 0.2 (4 ◊ ED95) mg/kg cisatracurium. Inaddition, population pharmacokinetic analyses revealed no statistically significant effect of initial dose on CL for doses between 0.1 (2 ◊ ED95) and 0.4 (8 ◊ ED95) mg/kg cisatracurium.
The volume of distribution of cisatracurium is limited by its large molecular weight and high polarity. The Vss was equal to 145 mL/kg (Table 4) in healthy 19- to 64-year-old surgical patients receiving opioid anesthesia. The Vss was 21% larger in similar patients receiving inhalation anesthesia (see Pharmacokinetics - Special Populations - Other Patient Factors).
The binding of cisatracurium to plasma proteins has not been successfully studied due to its rapid degradation at physiologic pH. Inhibition of degradation requires nonphysiological conditions of temperature and pH which are associated with changes in protein binding.
The degradation of cisatracurium is largely independent of liver metabolism. Results from in vitro experiments suggest that cisatracurium undergoes Hofmann elimination (a pH and temperature-dependent chemical process) to form laudanosine (see PRECAUTIONS – Longterm Use in the Intensive Care Unit) and the monoquaternary acrylate metabolite. The monoquaternary acrylate undergoes hydrolysis by non-specific plasma esterases to form the monoquaternary alcohol (MQA) metabolite. The MQA metabolite can also undergo Hofmann elimination but at a much slower rate than cisatracurium. Laudanosine is further metabolized to desmethyl metabolites which are conjugated with glucuronic acid and excreted in the urine.
Organ-independent Hofmann elimination is the predominant pathway for the elimination of cisatracurium. The liver and kidney play a minor role in the elimination of cisatracurium but are primary pathways for the elimination of metabolites. Therefore, the t½β values of metabolites (including laudanosine) are longer in patients with kidney or liver dysfunction and metabolite concentrations may be higher after long-term administration (see PRECAUTIONS - Long-term Use in the Intensive Care Unit). Most importantly, Cmax values of laudanosine are significantly lower in healthy surgical patients receiving infusions of NIMBEX than in patients receiving infusions of atracurium (mean plusmn; SD Cmax: 60 plusmn; 52 and 342 plusmn; 93 ng/mL, respectively).
Clearance and Half-life
Mean CL values for cisatracurium ranged from 4.5 to 5.7 mL/min/kg in studies of healthy surgical patients. Compartmental pharmacokinetic modeling suggests that approximately 80% of the CL is accounted for by Hofmann elimination and the remaining 20% by renal and hepatic elimination. These findings are consistent with the low magnitude of interpatient variability in CL (16%) estimated as part of the population PK/PD analyses and with the recovery of parentand metabolites in urine. Following 14C-cisatracurium administration to 6 healthy male patients, 95% of the dose was recovered in the urine (mostly as conjugated metabolites) and 4% in the feces; less than 10% of the dose was excreted as unchanged parent drug in the urine. In 12 healthy surgical patients receiving non-radiolabeled cisatracurium who had Foley catheters placed for surgical management, approximately 15% of the dose was excreted unchanged in the urine.
In studies of healthy surgical patients, mean t½β values of cisatracurium ranged from 22 to 29 minutes and were consistent with the t½β of cisatracurium in vitro (29 minutes). The mean plusmn; SD t½β values of laudanosine were 3.1 plusmn; 0.4 and 3.3 plusmn; 2.1 hours in healthy surgical patients receiving NIMBEX (n = 10) or atracurium (n = 10), respectively. During IV infusions of NIMBEX, peak plasma concentrations (Cmax) of laudanosine and the MQA metabolite are approximately 6% and 11% of the parent compound, respectively.
