PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Rocuronium 50mg/5ml Inj Solution #10

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RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

Dosage and Administration

Important Dosing and Administration Information ( 2.1) 07/2018

Warnings and Precautions

Risk of Death due to Medication Errors ( 5.3) 07/2018

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DESCRIPTION SECTION

11 DESCRIPTION

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 C 32H 53BrN 2O 4 with a molecular weight of 609.70. The partition coefficient of rocuronium bromide in n-octanol/water is 0.5 at 20°C.

Rocuronium bromide 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.

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INDICATIONS & USAGE SECTION

Highlight: 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)

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.

DOSAGE & ADMINISTRATION SECTION

Highlight: 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 DOSAGE AND ADMINISTRATION

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.

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, 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 to 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 to 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 (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 to 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 to 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 (12.2)].

2.3 Rapid Sequence Intubation

In appropriately premedicated and adequately anesthetized patients, rocuronium bromide 0.6 to 1.2 mg/kg will provide excellent or good intubating conditions in most patients in less than 2 minutes [see Clinical Studies (14.1)].

2.4 Maintenance Dosing

Maintenance doses of 0.1, 0.15, and 0.2 mg/kg rocuronium bromide, administered at 25% recovery of control T1 (defined as 3 twitches of train-of-four), provide a median (range) of 12 (2 to 31), 17 (6 to 50), and 24 (7 to 69) minutes of clinical duration under opioid/nitrous oxide/oxygen anesthesia [see Clinical Pharmacology (12.2)]. In all cases, dosing should be guided based on the clinical duration following initial dose or prior maintenance dose and not administered until recovery of neuromuscular function is evident. A clinically insignificant cumulation of effect with repetitive maintenance dosing has been observed [see Clinical Pharmacology (12.2)].

2.5 Use by Continuous Infusion

Infusion at an initial rate of 10 to 12 mcg/kg/min of rocuronium bromide should be initiated only after early evidence of spontaneous recovery from an intubating dose. Due to rapid redistribution [see Clinical Pharmacology (12.3)] and the associated rapid spontaneous recovery, initiation of the infusion after substantial return of neuromuscular function (more than 10% of control T 1), may necessitate additional bolus doses to maintain adequate block for surgery.

Upon reaching the desired level of neuromuscular block, the infusion of rocuronium bromide must be individualized for each patient. The rate of administration should be adjusted according to the patient’s twitch response as monitored with the use of a peripheral nerve stimulator. In clinical trials, infusion rates have ranged from 4 to 16 mcg/kg/min.

Inhalation anesthetics, particularly enflurane and isoflurane, may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants. In the presence of steady-state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion by 30 to 50%, at 45 to 60 minutes after the intubating dose.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium bromide infusion may be expected to proceed at rates comparable to that following comparable total doses administered by repetitive bolus injections [see Clinical Pharmacology (12.2)].

Infusion solutions of rocuronium bromide can be prepared by mixing rocuronium bromide with an appropriate infusion solution such as 5% glucose in water or lactated Ringers [see Dosage and Administration (2.7)]. These infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions should be discarded.

Infusion rates of rocuronium bromide can be individualized for each patient using the following tables for 3 different concentrations of rocuronium bromide solution as guidelines:

Table 1. Infusion Rates Using Rocuronium Bromide Injection (0.5 mg/mL)*

• 50 mg rocuronium bromide in 100 mL solution.

Table 2. Infusion Rates Using Rocuronium Bromide Injection (1 mg/mL)*

• 100 mg rocuronium bromide in 100 mL solution.

Table 3: Infusion Rates Using Rocuronium Bromide Injection (5 mg/mL)*

• 500 mg rocuronium bromide in 100 mL solution.

2.6 Dosage in Specific Populations

Pediatric Patients

The recommended initial intubation dose of rocuronium bromide is 0.6 mg/kg; however, a lower dose of 0.45 mg/kg may be used depending on anesthetic technique and the age of the patient.

For sevoflurane (induction) rocuronium bromide doses of 0.45 mg/kg and 0.6 mg/kg in general produce excellent to good intubating conditions within 75 seconds. When halothane is used, a 0.6 mg/kg dose of rocuronium bromide resulted in excellent to good intubating conditions within 60 seconds.

The time to maximum block for an intubating dose was shortest in infants (28 days up to 3 months) and longest in neonates (birth to less than 28 days). The duration of clinical relaxation following an intubating dose is shortest in children (greater than 2 years up to 11 years) and longest in infants.

When sevoflurane is used for induction and isoflurane/nitrous oxide for maintenance of general anesthesia, maintenance dosing of rocuronium bromide can be administered as bolus doses of 0.15 mg/kg at reappearance of T 3 in all pediatric age groups. Maintenance dosing can also be administered at the reappearance of T 2 at a rate of 7 to 10 mcg/kg/min, with the lowest dose requirement for neonates (birth to less than 28 days) and the highest dose requirement for children (greater than 2 years up to 11 years).

