Atracurium - Tracrium ®
|The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.|
Standard Dilutions [Amount of drug] [Infusion volume] [Infusion rate]
| Package insert:
[20 mg] [ 100 ml ] [ Titrate]
[50 mg] [ 100 ml ] [ Titrate]
Alternatively (less support):
(Usual concentration: 0.2 to 5 mg/ ml)
Stability / Miscellaneous
Dosing (adult): initially 0.4 to 0.5 mg/kg IV bolus, followed by 0.08 to 0.1 mg/kg q20-45 min after initial dose. Continuous infusion: initially 0.4 to 0.5 mg IV bolus, followed by 9 to 10 mcg/kg/min initially. Maintenance infusion rates of 5 to 9 mcg/kg/min are usually adequate. (Range: 2 to 15 mcg/kg/min).
Toxic metabolite (laudanosine) may accumulate in renal failure.
Atracurium can be used most advantageously if muscle twitch response to peripheral nerve stimulation is monitored to assess degree of muscle relaxation.
The duration of neuromuscular block produced by atracurium is approximately one-third to one-half the duration of block by d-tubocurarine, metocurine, and pancuronium at initially equipotent doses. As with other nondepolarizing neuromuscular blockers, the time to onset of paralysis decreases and the duration of maximum effect increases with increasing atracurium doses.
The ED95 (dose required to produce 95% suppression of the muscle twitch response with balanced anesthesia) has averaged 0.23 mg/kg (0.11 to 0.26 mg/kg in various studies). An initial atracurium dose of 0.4 to 0.5 mg/kg generally produces maximum neuromuscular block within 3 to 5 minutes of injection, with good or excellent intubation conditions within 2 to 2.5 minutes in most patients. Recovery from neuromuscular block (under balanced anesthesia) can be expected to begin approximately 20 to 35 minutes after injection. 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 to 70 minutes after injection. The neuromuscular blocking action of atracurium is enhanced in the presence of potent inhalation anesthetics. Isoflurane and enflurane increase the potency of atracurium and prolong neuromuscular block by approximately 35%; however, halothane’s potentiating effect (approximately 20%) is marginal (see DOSAGE AND ADMINISTRATION).
Repeated administration of maintenance doses of atracurium has no cumulative effect on the duration of neuromuscular block if recovery is allowed to begin prior to repeat dosing. Moreover, the time needed to recover from repeat doses does not change with additional doses. Repeat doses can therefore be administered at relatively regular intervals with predictable results. After an initial dose of 0.4 to 0.5 mg/kg under balanced anesthesia, the first maintenance dose (suggested maintenance dose is 0.08 to 0.10 mg/kg) is generally required within 20 to 45 minutes, and subsequent maintenance doses are usually required at approximately 15 to 25 minute intervals.
Once recovery from atracurium’s neuromuscular blocking effects begins, it proceeds more rapidly than recovery from d-tubocurarine, metocurine, and pancuronium. Regardless of the atracurium dose, the time from start of recovery (from complete block) to complete (95%) recovery is approximately 30 minutes under balanced anesthesia, and approximately 40 minutes under halothane, enflurane or isoflurane. Repeated doses have no cumulative effect on recovery rate.
Reversal of neuromuscular block produced by atracurium can be achieved with an anticholinesterase agent such as neostigmine, edrophonium, or pyridostigmine, in conjunction with an anticholinergic agent such as atropine or glycopyrrolate. Under balanced anesthesia, reversal can usually be attempted approximately 20 to 35 minutes after an initial atracurium besylate dose of 0.4 to 0.5 mg/kg, or approximately 10 to 30 minutes after a 0.08 to 0.10 mg/kg maintenance dose, when recovery of muscle twitch has started. Complete reversal is usually attained within 8 to 10 minutes of the administration of reversing agents. Rare instances of breathing difficulties, possibly related to incomplete reversal, have been reported following attempted pharmacologic antagonism of atracurium-induced neuromuscular block. As with other agents in this class, the tendency for residual neuromuscular block is increased if reversal is attempted at deep levels of block or if inadequate doses of reversal agents are employed.