Geriatric Patients ( ≥ 65 years)
The results of conventional pharmacokinetic analysis from a study of 12 healthy elderly patients and 12 healthy young adult patients receiving a single IV dose of 0.1 mg/kg NIMBEX are summarized in Table 6. Plasma clearances of cisatracurium were not affected by age; however, the volumes of distribution were slightly larger in elderly patients than in young patients resulting in slightly longer t½β values for cisatracurium. The rate of equilibration between plasma cisatracurium concentrations and neuromuscular block was slower in elderly patients than in young patients (mean plusmn; SD keo: 0.071 plusmn; 0.036 and 0.105 plusmn; 0.021 minutes-1, respectively); there was no difference in the patient sensitivity to cisatracurium-induced block, as indicated by EC50 values (mean plusmn; SD EC50: 91 plusmn; 22 and 89 plusmn; 23 ng/mL, respectively). These changes were consistent with the 1-minute slower times to maximum block in elderly patients receiving 0.1 mg/kg NIMBEX, when compared to young patients receiving the same dose. The minor differences in PK/PD parameters of cisatracurium between elderly patients and young patients were not associated with clinically significant differences in the recovery profile of NIMBEX.
Table 6: Pharmacokinetic Parameters* of Cisatracurium
in Healthy Elderly and Young Adult Patients Following 0.1 mg/kg (2 ◊ ED95)
NIMBEX (Isoflurane/Nitrous Oxide/Oxygen Anesthesia)
|Parameter||Healthy Elderly Patients||Healthy Young Adult Patients|
|Elimination Half-Life (t½β, min)||25.8 ± 3.6†||22.1 ± 2.5|
|Volume of Distribution at Steady State‡ (mL/kg)||156 ± 17†||133 ± 15|
|Plasma Clearance (mL/min/kg)||5.7 ± 1.0||5.3 ± 0.9|
|* Values presented are mean plusmn; SD.
† P < 0.05 for comparisons between healthy elderly and healthy young adult patients.
‡ Volume of distribution is underestimated because elimination from the peripheral compartment is ignored.
Patients with Hepatic Disease
Table 7 summarizes the conventional pharmacokinetic analysis from a study of NIMBEX in 13 patients with end-stage liver disease undergoing liver transplantation and 11 healthy adult patients undergoing elective surgery. The slightly larger volumes of distribution in liver transplant patients were associated with slightly higher plasma clearances of cisatracurium. The parallel changes in these parameters resulted in no difference in t½β values. There were no differences in keo or EC50 between patient groups. The times to maximum block were approximately one minute faster in liver transplant patients than in healthy adult patients receiving 0.1 mg/kg NIMBEX. These minor differences in pharmacokinetics were not associated with clinically significant differences in the recovery profile of NIMBEX.
The t½β values of metabolites are longer in patients with hepatic disease and concentrations may be higher after long-term administration (see Pharmacokinetics - Special Populations - Intensive Care Unit Patients).
Table 7: Pharmacokinetic Parameters* of Cisatracurium
in Healthy Adult Patients and in Patients Undergoing Liver Transplantation
Following 0.1 mg/kg (2 ◊ ED95) NIMBEX (Isoflurane/Nitrous Oxide/Oxygen
|Parameter||Liver Transplant Patients||Healthy Adult Patients|
|Elimination Half-Life (t½β, min)||24.4 ± 2.9||23.5 ± 3.5|
|Volume of Distribution at Steady State‡ (mL/kg)||195 ± 38†||161 ± 23|
|Plasma Clearance (mL/min/kg)||6.6 ± 1.1†||5.7 ± 0.8|
|* Values presented are mean plusmn; SD.
† P < 0.05 for comparisons between liver transplant patients and healthy adult patients.
‡ Volume of distribution is underestimated because elimination from the peripheral compartment is ignored.
Patients with Renal Dysfunction
Results from a conventional pharmacokinetic study of NIMBEX in 13 healthy adult patients and 15 patients with end-stage renal disease (ESRD) undergoing elective surgery are summarized in Table 8. The PK/PD parameters of cisatracurium were similar in healthy adult patients and ESRD patients. The times to 90% block were approximately one minute slower in ESRD patients following 0.1 mg/kg NIMBEX. There were no differences in the durations or rates of recovery of NIMBEX between ESRD and healthy adult patients.