When halothane is used for general anesthesia, patients ranging from 3 months old through adolescence can be administered rocuronium bromide maintenance doses of 0.075 to 0.125 mg/kg upon return of T 1 to 0.25% to provide clinical relaxation for 7 to 10 minutes. Alternatively, a continuous infusion of rocuronium bromide initiated at a rate of 12 mcg/kg/min upon return of T 1 to 10% (one twitch present in train-of-four) may also be used to maintain neuromuscular blockade in pediatric patients.

Additional information for administration to pediatric patients of all age groups is presented elsewhere in the label

[see Clinical Pharmacology ( 12.2)].

The infusion of rocuronium bromide must be individualized for each patient. The rate of administration should be adjusted according to the patient’s twitch response as monitored with the use of a peripheral nerve stimulator. Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium bromide infusion may be expected to proceed at rates comparable to that following similar total exposure to single bolus doses [see Clinical Pharmacology ( 12.2)].

Rocuronium bromide is not recommended for rapid sequence intubation in pediatric patients.

Geriatric Patients

Geriatric patients (65 years or older) exhibited a slightly prolonged median (range) clinical duration of 46 (22 to 73), 62

(49 to 75), and 94 (64 to 138) minutes under opioid/nitrous oxide/oxygen anesthesia following doses of 0.6, 0.9, and 1.2 mg/kg, respectively. No differences in duration of neuromuscular blockade following maintenance doses of rocuronium bromide were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology ( 12.2) and Clinical Studies ( 14.2)]. [See also Warnings and Precautions ( 5.5)].

Patients with Renal or Hepatic Impairment

No differences from patients with normal hepatic and kidney function were observed for onset time at a dose of 0.6 mg/kg rocuronium bromide. When compared to patients with normal renal and hepatic function, the mean clinical duration is similar in patients with end-stage renal disease undergoing renal transplant, and is about 1.5 times longer in patients with hepatic disease. Patients with renal failure may have a greater variation in duration of effect [see Use in Specific Populations ( 8.6, 8.7) and Clinical Pharmacology ( 12.3)].

Obese Patients

In obese patients, the initial dose of rocuronium bromide 0.6 mg/kg should be based upon the patient’s actual body weight [see Clinical Studies ( 14.1)].

An analysis across all US controlled clinical studies indicates that the pharmacodynamics of rocuronium bromide are not different between obese and non-obese patients when dosed based upon their actual body weight.

Patients with Reduced Plasma Cholinesterase Activity

Rocuronium metabolism does not depend on plasma cholinesterase so dosing adjustments are not needed in patients with reduced plasma cholinesterase activity.

Patients with Prolonged Circulation Time

Because higher doses of rocuronium bromide produce a longer duration of action, the initial dosage should usually not be increased in these patients to reduce onset time; instead, in these situations, when feasible, more time should be allowed for the drug to achieve onset of effect [see Warnings and Precautions (5.8)].

Patients with Drugs or Conditions Causing Potentiation of Neuromuscular Block

The neuromuscular blocking action of rocuronium bromide is potentiated by isoflurane and enflurane anesthesia. Potentiation is minimal when administration of the recommended dose of rocuronium bromide occurs prior to the administration of these potent inhalation agents. The median clinical duration of a dose of 0.57 to 0.85 mg/kg was 34, 38, and 42 minutes under opioid/nitrous oxide/oxygen, enflurane and isoflurane maintenance anesthesia, respectively. During 1 to 2 hours of infusion, the infusion rate of rocuronium bromide required to maintain about 95% block was decreased by as much as 40% under enflurane and isoflurane anesthesia [see Drug Interactions (7.3)].

2.7 Preparation for Administration of Rocuronium Bromide Injection

Diluent Compatibility

Rocuronium bromide injection is compatible in solution with:

Rocuronium bromide injection is compatible in the above solutions at concentrations up to 5 mg/mL for 24 hours at room temperature in plastic bags, glass bottles, and plastic syringe pumps.

Drug Admixture Incompatibility

Rocuronium bromide injection is physically incompatible when mixed with the following drugs:

If rocuronium bromide injection is administered via the same infusion line that is also used for other drugs, it is important that this infusion line is adequately flushed between administration of rocuronium bromide and drugs for which incompatibility with rocuronium bromide has been demonstrated or for which compatibility with rocuronium bromide has not been established.

Infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions should be discarded.

Rocuronium bromide injection should not be mixed with alkaline solutions [see Warnings and Precautions (5.11)].