The pharmacokinetics of atracurium in humans are essentially linear within the 0.3 to 0.6 mg/kg dose range. The elimination half-life is approximately 20 minutes. THE DURATION OF NEUROMUSCULAR BLOCK PRODUCED BY ATRACURIUM BESYLATE DOES NOT CORRELATE WITH PLASMA PSEUDOCHOLINESTERASE LEVELS AND IS NOT ALTERED BY THE ABSENCE OF RENAL FUNCTION. This is consistent with the results of in vitro studies which have shown that atracurium is inactivated in plasma via two nonoxidative pathways: ester hydrolysis, catalyzed by nonspecific esterases; and Hofmann elimination, a nonenzymatic chemical process which occurs at physiological pH. Some placental transfer occurs in humans.
Radiolabel studies demonstrated that atracurium undergoes extensive degradation in cats, and that neither kidney nor liver plays a major role in this elimination. Biliary and urinary excretion were the major routes of excretion of radioactivity (totaling >90% of the labeled dose within 7 hours of dosing), of which atracurium represented only a minor fraction. The metabolites in bile and urine were similar, including products of Hofmann elimination and ester hydrolysis.
Elderly patients may have slightly altered pharmacokinetic parameters compared to younger patients, with a slightly decreased total plasma clearance which is offset by a corresponding increase in volume of distribution. The net effect is that there has been no significant difference in clinical duration and recovery from neuromuscular block observed between elderly and younger patients receiving atracurium besylate.
Atracurium is a less potent histamine releaser than d-tubocurarine or metocurine. Histamine release is minimal with initial atracurium besylate doses up to 0.5 mg/kg, and hemodynamic changes are minimal within the recommended dose range. A moderate histamine release and significant falls in blood pressure have been seen following 0.6 mg/kg of atracurium besylate. The histamine and hemodynamic responses were poorly correlated. The effects were generally short-lived and manageable, but the possibility of substantial histamine release in sensitive individuals or in patients in whom substantial histamine release would be especially hazardous (e.g., patients with significant cardiovascular disease) must be considered.
lt is not known whether the prior use of other nondepolarizing neuromuscular blocking agents has any effect on the activity of atracurium. The prior use of succinylcholine decreases by approximately 2 to 3 minutes the time to maximum block induced by atracurium besylate, and may increase the depth of block. Atracurium should be administered only after a patient recovers from succinylcholine-induced neuromuscular block.
INDICATIONS AND USAGE
DO NOT GIVE ATRACURIUM BESYLATE BY INTRAMUSCULAR ADMINISTRATION.
Atracurium has no known effect on consciousness, pain threshold, or cerebration. It should be used only with adequate anesthesia.
Atracurium besylate injection, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle. Depending on the resultant pH of such mixtures, atracurium may be inactivated and a free acid may be precipitated.
Atracurium besylate injection 10 mL multiple dose vials contain benzyl alcohol. In neonates, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal. Atracurium besylate 5 mL single use vials do not contain benzyl alcohol (see PRECAUTIONS: Pediatric Use).
Since atracurium has no clinically significant effects on heart rate in the recommended dosage range, it will not counteract the bradycardia produced by many anesthetic agents or vagal stimulation. As a result, bradycardia during anesthesia may be more common with atracurium than with other muscle relaxants.
Atracurium may have profound effects in patients with myasthenia gravis, Eaton-Lambert syndrome, or other neuromuscular diseases in which potentiation of nondepolarizing agents has been noted. The use of a peripheral nerve stimulator is especially important for assessing neuromuscular block in these patients. Similar precautions should be taken in patients with severe electrolyte disorders or carcinomatosis.
Multiple factors in anesthesia practice are suspected of triggering malignant hyperthermia (MH), a potentially fatal hypermetabolic state of skeletal muscle. Halogenated anesthetic agents and succinylcholine are recognized as the principal pharmacologic triggering agents in MH-susceptible patients; however, since MH can develop in the absence of established triggering agents, the clinician should be prepared to recognize and treat MH in any patient scheduled for general anesthesia. Reports of MH have been rare in cases in which atracurium has been used. In studies of MH-susceptible animals (swine) and in a clinical study of MH-susceptible patients, atracurium did not trigger this syndrome.
Resistance to nondepolarizing neuromuscular blocking agents may develop in burn patients. Increased doses of nondepolarizing muscle relaxants may be required in burn patients and are dependent on the time elapsed since the burn injury and the size of the burn.
The safety of atracurium has not been established in patients with bronchial asthma.
