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NIMBEX® INJECTION
(cisatracurium besylate)

This drug should be administered only by adequately trained individuals familiar with its actions, characteristics, and hazards.

DESCRIPTION

NIMBEX (cisatracurium besylate) is a nondepolarizing skeletal muscle relaxant for intravenous administration. Compared to other neuromuscular blocking agents, it is intermediate in its onset and duration of action. Cisatracurium besylate is one of 10 isomers of atracurium besylate and constitutes approximately 15% of that mixture. Cisatracurium besylate is [1R-[1α,2α(1'R*,2'R*)]]-2,2'-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium] dibenzenesulfonate. The molecular formula of the cisatracurium parent bis-cation is C53H72N2O12 and the molecular weight is 929.2. The molecular formula of cisatracurium as the besylate salt is C65H82N2O18S2 and the molecular weight is 1243.50. The structural formula of cisatracurium besylate is:

The log of the partition coefficient of cisatracurium besylate is -2.12 in a 1-octanol/distilled water system at 25°C.

NIMBEX Injection is a sterile, non-pyrogenic aqueous solution provided in 5 mL, 10 mL, and 20 mL vials. The pH is adjusted to 3.25 to 3.65 with benzenesulfonic acid. The 5 mL and 10 mL vials each contain cisatracurium besylate, equivalent to 2 mg/mL cisatracurium. The 20 mL vial, intended for ICU use only, contains cisatracurium besylate, equivalent to 10 mg/mL cisatracurium. The 10 mL vial, intended for multiple-dose use, contains 0.9% benzyl alcohol as a preservative. The 5 mL and 20 mL vials are single-use vials and do not contain benzyl alcohol.

Cisatracurium besylate slowly loses potency with time at a rate of approximately 5% per year under refrigeration (5°C). NIMBEX should be refrigerated at 2° to 8°C (36° to 46°F) in the carton to preserve potency. The rate of loss in potency increases to approximately 5% per month at 25°C (77°F). Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use NIMBEX within 21 days, even if rerefrigerated.

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

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
Time to Spontaneous Recovery
Initial Dose of NIMBEX (mg/kg)Time to 90% Block (min)Time to Maximum Block (min)5% Recovery (min) 25% Recovery (min) 95% Recovery (min) T4:T 1 Ratio≥ 70% (min)25%-75% Recovery Index (min)

*   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

Adults
0.1
(2 × ED95)
(n§= 98)
3.3
(1.0-8.7)
5.0
(1.2-17.2)
33
(15-51)
42
(22-63)
64
(25-93)
64
(32-91)
13
(5-30)
0.15||
(3 × ED95)
(n = 39)
2.6
(1.0-4.4)
3.5
(1.6-6.8)
46
(28-65)
55
(44-74)
76
(60-103)
75
(63-98)
13
(11-16)
0.2
(4 × ED95)
(n = 30)
2.4
(1.5-4.5)
2.9
(1.9-5.2)
59
(31-103)
65
(43-103)
81
(53-114)
85
(55-114)
12
(2-30)
0.25
(5 × ED95)
(n = 15)
1.6
(0.8-3.3)
2.0
(1.2-3.7)
70
(58-85)
78
(66-86)
91
(76-109)
97
(82-113)
8
(5-12)
0.4
(8 × ED95)
(n = 15)
1.5
(1.3-1.8)
1.9
(1.4-2.3)
83
(37-103)
91
(59-107)
121
(110-134)
126
(115-137)
14
(10-18)
Infants (1-23 mos.)
0.15**
(n = 18-26)
1.5
(0.7-3.2)
2.0
(1.3-4.3)
36
(28-50)
43
(34-58)
64
(54-84)
59
(49-76)
11.3
(7.3-18.3)
Children (2-12 yr)
0.08¶
(2 × ED95)
(n = 60)
2.2
(1.2-6.8)
3.3
(1.7-9.7)
22
(11-38)
29
(20-46)
52
(37-64)
50
(37-62)
11
(7-15)
0.1
(n = 16)
1.7
(1.3-2.7)
2.8
(1.8-6.7)
21
(13-31)
28
(21-38)
46
(37-58)
44
(36-58)
10
(7-12)
0.15**
(n = 23-24)
2.1
(1.3-2.8)
3.0
(1.5-8.0)
29
(19-38)
36
(29-46)
55
(45-72)
54
(44-66)
10.6
(8.5-17.7)