The t½β values of metabolites are longer in patients with renal failure and concentrations may be higher after long-term administration (see Pharmacokinetics - Special Populations – Intensive Care Unit Patients).
Table 8: Pharmacokinetic Parameters* for Cisatracurium
in Healthy Adult Patients and in Patients With End-Stage Renal Disease (ESRD)
Receiving 0.1 mg/kg (2 ◊ ED95) NIMBEX (Opioid/Nitrous Oxide/Oxygen Anesthesia)
|Parameter||Healthy Adult Patients||ESRD Patients|
|Elimination Half-Life (t½β, min)||29.4 ± 4.1||32.3 ± 6.3|
|Volume of Distribution at Steady Statet (mL/kg)||149 ± 35||160 ± 32|
|Plasma Clearance (mL/min/kg)||4.66 ± 0.86||4.26 ± 0.62|
|* Values presented are mean plusmn; SD.
† Volume of distribution is underestimated because elimination from the peripheral compartment is ignored.
Population pharmacokinetic analyses revealed that patients with creatinine clearances ≤ 70 mL/min had a slower rate of equilibration between plasma concentrations and neuromuscular block than patients with normal renal function; this change was associated with a slightly slower (~ 40 seconds) predicted time to 90% T1 suppression in patients with renal dysfunction following 0.1 mg/kg NIMBEX. There was no clinically significant alteration in the recovery profile of NIMBEX in patients with renal dysfunction. The recovery profile of NIMBEX is unchanged in the presence of renal or hepatic failure, which is consistent with predominantly organindependent elimination.
Intensive Care Unit (ICU) Patients
The pharmacokinetics of cisatracurium, atracurium, and their metabolites were determined in six ICU patients receiving NIMBEX and in six ICU patients receiving atracurium and are presented in Table 9. The plasma clearances of cisatracurium and atracurium are similar. The volume of distribution was larger and the t½β was longer for cisatracurium than for atracurium. The relationships between plasma cisatracurium or atracurium concentrations and neuromuscular block have not been evaluated in ICU patients. The minor differences in pharmacokinetics were not associated with any differences in the recovery profiles of NIMBEX and atracurium in ICU patients.
Table 9: Parameter Estimates* for Cisatracurium,
Atracurium, and Metabolites in ICU Patients After Long- Term (24-48 Hour)
Administration of NIMBEX or Atracurium Besylate
(n = 6)
(n = 6)
|Parent Compound||CL (mL/min/kg)||7.45 ± 1.02||7.49 ± 0.66†|
|t½β(min)||26.8 ± 11.1||16.5 ± 6.0†|
|Vβ (mL/kg)‡||280 ± 103||178 ± 71†|
|Laudanosine||Cmax (ng/mL)||707 ± 360||2318± 1498|
|t½β (hrs)||6.6 ± 4.1||8.4 ± 7.3|
|MQA metabolite||Cmax (ng/mL)||152-181§||943 ± 333|||
|* Presented as mean plusmn; standard deviation.
† n = 5.
‡ Volume of distribution during the terminal elimination phase, an underestimate because elimination from the peripheral compartment is ignored.
§ n = 2, range presented.
|| n = 3.
