Rocunium

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Rocunium uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Rocunium reviews

1 INDICATIONS AND USAGE

Rocunium 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.

Rocunium 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

Rocunium 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 Rocunium 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 Rocunium injection.

In patients in whom potentiation of, or resistance to, neuromuscular block is anticipated, a dose adjustment should be considered [ see Dosage and Administration , Warnings and Precautions ( 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) ].

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)

• Individualize the dose for each patient. (2)
• Peripheral nerve stimulator recommended for determination of drug response and need for additional doses, and to evaluate recovery. (2)
• Tracheal intubation: Recommended initial dose is 0.6 mg/kg. (2.1)
• Rapid sequence intubation: 0.6 to 1.2 mg/kg. (2.2)
• Maintenance doses: Guided by response to prior dose, not administered until recovery is evident. (2.3)
• Continuous infusion: Initial rate of 10 to 12 mcg/kg/min. Start only after early evidence of spontaneous recovery from an intubating dose. (2.4)

2.1 Dose for Tracheal Intubation

The recommended initial dose of Rocunium 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 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 Rocunium 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 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) ].

2.2 Rapid Sequence Intubation

In appropriately premedicated and adequately anesthetized patients, Rocunium injection 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 ].

2.3 Maintenance Dosing

Maintenance doses of 0.1, 0.15, and 0.2 mg/kg Rocunium injection, 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) ].

2.4 Use by Continuous Infusion

Infusion at an initial rate of 10 to 12 mcg/kg/min of Rocunium injection should be initiated only after early evidence of spontaneous recovery from an intubating dose. Due to rapid redistribution [ see Clinical Pharmacology ] 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 Rocunium injection 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 Rocunium 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 Rocunium injection can be prepared by mixing Rocunium injection 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 Rocunium injection can be individualized for each patient using the following tables for three different concentrations of Rocunium injection solution as guidelines:

* 50 mg Rocunium injection in 100 mL solution
Patient Weight		Drug Delivery Rate (mcg/kg/min)
(kg)	(lbs)	4	5	6	7	8	9	10	12	14	16
		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

** 100 mg Rocunium injection in 100 mL solution
Patient Weight		Drug Delivery Rate (mcg/kg/min)
(kg)	(lbs)	4	5	6	7	8	9	10	12	14	16
		Infusion Delivery Rate (mL/hr)
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

*** 500 mg Rocunium injection in 100 mL solution
Patient Weight		Drug Delivery Rate (mcg/kg/min)
(kg)	(lbs)	4	5	6	7	8	9	10	12	14	16
		Infusion Delivery Rate (mL/hr)
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

2.5 Dosage in Specific Populations

Pediatric Patients

The recommended initial intubation dose of Rocunium injection 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) Rocunium 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 Rocunium injection 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 Rocunium injection can be administered as bolus doses of 0.15 mg/kg at reappearance of T₃ in all pediatric age groups. Maintenance dosing can also be administered at the reappearance of T₂ 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 Rocunium injection 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 Rocunium injection 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 of all age groups is presented elsewhere in the label [ see Clinical Pharmacology (12.2) ].

The infusion of Rocunium injection 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 Rocunium infusion may be expected to proceed at rates comparable to that following similar total exposure to single bolus doses [ see Clinical Pharmacology (12.2) ].

Rocunium injection 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 Rocunium injection 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 Rocunium injection. 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 Rocunium injection 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 Rocunium injection 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 Rocunium injection 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 Rocunium injection is potentiated by isoflurane and enflurane anesthesia. Potentiation is minimal when administration of the recommended dose of Rocunium injection 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 Rocunium injection required to maintain about 95% block was decreased by as much as 40% under enflurane and isoflurane anesthesia [ see Drug Interactions (7.3) ].

2.6 Preparation for Administration of Rocunium Injection

Diluent Compatibility

Rocunium injection is compatible in solution with:

0.9% NaCl solution sterile water for injection

5% glucose in water lactated Ringers

5% glucose in saline

Rocunium 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

Rocunium injection 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 Rocunium 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 Rocunium injection and drugs for which incompatibility with Rocunium injection has been demonstrated or for which compatibility with Rocunium injection has not been established.

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

Rocunium injection 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.

3 DOSAGE FORMS AND STRENGTHS

Rocunium is available as

• 5 mL multiple dose vials containing 50 mg Rocunium injection (10 mg/mL)
• 10 mL multiple dose vials containing 100 mg Rocunium injection (10 mg/mL)

• 5 mL multiple dose vials containing 50 mg Rocunium injection (10 mg/mL). (3)
• 10 mL multiple dose vials containing 100 mg Rocunium injection (10 mg/mL). (3)

4 CONTRAINDICATIONS

Rocunium is contraindicated in patients known to have hypersensitivity (e.g., anaphylaxis) to Rocunium or other neuromuscular blocking agents [ see Warnings and Precautions (5.2) ].

