Rocuronium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
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Overview
Rocuronium is a skeletal muscle relaxant, neuromuscular blocking drug that is FDA approved for the {{{indicationType}}} of general anesthesia; adjunct - induction of neuromuscular blockade, during surgery or mechanical ventilation, induction of neuromuscular blockade intubation, routine tracheal, rapid sequence intubation.. Common adverse reactions include cardiovascular: hypertension (0.1% to 2% ), hypotension (0.1% to 2% ), tachycardia (less than 1% to 5.3% )dermatologic: injection site pain, respiratory: Increased pulmonary vascular resistance (24% ).
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- Dosage should be individualized and guided by neuromuscular transmission recovery.
- General anesthesia; Adjunct
- Induction of neuromuscular blockade, During surgery or mechanical ventilation
- Initial, 0.6 mg/kg IV
- Maintenance, 0.1 to 0.2 mg/kg IV push, repeat as needed or 0.01 to 0.012 mg/kg/minute continuous IV infusion.
- Induction of neuromuscular blockade - Intubation, Routine tracheal
- Initial, (regardless of anesthesic technique) 0.6 mg/kg IV; or a lower dose of 0.45 mg/kg IV may be used.
- Initial, (with opioid/nitrous oxide/oxygen anesthesia) 0.9 or 1.2 mg/kg large bolus may be used.
- Maintenance, (only after spontaneous recovery from intubation dose) 0.1 to 0.2 mg/kg IV , repeat as needed or 0.01 to 0.012 mg/kg/minute continuous IV infusion.
- Premedication for anesthetic procedure
- Preinduction defasciculating dose: 0.05 to 0.06 mg/kg IV 1.5-3 min prior to succinylcholine administration.
- Rapid sequence intubation: 0.6 to 1.2 mg/kg IV.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
- Premedication for anesthetic procedure, Preinduction defasciculating dose.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rocuronium in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
- General anesthesia; Adjunct
- Induction of neuromuscular blockade, during surgery or mechanical ventilation: 3 mo to 14 yr
- Initial, 0.6 mg/kg/dose IV
- Maintenance, 0.075 to 0.15 mg/kg IV push as needed (anesthetic agent dependent) or 0.012 mg/kg/min continuous IV infusion
- Induction of neuromuscular blockade - Intubation, Routine tracheal: 3 mo to 14 yr
- Initial, 0.6 mg/kg/dose IV
- Initial, (anesthetic technique and age dependent) 0.45 mg/kg IV may be used
- Maintenance, 0.075 to 0.125 mg/kg IV push as needed or 0.012 mg/kg/min continuous IV infusion
- Rapid sequence intubation: not recommended in pediatric patients although 0.6 to 1.2 mg/kg IV have been used in clinical trials
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Premedication for anesthetic procedure, Preinduction defasciculating dose
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rocuronium in pediatric patients.
Contraindications
ZEMURON is contraindicated in patients known to have hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other neuromuscular blocking agents.
Warnings
Appropriate Administration and Monitoring
ZEMURON should be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are familiar with the drug's actions and the possible complications of its use. The drug should not be administered unless facilities for intubation, mechanical ventilation, oxygen therapy, and an antagonist are immediately available. It is recommended that clinicians administering neuromuscular blocking agents such as ZEMURON employ a peripheral nerve stimulator to monitor drug effect, need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the complications of overdosage if additional doses are administered.
5.2 Anaphylaxis
Severe anaphylactic reactions to neuromuscular blocking agents, including ZEMURON, have been reported. These reactions have, in some cases (including cases with ZEMURON), 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 patients who have had previous anaphylactic reactions to other neuromuscular blocking agents, since cross-reactivity between neuromuscular blocking agents, both depolarizing and nondepolarizing, has been reported.
5.3 Need for Adequate Anesthesia
ZEMURON has no known effect on consciousness, pain threshold, or cerebration. Therefore, its administration must be accompanied by adequate anesthesia or sedation.
5.4 Residual Paralysis
In order to prevent complications resulting from residual paralysis, it is recommended to extubate only after the patient has recovered sufficiently from neuromuscular block. Other factors which could cause residual paralysis after extubation in the post-operative phase (such as drug interactions or patient condition) should also be considered. If not used as part of standard clinical practice the use of a reversal agent should be considered, especially in those cases where residual paralysis is more likely to occur.