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 seconds3 × ED95
0.15 mg/kg n = 26
4 × ED95
0.20 mg/kg n = 25
Excellent and Good
     Proportion23/2624/25
     Percent88%96%
     95% CI76,10088,100
Excellent
     Proportion8/2615/26
     Percent31%60%
Good
     Proportion15/269/25
     Percent58%36%

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 propofol anesthesia. 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 seconds3 × ED95
0.15 mg/kg
Propofol
n = 31
3 × ED95
0.15 mg/kg
Thiopental
n = 31
4 × ED95
0.20 mg/kg
Propofol
n = 30
4 × ED95
0.20 mg/kg
Thiopental
n = 28
Excellent and Good
     Proportion29/3128/3128/3027/28
     Percent94%90%93%96%
     95% CI85,10080,10084,10090,100
Excellent
     Proportion18/3117/3122/3016/28
     Percent58%55%70%57%
Good
     Proportion11/3111/316/3011/28
     Percent35%35%20%39%

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/ Fentanyl Anesthesia)
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
Intubating Conditions at 120 seconds**Halothane Anesthesia Thiopentone/ Fentanyl AnesthesiaHalothane AnesthesiaThiopentone/ Fentanyl AnesthesiaHalothane Anesthesia Thiopentone/ Fentanyl Anesthesia

**   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 and Good
     Proportion30/3030/3029/3026/3029/3029/30
     Percent100%100%97%87%97%97%
Excellent
     Proportion30/3025/3027/3019/3022/3021/30
     Percent100%83%90%63%73%70%
Good
     Proportion05/302/307/307/308/30
     Percent0%17%7%23%23%27%
Poor
     Proportion0/300/301/304/301/301/30
     Percent0%0%3%13%3%3%

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.

Hemodynamics Profile

The cardiovascular profile of NIMBEX allows it to be administered by rapid bolus at higher multiples 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 in HR 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 Group Treatment Group: NIMBEX 0:3 × ED95 Opioid Intubation at 120 Sec.

1-11 Months

1-5 Years

5-13 Years

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.

1-11 Months

1-5 Years

5-13 Years

Pharmacokinetics

Elimination

Special Populations

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.

INDICATIONS AND USAGE

NIMBEX is an intermediate-onset/intermediate-duration neuromuscular blocking agent indicated for inpatients and outpatients as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the ICU.

CONTRAINDICATIONS

NIMBEX is contraindicated in patients known to have an allergic hypersensitivity to NIMBEX or other bis-benzylisoquinolinium agents. Use of NIMBEX from vials containing benzyl alcohol as a preservative is contraindicated in patients with a known hypersensitivity to benzyl alcohol.

WARNINGS

NIMBEX 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 PERSONNEL AND FACILITIES FOR RESUSCITATION AND LIFE SUPPORT (TRACHEAL INTUBATION, ARTIFICIAL VENTILATION, OXYGEN THERAPY), AND AN ANTAGONIST OF NIMBEX ARE IMMEDIATELY AVAILABLE. IT IS RECOMMENDED THAT A PERIPHERAL NERVE STIMULATOR BE USED TO MEASURE NEUROMUSCULAR FUNCTION DURING THE ADMINISTRATION OF NIMBEX IN ORDER TO MONITOR DRUG EFFECT, DETERMINE THE NEED FOR ADDITIONAL DOSES, AND CONFIRM RECOVERY FROM NEUROMUSCULAR BLOCK.

NIMBEX HAS NO KNOWN EFFECT ON CONSCIOUSNESS, PAIN THRESHOLD, OR CEREBRATION. TO AVOID DISTRESS TO THE PATIENT, NEUROMUSCULAR BLOCK SHOULD NOT BE INDUCED BEFORE UNCONSCIOUSNESS.

NIMBEX Injection is acidic (pH 3.25 to 3.65) and may not be compatible with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions).

The 10 mL multiple-dose vials of NIMBEX contain benzyl alcohol. In newborn infants, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal. Single-use vials (5 mL and 20 mL) of NIMBEX do not contain benzyl alcohol (see PRECAUTIONS - Pediatric Use).