Visual Inspection

Parenteral drug products should be inspected visually for particulate matter and clarity prior to administration whenever solution and container permit. Do not use solution if particulate matter is present.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: * 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)

3 DOSAGE FORMS AND STRENGTHS

Rocuronium bromide injection is available as
• 50 mg/5 mL (10 mg/mL), multiple dose vials
• 100 mg/10 ml (10 mg/mL), multiple dose vials

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CONTRAINDICATIONS SECTION

Highlight: * Hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other neuromuscular blocking agents. ( 4)

4 CONTRAINDICATIONS

Rocuronium bromide 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)].

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DRUG INTERACTIONS SECTION

Highlight: * Succinylcholine: Use before succinylcholine has not been studied. ( 7.11)

• Nondepolarizing muscle relaxants: Interactions have been observed. ( 7.7)
• Enhanced rocuronium bromide 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 activity possible: Anticonvulsants. ( 7.2)

7 DRUG INTERACTIONS

7.1 Antibiotics

Drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as rocuronium bromide include certain antibiotics (e.g., aminoglycosides; vancomycin; tetracyclines; bacitracin; polymyxins; colistin; and sodium colistimethate). If these antibiotics are used in conjunction with rocuronium bromide, 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 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 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 and decrease the average infusion requirement of rocuronium bromide by 40% compared to opioid/nitrous oxide/oxygen anesthesia. No definite interaction between rocuronium bromide 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 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 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 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 toxemia 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 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.

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 [see Warnings and Precautions (5.10)].

7.11 Succinylcholine

The use of rocuronium bromide before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied.

If rocuronium bromide 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 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 to 57, n=12) vs. 28 minutes (range: 17 to 51, n=12) without succinylcholine.

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Labor and Delivery: Not recommended for rapid sequence induction in patients undergoing Cesarean section. ( 8.2)

• 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)

See 17 for PATIENT COUNSELING INFORMATION.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 to 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. Rocuronium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.2 Labor and Delivery

The use of rocuronium bromide in Cesarean section has been studied in a limited number of patients [see Clinical Studies (14.1)]. Rocuronium bromide is not recommended for rapid sequence induction in Cesarean section patients.

8.4 Pediatric Use

The use of rocuronium bromide 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) and Clinical Studies (14.3)].

Rocuronium bromide 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 rocuronium bromide with general anesthetic agents can prolong the QTc interval. The data also suggest that rocuronium bromide 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) and Clinical Studies (14.3)].

Rocuronium bromide 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 (2.6) and Clinical Pharmacology (12.2)].

8.5 Geriatric Use

Rocuronium bromide was administered to 140 geriatric patients (65 years or greater) in U.S. 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 (2.6), Warnings and Precautions (5.5), Clinical Pharmacology (12.2), and Clinical Studies (14.2)].

8.6 Patients with Hepatic Impairment

Since rocuronium bromide is primarily excreted by the liver, it should be used with caution in patients with clinically significant hepatic impairment. Rocuronium bromide 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 rocuronium bromide 0.6 mg/kg, the median (range) clinical duration of 60 (35 to 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 rocuronium bromide 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 (2.6)].

8.7 Patients with Renal Impairment

Due to the limited role of the kidney in the excretion of rocuronium bromide, 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 to 90 minutes) [see Clinical Pharmacology (12.3)].

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ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions (2%) are transient hypotension and hypertension. ( 6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Piramal Critical Care at 1-888-822-8431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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)]

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 (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 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 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 Post-Marketing Experience

In clinical practice, there have been reports of severe allergic reactions (anaphylactic and anaphylactoid reactions and shock) with rocuronium bromide, 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.

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OVERDOSAGE SECTION

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.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 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.

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PATIENT COUNSELING INFORMATION

17 PATIENT COUNSELING INFORMATION

Obtain information about your patient’s medical history, current medications, any history of hypersensitivity to rocuronium bromide or other neuromuscular blocking agents. If applicable, inform your patients that certain medical conditions and medications might influence how rocuronium bromide injection works.

In addition, inform your patient that severe anaphylactic reactions to neuromuscular blocking agents, including rocuronium bromide injection, have been reported. Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents.

Manufactured for:
Piramal Critical Care
Bethlehem, PA 18017, USA

Manufactured by:

Sanovel İlaç San. ve Tic. A.Ş.

İstanbul, Turkey

Rev.: November 2019

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Rocuronium bromide injection is available in the following:

50 mg/5 mL (10 mg/mL)

NDC: 72162-2263-2: multiple-dose vials of 5 mL in boxes of 10

The packaging of this product contains no natural rubber (latex).

Rocuronium bromide should be stored in a refrigerator, 2-8°C (36-46°F). DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use rocuronium bromide within 60 days. Use opened vials of rocuronium bromide 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.

Repackaged/Relabeled by:

Bryant Ranch Prepack, Inc.

Burbank, CA 91504

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