5.5 Long-Term Use in an Intensive Care Unit
ZEMURON has not been studied for long-term use in the intensive care unit (ICU). As with other nondepolarizing neuromuscular blocking drugs, apparent tolerance to ZEMURON may develop during chronic administration in the ICU. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor. It is strongly recommended that neuromuscular transmission be monitored continuously during administration and recovery with the help of a nerve stimulator. Additional doses of ZEMURON or any other neuromuscular blocking agent should not be given until there is a definite response (one twitch of the train-of-four) to nerve stimulation. Prolonged paralysis and/or skeletal muscle weakness may be noted during initial attempts to wean from the ventilator patients who have chronically received neuromuscular blocking drugs in the ICU.
Myopathy after long-term administration of other nondepolarizing neuromuscular blocking agents in the ICU alone or in combination with corticosteroid therapy has been reported. Therefore, for patients receiving both neuromuscular blocking agents and corticosteroids, the period of use of the neuromuscular blocking agent should be limited as much as possible and only used in the setting where in the opinion of the prescribing physician, the specific advantages of the drug outweigh the risk.
5.6 Malignant Hyperthermia (MH)
ZEMURON has not been studied in MH-susceptible patients. Because ZEMURON is always used with other agents, and the occurrence of malignant hyperthermia during anesthesia is possible even in the absence of known triggering agents, clinicians should be familiar with early signs, confirmatory diagnosis, and treatment of malignant hyperthermia prior to the start of any anesthetic.
In an animal study in MH-susceptible swine, the administration of ZEMURON Injection did not appear to trigger malignant hyperthermia.
5.7 Prolonged Circulation Time
Conditions associated with an increased circulatory delayed time, e.g., cardiovascular disease or advanced age, may be associated with a delay in onset time [see Dosage and Administration (2.5)].
5.8 QT Interval Prolongation
The overall analysis of ECG data in pediatric patients indicates that the concomitant use of ZEMURON with general anesthetic agents can prolong the QTc interval [see Clinical Studies (14.3)].
5.9 Conditions/Drugs Causing Potentiation of, or Resistance to, Neuromuscular Block
Potentiation: Nondepolarizing neuromuscular blocking agents have been found to exhibit profound neuromuscular blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with carcinomatosis.
Certain inhalation anesthetics, particularly enflurane and isoflurane, antibiotics, magnesium salts, lithium, local anesthetics, procainamide, and quinidine have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Drug Interactions (7.3)].
In these or other patients in whom potentiation of neuromuscular block or difficulty with reversal may be anticipated, a decrease from the recommended initial dose of ZEMURON should be considered [see Dosage and Administration (2.5)].
Resistance: Resistance to nondepolarizing agents, consistent with up-regulation of skeletal muscle acetylcholine receptors, is associated with burns, disuse atrophy, denervation, and direct muscle trauma. Receptor up-regulation may also contribute to the resistance to nondepolarizing muscle relaxants which sometimes develops in patients with cerebral palsy, patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, or with chronic exposure to nondepolarizing agents. When ZEMURON is administered to these patients, shorter durations of neuromuscular block may occur, and infusion rates may be higher due to the development of resistance to nondepolarizing muscle relaxants.
Potentiation or Resistance: Severe acid-base and/or electrolyte abnormalities may potentiate or cause resistance to the neuromuscular blocking action of ZEMURON. No data are available in such patients and no dosing recommendations can be made.
ZEMURON-induced neuromuscular blockade was modified by alkalosis and acidosis in experimental pigs. Both respiratory and metabolic acidosis prolonged the recovery time. The potency of ZEMURON was significantly enhanced in metabolic acidosis and alkalosis, but was reduced in respiratory alkalosis. In addition, experience with other drugs has suggested that acute (e.g., diarrhea) or chronic (e.g., adrenocortical insufficiency) electrolyte imbalance may alter neuromuscular blockade. Since electrolyte imbalance and acid-base imbalance are usually mixed, either enhancement or inhibition may occur.
