Atracurium Besylate Injection

Atracurium besylate injection is indicated, as an adjunct to general anesthesia, to facilitate endotra-cheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

There has been limited experience with overdosage of atracurium besylate. The possibility of iatrogenic overdosage can be minimized by carefully monitoring muscle twitch response to peripheral nerve stimulation. Excessive doses of atracurium can be expected to produce enhanced pharmacological effects. Overdosage may increase the risk of histamine release and cardiovascular effects, especially hypotension. If cardiovascular support is necessary, this should include proper positioning, fluid administration, and the use of vasopressor agents if necessary. The patient's airway should be assured, with manual or mechanical ventilation maintained as necessary. A longer duration of neuromuscular block may result from overdosage and a peripheral nerve stimulator should be used to monitor recovery. Recovery may be facilitated by administration of an anticholinesterase reversing agent such as neostigmine, edrophonium, or pyridostig-mine, in conjunction with an anticholinergic agent such as atropine or glycopyrrolate. The appropriate package inserts should be consulted for prescribing information.

Three pediatric patients (3 weeks, 4 and 5 months of age) unintentionally received doses of 0.8 mg/kg to 1 mg/kg of atracurium besylate. The time to 25% recovery (50 to 55 minutes) following these doses, which were 5 to 6 times the ED95 dose, was moderately longer than the corresponding time observed following doses 2 to 2.5 times the atracurium ED95 dose in infants (22 to 36 minutes). Cardiovascular changes were minimal. Nonetheless the possibility of cardiovascular changes must be considered in the case of overdose.

An adult patient (17 years of age) unintentionally received an initial dose of 1.3 mg/kg of atracurium besylate. The time from injection to 25% recovery (83 minutes) was approximately twice that observed following maximum recommended doses in adults (35 to 45 minutes). The patient experienced moderate hemodynamic changes (13% increase in mean arterial pressure and 27% increase in heart rate) which persisted for 40 minutes and did not require treatment.

The intravenous LD50s determined in non-ventilated male and female albino mice and male Wistar rats were 1.9, 2.01 and 1.31 mg/kg, respectively. Deaths occurred within 2 minutes and were caused by respiratory paralysis. The subcutaneous LD50 determined in non-ventilated male Wistar rats was 282.8 mg/kg. Tremors, ptosis, loss of reflexes and respiratory failure preceded death which occurred 45 to 120 minutes after injection.

Atracurium Besylate Injection is indicated, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

Atracurium besylate is contraindicated in patients known to have a hypersensitivity to it. Use of atracurium besylate from multiple dose vials containing benzyl alcohol as a preservative is contraindicated in patients with a known hypersensitivity to benzyl alcohol.

To avoid distress to the patient, atracurium should not be administered before unconsciousness has been induced. Atracurium should not be mixed in the same syringe, or administered simultaneously through the same needle, with alkaline solutions (e.g., barbiturate solutions).

Atracurium besylate should be administered intravenously. DO NOT GIVE ATRACURIUM BESYLATE BY INTRAMUSCULAR ADMINISTRATION. Intramuscular administration of atracurium besylate may result in tissue irritation and there are no clinical data to support this route of administration.

As with other neuromuscular blocking agents, the use of a peripheral nerve stimulator will permit the most advantageous use of atracurium besylate, minimizing the possibility of overdosage or underdosage, and assist in the evaluation of recovery.

Bolus Doses for Intubation and Maintenance of Neuromuscular Block:

Adults: An atracurium besylate dose of 0.4 to 0.5 mg/kg (1.7 to 2.2 times the ED95), given as an intravenous bolus injection, is the recommended initial dose for most patients. With this dose, good or excellent conditions for nonemergency intubation can be expected in 2 to 2.5 minutes in most patients, with maximum neuromuscular block achieved approximately 3 to 5 minutes after injection. Clinically required neuromuscular block generally lasts 20 to 35 minutes under balanced anesthesia. Under balanced anesthesia, recovery to 25% of control is achieved approximately 35 to 45 minutes after injection, and recovery is usually 95% complete approximately 60 minutes after injection.

Atracurium is potentiated by isoflurane or enflurane anesthesia. The same initial atracurium besylate dose of 0.4 to 0.5 mg/kg may be used for intubation prior to administration of these inhalation agents; however, if atracurium is first administered under steady-state of isoflurane or enflurane, the initial atracurium besylate dose should be reduced by approximately one-third, i.e., to 0.25 to 0.35 mg/kg, to adjust for the potentiating effects of these anesthetic agents. With halothane, which has only a marginal (approximately 20%) potentiating effect on atracurium, smaller dosage reductions may be considered.