• Hypersensitivity (e.g., anaphylaxis) to Rocunium or other neuromuscular blocking agents. (4)

5 WARNINGS AND PRECAUTIONS

• Appropriate Administration and Monitoring: Use only if facilities for intubation, mechanical ventilation, oxygen therapy, and an antagonist are immediately available.
• Anaphylaxis: Severe anaphylaxis has been reported. Consider cross-reactivity among neuromuscular blocking agents. (5.2)
• Need for Adequate Anesthesia: Must be accompanied by adequate anesthesia or sedation. (5.3)
• Residual Paralysis: Consider using a reversal agent in cases where residual paralysis is more likely to occur. (5.4)

5.1 Appropriate Administration and Monitoring

Rocunium 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 Rocunium 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 Rocunium, have been reported. These reactions have, in some cases, been life threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those patients who have had previous anaphylactic reactions to other neuromuscular blocking agents, since cross-reactivity between neuromuscular blocking agents, both depolarizing and nondepolarizing, has been reported.

5.3 Need for Adequate Anesthesia

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

5.4 Residual Paralysis

In order to prevent complications resulting from residual paralysis, it is recommended to extubate only after the patient has recovered sufficiently from neuromuscular block. Other factors which could cause residual paralysis after extubation in the post-operative phase should also be considered. If not used as part of standard clinical practice the use of a reversal agent should be considered, especially in those cases where residual paralysis is more likely to occur.

5.5 Long-Term Use in an Intensive Care Unit

Rocunium has not been studied for long-term use in the intensive care unit (ICU). As with other nondepolarizing neuromuscular blocking drugs, apparent tolerance to Rocunium may develop during chronic administration in the ICU. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor. It is strongly recommended that neuromuscular transmission be monitored continuously during administration and recovery with the help of a nerve stimulator. Additional doses of Rocunium 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 non-depolarizing neuromuscular blocking agents in the ICU alone or in combination with corticosteroid therapy has been reported. Therefore, for patients receiving both neuromuscular blocking agents and corticosteroids, the period of use of the neuromuscular blocking agent should be limited as much as possible and only used in the setting where in the opinion of the prescribing physician, the specific advantages of the drug outweigh the risk.

5.6 Malignant Hyperthermia

Rocunium has not been studied in MH-susceptible patients. Because Rocunium is always used with other agents, and the occurrence of malignant hyperthermia during anesthesia is possible even in the absence of known triggering agents, clinicians should be familiar with early signs, confirmatory diagnosis, and treatment of malignant hyperthermia prior to the start of any anesthetic.

In an animal study in MH-susceptible swine, the administration of Rocunium injection did not appear to trigger malignant hyperthermia.

5.7 Prolonged Circulation Time

Conditions associated with an increased circulatory delayed time, e.g., cardiovascular disease or advanced age, may be associated with a delay in onset time [ see Dosage and Administration ].

5.8 QT Interval Prolongation

The overall analysis of ECG data in pediatric patients indicates that the concomitant use of Rocunium with general anesthetic agents can prolong the QTc interval [ see Clinical Studies (14.3) ] .

5.9 Conditions/Drugs Causing Potentiation of, or Resistance to, Neuromuscular Block

Potentiation

Nondepolarizing neuromuscular blocking agents have been found to exhibit profound neuromuscular blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with carcinomatosis.

Certain inhalation anesthetics, particularly enflurane and isoflurane, antibiotics, magnesium salts, lithium, local anesthetics, procainamide, and quinidine have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [ see Drug Interactions ].

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 Rocunium should be considered [ see Dosage and Administration (2.5) ].

Resistance

Resistance to nondepolarizing agents, consistent with up-regulation of skeletal muscle acetylcholine receptors, is associated with burns, disuse atrophy, denervation, and direct muscle trauma. Receptor up-regulation may also contribute to the resistance to nondepolarizing muscle relaxants which sometimes develops in patients with cerebral palsy, patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, or with chronic exposure to nondepolarizing agents. When Rocunium is administered to these patients, shorter durations of neuromuscular block may occur, and infusion rates may be higher due to the development of resistance to nondepolarizing muscle relaxants.

