Atracurium Besylate

Observed in Controlled Clinical Studies

TRACRIUM (atracurium besylate) 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, TRACRIUM (atracurium besylate) was discontinued in only one patient (who required treatment for bronchial secretions), and six other patients required treatment for adverse reactions attributable to TRACRIUM (atracurium besylate) (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 TRACRIUM (atracurium besylate) during clinical trials with 875 patients.

Table 1: Percent of Patients Reporting Adverse Reactions Initial Dose of TRACRIUM (atracurium besylate) (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 clinical trials of TRACRIUM (atracurium besylate) 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 TRACRIUM (atracurium besylate)

Observed in Clinical Practice

Based on initial clinical practice experience in approximately 3 million patients who received TRACRIUM (atracurium besylate) in the US 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 [ICU]).

Nondepolarizing neuromuscular blocking agent.1

General

• Adjust dosage carefully according to individual requirements and response.1

• Assess neuromuscular blockade and recovery in patients undergoing anesthesia; a peripheral nerve stimulator is recommended to accurately monitor the degree of muscle relaxation and to minimize the possibility of overdosage.1

• To avoid patient distress, administer only after unconsciousness has been induced.1

Facilitation of Endotracheal Intubation

• Endotracheal intubation for nonemergency surgical procedures generally can be performed within 2–2.5 minutes following administration.1 2 (See Onset and also Duration under Pharmacokinetics.)

Maintenance of Neuromuscular Blockade

• Repeated administration of maintenance doses does not have a cumulative effect on duration of neuromuscular blockade,1 2 9 24 42 43 provided recovery from blockade is allowed to begin prior to administering maintenance doses.1

• Rate of spontaneous recovery from neuromuscular blockade following discontinuance of maintenance infusion usually is comparable to that following administration of a single IV injection.1 (See Onset and also Duration under Pharmacokinetics.)

Reversal of Neuromuscular Blockade

• To reverse neuromuscular blockade, administer a cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium), usually in conjunction with an antimuscarinic (e.g., atropine, glycopyrrolate) to block adverse muscarinic effects of the cholinesterase inhibitor.1 9 16 17 18 19 21 23 24 26

• Under balanced anesthesia, reversal generally can be attempted about 20–35 minutes after the initial dose or 10–30 minutes after the last maintenance dose, when recovery of muscle twitch has started.1

• Complete reversal generally is achieved within 8–10 minutes after administration of the cholinesterase inhibitor and antimuscarinic.1

Administration

Administer IV only; do not administer IM.1 2

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer initial (intubating) dose by rapid IV injection;1 2 HID administer maintenance dosage for prolonged surgical procedures by intermittent IV injection1 2 or continuous IV infusion.1 3 57 60 90 118 119

Consult specialized references for specific procedures and techniques of administration.

Do not mix in the same syringe or administer through the same needle as an alkaline solution.1

For continuous IV infusion, dilute atracurium besylate injection to the desired concentration (usually 0.2 or 0.5 mg/mL) in 5% dextrose, 5% dextrose and 0.9% sodium chloride, or 0.9% sodium chloride injection.1 Use within 24 hours.1

Dosage

Available as atracuium besylate; dosage expressed in terms of the salt.1

Pediatric Patients

Infants and children 1 month to 2 years of age: 0.3–0.4 mg/kg when used concomitantly with halothane anesthesia.1 132 169 170 171 (See Onset and also Duration under Pharmacokinetics.)

Children >2 years of age should receive dosages recommended for adults.1 (See Adults under Dosage and Administration.)

Insufficient data for recommendation of a specific initial dose of atracurium besylate in infants and children following administration of succinylcholine.132

Infants and children may require more frequent doses than adults.1 2 132

Children >2 years of age should receive doses recommended for adults.1 (See Adults under Dosage and Administration.)

Not recommended in children <2 years of age.1 169 170 171

Children >2 years of age should receive dosages recommended for adults.1 (See Adults under Dosage and Administration.)