PRECAUTIONS

Because of its intermediate onset of action, NIMBEX is not recommended for rapid sequence endotracheal intubation.

Recommended doses of NIMBEX have no clinically significant effects on heart rate; therefore, NIMBEX will not counteract the bradycardia produced by many anesthetic agents or by vagal stimulation.

Neuromuscular blocking agents may have a profound effect in patients with neuromuscular diseases (e.g., myasthenia gravis and the myasthenic syndrome). In these and other conditions in which prolonged neuromuscular block is a possibility (e.g., carcinomatosis), the use of a peripheral nerve stimulator and a dose of not more than 0.02 mg/kg NIMBEX is recommended to assess the level of neuromuscular block and to monitor dosage requirements.

Patients with burns have been shown to develop resistance to nondepolarizing neuromuscular blocking agents, including atracurium. The extent of altered response depends upon the size of the burn and the time elapsed since the burn injury. NIMBEX has not been studied in patients with burns; however, based on its structural similarity to atracurium, the possibility of increased dosing requirements and shortened duration of action must be considered if NIMBEX is administered to burn patients.

Patients with hemiparesis or paraparesis also may demonstrate resistance to nondepolarizing muscle relaxants in the affected limbs. To avoid inaccurate dosing, neuromuscular monitoring should be performed on a non-paretic limb.

Acid-base and/or serum electrolyte abnormalities may potentiate or antagonize the action of neuromuscular blocking agents. No data are available to support the use of NIMBEX by intramuscular injection.

Renal and Hepatic Disease

No clinically significant alterations in the recovery profile were observed in patients with renal dysfunction or in patients with end-stage liver disease following a 0.1 mg/kg dose of cisatracurium. The onset time was approximately 1 minute faster in patients with end-stage liver disease and approximately 1 minute slower in patients with renal dysfunction than in healthy adult control patients.

Malignant Hyperthermia (MH)

In a study of MH-susceptible pigs, cisatracurium besylate (highest dose 2000 mcg/kg equivalent to 3 × ED95 in pigs and 40 × ED95 in humans) did not trigger MH. Cisatracurium besylate has not been studied in MH-susceptible patients. Because MH can develop in the absence of established triggering agents, the clinician should be prepared to recognize and treat MH in any patient undergoing general anesthesia.

Long-Term Use in the Intensive Care Unit (ICU)

Long-term infusion (up to 6 days) of NIMBEX during mechanical ventilation in the ICU has been safely used in two studies. Dosage requirements may increase or decrease with time (see CLINICAL PHARMACOLOGY - Individualization of Doses).

Little information is available on the plasma levels and clinical consequences of cisatracurium metabolites that may accumulate during days to weeks of cisatracurium administration in ICU patients. Laudanosine, a major, biologically active metabolite of atracurium and cisatracurium without neuromuscular blocking activity, produces transient hypotension and, in higher doses, cerebral excitatory effects (generalized muscle twitching and seizures) when administered to several species of animals. There have been rare spontaneous reports of seizures in ICU patients who have received atracurium or other agents. These patients usually had predisposing causes (such as cranial trauma, cerebral edema, hypoxic encephalopathy, viral encephalitis, uremia). There are insufficient data to determine whether or not laudanosine contributes to seizures in ICU patients. Consistent with the decreased infusion rate requirements for NIMBEX, laudanosine concentrations were lower in patients receiving NIMBEX than in patients receiving atracurium for up to 48 hours (see Pharmacokinetics -Special Populations - Intensive Care Unit Patients).

In a randomized, double-blind study using train-of-four nerve stimulator monitoring to maintain at least one visible twitch, evaluable 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 evaluable vecuronium-treated patients (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).

WHENEVER THE USE OF NIMBEX OR ANY OTHER NEUROMUSCULAR BLOCKING AGENT IN THE ICU IS CONTEMPLATED, IT IS RECOMMENDED THAT NEUROMUSCULAR FUNCTION BE MONITORED DURING ADMINISTRATION WITH A NERVE STIMULATOR. ADDITIONAL DOSES OF NIMBEX OR ANY OTHER NEUROMUSCULAR BLOCKING AGENT SHOULD NOT BE GIVEN BEFORE THERE IS A DEFINITE RESPONSE TO NERVE STIMULATION. IF NO RESPONSE IS ELICITED, INFUSION ADMINISTRATION SHOULD BE DISCONTINUED UNTIL A RESPONSE RETURNS.