5.10 Incompatibility with Alkaline Solutions
ZEMURON, 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.
5.11 Increase in Pulmonary Vascular Resistance
ZEMURON may be associated with increased pulmonary vascular resistance, so caution is appropriate in patients with pulmonary hypertension or valvular heart disease [see Clinical Studies (14.1)].
5.12 Use In Patients with Myasthenia
In patients with myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, small doses of nondepolarizing neuromuscular blocking agents may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants.
5.13 Extravasation
If extravasation occurs, it may be associated with signs or symptoms of local irritation. The injection or infusion should be terminated immediately and restarted in another vein.
Adverse Reactions
Clinical Trials Experience
In clinical trials, the most common adverse reactions (2%) are transient hypotension and hypertension.
The following adverse reactions are described, or described in greater detail, in other sections:
Anaphylaxis [see Warnings and Precautions (5.2)] Residual paralysis [see Warnings and Precautions (5.4)] Myopathy [see Warnings and Precautions (5.5)] Increased pulmonary vascular resistance [see Warnings and Precautions (5.11)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical studies in the US (n=1137) and Europe (n=1394) totaled 2531 patients. The patients exposed in the US clinical studies provide the basis for calculation of adverse reaction rates. The following adverse reactions were reported in patients administered ZEMURON (all events judged by investigators during the clinical trials to have a possible causal relationship):
Adverse reactions in greater than 1% of patients: None
Adverse reactions in less than 1% of patients (probably related or relationship unknown):
Cardiovascular: arrhythmia, abnormal electrocardiogram, tachycardia Digestive: nausea, vomiting Respiratory: asthma (bronchospasm, wheezing, or rhonchi), hiccup Skin and Appendages: rash, injection site edema, pruritus
In the European studies, the most commonly reported reactions were transient hypotension (2%) and hypertension (2%); these are in greater frequency than the US studies (0.1% and 0.1%). Changes in heart rate and blood pressure were defined differently from in the US studies in which changes in cardiovascular parameters were not considered as adverse events unless judged by the investigator as unexpected, clinically significant, or thought to be histamine related.
In a clinical study in patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft, hypertension and tachycardia were reported in some patients, but these occurrences were less frequent in patients receiving beta or calcium channel-blocking drugs. In some patients, ZEMURON was associated with transient increases (30% or greater) in pulmonary vascular resistance. In another clinical study of patients undergoing abdominal aortic surgery, transient increases (30% or greater) in pulmonary vascular resistance were observed in about 24% of patients receiving ZEMURON 0.6 or 0.9 mg/kg.
In pediatric patient studies worldwide (n=704), tachycardia occurred at an incidence of 5.3% (n=37), and it was judged by the investigator as related in 10 cases (1.4%).
Postmarketing Experience
In clinical practice, there have been reports of severe allergic reactions (anaphylactic and anaphylactoid reactions and shock) with ZEMURON, including some that have been life-threatening and fatal [see Warnings and Precautions (5.2)].
Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.
Drug Interactions
Antibiotics
Drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as ZEMURON include certain antibiotics (e.g., aminoglycosides; vancomycin; tetracyclines; bacitracin; polymyxins; colistin; and sodium colistimethate). If these antibiotics are used in conjunction with ZEMURON, prolongation of neuromuscular block may occur.
7.2 Anticonvulsants
In 2 of 4 patients receiving chronic anticonvulsant therapy, apparent resistance to the effects of ZEMURON was observed in the form of diminished magnitude of neuromuscular block, or shortened clinical duration. As with other nondepolarizing neuromuscular blocking drugs, if ZEMURON is administered to patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, shorter durations of neuromuscular block may occur and infusion rates may be higher due to the development of resistance to nondepolarizing muscle relaxants. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor [see Warnings and Precautions (5.9)].
7.3 Inhalation Anesthetics
Use of inhalation anesthetics has been shown to enhance the activity of other neuromuscular blocking agents (enflurane > isoflurane > halothane).
