RETALEX

A non-depolarizing neuromuscular blocking agent with short duration of action.

Its lack of significant cardiovascular effects and its lack of dependence on good kidney function for elimination provide clinical advantage over alternate non-depolarizing neuromuscular blocking agents.

For use, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

Atracurium is a nondepolarizing skeletal muscle relaxant.

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 doses of Atracurium.

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.

The elimination half-life is approximately 20 minutes.

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Excessive doses can be expected to produce enhanced pharmacological effects.

Overdosage may increase the risk of histamine release and cardiovascular effects, especially hypotension.

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-dose vials do not contain benzyl alcohol.

Severe anaphylactic reactions to neuromuscular blocking agents, including atracurium 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.

Risk of Death due to Medication Errors Administration of atracurium besylate results in paralysis, which may lead to respiratory arrest and death; this progression may be more likely to occur in a patient for whom it is not intended.

Confirm proper selection of intended product and avoid confusion with other injectable solutions that are present in critical care and other clinical settings.

If another healthcare provider is administering the product, ensure that the intended dose is clearly labeled and communicated.

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 ED 95 ), 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 to 2.5 minutes in most patients, with maximum neuromuscular block achieved approximately to 5 minutes after injection.

Clinically required neuromuscular block generally lasts to 35 minutes under balanced anesthesia.

Under balanced anesthesia, recovery to 25% of control is achieved approximately 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 0.1 mg/kg are recommended for maintenance of neuromuscular block during prolonged surgical procedures.

The first maintenance dose will generally be required 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 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.

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.

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 to 10 mcg/kg/min may be required to rapidly counteract the spontaneous recovery of neuromuscular function.

Thereafter, a rate of 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.

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

An infusion rate of 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 ).

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.

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.

Table 3: Atracurium Besylate Infusion Rates for a Concentration of 0.2 mg/mL Patient Weight (kg) Drug Delivery Rate (mcg/kg/min) 5 6 7 8 9 10 11 12 13 Infusion Delivery Rate (mL/hr) 30 45 54 63 72 81 90 99 108 117 35 53 63 74 84 95 105 116 126 137 40 60 72 84 96 108 120 132 144 156 45 68 81 95 108 122 135 149 162 176 50 75 90 105 120 135 150 165 180 195 55 83 99 116 132 149 165 182 198 215 60 90 108 126 144 162 180 198 216 234 65 98 117 137 156 176 195 215 234 254 70 105 126 147 168 189 210 231 252 273 75 113 135 158 180 203 225 248 270 293 80 120 144 168 192 216 240 264 288 312 90 135 162 189 216 243 270 297 324 351 100 150 180 210 240 270 300 330 360 390 Table 4: Atracurium Besylate Infusion Rates for a Concentration of 0.5 mg/mL Patient Weight (kg) Drug Delivery Rate (mcg/kg/min) 5 6 7 8 9 10 11 12 13 Infusion Delivery Rate (mL/hr) 30 18 22 25 29 32 36 40 43 47 35 21 25 29 34 38 42 46 50 55 40 24 29 34 38 43 48 53 58 62 45 27 32 38 43 49 54 59 65 70 50 30 36 42 48 54 60 66 72 78 55 33 40 46 53 59 66 73 79 86 60 36 43 50 58 65 72 79 86 94 65 39 47 55 62 70 78 86 94 101 70 42 50 59 67 76 84 92 101 109 75 45 54 63 72 81 90 99 108 117 80 48 58 67 77 86 96 106 115 125 90 54 65 76 86 97 108 119 130 140 100 60 72 84 96 108 120 132 144 156 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.

Accidental administration of neuromuscular blocking agents may be fatal.

Store atracurium besylate injection with the cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product.

Injection, USP is a sterile, non-pyrogenic, clear, colorless aqueous solution free from visible particles and is supplied as follows: 50 mg per 5 mL (10 mg/mL) 5 mL single-dose vials packaged in cartons of 10 vials NDC 55150-216-05 Storage Atracurium Besylate Injection should be refrigerated at 2° to 8°C (36° to 46°F) to preserve potency.

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

Protect from light.

The vial stoppers are not made with natural rubber latex.

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E. Windsor, NJ 08520.

Atracurium besylate has been shown to be potentially teratogenic in rabbits when given in doses up to approximately one-half the human dose.

There are no adequate and well-controlled studies in pregnant women.

Atracurium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Atracurium besylate was administered subcutaneously on days 6 through 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 of 19 and in 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.

It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when atracurium besylate is administered to a nursing woman.

Safety and effectiveness in pediatric patients below the age of 1 month have not been established.

Since marketing in 1983, uncontrolled clinical experience and limited data from controlled trials have not identified differences in effectiveness, safety, or dosage requirements between healthy elderly and younger patients; however, as with other neuromuscular blocking agents, the use of a peripheral nerve stimulator to monitor neuromuscular function is suggested See DOSAGE AND ADMINISTRATION.