The effects of hemofiltration, hemodialysis, and hemoperfusion on plasma levels of NIMBEX and its metabolites are unknown.

Drug Interactions

NIMBEX has been used safely following varying degrees of recovery from succinylcholine-induced neuromuscular block. Administration of 0.1 mg/kg (2 × ED95) NIMBEX at 10% or 95% recovery following an intubating dose of succinylcholine (1 mg/kg) produced ≥ 95% neuromuscular block. The time to onset of maximum block following NIMBEX is approximately 2 minutes faster with prior administration of succinylcholine. Prior administration of succinylcholine had no effect on the duration of neuromuscular block following initial or maintenance bolus doses of NIMBEX. Infusion requirements of NIMBEX in patients administered succinylcholine prior to infusions of NIMBEX were comparable to or slightly greater than when succinylcholine was not administered.

The use of NIMBEX before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied.

Although not studied systematically in clinical trials, no drug interactions were observed when vecuronium, pancuronium, or atracurium were administered following varying degrees of recovery from single doses or infusions of NIMBEX.

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 of NIMBEX and decrease the required infusion rate 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%.

In clinical studies propofol had no effect on the duration of action or dosing requirements for NIMBEX.

Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as NIMBEX include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, coulin, and sodium coulemethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine.

Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of NIMBEX are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher.

Drug/Laboratory Test Interactions

None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and fertility studies have not been performed. Cisatracurium besylate was evaluated in a battery of four short-term mutagenicity tests. It was non-mutagenic in the Ames Salmonella assay, a rat bone marrow cytogenetic assay, and an in vitro human lymphocyte cytogenetics assay. As was the case with atracurium, the mouse lymphoma assay was positive both in the presence and absence of exogenous metabolic activation (rat liver S-9). In the absence of S-9, cisatracurium besylate was positive at in vitro cisatracurium concentrations of 40 mcg/mL and higher. The highest non-mutagenic concentration (30 mcg/mL) and incubation time (4 hours) resulted in an AUC approximately 120 times that noted in clinical studies and approximately 8.5 times the mean peak clinical concentration noted. In the presence of S-9, cisatracurium besylate was positive at a cisatracurium concentration of 300 mcg/mL but not at lower or higher concentrations.

Pregnancy

Teratogenic Effects

Labor and Delivery

The use of NIMBEX during labor, vaginal delivery, or cesarean section has not been studied in humans and it is not known whether NIMBEX administered to the mother has effects on the fetus. Doses of 0.2 or 0.4 mg/kg cisatracurium given to female beagles undergoing cesarean section resulted in negligible levels of cisatracurium in umbilical vessel blood of neonates and no deleterious effects on the puppies. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy.

Nursing Mothers

It is not known whether cisatracurium besylate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised following administration of NIMBEX to a nursing woman.

Pediatric Use

NIMBEX has not been studied in pediatric patients below the age of 1 month (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION for clinical experience and recommendations for use in children 1 month to 12 years of age). Intubation of the trachea in patients 1-4 years old was facilitated more reliably when NIMBEX was used in combination with Halothane than when opioids and nitrous oxide were used for induction of anesthesia.

Geriatric Use

Of the total number of subjects in clinical studies of NIMBEX, 57 were 65 and over, 63 were 70 and over, and 15 were 80 and over. The geriatric population included a subset of patients with significant cardiovascular disease (see CLINICAL PHARMACOLOGY - Hemodynamics Profile and Special Populations - Geriatric Patients subsections). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between elderly and younger subjects, but greater sensitivity of some older individuals to NIMBEX cannot be ruled out.

Minor differences in the pharmacokinetics of cisatracurium between elderly and young adult patients are not associated with clinically significant differences in the recovery profile of NIMBEX following a single 0.1 mg/kg dose; the time to maximum block is approximately 1 minute slower in elderly patients (see CLINICAL PHARMACOLOGY - Pharmacokinetics).

