Rocuronium Bromide

Rocuronium Bromide Injection is indicated as an adjunct to general anesthesia to facilitate both rapid sequence and routine tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Rocuronium Bromide Injection is a nondepolarizing neuromuscular blocking agent indicated as an adjunct to general anesthesia to facilitate both rapid sequence and routine tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation. ( 1 )

Rocuronium Bromide Injection is a clear, colorless to yellow/orange solution, free from visible particulate matter available as: 50 mg/5 mL (10 mg/mL), single-dose vials 100 mg/10 mL (10 mg/mL), single-dose vials 50 mg/5 mL (10 mg/mL), single-dose prefilled syringes Injection: 50 mg/5 mL (10 mg/mL), single-dose vial and single-dose prefilled syringe. ( 3 ) 100 mg/10 mL (10 mg/mL), single-dose vial. ( 3 )

Rocuronium Bromide Injection is contraindicated in patients known to have hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other neuromuscular blocking agents [see Warnings and Precautions ( 5.2 )] . Hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other neuromuscular blocking agents. ( 4 )

Appropriate Administration and Monitorin g: Use only if facilities for intubation, mechanical ventilation, oxygen therapy, and an antagonist are immediately available. ( 5.1 ) Anaphylaxis : Severe anaphylaxis has been reported. Consider cross-reactivity among neuromuscular blocking agents. ( 5.2 ) Risk of Death due to Medication Errors : Accidental administration can cause death. ( 5.3 ) Need for Adequate Anesthesia : Must be accompanied by adequate anesthesia or sedation. ( 5.4 ) Residual Paralysis : Consider using a reversal agent in cases where residual paralysis is more likely to occur. ( 5.5 )

5.1 Appropriate Administration and Monitoring Rocuronium Bromide Injection 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. Rocuronium Bromide Injection 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 Rocuronium Bromide Injection 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 Rocuronium Bromide Injection, have been reported. These reactions have, in some cases (including cases with Rocuronium Bromide Injection), 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 Risk of Death due to Medication Errors Administration of Rocuronium Bromide Injection results in paralysis, which may lead to respiratory arrest and death, a progression that 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 Rocuronium Bromide Injection, ensure that the intended dose is clearly labeled and communicated.

5.4 Need for Adequate Anesthesia Rocuronium Bromide Injection has no known effect on consciousness, pain threshold, or cerebration. Therefore, its administration must be accompanied by adequate anesthesia or sedation.

5.5 Residual Paralysis To prevent complications resulting from residual paralysis from Rocuronium Bromide Injection, it is recommended to extubate only after the patient has recovered sufficiently from neuromuscular block. Geriatric patients (65 years or older) may be at increased risk for residual 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.

5.6 Long-Term Use in an Intensive Care Unit Rocuronium Bromide Injection has not been studied for long-term use in the intensive care unit (ICU). As with other nondepolarizing neuromuscular blocking drugs, apparent tolerance to Rocuronium Bromide Injection 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 Rocuronium Bromide Injection administration and recovery with the help of a nerve stimulator. Additional doses of Rocuronium Bromide Injection 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 (including Rocuronium Bromide Injection) 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.

5.7 Malignant Hyperthermia Rocuronium Bromide Injection has not been studied in malignant hyperthermia (MH)-susceptible patients. In an animal study in MH-susceptible swine, the administration of Rocuronium Bromide Injection did not appear to trigger malignant hyperthermia. Because Rocuronium Bromide Injection is always used with other agents, and the occurrence of MH during anesthesia is possible even in the absence of known triggering agents, clinicians should be familiar with early signs, confirmatory diagnosis, and treatment of MH prior to the start of any anesthetic [see Adverse Reactions ( 6.2 )] .

5.8 Prolonged Circulation Time Conditions associated with an increased circulatory delayed time, e.g., cardiovascular disease or advanced age, in patients treated with Rocuronium Bromide Injection may be associated with a delay in onset time [see Dosage and Administration ( 2.6 )] . 5.9 QT Interval Prolongation The overall analysis of ECG data in pediatric patients indicates that the concomitant use of Rocuronium Bromide Injection with general anesthetic agents can prolong the QTc interval [see Clinical Studies ( 14.3 )].