Long-Term Use in Intensive Care Unit (ICU)
Little information is available on the plasma levels and clinical consequences of atracurium metabolites that may accumulate during days to weeks of atracurium administration in ICU patients. Laudanosine, a major biologically active metabolite of atracurium 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 head trauma, cerebral edema, hypoxic encephalopathy, viral encephalitis, uremia). There are insufficient data to determine whether or not laudanosine contributes to seizures in ICU patients.
WWHENEVER THE USE OF ATRACURIUM OR ANY NEUROMUSCULAR BLOCKING AGENT IS CONTEMPLATED IN THE ICU, IT IS RECOMMENDED THAT NEUROMUSCULAR TRANSMISSION BE MONITORED CONTINUOUSLY DURING ADMINISTRATION WITH THE HELP OF A NERVE STIMULATOR. ADDITIONAL DOSES OF ATRACURIUM OR ANY OTHER NEUROMUSCULAR BLOCKING AGENT SHOULD NOT BE GIVEN BEFORE THERE IS A DEFINITE RESPONSE TO T1 OR TO THE FIRST TWITCH. IF NO RESPONSE IS ELICITED, INFUSION ADMINISTRATION SHOULD BE DISCONTINUED UNTIL A RESPONSE RETURNS.
Hemofiltration has a minimal effect on plasma levels of atracurium and its metabolites, including laudanosine. The effects of hemodialysis and hemoperfusion on plasma levels of atracurium and its metabolites are unknown.
If other muscle relaxants are used during the same procedure, the possibility of a synergistic or antagonist effect should be considered.
The prior administration of succinylcholine does not enhance the duration, but quickens the onset and may increase the depth, of neuromuscular block induced by atracurium besylate. Atracurium should not be administered until a patient has recovered from succinylcholine-induced neuromuscular block.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Mutagenicity testing is intended to simulate chronic (years to lifetime) exposure in an effort to determine potential carcinogenicity. Thus, a single positive mutagenicity response for a drug used infrequently and/or briefly is of questionable clinical relevance.
Teratogenic Effects: Pregnancy Category C
Atracurium besylate was administered subcutaneously on days 6 through 18 of gestation to non-ventilated Dutch rabbits. Treatment groups were given either 0.15 mg/kg once daily or 0.10 mg/kg twice daily. Lethal respiratory distress occurred in two 0.15 mg/kg animals and in one 0.10 mg/kg animal, with transient respiratory distress or other evidence of neuromuscular block occurring in 10 of 19 and in 4 of 20 of the 0.15 mg/kg and 0.10 mg/kg animals, respectively. There was an increased incidence of certain spontaneously occurring visceral and skeletal anomalies or variations in one or both treated groups when compared to non-treated controls. The percentage of male fetuses was lower (41% vs. 51%) and the post-implantation losses were increased (15% vs. 8%) in the group given 0.15 mg/kg once daily when compared to the controls; the mean numbers of implants (6.5 vs. 4.4) and normal live fetuses (5.4 vs. 3.8) were greater in this group when compared to the control group.
Labor and Delivery
Atracurium besylate (0.3 mg/kg) has been administered to 26 pregnant women during delivery by cesarean section. No harmful effects were attributable to atracurium in any of the neonates, although small amounts of atracurium were shown to cross the placental barrier. The possibility of respiratory depression in the neonate should always be considered following cesarean section during which a neuromuscular blocking agent has been administered. In patients receiving magnesium sulfate, the reversal of neuromuscular block may be unsatisfactory and the dose of atracurium besylate should be lowered as indicated.
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.
DOSAGE AND ADMINISTRATION
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
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.
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)
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)
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 re-establish neuromuscular block prior to reinstitution of the infusion.
Infusion Rate Tables
Table 3: Atracurium Besylate Infusion Rates for a Concentration of 0.2 mg/mL
Compatibility and Admixtures
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.
5 mL Single Dose Vial (50 mg atracurium besylate per vial). Carton of 10. NDC 55390-102-05.
10 mL Multiple Dose Vial (100 mg atracurium besylate per vial). Contains benzyl alcohol (see WARNINGS).
Carton of 10. NDC 55390-103-10.
Atracurium Besylate Injection should be refrigerated at 2° to 8°C (36° to 46°F) to preserve potency. DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use Atracurium Besylate Injection within 14 days even if rerefrigerated.
Manufactured for: Manufactured by:
Bedford, OH 44146