Plasma metabolite pharmacokinetics are listed in Table 9. Limited pharmacokinetic data are available for patients with liver/kidney dysfunction receiving NIMBEX. Data from studies of atracurium demonstrate that renal/hepatic failure in ICU patients produces little to no effect on its pharmacokinetics, but decreases the biotransformation and elimination of the metabolites. Following atracurium, t½β values for laudanosine were longer in ICU patients with renal failure than in ICU patients with normal renal function (15 and 6 hours, respectively). The t½β values of laudanosine were 39 plusmn; 14 hours in ICU patients with liver failure receiving atracurium after an unsuccessful liver transplantation and 5 plusmn; 2 hours in similar ICU patients after successful liver transplantation. Therefore, relative to ICU patients with normal renal and hepatic function receiving NIMBEX, metabolite concentrations (plasma and tissues) may be higher in ICU patients with renal or hepatic failure (see PRECAUTIONS - Long-term Use in the Intensive Care Unit). Consistent with the decreased infusion rate requirements for NIMBEX, metabolite concentrations were lower in patients receiving NIMBEX than in patients receiving atracurium besylate.
The population PK/PD of cisatracurium were described in 20 healthy pediatric patients during halothane anesthesia, using the same model developed for healthy adult patients. The CL was higher in healthy pediatric patients (5.89 mL/min/kg) than in healthy adult patients (4.57 mL/min/kg) during opioid anesthesia. The rate of equilibration between plasma concentrations and neuromuscular block, as indicated by keo, was faster in healthy pediatric patients receiving halothane anesthesia (0.1330 minutes-1) than in healthy adult patients receiving opioid anesthesia (0.0575 minutes-1). The EC50 in healthy pediatric patients (125 ng/mL) was similar to the value in healthy adult patients (141 ng/mL) during opioid anesthesia. The minor differences in the PK/PD parameters of cisatracurium were associated with a faster time to onset and a shorter duration of cisatracurium-induced neuromuscular block in pediatric patients.
Other Patient Factors
Population PK/PD analyses revealed that gender and obesity were associated with statistically significant effects on the pharmacokinetics and/or pharmacodynamics of cisatracurium; these factors were not associated with clinically significant alterations in the predicted onset or recovery profile of NIMBEX. The use of inhalation agents was associated with a 21% larger Vss, a 78% larger keo, and a 15% lower EC50 for cisatracurium. These changes resulted in a slightly faster (~ 45 seconds) predicted time to 90% T1 suppression in patients receiving 0.1 mg/kg cisatracurium during inhalation anesthesia than in patients receiving the same dose of cisatracurium during opioid anesthesia; however, there were no clinically significant differences in the predicted recovery profile of NIMBEX between patient groups.
Individualization of Dosages
DOSES OF NIMBEX SHOULD BE INDIVIDUALIZED AND A PERIPHERAL NERVE STIMULATOR SHOULD BE USED TO MEASURE NEUROMUSCULAR FUNCTION DURING ADMINISTRATION OF NIMBEX IN ORDER TO MONITOR DRUG EFFECT, TO DETERMINE THE NEED FOR ADDITIONAL DOSES, AND TO CONFIRM RECOVERY FROM NEUROMUSCULAR BLOCK.
Based on the known action of NIMBEX and other neuromuscular blocking agents, the following factors should be considered when administering NIMBEX.
Renal and Hepatic Disease
See PRECAUTIONS section.
Long-Term Use in the Intensive Care Unit (ICU)
The long-term infusion (up to 6 days) of NIMBEX during mechanical ventilation in the ICU has been evaluated in two studies. Average infusion rates of approximately 3 mcg/kg/min (range: 0.5 to 10.2) were required to achieve adequate neuromuscular block. As with other neuromuscular blocking agents, these data indicate the presence of wide interpatient variability in dosage requirements. In addition, dosage requirements may increase or decrease with time (see PRECAUTIONS ). Use of NIMBEX in the ICU for longer than 6 days has not been studied.
Drugs or Conditions Causing Potentiation of or Resistance to Neuromuscular Block
Persons with certain pre-existing conditions or receiving certain drugs may require individualization of dosing (see PRECAUTIONS).
Patients with burns have been shown to develop resistance to nondepolarizing neuromuscular blocking agents, and may require individualization of dosing (see PRECAUTIONS).
Last reviewed on RxList: 2/8/2016
This monograph has been modified to include the generic and brand name in many instances.
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