Potentiation or Resistance

Severe acid-base and/or electrolyte abnormalities may potentiate or cause resistance to the neuromuscular blocking action of Rocunium. No data are available in such patients and no dosing recommendations can be made.

Rocuronium bromide-induced neuromuscular blockade was modified by alkalosis and acidosis in experimental pigs. Both respiratory and metabolic acidosis prolonged the recovery time. The potency of Rocunium was significantly enhanced in metabolic acidosis and alkalosis, but was reduced in respiratory alkalosis. In addition, experience with other drugs has suggested that acute (e.g., diarrhea) or chronic (e.g., adrenocortical insufficiency) electrolyte imbalance may alter neuromuscular blockade. Since electrolyte imbalance and acid-base imbalance are usually mixed, either enhancement or inhibition may occur.

5.10 Incompatibility with Alkaline Solutions

Rocunium, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle.

5.11 Increase in Pulmonary Vascular Resistance

Rocunium may be associated with increased pulmonary vascular resistance, so caution is appropriate in patients with pulmonary hypertension or valvular heart disease [ see Clinical Studies ].

5.12 Use In Patients with Myasthenia

In patients with myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, small doses of nondepolarizing neuromuscular blocking agents may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants.

5.13 Extravasation

If extravasation occurs, it may be associated with signs or symptoms of local irritation. The injection or infusion should be terminated immediately and restarted in another vein.

6 ADVERSE REACTIONS

In clinical trials, the most common adverse reactions are transient hypotension and hypertension.

The following adverse reactions are described, or described in greater detail, in other sections:

• Anaphylaxis [ see Warnings and Precautions (5.2) ]
• Residual paralysis [ see Warnings and Precautions (5.4) ]
• Myopathy [ see Warnings and Precautions (5.5) ]
• Increased pulmonary vascular resistance [ see Warnings and Precautions (5.11) ]

Most common adverse reactions (2%) are transient hypotension and hypertension. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at ProductComplaintsPPRocuniumhospira.com, 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 Rocunium (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, Rocunium 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 Rocunium 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

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

7 DRUG INTERACTIONS

• Succinylcholine: Use before succinylcholine has not been studied.
• Nondepolarizing muscle relaxants: Interactions have been observed. (7.7)
• Enhanced Rocunium 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 Rocunium injection activity possible: Anticonvulsants. (7.2)

7.1 Antibiotics

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

7.2 Anticonvulsants

In 2 of 4 patients receiving chronic anticonvulsant therapy, apparent resistance to the effects of Rocunium was observed in the form of diminished magnitude of neuromuscular block, or shortened clinical duration. As with other nondepolarizing neuromuscular blocking drugs, if Rocunium 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 ].

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 Rocunium and decrease the average infusion requirement of Rocunium by 40% compared to opioid/nitrous oxide/oxygen anesthesia. No definite interaction between Rocunium 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 Rocunium 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 Rocunium required to maintain approximately 95% neuromuscular block. Under isoflurane and enflurane anesthesia, the infusion rates are decreased by approximately 40% compared to opioid/nitrous oxide/oxygen anesthesia. The median spontaneous recovery time (from 25% to 75% of control T₁) is not affected by halothane, but is prolonged by enflurane (15% longer) and isoflurane (62% longer). Reversal-induced recovery of Rocunium neuromuscular block is minimally affected by anesthetic technique [ see Dosage and Administration (2.5) and Warnings and Precautions (5.9) ].

7.4 Lithium Carbonate

Lithium has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [ see Warnings and Precautions ].

7.5 Local Anesthetics

Local anesthetics have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [ see Warnings and Precautions (5.9) ].

7.6 Magnesium

Magnesium salts administered for the management of toxemia of pregnancy may enhance neuromuscular blockade [ see Warnings and Precautions ].

7.7 Nondepolarizing Muscle Relaxants

There are no controlled studies documenting the use of Rocunium 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 ].

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 Rocunium.

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 Rocunium [ see Warnings and Precautions ].

7.11 Succinylcholine

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

If Rocunium is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of Rocunium 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T₁ returned to 75% of control was 36 minutes (range 14 to 57, n=12) vs. 28 minutes (17 to 51, n=12) without succinylcholine.

8 USE IN SPECIFIC POPULATIONS

• Labor and Delivery: Not recommended for rapid sequence induction in patients undergoing Cesarean section.
• 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

Pregnancy Category C

Developmental toxicology studies have been performed with Rocunium 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/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. Rocunium 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 Rocunium in Cesarean section has been studied in a limited number of patients [ see Clinical Studies ]. Rocunium is not recommended for rapid sequence induction in Cesarean section patients.

