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Nimbex

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Nimbex

Nimbex

WARNINGS

Anaphylaxis

Severe anaphylactic reactions to neuromuscular blocking agents, including NIMBEX (cisatracurium besylate) , have been reported. These reactions have in some cases been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported in this class of drugs.

Administration

NIMBEX (cisatracurium besylate) 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 (cisatracurium besylate) ARE IMMEDIATELY AVAILABLE. IT IS RECOMMENDED THAT A PERIPHERAL NERVE STIMULATOR BE USED TO MEASURE NEUROMUSCULAR FUNCTION DURING THE ADMINISTRATION OF NIMBEX (cisatracurium besylate) IN ORDER TO MONITOR DRUG EFFECT, DETERMINE THE NEED FOR ADDITIONAL DOSES, AND CONFIRM RECOVERY FROM NEUROMUSCULAR BLOCK.

NIMBEX (cisatracurium besylate) 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 (cisatracurium besylate) 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 (cisatracurium besylate) contain benzyl alcohol, which is potentially toxic when administered locally to neural tissue. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources. Single-use vials (5 mL and 20 mL) of NIMBEX (cisatracurium besylate) do not contain benzyl alcohol (see WARNINGS and PRECAUTIONS: Pediatric Use).

PRECAUTIONS

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

Recommended doses of NIMBEX (cisatracurium besylate) have no clinically significant effects on heart rate; therefore, NIMBEX (cisatracurium besylate) 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 (cisatracurium besylate) 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 (cisatracurium besylate) 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 (cisatracurium besylate) 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 (cisatracurium besylate) 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 NIMBEX 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 × 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 (cisatracurium besylate) 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 (cisatracurium besylate) , laudanosine concentrations were lower in patients receiving NIMBEX (cisatracurium besylate) 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 (cisatracurium besylate) (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 (cisatracurium besylate) and atracurium, patients recovered neuromuscular function in approximately 50 minutes for both NIMBEX (cisatracurium besylate) (range: 20 to 175; n = 34) and atracurium (range: 35 to 85; n = 15).

WHENEVER THE USE OF NIMBEX (cisatracurium besylate) 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 (cisatracurium besylate) 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 (cisatracurium besylate) and its metabolites are unknown.

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 × the human ED95 following a bolus dose of 0.2 mg/kg IV) and in ventilated rats treated intravenously with paralyzing doses of NIMBEX (cisatracurium besylate) at 0.5 and 1.0 mg/kg; equivalent to 10 × and 20 × the human ED95 dose, respectively, revealed no maternal or fetal toxicity or teratogenic effects. There are no adequate and well-controlled studies of NIMBEX (cisatracurium besylate) in pregnant women. Because animal studies are not always predictive of human response, NIMBEX (cisatracurium besylate) should be used during pregnancy only if clearly needed.

Labor and Delivery

The use of NIMBEX (cisatracurium besylate) during labor, vaginal delivery, or cesarean section has not been studied in humans and it is not known whether NIMBEX (cisatracurium besylate) 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 (cisatracurium besylate) to a nursing woman.

Pediatric Use

NIMBEX (cisatracurium besylate) 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 (cisatracurium besylate) 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 NIMBEX (cisatracurium besylate) 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 NIMBEX (cisatracurium besylate) , 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 (cisatracurium besylate) 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 (cisatracurium besylate) 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).

Last reviewed on RxList: 1/4/2011
This monograph has been modified to include the generic and brand name in many instances.

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