Isoflurane and enflurane may also prolong the duration of action of initial and maintenance doses of ZEMURON and decrease the average infusion requirement of ZEMURON by 40% compared to opioid/nitrous oxide/oxygen anesthesia. No definite interaction between ZEMURON and halothane has been demonstrated. In one study, use of enflurane in 10 patients resulted in a 20% increase in mean clinical duration of the initial intubating dose, and a 37% increase in the duration of subsequent maintenance doses, when compared in the same study to 10 patients under opioid/nitrous oxide/oxygen anesthesia. The clinical duration of initial doses of ZEMURON of 0.57 to 0.85 mg/kg under enflurane or isoflurane anesthesia, as used clinically, was increased by 11% and 23%, respectively. The duration of maintenance doses was affected to a greater extent, increasing by 30% to 50% under either enflurane or isoflurane anesthesia.
Potentiation by these agents is also observed with respect to the infusion rates of ZEMURON required to maintain approximately 95% neuromuscular block. Under isoflurane and enflurane anesthesia, the infusion rates are decreased by approximately 40% compared to opioid/nitrous oxide/oxygen anesthesia. The median spontaneous recovery time (from 25% to 75% of control T1) is not affected by halothane, but is prolonged by enflurane (15% longer) and isoflurane (62% longer). Reversal-induced recovery of ZEMURON neuromuscular block is minimally affected by anesthetic technique [see Dosage and Administration (2.5) and Warnings and Precautions (5.9)].
7.4 Lithium Carbonate
Lithium has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Warnings and Precautions (5.9)].
7.5 Local Anesthetics
Local anesthetics have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Warnings and Precautions (5.9)].
7.6 Magnesium
Magnesium salts administered for the management of toxemia of pregnancy may enhance neuromuscular blockade [see Warnings and Precautions (5.9)].
7.7 Nondepolarizing Muscle Relaxants
There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession.
7.8 Procainamide
Procainamide has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Warnings and Precautions (5.9)].
7.9 Propofol
The use of propofol for induction and maintenance of anesthesia does not alter the clinical duration or recovery characteristics following recommended doses of ZEMURON.
7.10 Quinidine
Injection of quinidine during recovery from use of muscle relaxants is associated with recurrent paralysis. This possibility must also be considered for ZEMURON [see Warnings and Precautions (5.9)].
7.11 Succinylcholine
The use of ZEMURON before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied.
If ZEMURON is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T1 returned to 75% of control was 36 minutes (range: 14-57, n=12) vs. 28 minutes (range: 17-51, n=12) without succinylcholine.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): C
Developmental toxicology studies have been performed with rocuronium bromide in pregnant, conscious, nonventilated rabbits and rats. Inhibition of neuromuscular function was the endpoint for high-dose selection. The maximum tolerated dose served as the high dose and was administered intravenously 3 times a day to rats (0.3 mg/kg, 15%-30% of human intubation dose of 0.6-1.2 mg/kg based on the body surface unit of mg/m2) from Day 6 to 17 and to rabbits (0.02 mg/kg, 25% human dose) from Day 6 to 18 of pregnancy. High-dose treatment caused acute symptoms of respiratory dysfunction due to the pharmacological activity of the drug. Teratogenicity was not observed in these animal species. The incidence of late embryonic death was increased at the high dose in rats, most likely due to oxygen deficiency. Therefore, this finding probably has no relevance for humans because immediate mechanical ventilation of the intubated patient will effectively prevent embryo-fetal hypoxia. However, there are no adequate and well-controlled studies in pregnant women. ZEMURON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rocuronium in women who are pregnant.
Labor and Delivery
The use of ZEMURON in Cesarean section has been studied in a limited number of patients [see Clinical Studies (14.1)]. ZEMURON is not recommended for rapid sequence induction in Cesarean section patients.
Nursing Mothers
There is no FDA guidance on the use of Rocuronium in women who are nursing.
Pediatric Use
The use of ZEMURON has been studied in pediatric patients 3 months to 14 years of age under halothane anesthesia. Of the pediatric patients anesthetized with halothane who did not receive atropine for induction, about 80% experienced a transient increase (30% or greater) in heart rate after intubation. One of the 19 infants anesthetized with halothane and fentanyl who received atropine for induction experienced this magnitude of change [see Dosage and Administration (2.5) and Clinical Studies (14.3)].