8.4 Pediatric Use

The use of Rocunium has been studied in pediatric patients 3 months to 14 years of age under halothane anesthesia. Of the pediatric patients anesthetized with halothane who did not receive atropine for induction, about 80% experienced a transient increase (30% or greater) in heart rate after intubation. One of the 19 infants anesthetized with halothane and fentanyl who received atropine for induction experienced this magnitude of change [ see Dosage and Administration (2.5) and Clinical Studies (14.3) ].

Rocunium 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 Rocunium with general anesthetic agents can prolong the QTc interval. The data also suggest that Rocunium may increase heart rate. However, it was not possible to conclusively identify an effect of Rocunium independent of that of anesthesia and other factors. Additionally, when examining plasma levels of Rocunium in correlation to QTc interval prolongation, no relationship was observed [ see Dosage and Administration (2.5) , Warnings and Precautions (5.8), and Clinical Studies (14.3) ].

Rocunium is not recommended for rapid sequence intubation in pediatric patients. Recommendations for use in pediatric patients are discussed in other sections [ see Dosage and Administration (2.5) and Clinical Pharmacology (12.2) ].

8.5 Geriatric Use

Rocunium was administered to 140 geriatric patients 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 (2.5), Clinical Pharmacology (12.2) , and Clinical Studies (14.2) ] .

8.6 Patients with Hepatic Impairment

Since Rocunium is primarily excreted by the liver, it should be used with caution in patients with clinically significant hepatic impairment. Rocunium 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 Rocunium 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 eight patients with cirrhosis, who received Rocunium 0.6 mg/kg under opioid/nitrous oxide/oxygen anesthesia, did not achieve complete block. These findings are consistent with the increase in volume of distribution at steady state observed in patients with significant hepatic impairment [ see Clinical Pharmacology (12.3) ]. If used for rapid sequence induction in patients with ascites, an increased initial dosage may be necessary to assure complete block. Duration will be prolonged in these cases. The use of doses higher than 0.6 mg/kg has not been studied [ see Dosage and Administration (2.5) ] .

8.7 Patients with Renal Impairment

Due to the limited role of the kidney in the excretion of Rocunium, 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) ].

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.

11 DESCRIPTION

Rocunium injection is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. Rocunium is chemically designated as 1-[17β-(acetyloxy)-3α-hydroxy-2β-(4-morpholinyl)-5α-androstan-16β-yl]-1-(2-propenyl) pyrrolidinium bromide.

The structural formula is:

The chemical formula is C₃₂H₅₃BrN₂O₄ with a molecular weight of 609.70. The partition coefficient of Rocunium in n-octanol/water is 0.5 at 20°C.

Rocunium is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellow/orange, for intravenous injection only. Each mL contains 10 mg Rocunium 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.

structural formula Rocunium

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rocunium 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.

12.2 Pharmacodynamics

The ED₉₅ during opioid/nitrous oxide/oxygen anesthesia is approximately 0.3 mg/kg. Patient variability around the ED₉₅ dose suggests that 50% of patients will exhibit T₁ depression of 91% to 97%.

Table 4 presents intubating conditions in patients with intubation initiated at 60 to 70 seconds.

* Excludes patients undergoing Cesarean section ** Pediatric patients were under halothane anesthesia Excellent intubating conditions = jaw relaxed, vocal cords apart and immobile, no diaphragmatic movement Good intubating conditions = same as excellent but with some diaphragmatic movement
Rocunium Dose (mg/kg) Administered over 5 sec	Percent of Patients With Excellent or Good Intubating Conditions	Time to Completion of Intubation (min)
Adults* 18 to 64 yrs 0.45 (n=43) 0.6 (n=51)	86% 96%	1.6 (1.0 to 7.0) 1.6 (1.0 to 3.2)
Infants** 3 mo to 1 yr 0.6 (n=18) Pediatric** 1 to 12 yrs 0.6 (n=12)	100% 100%	1.0 (1.0 to 1.5) 1.0 (0.5 to 2.3)

Table 5 presents the time to onset and clinical duration for the initial dose of Rocunium injection under opioid/nitrous oxide/oxygen anesthesia in adults and geriatric patients, and under halothane anesthesia in pediatric patients.