Adults

0.4–0.5 mg/kg.1 2 (See Onset and also Duration under Pharmacokinetics.)

Reduce initial dosage by about 33% (i.e., to 0.25–0.35 mg/kg) if steady-state anesthesia has been induced with enflurane or isoflurane.1 2 37 169 170 171 (See Specific Drugs under Interactions.)

Consider reducing initial dosage by about 20% if steady-state anesthesia has been induced with halothane.1 2 86 (See Specific Drugs under Interactions.)

If administering following succinylcholine, reduce dosage to 0.3–0.4 mg/kg.1 2 86 Reduce dosage further (e.g., to 0.2–0.3 mg/kg) when inhalation anesthetics are also administered concomitantly.1 2 86 (See Specific Drugs under Interactions.)

0.08–0.1 mg/kg, administered as necessary.1 2 (See Onset and also Duration under Pharmacokinetics.)

Administer first maintenance dose generally 20–45 minutes after the initial dose in patients undergoing balanced anesthesia.1 2

Administer repeat maintenance doses at relatively regular intervals (i.e., from 15–25 minutes in patients undergoing balanced anesthesia).1 2 Administration at longer intervals may be possible if higher maintenance doses (i.e., up to 0.2 mg/kg) are used or if used with enflurane or isoflurane.1 2

Initially, 9–10 mcg/kg per minute may be necessary to rapidly counteract spontaneous recovery from neuromuscular blockade.1 3 57 118 5–9 mcg/kg per minute generally maintains 89–99% neuromuscular blockade in patients receiving balanced anesthesia; however, adequate blockade may occur with infusion rates of 2–15 mcg/kg per minute.1

Initiate continuous IV infusion only after early spontaneous recovery from IV dose is evident.1

Reduce infusion rate by about 33% if steady-state anesthesia has been induced with enflurane or isoflurane.1 (See Specific Drugs under Interactions.)

Consider a smaller reduction in the infusion rate if steady-state anesthesia has been induced with halothane.1 (See Specific Drugs under Interactions.)

Special Populations

Renal Impairment

Dosage adjustments not required.1 2 169 170 171

Burn Patients

Substantially increased doses may be required due to development of resistance.1 143 144 145 146 147 (See Burn Patients under Cautions.)

Cardiopulmonary Bypass Patients with Induced Hypothermia

Infusion rate required to maintain adequate surgical relaxation during hypothermia (i.e., 25–28°C) is approximately 50% of the infusion rate necessary in normothermic patients.1 57 79

Intensive Care Settings

Average infusion rates of 11–13 mcg/kg per minute (range: 4.5–29.5 mcg/kg per minute) have been used in adults; infusion rates may be higher in pediatric patients.1 Dosage requirements may increase or decrease with time.168 (See Intensive Care Settings under Cautions.)

Patients with Myasthenia Gravis

Administer at low initial doses and with careful monitoring in well-controlled patients whose usual therapy is continued up to the time of surgery.114 115 116 130

Patients with Cardiovascular Disease

Initial dose of 0.3–0.4 mg/kg administered slowly or in fractional doses over 1 minute.1 2 132 169 170 171 (See Cardiovascular Effects under Cautions.)

Other Populations

Patients with an increased risk of histamine release (e.g., history of severe anaphylactoid reactions or asthma): Initial dose of 0.3–0.4 mg/kg administered slowly or in fractional doses over 1 minute.1 2 132 169 170 171

Patients in whom potentiation of neuromuscular blockade or difficulties with reversal of blockade may occur (e.g., neuromuscular disease, severe electrolyte disturbances, carcinomatosis): Consider dosage reduction.1 2 However, no clinical experience to date in these patients, and no specific doses are recommended.1 2 (See Neuromuscular Disease and also Electrolyte Disturbances under Cautions.)

Specific Drugs

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, neuromuscular disease).1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name