ADVERSE REACTIONS

Observed in Clinical Trials of Surgical Patients

Adverse experiences were uncommon among the 945 surgical patients who received NIMBEX in conjunction with other drugs in US and European clinical studies in the course of a wide variety of procedures in patients receiving opioid, propofol, or inhalation anesthesia. The following adverse experiences were judged by investigators during the clinical trials to have a possible causal relationship to administration of NIMBEX:

Incidence Less than 1%

Observed in Clinical Trials of Intensive Care Unit Patients

Adverse experiences were uncommon among the 68 ICU patients who received NIMBEX in conjunction with other drugs in US and European clinical studies. One patient experienced bronchospasm. In one of the two ICU studies, a randomized and double-blind study of ICU patients using TOF neuromuscular monitoring, there were two reports of prolonged recovery (167 and 270 minutes) among 28 patients administered NIMBEX and 13 reports of prolonged recovery (range: 90 minutes to 33 hours) among 30 patients administered vecuronium.

Observed During Clinical Practice

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of cisatracurium besylate in conjunction with one or more anesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to cisatracurium besylate.

OVERDOSAGE

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 recovery from neuromuscular block begins, 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).

Antagonism of Neuromuscular Block

ANTAGONISTS (SUCH AS NEOSTIGMINE AND EDROPHONIUM) SHOULD NOT BE ADMINISTERED WHEN COMPLETE NEUROMUSCULAR BLOCK IS EVIDENT OR SUSPECTED. THE USE OF A PERIPHERAL NERVE STIMULATOR TO EVALUATE RECOVERY AND ANTAGONISM OF NEUROMUSCULAR BLOCK IS RECOMMENDED.

Administration of 0.04 to 0.07 mg/kg neostigmine at approximately 10% recovery from neuromuscular block (range: 0 to 15%) produced 95% recovery of the muscle twitch response and a T4:T1 ratio ≥ 70% in an average of 9 to 10 minutes. The times from 25% recovery of the muscle twitch response to a T4:T1 ratio ≥ 70% following these doses of neostigmine averaged 7 minutes. The mean 25% to 75% recovery index following reversal was 3 to 4 minutes.

Administration of 1.0 mg/kg edrophonium at approximately 25% recovery from neuromuscular block (range: 16% to 30%) produced 95% recovery and a T4:T1 ratio≥ 70% in an average of 3 to 5 minutes.

Patients administered antagonists should be evaluated for evidence of adequate clinical recovery (e.g., 5-second head lift and grip strength). Ventilation must be supported until no longer required.

The onset of antagonism may be delayed in the presence of debilitation, cachexia, 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 (see OVERDOSAGE ).

DOSAGE AND ADMINISTRATION

NIMBEX SHOULD ONLY BE ADMINISTERED INTRAVENOUSLY.

The dosage information provided below is intended as a guide only. Doses of NIMBEX should be individualized (see CLINICAL PHARMACOLOGY - Individualization of Dosages). The use of a peripheral nerve stimulator will permit the most advantageous use of NIMBEX, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery.

Adults

Children

Infants

Use by Continuous Infusion

NIMBEX Injection Compatibility and Admixtures

HOW SUPPLIED

NIMBEX Injection, 2 mg cisatracurium per mL, is supplied in the following:

List No.ContainerSize
4378Single-dose Vial5 mL
4380Multiple-dose Vial10 mL

NOTE:10 mL Multiple-dose Vials contain 0.9% w/v benzyl alcohol as a preservative (see WARNINGS concerning newborn infants).

NIMBEX Injection, 10 mg cisatracurium per mL is supplied in the following:

4382Single-dose Vial20 mL

Intended only for use in the ICU.

Storage

NIMBEX Injection should be refrigerated at 2° to 8°C (36° to 46°F) in the carton to preserve potency. Protect from light. DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use NIMBEX Injection within 21 days even if rerefrigerated.

U.S. Patent No. 5,453,510
Registered trademark of GlaxoSmithKline, licensed for use by Abbott Laboratories.

Mfd By: Hospira, Inc.

Lake Forest, IL 60045 USA

For: Abbott Laboratories

North Chicago, IL 60064 USA