PRECAUTIONS: Because of its intermediate onset of action, cisatracurium is not recommended for rapid sequence endotracheal intubation. Recommended doses of cisatracurium have no clinically significant effects on heart rate; therefore, cisatracurium 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 cisatracurium is recommended to assess the level of neuromuscular block and to monitor dosage requirements. Patients with burns have been shown to develop resistance to non-depolarizing 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. Cisatracurium 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 cisatracurium is administered to burn patients. Patients with hemiparesis or paraparesis also may demonstrate resistance to non-depolarizing 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 cisatracurium by intramuscular injection. Allergic Reactions Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents. In addition, inform your patients that severe anaphylactic reactions to neuromuscular blocking agents, including cisatracurium have been reported (see CONTRAINDICATIONS ). 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 x ED95 in pigs and 40 x 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 cisatracurium 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 Dosages ). 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 cisatracurium, laudanosine concentrations were lower in patients receiving cisatracurium 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 cisatracurium (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 cisatracurium and atracurium, patients recovered neuromuscular function in approximately 50 minutes for both cisatracurium (range: 20 to 175; n = 34) and atracurium (range: 35 to 85; n = 15). WHENEVER THE USE OF CISATRACURIUM 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 CISATRACURIUM 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 cisatracurium and its metabolites are unknown. Drug Interactions Cisatracurium has been used safely following varying degrees of recovery from succinylcholine-induced neuromuscular block. Administration of 0.1 mg/kg (2 x ED95) cisatracurium 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 cisatracurium 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 cisatracurium. Infusion requirements of cisatracurium in patients administered succinylcholine prior to infusions of cisatracurium were comparable to or slightly greater than when succinylcholine was not administered. The use of cisatracurium 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 cisatracurium. 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 cisatracurium and decrease the required infusion rate of cisatracurium. 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 cisatracurium and therefore, no adjustment to the initial dose should be necessary when cisatracurium 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 cisatracurium 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 cisatracurium. Other drugs which may enhance the neuromuscular blocking action of non-depolarizing agents such as cisatracurium include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. Resistance to the neuromuscular blocking action of non-depolarizing 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 cisatracurium 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 Pregnancy Category B Teratology testing in nonventilated pregnant rats treated subcutaneously with maximum subparalyzing doses (4 mg/kg daily; equivalent to 8 x the human ED95 following a bolus dose of 0.2 mg/kg intravenous) and in ventilated rats treated intravenously with paralyzing doses of cisatracurium at 0.5 and 1 mg/kg; equivalent to 10 x and 20 x the human ED95 dose, respectively, revealed no maternal or fetal toxicity or teratogenic effects. There are no adequate and well-controlled studies of cisatracurium in pregnant women. Because animal studies are not always predictive of human response, cisatracurium should be used during pregnancy only if clearly needed. Labor and Delivery The use of cisatracurium during labor, vaginal delivery, or cesarean section has not been studied in humans and it is not known whether cisatracurium 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 cisatracurium to a nursing woman. Pediatric Use Cisatracurium 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 to 4 years old was facilitated more reliably when cisatracurium was used in combination with halothane than when opioids and nitrous oxide were used for induction of anesthesia. The 10 mL multiple dose vials of cisatracurium contain benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. Geriatric Use Of the total number of subjects in clinical studies of cisatracurium, 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 ). 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 cisatracurium 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 cisatracurium 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 ).