5.10 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 Rocuronium Bromide Injection should be considered [see Dosage and Administration ( 2.6 )] . 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 Rocuronium Bromide Injection 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. […]

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 ( 5.5 )] Myopathy [see Warnings and Precautions ( 5.6 )] Increased pulmonary vascular resistance [see Warnings and Precautions ( 5.12 )] Most common adverse reactions (2%) are transient hypotension and hypertension. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 of another rocuronium bromide injection product in the U.S. (n=1137) and Europe (n=1394) totaled 2531 patients. The following adverse reactions were reported in patients administered another rocuronium bromide injection (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 of another rocuronium bromide injection product, 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 of another rocuronium bromide injection product 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, the use of another rocuronium bromide injection product 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 who received another rocuronium bromide injection product at 0.6 mg/kg or 0.9 mg/kg. In pediatric patient studies worldwide of another rocuronium bromide injection product (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%).

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of rocuronium bromide injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: In clinical practice, there have been reports of severe allergic reactions (anaphylactic reactions and shock) with rocuronium bromide injection, including some that have been life-threatening and fatal [see Warnings and Precautions ( 5.2 )] . General disorders and administration site conditions: There have been reports of malignant hyperthermia with the use of rocuronium bromide injection [see Warnings and Precautions ( 5.7 )].

Succinylcholine : Use before succinylcholine has not been studied. ( 7.11 ) Nondepolarizing muscle relaxants : Interactions have been observed. ( 7.7 ) Enhanced Rocuronium Bromide Injection activity possible : Inhalation anesthetics ( 7.3 ), certain antibiotics ( 7.1 ), quinidine ( 7.10 ), magnesium ( 7.6 ), lithium ( 7.4 ), local anesthetics ( 7.5 ), procainamide ( 7.8 ) Reduced Rocuronium Bromide Injection activity possible : Anticonvulsants. ( 7.2 )

7.1 Antibiotics Drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as Rocuronium Bromide Injection include certain antibiotics (e.g., aminoglycosides; vancomycin; tetracyclines; bacitracin; polymyxins; colistin; and sodium colistimethate). If these antibiotics are used in conjunction with Rocuronium Bromide Injection, prolongation of neuromuscular block may occur.

7.2 Anticonvulsants In 2 of 4 patients who received chronic anticonvulsant therapy, apparent resistance to the effects of another rocuronium bromide injection product was observed in the form of diminished magnitude of neuromuscular block or shortened clinical duration. As with other nondepolarizing neuromuscular blocking drugs, if Rocuronium Bromide Injection 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 ( 5.10 )] .

7.3 Inhalation Anesthetics Use of inhalation anesthetics (enflurane > isoflurane > halothane) has been shown to enhance the activity of other neuromuscular blocking agents. Isoflurane and enflurane may also prolong the duration of action of initial and maintenance doses of Rocuronium Bromide Injection and decrease the average infusion requirement of Rocuronium Bromide Injection by 40% compared to opioid/nitrous oxide/oxygen anesthesia. No definite interaction between rocuronium bromide injection and halothane has been demonstrated. In one study, use of enflurane in 10 patients who received another rocuronium bromide injection product 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 another rocuronium bromide injection product (0.57 mg/kg 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 was also observed with respect to the infusion rates of rocuronium bromide injection required to maintain approximately 95% neuromuscular block. Under isoflurane and enflurane anesthesia, the infusion rates were decreased by approximately 40% compared to opioid/nitrous oxide/oxygen anesthesia. The median spontaneous recovery time (from 25% to 75% of control T 1 ) was not affected by halothane but is prolonged by enflurane (15% longer) and isoflurane (62% longer). Reversal-induced recovery of Rocuronium Bromide Injection neuromuscular block is minimally affected by anesthetic technique [see Dosage and Administration ( 2.6 ) and Warnings and Precautions ( 5.10 )] .

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 ( 5.10 )] .

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 ( 5.10 )] .

7.6 Magnesium Magnesium salts administered for the management of pre-eclampsia or eclampsia of pregnancy may enhance neuromuscular blockade [see Warnings and Precautions ( 5.10 )] .

7.7 Nondepolarizing Muscle Relaxants There are no controlled studies documenting the use of Rocuronium Bromide Injection 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 ( 5.10 )] .

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 Rocuronium Bromide Injection.

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 Rocuronium Bromide Injection [see Warnings and Precautions ( 5.10 )] .

7.11 Succinylcholine The use of Rocuronium Bromide Injection before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied. If Rocuronium Bromide Injection is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of Rocuronium Bromide Injection 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range: 14-57, n=12) vs. 28 minutes (range: 17-51, n=12) without succinylcholine.