n = the number of patients who had time to maximum block recorded Clinical duration = time until return to 25% of control T1. Patients receiving doses of 0.45 mg/kg who achieved less than 90% block (16% of these patients) had about 12 to 15 minutes to 25% recovery.
Rocunium Dose (mg/kg) Administered over 5 sec	Time to ≥80% Block (min)	Time to Maximum Block (min)	Clinical Duration (min)
Adults 18 to 64 yrs
0.45 (n=50)	1.3 (0.8 to 6.2)	3.0 (1.3 to 8.2)	22 (12 to 31)
0.6 (n=142)	1.0 (0.4 to 6.0)	1.8 (0.6 to 13.0)	31 (15 to 85)
0.9 (n=20)	1.1 (0.3 to 3.8)	1.4 (0.8 to 6.2)	58 (27 to 111)
1.2 (n=18)	0.7 (0.4 to 1.7)	1.0 (0.6 to 4.7)	67 (38 to 160)
Geriatric ≥65 yrs
0.6 (n=31)	2.3 (1.0 to 8.3)	3.7 (1.3 to 11.3)	46 (22 to 73)
0.9 (n=5)	2.0 (1.0 to 3.0)	2.5 (1.2 to 5.0)	62 (49 to 75)
1.2 (n=7)	1.0 (0.8 to 3.5)	1.3 (1.2 to 4.7)	94 (64 to 138)
Infants 3 mo to 1 yr
0.6 (n=17)	-	0.8 (0.3 to 3.0)	41 (24 to 68)
0.8 (n=9)	-	0.7 (0.5 to 0.8)	40 (27 to 70)
Pediatric 1 to 12 yrs
0.6 (n=27)	0.8 (0.4 to 2.0)	1.0 (0.5 to 3.3)	26 (17 to 39)
0.8 (n=18)	-	0.5 (0.3 to 1.0)	30 (17 to 56)

Table 6 presents the time to onset and clinical duration for the initial dose of Rocunium Injection under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia in pediatric patients.

n=the number of patients with the highest number of observations for time to maximum block or reappearance T3.
Rocunium Dose (mg/kg) Administered over 5 sec	Time to Maximum Block (min)	Time to Reappearance T3 (min)
Neonates birth to <28 days 0.45 (n=5) 0.6 (n=10) 1 (n=6)	1.1 (0.6-2.2) 1.0 (0.2-2.1) 0.6 (0.3-1.8)	40.3 (32.5-62.6) 49.7 (16.6-119.0) 114.4 (92.6-136.3)
Infants 28 days to ≤3 mo 0.45 (n=9) 0.6 (n=11) 1 (n=5)	0.5 (0.4-1.3) 0.4 (0.2-0.8) 0.3 (0.2-0.7)	49.1 (13.5-79.9) 59.8 (32.3-87.8) 103.3 (90.8-155.4)
Toddlers >3 mo to ≤2 yrs 0.45 (n=17) 0.6 (n=29) 1 (n=15)	0.8 (0.3-1.9) 0.6 (0.2-1.6) 0.5 (0.2-1.5)	39.2 (16.9-59.4) 44.2 (18.9-68.8) 72.0 (36.2-128.2)
Children >2 yrs to ≤11 yrs 0.45 (n=14) 0.6 (n=37) 1 (n=16)	0.9 (0.4-1.9) 0.8 (0.3-1.7) 0.7 (0.4-1.2)	21.5 (17.5-38.0) 36.7 (20.1-65.9) 53.1 (31.2-89.9)
Adolescents >11 to ≤17 yrs 0.45 (n=18) 0.6 (n=31) 1 (n=14)	1.0 (0.5-1.7) 0.9 (0.2-2.1) 0.7 (0.5-1.2)	37.5 (18.3-65.7) 41.4 (16.3-91.2) 67.1 (25.6-93.8)

The time to 80% or greater block and clinical duration as a function of dose are presented in Figures 1 and 2.

The clinical durations for the first five maintenance doses, in patients receiving five or more maintenance doses are represented in Figure 3 [ see Dosage and Administration (2.3) ].

Once spontaneous recovery has reached 25% of control T₁, the neuromuscular block produced by Rocunium is readily reversed with anticholinesterase agents, e.g., edrophonium or neostigmine.

The median spontaneous recovery from 25% to 75% T₁ was 13 minutes in adult patients. When neuromuscular block was reversed in 36 adults at a T₁ of 22% to 27%, recovery to a T₁ of 89 (50 to 132)% and T₄/T₁ of 69 (38 to 92)% was achieved within 5 minutes. Only five of 320 adults reversed received an additional dose of reversal agent. The median (range) dose of neostigmine was 0.04 (0.01 to 0.09) mg/kg and the median (range) dose of edrophonium was 0.5 (0.3 to 1.0) mg/kg.