ZEMURON was also studied in pediatric patients up to 17 years of age, including neonates, under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. Onset time and clinical duration varied with dose, the age of the patient, and anesthetic technique. The overall analysis of ECG data in pediatric patients indicates that the concomitant use of ZEMURON with general anesthetic agents can prolong the QTc interval. The data also suggest that ZEMURON may increase heart rate. However, it was not possible to conclusively identify an effect of ZEMURON independent of that of anesthesia and other factors. Additionally, when examining plasma levels of ZEMURON in correlation to QTc interval prolongation, no relationship was observed [see Dosage and Administration (2.5), Warnings and Precautions (5.8), and Clinical Studies (14.3)].
ZEMURON is not recommended for rapid sequence intubation in pediatric patients. Recommendations for use in pediatric patients are discussed in other sections [see Dosage and Administration (2.5) and Clinical Pharmacology (12.2)].
Geriatic Use
ZEMURON was administered to 140 geriatric patients (65 years or greater) in US clinical trials and 128 geriatric patients in European clinical trials. The observed pharmacokinetic profile for geriatric patients (n=20) was similar to that for other adult surgical patients [see Clinical Pharmacology (12.3)]. Onset time and duration of action were slightly longer for geriatric patients (n=43) in clinical trials. Clinical experiences and recommendations for use in geriatric patients are discussed in other sections [see Dosage and Administration (2.5), Clinical Pharmacology (12.2), and Clinical Studies (14.2)].
Gender
There is no FDA guidance on the use of Rocuronium with respect to specific gender populations.
Race
There is no FDA guidance on the use of Rocuronium with respect to specific racial populations.
Renal Impairment
Due to the limited role of the kidney in the excretion of ZEMURON, usual dosing guidelines should be followed. In patients with renal dysfunction, the duration of neuromuscular blockade was not prolonged; however, there was substantial individual variability (range: 22-90 minutes) [see Clinical Pharmacology (12.3)].
Hepatic Impairment
Since ZEMURON is primarily excreted by the liver, it should be used with caution in patients with clinically significant hepatic impairment. ZEMURON 0.6 mg/kg has been studied in a limited number of patients (n=9) with clinically significant hepatic impairment under steady-state isoflurane anesthesia. After ZEMURON 0.6 mg/kg, the median (range) clinical duration of 60 (35-166) minutes was moderately prolonged compared to 42 minutes in patients with normal hepatic function. The median recovery time of 53 minutes was also prolonged in patients with cirrhosis compared to 20 minutes in patients with normal hepatic function. Four of 8 patients with cirrhosis, who received ZEMURON 0.6 mg/kg under opioid/nitrous oxide/oxygen anesthesia, did not achieve complete block. These findings are consistent with the increase in volume of distribution at steady state observed in patients with significant hepatic impairment [see Clinical Pharmacology (12.3)]. If used for rapid sequence induction in patients with ascites, an increased initial dosage may be necessary to assure complete block. Duration will be prolonged in these cases. The use of doses higher than 0.6 mg/kg has not been studied [see Dosage and Administration (2.5)].
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rocuronium in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Rocuronium in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Rocuronium Administration in the drug label.
Monitoring
There is limited information regarding Rocuronium Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Rocuronium and IV administrations.
Overdosage
Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway, controlled ventilation, and adequate sedation until recovery of normal neuromuscular function is assured. Once evidence of recovery from neuromuscular block is observed, further recovery may be facilitated by administration of an anticholinesterase agent in conjunction with an appropriate anticholinergic agent.
Reversal of Neuromuscular Blockade: Anticholinesterase agents should not be administered prior to the demonstration of some spontaneous recovery from neuromuscular blockade. The use of a nerve stimulator to document recovery is recommended.
Patients should be evaluated for adequate clinical evidence of neuromuscular recovery, e.g., 5-second head lift, adequate phonation, ventilation, and upper airway patency. Ventilation must be supported while patients exhibit any signs of muscle weakness.
Recovery may be delayed in the presence of debilitation, carcinomatosis, and concomitant use of certain drugs which enhance neuromuscular blockade or separately cause respiratory depression. Under such circumstances the management is the same as that of prolonged neuromuscular blockade.
