Atracurium Besylate

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.

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 use 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 injection 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.

Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents. In addition, inform your patients that severe anaphylactic reactions to neuromuscular blocking agents, including atracurium besylate have been reported. General Although atracurium is a less potent histamine releaser than d-tubocurarine or metocurine, the possibility of substantial histamine release in sensitive individuals must be considered. Special caution should be exercised in administering atracurium to patients in whom substantial histamine release would be especially hazardous (e.g., patients with clinically significant cardiovascular disease) and in patients with any history (e.g., severe anaphylactoid reactions or asthma) suggesting a greater risk of histamine release. In these patients, the recommended initial atracurium besylate dose is lower (0.3 to 0.4 mg/kg) than for other patients and should be administered slowly or in divided doses over one minute. 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) When there is a need for long-term mechanical ventilation, the benefits-to-risk ratio of neuromuscular block must be considered. The long-term (1 to 10 days) infusion of atracurium besylate during mechanical ventilation in the ICU has been evaluated in several studies. Average infusion rates of 11 to 13 mcg/kg per minute (range: 4.5 to 29.5) were required to achieve adequate neuromuscular block. These data suggest that there is wide interpatient variability in dosage requirements. In addition, these studies have shown that dosage requirements may decrease or increase with time. Following discontinuation of infusion of atracurium besylate in these ICU studies, spontaneous recovery of four twitches in a train-of-four occurred in an average of approximately 30 minutes (range: 15 to 75 minutes) and spontaneous recovery to a train-of-four ratio >75% (the ratio of height of the fourth to the first twitch in a train-of-four) occurred in an average of approximately 60 minutes (range: 32 to 108 minutes). 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. WHENEVER 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 T 1 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. Drug Interactions Drugs which may enhance the neuromuscular blocking action of atracurium include: enflurane; isoflurane; halothane; certain antibiotics, especially the aminoglycosides and polymyxins; lithium; magnesium salts; procainamide; and quinidine. 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 Carcinogenesis and fertility studies have not been performed. Atracurium was evaluated in a battery of three short-term mutagenicity tests. It was non-mutagenic in both the Ames Salmonella assay at concentrations up to 1000 mcg/plate, and in a rat bone marrow cytogenicity assay at up to paralyzing doses. A positive response was observed in the mouse lymphoma assay under conditions (80 and 100 mcg/mL, in the absence of metabolic activation) which killed over 80% of the treated cells; there was no mutagenicity at 60 mcg/mL and lower, concentrations which killed up to half of the treated cells. A far weaker response was observed in the presence of metabolic activation at concentrations (1200 mcg/mL and higher) which also killed over 80% of the treated cells. 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. Pregnancy Teratogenic Effects: Pregnancy Category C 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 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. […]

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) 0.00-0.30 (n = 485) 0.31-0.50* (n = 366) ≥0.60 (n = 24) Total (n = 875) Skin Flush 1.0% 8.7% 29.2% 5.0% 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) 0.00-0.30 (n = 365) 0.31-0.50* (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 ). To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drugs which may enhance the neuromuscular blocking action of atracurium include: enflurane; isoflurane; halothane; certain antibiotics, especially the aminoglycosides and polymyxins; lithium; magnesium salts; procainamide; and quinidine. 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.

Teratogenic Effects: Pregnancy Category C 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 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.

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 (see CLINICAL PHARMACOLOGY ); however, as with other neuromuscular blocking agents, the use of a peripheral nerve stimulator to monitor neuromuscular function is suggested (see DOSAGE AND ADMINISTRATION ).