In geriatric patients (n=51) reversed with neostigmine, the median T₄/T₁ increased from 40% to 88% in 5 minutes.

In clinical trials with halothane, pediatric patients (n=27) who received 0.5 mg/kg edrophonium had increases in the median T₄/T₁ from 37% at reversal to 93% after 2 minutes. Pediatric patients (n=58) who received 1 mg/kg edrophonium had increases in the median T₄/T₁ from 72% at reversal to 100% after 2 minutes. Infants (n=10) who were reversed with 0.03 mg/kg neostigmine recovered from 25% to 75% T₁ within 4 minutes.

There were no reports of less than satisfactory clinical recovery of neuromuscular function.

The neuromuscular blocking action of Rocunium may be enhanced in the presence of potent inhalation anesthetics [ see Drug Interactions (7.3) ].

Hemodynamics

There were no dose-related effects on the incidence of changes from baseline (30% or greater) in mean arterial blood pressure (MAP) or heart rate associated with Rocunium administration over the dose range of 0.12 to 1.2 mg/kg (4 x ED₉₅) within 5 minutes after Rocunium administration and prior to intubation. Increases or decreases in MAP were observed in 2% to 5% of geriatric and other adult patients, and in about 1% of pediatric patients. Heart rate changes (30% or greater) occurred in 0% to 2% of geriatric and other adult patients. Tachycardia (30% or greater) occurred in 12 of 127 pediatric patients. Most of the pediatric patients developing tachycardia were from a single study where the patients were anesthetized with halothane and who did not receive atropine for induction [ see Clinical Studies (14.3) ]. In U.S. studies, laryngoscopy and tracheal intubation following Rocunium administration were accompanied by transient tachycardia (30% or greater increases) in about one-third of adult patients under opioid/nitrous oxide/oxygen anesthesia. Animal studies have indicated that the ratio of vagal:neuromuscular block following Rocunium administration is less than vecuronium but greater than pancuronium. The tachycardia observed in some patients may result from this vagal blocking activity.

Histamine Release

In studies of histamine release, clinically significant concentrations of plasma histamine occurred in 1 of 88 patients. Clinical signs of histamine release (flushing, rash, or bronchospasm) associated with the administration of Rocunium were assessed in clinical trials and reported in 9 of 1137 (0.8%) patients.

FIGURE 1: Time to 80% or greater Block vs. Initial Dose of Rocunium by Age Group (Median, 25th and 75th percentile, and individual values) FIGURE 2: Duration of Clinical Effect vs. Initial Dose of Rocunium by Age Group (Median, 25th and 75th percentile, and individual values) FIGURE 3: Duration of Clinical Effect vs. Number of Rocunium Maintenance Doses, by Dose

12.3 Pharmacokinetics

Adult and Geriatric Patients

In an effort to maximize the information gathered in the in vivo pharmacokinetic studies, the data from the studies was used to develop population estimates of the parameters for the subpopulations represented (e.g., geriatric, pediatric, renal, and hepatic impairment). These population-based estimates and a measure of the estimate variability are contained in the following section.

Following intravenous administration of Rocunium, plasma levels of rocuronium follow a three-compartment open model. The rapid distribution half-life is 1 to 2 minutes and the slower distribution half-life is 14 to 18 minutes. Rocuronium is approximately 30% bound to human plasma proteins. In geriatric and other adult surgical patients undergoing either opioid/nitrous oxide/oxygen or inhalational anesthesia, the observed pharmacokinetic profile was essentially unchanged.

PK Parameters	Adults (Ages 27 to 58 yrs)	Geriatrics (≥65 yrs)
Clearance (L/kg/hr)	0.25 (0.08)	0.21 (0.06)
Volume of Distribution at Steady State (L/kg)	0.25 (0.04)	0.22 (0.03)
t1/2 β Elimination (hr)	1.4 (0.4)	1.5 (0.4)

In general, studies with normal adult subjects did not reveal any differences in the pharmacokinetics of rocuronium due to gender.

Studies of distribution, metabolism, and excretion in cats and dogs indicate that rocuronium is eliminated primarily by the liver. The rocuronium analog 17-desacetyl-rocuronium, a metabolite, has been rarely observed in the plasma or urine of humans administered single doses of 0.5 to 1 mg/kg with or without a subsequent infusion (for up to 12 hr) of rocuronium. In the cat, 17-desacetyl-rocuronium has approximately one-twentieth the neuromuscular blocking potency of rocuronium. The effects of renal failure and hepatic disease on the pharmacokinetics and pharmacodynamics of rocuronium in humans are consistent with these findings.