Pharmacology
There is limited information regarding Rocuronium Pharmacology in the drug label.
Mechanism of Action
ZEMURON is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. It acts by competing for cholinergic receptors at the motor end-plate. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine and edrophonium.
Structure
ZEMURON (rocuronium bromide) injection is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. Rocuronium bromide is chemically designated as 1-[17β-(acetyloxy)-3α-hydroxy-2β-(4-morpholinyl)-5α-androstan-16β-yl]-1-(2-propenyl)pyrrolidinium bromide.
The structural formula is:
The chemical formula is C32H53BrN2O4 with a molecular weight of 609.70. The partition coefficient of rocuronium bromide in n-octanol/water is 0.5 at 20°C.
ZEMURON is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellow/orange, for intravenous injection only. Each mL contains 10 mg rocuronium bromide and 2 mg sodium acetate. The aqueous solution is adjusted to isotonicity with sodium chloride and to a pH of 4 with acetic acid and/or sodium hydroxide.
Pharmacodynamics
The ED95 (dose required to produce 95% suppression of the first [T1] mechanomyographic [MMG] response of the adductor pollicis muscle [thumb] to indirect supramaximal train-of-four stimulation of the ulnar nerve) during opioid/nitrous oxide/oxygen anesthesia is approximately 0.3 mg/kg. Patient variability around the ED95 dose suggests that 50% of patients will exhibit T1 depression of 91% to 97%.
Table 4 presents intubating conditions in patients with intubation initiated at 60 to 70 seconds.
Once spontaneous recovery has reached 25% of control T1, the neuromuscular block produced by ZEMURON is readily reversed with anticholinesterase agents, e.g., edrophonium or neostigmine.
The median spontaneous recovery from 25% to 75% T1 was 13 minutes in adult patients. When neuromuscular block was reversed in 36 adults at a T1 of 22% to 27%, recovery to a T1 of 89 (50-132)% and T4/T1 of 69 (38-92)% was achieved within 5 minutes. Only 5 of 320 adults reversed received an additional dose of reversal agent. The median (range) dose of neostigmine was 0.04 (0.01-0.09) mg/kg and the median (range) dose of edrophonium was 0.5 (0.3-1.0) mg/kg.
In geriatric patients (n=51) reversed with neostigmine, the median T4/T1 increased from 40% to 88% in 5 minutes.
In clinical trials with halothane, pediatric patients (n=27) who received 0.5 mg/kg edrophonium had increases in the median T4/T1 from 37% at reversal to 93% after 2 minutes. Pediatric patients (n=58) who received 1 mg/kg edrophonium had increases in the median T4/T1 from 72% at reversal to 100% after 2 minutes. Infants (n=10) who were reversed with 0.03 mg/kg neostigmine recovered from 25% to 75% T1 within 4 minutes.
There were no reports of less than satisfactory clinical recovery of neuromuscular function.
The neuromuscular blocking action of ZEMURON may be enhanced in the presence of potent inhalation anesthetics [see Drug Interactions (7.3)].
Hemodynamics: There were no dose-related effects on the incidence of changes from baseline (30% or greater) in mean arterial blood pressure (MAP) or heart rate associated with ZEMURON administration over the dose range of 0.12 to 1.2 mg/kg (4 × ED95) within 5 minutes after ZEMURON administration and prior to intubation. Increases or decreases in MAP were observed in 2% to 5% of geriatric and other adult patients, and in about 1% of pediatric patients. Heart rate changes (30% or greater) occurred in 0% to 2% of geriatric and other adult patients. Tachycardia (30% or greater) occurred in 12 of 127 pediatric patients. Most of the pediatric patients developing tachycardia were from a single study where the patients were anesthetized with halothane and who did not receive atropine for induction [see Clinical Studies (14.3)]. In US studies, laryngoscopy and tracheal intubation following ZEMURON administration were accompanied by transient tachycardia (30% or greater increases) in about one-third of adult patients under opioid/nitrous oxide/oxygen anesthesia. Animal studies have indicated that the ratio of vagal:neuromuscular block following ZEMURON administration is less than vecuronium but greater than pancuronium. The tachycardia observed in some patients may result from this vagal blocking activity.