Atracurium besylate doses of 0.08 to 0.10 mg/kg are recommended for maintenance of neuromuscular block during prolonged surgical procedures. The first maintenance dose will generally be required 20 to 45 minutes after the initial Atracurium Besylate Injection, but the need for maintenance doses should be determined by clinical criteria. Because atracurium lacks cumulative effects, maintenance doses may be administered at relatively regular intervals for each patient, ranging approximately from 15 to 25 minutes under balanced anesthesia, slightly longer under isoflurane or enflurane. Higher atracurium doses (up to 0.2 mg/kg) permit maintenance dosing at longer intervals.

Pediatric Patients: No atracurium dosage adjustments are required for pediatric patients two years of age or older. An atracurium besylate dose of 0.3 to 0.4 mg/kg is recommended as the initial dose for infants (1 month to 2 years of age) under halothane anesthesia. Maintenance doses may be required with slightly greater frequency in infants and children than in adults.

Special Considerations: An initial atracurium besylate dose of 0.3 to 0.4 mg/kg, given slowly or in divided doses over one minute, is recommended for adults, children, or infants with significant cardiovascular disease and for adults, children, or infants with any history (e.g., severe anaphylactoid reactions or asthma) suggesting a greater risk of histamine release.

Dosage reductions must be considered also in patients with neuromuscular disease, severe electrolyte disorders, or carcinomatosis in which potentiation of neuromuscular block or difficulties with reversal have been demonstrated. There has been no clinical experience with atracurium in these patients, and no specific dosage adjustments can be recommended. No atracurium dosage adjustments are required for patients with renal disease.

An initial atracurium besylate dose of 0.3 to 0.4 mg/kg is recommended for adults following the use of succinylcholine for intubation under balanced anesthesia. Further reductions may be desirable with the use of potent inhalation anesthetics. The patient should be permitted to recover from the effects of succinylcholine prior to atracurium administration. Insufficient data are available for recommendation of a specific initial atracurium dose for administration following the use of succinylcholine in children and infants.

Use by Continuous Infusion:

Infusion in the Operating Room (OR): After administration of a recommended initial bolus dose of Atracurium Besylate Injection (0.3 to 0.5 mg/kg), a diluted solution of atracurium besylate can be administered by continuous infusion to adults and pediatric patients aged 2 or more years for maintenance of neuromuscular block during extended surgical procedures.

Infusion of atracurium should be individualized for each patient. The rate of administration should be adjusted according to the patient’s response as determined by peripheral nerve stimulation. Accurate dosing is best achieved using a precision infusion device.

Infusion of atracurium should be initiated only after early evidence of spontaneous recovery from the bolus dose. An initial infusion rate of 9 to 10 mcg/kg/min may be required to rapidly counteract the spontaneous recovery of neuromuscular function. Thereafter, a rate of 5 to 9 mcg/kg/min should be adequate to maintain continuous neuromuscular block in the range of 89% to 99% in most pediatric and adult patients under balanced anesthesia. Occasional patients may require infusion rates as low as 2 mcg/kg/min or as high as 15 mcg/kg/min.

The neuromuscular blocking effect of atracurium administered by infusion is potentiated by enflurane or isoflurane and, to a lesser extent, by halothane. Reduction in the infusion rate of atracurium should, therefore, be considered for patients receiving inhalation anesthesia. The rate of atracurium infusion should be reduced by approximately one-third in the presence of steady-state enflurane or isoflurane anesthesia; smaller reductions should be considered in the presence of halothane.

In patients undergoing cardiopulmonary bypass with induced hypothermia, the rate of infusion of atracurium required to maintain adequate surgical relaxation during hypothermia (25° to 28°C) has been shown to be approximately half the rate required during normothermia.

Spontaneous recovery from neuromuscular block following discontinuation of atracurium infusion may be expected to proceed at a rate comparable to that following administration of a single bolus dose.

Infusion in the Intensive Care Unit (ICU): The principles for infusion of atracurium in the OR are also applicable to use in the ICU.

An infusion rate of 11 to 13 mcg/kg/min (range: 4.5 to 29.5) should provide adequate neuromuscular block in adult patients in an ICU. Limited information suggests that infusion rates required for pediatric patients in the ICU may be higher than in adult patients. There may be wide interpatient variability in dosage requirements and these requirements may increase or decrease with time (see PRECAUTIONS: Long-Term Use in Intensive Care Unit [ICU]). Following recovery from neuromuscular block, readministration of a bolus dose may be necessary to quickly reestablish neuromuscular block prior to reinstitution of the infusion.