In general, patients undergoing cadaver kidney transplant have a small reduction in clearance which is offset pharmacokinetically by a corresponding increase in volume, such that the net effect is an unchanged plasma half-life. Patients with demonstrated liver cirrhosis have a marked increase in their volume of distribution resulting in a plasma half-life approximately twice that of patients with normal hepatic function. Table 8 shows the pharmacokinetic parameters in subjects with either impaired renal or hepatic function.

* Differences in the calculated t1/2 β and Cl between this study and the study in young adults vs. geriatrics (≥65 years) is related to the different sample populations and anesthetic techniques.
PK Parameters	Normal Renal and Hepatic Function	Renal Transplant Patients	Hepatic Dysfunction Patients
Clearance (L/kg/hr)	0.16 (0.05)*	0.13 (0.04)	0.13 (0.06)
Volume of Distribution at Steady State (L/kg)	0.26 (0.03)	0.34 (0.11)	0.53 (0.14)
t1/2 β Elimination (hr)	2.4 (0.8)*	2.4 (1.1)	4.3 (2.6)

The net result of these findings is that subjects with renal failure have clinical durations that are similar to but somewhat more variable than the duration that one would expect in subjects with normal renal function. Hepatically impaired patients, due to the large increase in volume, may demonstrate clinical durations approaching 1.5 times that of subjects with normal hepatic function. In both populations the clinician should individualize the dose to the needs of the patient [ see Dosage and Administration (2.5) ].

Tissue redistribution accounts for most (about 80%) of the initial amount of rocuronium administered. As tissue compartments fill with continued dosing (4 to 8 hours), less drug is redistributed away from the site of action and, for an infusion-only dose, the rate to maintain neuromuscular blockade falls to about 20% of the initial infusion rate. The use of a loading dose and a smaller infusion rate reduces the need for adjustment of dose.

Pediatric Patients

Under halothane anesthesia, the clinical duration of effects of Rocunium did not vary with age in patients 4 months to 8 years of age. The terminal half-life and other pharmacokinetic parameters of rocuronium in these pediatric patients are presented in Table 9.

PK Parameters	Patient Age Range
	3 to <12 mos	1 to <3 yrs	3 to <8 yrs
Clearance (L/kg/hr)	0.35 (0.08)	0.32 (0.07)	0.44 (0.16)
Volume of Distribution at Steady State (L/kg)	0.30 (0.04)	0.26 (0.06)	0.21 (0.03)
t1/2 β Elimination (hr)	1.3 (0.5)	1.1 (0.7)	0.8 (0.3)

Pharmacokinetics of Rocunium were evaluated using a population analysis of the pooled pharmacokinetic datasets from 2 trials under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. All pharmacokinetic parameters were found to be linearly proportional to body weight. In patients under the age of 18 years clearance (CL) and volume of distribution (Vss) increase with bodyweight (kg) and age (years). As a result the terminal half-life of Rocunium decreases with increasing age from 1.1 hour to 0.7-0.8 hour. Table 10 presents the pharmacokinetic parameters in the different age groups in the studies with sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia.

PK Parameters	Patient Age Range
	Birth to <28 days	28 days to ≤3 mos	3 mos to ≤2 yrs	2 to ≤11 yrs	11 to ≤17 yrs
CL (L/kg/hr)	0.31 (0.07)	0.30 (0.08)	0.33 (0.10)	0.35 (0.09)	0.29 (0.14)
Volume of Distribution (L/kg)	0.42 (0.06)	0.31 (0.03)	0.23 (0.03)	0.18 (0.02)	0.18 (0.01)
t1/2 β (hr)	1.1 (0.2)	0.9 (0.3)	0.8 (0.2)	0.7 (0.2)	0.8 (0.3)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed with Rocunium to evaluate carcinogenic potential or impairment of fertility. Mutagenicity studies (Ames test, analysis of chromosomal aberrations in mammalian cells, and micronucleus test) conducted with Rocunium did not suggest mutagenic potential.

14 CLINICAL STUDIES

In U.S. clinical studies, a total of 1137 patients received Rocunium, including 176 pediatric, 140 geriatric, 55 obstetric, and 766 other adults. Most patients were ASA physical status I or II, about 9% were ASA III, and 10 patients (undergoing coronary artery bypass grafting or valvular surgery) were ASA IV. In European clinical studies, a total of 1394 patients received Rocunium, including 52 pediatric, 128 geriatric (65 years or greater), and 1214 other adults.