Pregnancy : Not recommended for rapid sequence induction in patients undergoing Cesarean section. ( 8.1 , 14.1 ) Pediatric Use : Onset time and duration will vary with dose, age, and anesthetic technique. Not recommended for rapid sequence intubation in pediatric patients. ( 8.4 )

8.1 Pregnancy Risk Summary Available data from controlled trials and case series and over decades of use of rocuronium bromide in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are potential risks when rocuronium bromide is used during labor or delivery (see Clinical Considerations ). Based on data from umbilical cord blood sampling, rocuronium bromide is transferred across the placenta [see Clinical Studies ( 14.1 )] . In animal reproduction studies, there was no evidence of teratogenicity when rocuronium bromide was administered intravenously to pregnant, conscious, nonventilated rats and rabbits at 15% to 30% and 25%, respectively, the human intubation dose of 0.6 mg/kg to 1.2 mg/kg during the period of organogenesis (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Labor or Delivery: Magnesium sulfate used in the management of pre-eclampsia or eclampsia in pregnancy may enhance neuromuscular blockade [see Warning and Precautions 5.10 ]. The use of another rocuronium bromide injection product in Cesarean section has been studied in a limited number of patients. Adverse events in this study included low APGAR scores in neonates at 5 minutes and poor intubation conditions in some pregnant women who received rocuronium bromide [see Clinical Studies ( 14.1 )] . Rocuronium Bromide Injection is not recommended for rapid sequence induction in Cesarean section patients. Data Animal Data: 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% to 30% of human intubation dose of 0.6 mg/kg to 1.2 mg/kg based on the body surface unit of mg/m 2 ) 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.

8.2 Lactation Risk Summary There are no available data on the presence of rocuronium bromide in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for rocuronium bromide and any potential adverse effects on the breastfed child from rocuronium bromide or from the underlying maternal condition.

8.4 Pediatric Use The use of another rocuronium bromide injection product 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 ( 2.6 ), Clinical Studies ( 14.3 )] . Another rocuronium bromide injection product 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 indicated that the concomitant use of Rocuronium Bromide Injection with general anesthetic agents can prolong the QTc interval. The data also suggest that Rocuronium Bromide Injection may increase heart rate. However, it was not possible to conclusively identify an effect of rocuronium bromide independent of that of anesthesia and other factors. Additionally, when examining plasma levels of rocuronium bromide in correlation to QTc interval prolongation, no relationship was observed [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.9 ), Clinical Studies ( 14.3 )]. Rocuronium Bromide Injection is not recommended for rapid sequence intubation in pediatric patients. Recommendations for use in pediatric patients are discussed in other sections of labeling [see Dosage and Administration ( 2.6 ) Clinical Pharmacology ( 12.2 )] .

8.5 Geriatric Use Another rocuronium bromide injection product was administered to 140 geriatric patients (65 years of age or older) in U.S. clinical trials and 128 geriatric patients in European clinical trials. The observed pharmacokinetic profile of rocuronium bromide for geriatric patients (n=20) was similar to that for other adult surgical patients [see Clinical Pharmacology ( 12.3 )] . However, onset time and duration of action of rocuronium bromide were slightly longer for geriatric patients (n=43) in clinical trials. Clinical experiences and recommendations for use of Rocuronium Bromide Injection in geriatric patients are discussed in other sections of the labeling [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.2 ), Clinical Studies ( 14.2 )].

8.6 Patients with Hepatic Impairment Because rocuronium bromide is primarily excreted by the liver, it should be used with caution in patients with clinically significant hepatic impairment. Another rocuronium bromide injection product (0.6 mg/kg) was studied in a limited number of patients (n=9) with clinically significant hepatic impairment under steady-state isoflurane anesthesia. After rocuronium bromide injection administration (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 the other rocuronium bromide injection product (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 of Rocuronium Bromide Injection may be necessary to assure complete block. Duration will be prolonged in these cases. The use of Rocuronium Bromide Injection doses higher than 0.6 mg/kg has not been studied [see Dosage and Administration ( 2.6 )].

8.7 Patients with Renal Impairment Due to the limited role of the kidney in the excretion of rocuronium bromide, usual dosing recommendations Rocuronium Bromide Injection for should be followed. […]

Rocuronium Bromide Injection 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.