Infusion Rate Tables: The amount of infusion solution required per minute will depend upon the concentration of atracurium in the infusion solution, the desired dose of atracurium, and the patient’s weight. The following tables provide guidelines for delivery, in mL/hr (equivalent to microdrops/min when 60 microdrops = 1 mL), of atracurium solutions in concentrations of 0.2 mg/mL (20 mg in 100 mL) or 0.5 mg/mL (50 mg in 100 mL) with an infusion pump or a gravity flow device.

Compatibility and Admixtures: Atracurium besylate infusion solutions may be prepared by admixing Atracurium Besylate Injection with an appropriate diluent such as 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection. Infusion solutions should be used within 24 hours of preparation. Unused solutions should be discarded. Solutions containing 0.2 mg/mL or 0.5 mg/mL atracurium besylate in the above diluents may be stored either under refrigeration or at room temperature for 24 hours without significant loss of potency. Care should be taken during admixture to prevent inadvertent contamination. Visually inspect prior to administration.

Spontaneous degradation of atracurium besylate has been demonstrated to occur more rapidly in Lactated Ringer’s solution than in 0.9% sodium chloride solution. Therefore, it is recommended that Lactated Ringer’s Injection not be used as a diluent in preparing solutions of Atracurium Besylate Injection for infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Atracurium Besylate Injection USP, each mL containing 10 mg atracurium besylate, is supplied as follows:

NDC 0409-1109-01. 5 mL Single Dose Vial (50 mg atracurium besylate per vial). Carton of 10.

NDC 0409-1105-02. 10 mL Multiple Dose Vial (100 mg atracurium besylate per vial). Contains benzyl alcohol (see WARNINGS). Carton of 10.

Atracurium Besylate Injection should be refrigerated at 2°C to 8°C (36°F to 46°F) to preserve potency. DO NOT FREEZE. Protect from light. Keep vials in carton until time of use.

Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use Atracurium Besylate Injection within 14 days even if rerefrigerated.

Manufactured by:

Gland Pharma Limited;

Hyderabad 500043, India

Manufactured for:

Hospira, Inc.

Lake Forest, IL 60045 USA

Product of India

M.L.No.: 103/AP/RR/97/F/R 

Revised: February 2012

EN-3011

Observed in Controlled Clinical Studies: Atracurium was well tolerated and produced few adverse reactions during extensive clinical trials. Most adverse reactions were suggestive of histamine release. In studies including 875 patients, atracurium was discontinued in only one patient (who required treatment for bronchial secretions) and six other patients required treatment for adverse reactions attributable to atracurium (wheezing in one, hypotension in five). Of the five patients who required treatment for hypotension, three had a history of significant cardiovascular disease. The overall incidence rate for clinically important adverse reactions, therefore, was 7/875 or 0.8%.

Table 1 includes all adverse reactions reported attributable to atracurium during clinical trials with 875 patients.

TABLE 1: PERCENT OF PATIENTS REPORTING ADVERSE REACTIONS Adverse Reaction Initial Atracurium Dose (mg/kg)

Most adverse reactions were of little clinical significance unless they were associated with significant hemodynamic changes. Table 2 summarizes the incidences of substantial vital sign changes noted during atracurium clinical trials with 530 patients, without cardiovascular disease, in whom these parameters were assessed.

TABLE 2: PERCENT OF PATIENTS SHOWING > 30% VITAL SIGN CHANGES FOLLOWING ADMINISTRATION OF ATRACURIUM

*Includes the recommended initial dosage range for most patients.

Observed in Clinical Practice: Based on initial clinical practice experience in approximately 3 million patients who received atracurium in the U.S. and in the United Kingdom, spontaneously reported adverse reactions were uncommon (approximately 0.01% to 0.02%). The following adverse reactions are among the most frequently reported, but there are insufficient data to support an estimate of their incidence:

General: Allergic reactions (anaphylactic or anaphylactoid responses) which, in rare instances, were severe (e.g., cardiac arrest)

Musculoskeletal: Inadequate block, prolonged block

Cardiovascular: Hypotension, vasodilatation (flushing), tachycardia, bradycardia

Respiratory: Dyspnea, bronchospasm, laryngospasm

Integumentary: Rash, urticaria, reaction at injection site

There have been rare spontaneous reports of seizures in ICU patients following long-term infusion of atracurium to support mechanical ventilation. There are insufficient data to define the contribution, if any, of atracurium and/or its metabolite laudanosine. (See PRECAUTIONS: Long-Term Use in Intensive Care Unit [lCU]).

Read the entire FDA prescribing information for Atracurium Besylate Injection (Atracurium Besylate Injection)