Histamine Release: In studies of histamine release, clinically significant concentrations of plasma histamine occurred in 1 of 88 patients. Clinical signs of histamine release (flushing, rash, or bronchospasm) associated with the administration of ZEMURON were assessed in clinical trials and reported in 9 of 1137 (0.8%) patients.
Pharmacokinetics
Adult and Geriatric Patients: In an effort to maximize the information gathered in the in vivo pharmacokinetic studies, the data from the studies was used to develop population estimates of the parameters for the subpopulations represented (e.g., geriatric, pediatric, renal, and hepatic impairment). These population-based estimates and a measure of the estimate variability are contained in the following section.
Following intravenous administration of ZEMURON, plasma levels of rocuronium follow a three-compartment open model. The rapid distribution half-life is 1 to 2 minutes and the slower distribution half-life is 14 to 18 minutes. Rocuronium is approximately 30% bound to human plasma proteins. In geriatric and other adult surgical patients undergoing either opioid/nitrous oxide/oxygen or inhalational anesthesia, the observed pharmacokinetic profile was essentially unchanged.
In general, studies with normal adult subjects did not reveal any differences in the pharmacokinetics of rocuronium due to gender.
Studies of distribution, metabolism, and excretion in cats and dogs indicate that rocuronium is eliminated primarily by the liver. The rocuronium analog 17-desacetyl-rocuronium, a metabolite, has been rarely observed in the plasma or urine of humans administered single doses of 0.5 to 1 mg/kg with or without a subsequent infusion (for up to 12 hr) of rocuronium. In the cat, 17-desacetyl-rocuronium has approximately one-twentieth the neuromuscular blocking potency of rocuronium. The effects of renal failure and hepatic disease on the pharmacokinetics and pharmacodynamics of rocuronium in humans are consistent with these findings.
In general, patients undergoing cadaver kidney transplant have a small reduction in clearance which is offset pharmacokinetically by a corresponding increase in volume, such that the net effect is an unchanged plasma half-life. Patients with demonstrated liver cirrhosis have a marked increase in their volume of distribution resulting in a plasma half-life approximately twice that of patients with normal hepatic function. Table 8 shows the pharmacokinetic parameters in subjects with either impaired renal or hepatic function.
The net result of these findings is that subjects with renal failure have clinical durations that are similar to but somewhat more variable than the duration that one would expect in subjects with normal renal function. Hepatically impaired patients, due to the large increase in volume, may demonstrate clinical durations approaching 1.5 times that of subjects with normal hepatic function. In both populations the clinician should individualize the dose to the needs of the patient [see Dosage and Administration (2.5)].
Tissue redistribution accounts for most (about 80%) of the initial amount of rocuronium administered. As tissue compartments fill with continued dosing (4-8 hours), less drug is redistributed away from the site of action and, for an infusion-only dose, the rate to maintain neuromuscular blockade falls to about 20% of the initial infusion rate. The use of a loading dose and a smaller infusion rate reduces the need for adjustment of dose.
Pediatric Patients: Under halothane anesthesia, the clinical duration of effects of ZEMURON did not vary with age in patients 4 months to 8 years of age. The terminal half-life and other pharmacokinetic parameters of rocuronium in these pediatric patients are presented in Table 9.
Pharmacokinetics of ZEMURON were evaluated using a population analysis of the pooled pharmacokinetic datasets from 2 trials under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. All pharmacokinetic parameters were found to be linearly proportional to body weight. In patients under the age of 18 years clearance (CL) and volume of distribution (Vss) increase with bodyweight (kg) and age (years). As a result the terminal half-life of ZEMURON decreases with increasing age from 1.1 hour to 0.7-0.8 hour. Table 10 presents the pharmacokinetic parameters in the different age groups in the studies with sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies in animals have not been performed with rocuronium bromide to evaluate carcinogenic potential or impairment of fertility. Mutagenicity studies (Ames test, analysis of chromosomal aberrations in mammalian cells, and micronucleus test) conducted with rocuronium bromide did not suggest mutagenic potential.
Clinical Studies
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Precautions with Alcohol
Alcohol-Rocuronium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
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References
The contents of this FDA label are provided by the National Library of Medicine.