Rocuronium

Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Rocuronium

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 Dosage and Administration

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 (2.5), Warnings andPrecautions (5.9, 5.12), Drug Interactions (7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 7.10), and Use in Specific Populations (8.6)].

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)].

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)].

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)].

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 T1) 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 (2.6)]. 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
Patient Weight		Drug Delivery Rate (mcg/kg/min)
		4	5	6	7	8	9	10	12	14	16
(kg)	(lbs)	Infusion Delivery Rate (mL/hr)
10	22	4.8	6	7. 2	8. 4	9. 6	10.8	12	14. 4	16.8	19.2
15	33	7.2	9	10.8	12.6	14. 4	16.2	18	21.6	25.2	28.8
20	44	9.6	12	14. 4	16.8	19. 2	21.6	24	28.8	33.6	38.4
25	55	12	15	18	21	24	27	30	36	42	48
35	77	16.8	21	25.2	29.4	33. 6	37.8	42	50.4	58. 8	67. 2
50	110	24	30	36	42	48	54	60	72	84	96
60	132	28.8	36	43.2	50.4	57. 6	64.8	72	86.4	100.8	115. 2
70	154	33.6	42	50.4	58.8	67. 2	75.6	84	100.8	117.6	134. 4
80	176	38.4	48	57.6	67.2	76. 8	86.4	96	115.2	134.4	153. 6
90	198	43.2	54	64.8	75.6	86. 4	97.2	108	129.6	151.2	172. 8
100	220	48	60	72	84	96	108	120	144	168	192

TABLE 2: Infusion Rates Using Rocuronium Bromide Injection (1 mg/mL)*

Patient Weight		Drug Delivery Rate (mcg/kg/min)
		4	5	6	7	8	9	10	12	14	16
(kg)	(lbs)	Infusion Delivery Rate (mL/hr)
* 100 mg Rocuronium bromide in 100 mL solution
10	22	2.4	3	3.6	4.2	4.8	5.4	6	7.2	8.4	9.6
15	33	3.6	4. 5	5.4	6.3	7.2	8.1	9	10.8	12.6	14.4
20	44	4.8	6	7.2	8.4	9.6	10.8	12	14.4	16.8	19.2
25	55	6	7. 5	9	10.5	12	13.5	15	18	21	24
35	77	8.4	10. 5	12.6	14.7	16.8	18.9	21	25.2	29.4	33.6
50	110	12	15	18	21	24	27	30	36	42	48
60	132	14.4	18	21.6	25.2	28.8	32.4	36	43.2	50.4	57.6
70	154	16. 8	21	25.2	29.4	33.6	37.8	42	50.4	58.8	67.2
80	176	19.2	24	28.8	33.6	38.4	43.2	48	57.6	67.2	76.8
90	198	21.6	27	32.4	37.8	43.2	48.6	54	64.8	75.6	86.4
100	220	24	30	36	42	48	54	60	72	84	96

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

Patient Weight		Drug Delivery Rate (mcg/kg/min)
		4	5	6	7	8	9	10	12	14	16
(kg)	(lbs)	Infusion Delivery Rate (mL/hr)
* 500 mg Rocuronium bromide in 100 mL solution
10	22	0.5	0.6	0.7	0.8	1	1.1	1.2	1.4	1.7	1.9
15	33	0.7	0.9	1.1	1.3	1.4	1.6	1.8	2.2	2.5	2.9
20	44	1	1.2	1.4	1.7	1.9	2.2	2.4	2.9	3.4	3.8
25	55	1.2	1.5	1.8	2.1	2.4	2.7	3	3.6	4.2	4.8
35	77	1.7	2.1	2.5	2.9	3.4	3.8	4.2	5	5.9	6.7
50	110	2.4	3	3.6	4.2	4.8	5.4	6	7.2	8.4	9.6
60	132	2.9	3.6	4.3	5	5.8	6.5	7.2	8.6	10.1	11.5
70	154	3.4	4.2	5	5.9	6.7	7.6	8.4	10.1	11.8	13.4
80	176	3.8	4.8	5.8	6.7	7.7	8.6	9.6	11.5	13.4	15.4
90	198	4.3	5.4	6.5	7.6	8.6	9.7	10.8	13	15.1	17.3
100	220	4.8	6	7.2	8.4	9.6	10.8	12	14.4	16.8	19.2

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.

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 T1 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 T1 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 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.

Due to Organon USA Inc.'s marketing exclusivity rights, this drug product is not approved with certain pediatric dosing and administration information. Labeling describing additional dosing and administration information in pediatric populations is approved for Organon USA Inc.'s Rocuronium bromide injection.

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, and other reported clinical experience has not identified differences in response between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.2), (12.3)]. 

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 nonobese 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 (5.7)].

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)].

Preparation for Administration of Rocuronium Bromide

Diluent Compatibility

Rocuronium bromide is compatible in solution with:

0.9% NaCl solution	sterile water for injection
5% glucose in water	lactated Ringers
5% glucose in saline

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

amphotericin	hydrocortisone sodium succinate
amoxicillin	insulin
azathioprine	intralipid
cefazolin	ketorolac
cloxacillin	lorazepam
dexamethasone	methohexital
diazepam	methylprednisolone
erythromycin	thiopental
famotidine	trimethoprim
furosemide	vancomycin

If Rocuronium bromide 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 should not be mixed with alkaline solutions [see Warnings and Precautions (5.10)].

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 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)

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)].

Warnings and Precautions

Appropriate Administration and Monitoring

Rocuronium bromide 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 Rocuronium bromide 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.

Anaphylaxis

Severe anaphylactic reactions to neuromuscular blocking agents, including Rocuronium bromide, have been reported. These reactions have, in some cases (including cases with Rocuronium bromide), 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.

Need for Adequate Anesthesia

Rocuronium bromide has no known effect on consciousness, pain threshold, or cerebration. Therefore, its administration must be accompanied by adequate anesthesia or sedation.

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 t