Rocuronium Bromide

Dosage and Administration, Important Dosing and Administration Information ( 2.1 ) 03/2019 Warnings and Precautions, Risk of Death due to Medication Errors ( 5.3 ) 03/2019

1 INDICATIONS AND USAGE Rocuronium Bromide Injection is indicated for inpatients and outpatients 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 )

2 DOSAGE AND ADMINISTRATION To be administered only by experienced clinicians or adequately trained individuals supervised by an experienced clinician familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents. ( 2.1 ) Individualize the dose for each patient. ( 2.1 ) Peripheral nerve stimulator recommended for determination of drug response and need for additional doses, and to evaluate recovery. ( 2.1 ) Store rocuronium bromide injection with cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product. ( 2.1 ) Tracheal intubation : Recommended initial dose is 0.6 mg/kg. ( 2.2 ) Rapid sequence intubation : 0.6 to 1.2 mg/kg. ( 2.3 ) Maintenance doses : Guided by response to prior dose, not administered until recovery is evident. ( 2.4 ) Continuous infusion : Initial rate of 10 to 12 mcg/kg/min. Start only after early evidence of spontaneous recovery from an intubating dose. ( 2.5 ) 2.1 Important Dosing and Administration Information Rocuronium bromide injection is for intravenous use only. This drug should only be administered by experienced clinicians or trained individuals supervised by an experienced clinician familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents. Doses of rocuronium bromide injection should be individualized and a peripheral nerve stimulator should be used 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. The dosage information which follows is derived from studies based upon units of drug per unit of body weight. It is intended to serve as an initial guide to clinicians familiar with other neuromuscular blocking agents to acquire experience with rocuronium bromide injection. In patients in whom potentiation of, or resistance to, neuromuscular block is anticipated, a dose adjustment should be considered [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.10 , 5.13 ), Drug Interactions ( 7.2 , 7.3 , 7.4 , 7.5 , 7.6 , 7.8 , 7.10 ), and Use in Specific Populations ( 8.6 )] . Risk of Medication Errors Accidental administration of neuromuscular blocking agents may be fatal. Store rocuronium bromide injection with the cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product [see Warnings and Precautions ( 5.3 )] . 2.2 Dose for Tracheal Intubation The recommended initial dose of rocuronium bromide injection, regardless of anesthetic technique, is 0.6 mg/kg. Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1 (0.4-6) minute(s) and most patients have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 3 minutes. This dose may be expected to provide 31 (15-85) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Under halothane, isoflurane, and enflurane anesthesia, some extension of the period of clinical relaxation should be expected [see Drug Interactions ( 7.3 )] . A lower dose of rocuronium bromide injection (0.45 mg/kg) may be used. Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1.3 (0.8-6.2) minute(s), and most patients have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 4 minutes. This dose may be expected to provide 22 (12-31) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Patients receiving this low dose of 0.45 mg/kg who achieve less than 90% block (about 16% of these patients) may have a more rapid time to 25% recovery, 12 to 15 minutes. A large bolus dose of 0.9 or 1.2 mg/kg can be administered under opioid/nitrous oxide/oxygen anesthesia without adverse effects to the cardiovascular system [see Clinical Pharmacology ( …

3 DOSAGE FORMS AND STRENGTHS Rocuronium bromide injection is available as • 5 mL multiple-dose vials containing 50 mg rocuronium bromide injection (10 mg/mL) • 10 mL multiple-dose vials containing 100 mg rocuronium bromide injection (10 mg/mL) • 5 mL multiple dose vials containing 50 mg rocuronium bromide injection (10 mg/mL). ( 3 ) • 10 mL multiple dose vials containing 100 mg rocuronium bromide injection (10 mg/mL). ( 3 )

4 CONTRAINDICATIONS 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 )

6 ADVERSE REACTIONS 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 in the U.S. (n = 1137) and Europe (n = 1394) totaled 2531 patients. The patients exposed in the U.S. clinical studies provide the basis for calculation of adverse reaction rates. The following adverse reactions were reported in patients administered 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, the most commonly reported reactions were transient hypotension (2%) and hypertension (2%); these are in greater frequency than the U.S. studies (0.1% and 0.1%). Changes in heart rate and blood pressure were defined differently from in the U.S. 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, rocuronium bromide injection 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 rocuronium bromide injection 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%). 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 and anaphylactoid 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) ] .

7 DRUG INTERACTIONS • 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 receiving chronic anticonvulsant therapy, apparent resistance to the effects of rocuronium bromide injection 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 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 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 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 rocuronium bromide injection 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 rocuronium bromide injection 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 T 1 ) is 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 …

8 USE IN SPECIFIC POPULATIONS 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, 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 other 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%-30% and 25%, respectively, the human intubation dose of 0.6-1.2 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 Warnings 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) ] . Therefore, 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 three times a day to rats (0.3 mg/kg, 15% to 30% of human intubation dose of 0.6 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 INJECTION and any potential adverse effects on the breastfed infant from ROCURONIUM BROMIDE INJECTION 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 infant …

12.1 Mechanism of Action 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.

11 DESCRIPTION ROCURONIUM BROMIDE INJECTION is a nondepolarizing neuromuscular blocking agent. Rocuronium bromide is chemically designated as 1-[17β-(acetyloxy)-3α-hydroxy-2β-(4-morpholinyl)-5α-androstan-16β-yl]-1-(2-propenyl) pyrrolidinium bromide. The molecular formula is C 32 H 53 BrN 2 O 4 and its molecular weight is 609.70 g/mol. The structural formula is: Rocuronium bromide is an almost white to pale yellow, hygroscopic powder. It is soluble in water and dichloromethane, slightly soluble in ethanol and methanol. It has a partition coefficient of 0.5 at 20°C. ROCURONIUM BROMIDE INJECTION is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellowish in single-dose luer-lock prefilled glass syringes, for intravenous use only. Each mL contains 10 mg rocuronium bromide (equivalent to 8.7 mg of rocuronium) and the following inactive ingredients: 25 mg of gluconolactone, 5 mg sodium acetate trihydrate, 5 mg sodium citrate dihydrate in water for injection. The formulation has a pH of 3.8 – 4.2. Structural formula

10 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.

16 HOW SUPPLIED / STORAGE AND HANDLING Rocuronium Bromide Injection is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellow/orange, for intravenous injection only. Rocuronium Bromide Injection is available in the following: Rocuronium Bromide Injection 5 mL multiple dose vials containing 50 mg Rocuronium Bromide Injection (10 mg/mL) Box of 10 NDC 0143-9250-10 Rocuronium Bromide Injection 10 mL multiple dose vials containing 100 mg Rocuronium Bromide Injection (10 mg/mL) Box of 10 NDC 0143-9251-10 The container closure of this drug product does not contain natural rubber latex. Rocuronium Bromide Injection should be stored in a refrigerator, 2o to 8oC (36o to 46oF). DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25oC/77oF), use Rocuronium Bromide Injection within 60 days. Use opened vials of Rocuronium Bromide Injection within 30 days. Safety and Handling: There is no specific work exposure limit for Rocuronium Bromide Injection. In case of eye contact, flush with water for at least 10 minutes.