Atracurium

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

CLINICAL PHARMACOLOGY Atracurium besylate is a nondepolarizing skeletal muscle relaxant. Nondepolarizing agents antagonize the neurotransmitter action of acetylcholine by binding competitively with cholinergic receptor sites on the motor end-plate. This antagonism is inhibited, and neuromuscular block reversed, by acetylcholinesterase inhibitors such as neostigmine, edrophonium, and pyridostigmine. 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 ED 95 (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

DOSAGE AND ADMINISTRATION 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 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 0.1 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 adju

ADVERSE REACTIONS 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 * Includes the recommended initial dosage range for most patients. Adverse Reaction Initial Atracurium Dose (mg/kg) 0.00 to 0.30 (n = 485) 0.31 to 0.50 * (n = 366) > 0.60 (n = 24) Total (n = 875) Skin Flush 1% 8.7% 29.2% 5% Erythema 0.6% 0.5% 0% 0.6% Itching 0.4% 0% 0% 0.2% Wheezing/Bronchial Secretions 0.2% 0.3% 0% 0.2% Hives 0.2% 0% 0% 0.1% 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. Vital Sign Change Initial Atracurium Dose (mg/kg) 0.00 to 0.30 (n = 365) 0.31 to 0.50 * (n = 144) > 0.60 (n = 21) Total (n = 530) Mean Arterial Pressure Increase 1.9% 2.8% 0% 2.1% Decrease 1.1% 2.1% 14.3% 1.9% Heart Rate Increase 1.6% 2.8% 4.8% 2.1% Decrease 0.8% 0% 0% 0.6% 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 (ICU) ). There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with use of neuromuscular blocking agents, including atracurium besylate. These reactions, in some cases, have been life-threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see WARNINGS and PRECAUTIONS ).

WARNINGS ATRACURIUM SHOULD BE USED ONLY BY THOSE SKILLED IN AIRWAY MANAGEMENT AND RESPIRATORY SUPPORT. EQUIPMENT AND PERSONNEL MUST BE IMMEDIATELY AVAILABLE FOR ENDOTRACHEAL INTUBATION AND SUPPORT OF VENTILATION, INCLUDING ADMINISTRATION OF POSITIVE PRESSURE OXYGEN. ADEQUACY OF RESPIRATION MUST BE ASSURED THROUGH ASSISTED OR CONTROLLED VENTILATION. ANTICHOLINESTERASE REVERSAL AGENTS SHOULD BE IMMEDIATELY AVAILABLE. 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-dose vials do not contain benzyl alcohol (see PRECAUTIONS: Pediatric Use ). Anaphylaxis 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.

CONTRAINDICATIONS 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.

OVERDOSAGE 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 pyridostigmine, 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 ED 95 dose, was moderately longer than the corresponding time observed following doses 2 to 2.5 times the atracurium ED 95 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 LD 50 s 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 LD 50 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 12