14.1 Adult Patients

Intubation using doses of Rocunium 0.6 to 0.85 mg/kg was evaluated in 203 adults in 11 clinical studies. Excellent to good intubating conditions were generally achieved within 2 minutes and maximum block occurred within 3 minutes in most patients. Doses within this range provide clinical relaxation for a median (range) time of 33 (14 to 85) minutes under opioid/nitrous oxide/oxygen anesthesia. Larger doses (0.9 and 1.2 mg/kg) were evaluated in two studies with 19 and 16 patients under opioid/nitrous oxide/oxygen anesthesia and provided 58 (27 to 111) and 67 (38 to 160) minutes of clinical relaxation, respectively.

Cardiovascular Disease

In one clinical study, 10 patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft received an initial dose of 0.6 mg/kg Rocunium. Neuromuscular block was maintained during surgery with bolus maintenance doses of 0.3 mg/kg. Following induction, continuous 8 mcg/kg/min infusion of Rocunium produced relaxation sufficient to support mechanical ventilation for 6 to 12 hours in the surgical intensive care unit (SICU) while the patients were recovering from surgery.

Rapid Sequence Intubation

Intubating conditions were assessed in 230 patients in six clinical studies where anesthesia was induced with either thiopental (3 to 6 mg/kg) or propofol (1.5 to 2.5 mg/kg) in combination with either fentanyl (2 to 5 mcg/kg) or alfentanil (1 mg). Most of the patients also received a premedication such as midazolam or temazepam. Most patients had intubation attempted within 60 to 90 seconds of administration of Rocunium 0.6 mg/kg or succinylcholine 1 to 1.5 mg/kg. Excellent or good intubating conditions were achieved in 119/120 (99% [95% confidence interval 95% to 99.9%]) patients receiving Rocunium and in 108/110 (98% [94% to 99.8%]) patients receiving succinylcholine. The duration of action of Rocunium 0.6 mg/kg is longer than succinylcholine and at this dose is approximately equivalent to the duration of other intermediate-acting neuromuscular blocking drugs.

Obese Patients

Rocunium was dosed according to actual body weight (ABW) in most clinical studies. The administration of Rocunium in the 47 of 330 (14%) patients who were at least 30% or more above their ideal body weight (IBW) was not associated with clinically significant differences in the onset, duration, recovery, or reversal of rocuronium bromide-induced neuromuscular block.

In one clinical study in obese patients, Rocunium 0.6 mg/kg was dosed according to ABW (n=12) or IBW (n=11). Obese patients dosed according to IBW had a longer time to maximum block, a shorter median (range) clinical duration of 25 (14 to 29) minutes, and did not achieve intubating conditions comparable to those dosed based on ABW. These results support the recommendation that obese patients be dosed based on actual body weight [ see Dosage and Administration (2.5) ].

Obstetric Patients

Rocunium 0.6 mg/kg was administered with thiopental, 3 to 4 mg/kg (n=13) or 4 to 6 mg/kg (n=42), for rapid sequence induction of anesthesia for Cesarean section. No neonate had APGAR scores greater than 7 at 5 minutes. The umbilical venous plasma concentrations were 18% of maternal concentrations at delivery. Intubating conditions were poor or inadequate in 5 of 13 women receiving 3 to 4 mg/kg thiopental when intubation was attempted 60 seconds after drug injection. Therefore, Rocunium is not recommended for rapid sequence induction in Cesarean section patients.

14.2 Geriatric Patients

Rocunium was evaluated in 55 geriatric patients in six clinical studies. Doses of 0.6 mg/kg provided excellent to good intubating conditions in a median (range) time of 2.3 (1 to 8) minutes. Recovery times from 25% to 75% after these doses were not prolonged in geriatric patients compared to other adult patients [ see Dosage and Administration (2.5) and Use in Specific Populations (8.5) ].

14.3 Pediatric Patients

Rocunium 0.45, 0.6, or 1 mg/kg was evaluated under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia for intubation in 326 patients in 2 studies. In 1 of these studies maintenance bolus and infusion requirements were evaluated in 137 patients. In all age groups, doses of 0.6 mg/kg provided time to maximum block in about 1 minute. Across all age groups, median (range) time to reappearance of T₃ for doses of 0.6 mg/kg was shortest in the children [36.7 (20.1-65.9) minutes] and longest in infants [59.8 (32.3-87.8) minutes]. For pediatric patients older than 3 months, the time to recovery was shorter after stopping infusion maintenance when compared with bolus maintenance [ see Dosage and Administration (2.5) and Use in Specific Populations (8.4) ].

Rocunium 0.6 or 0.8 mg/kg was evaluated for intubation in 75 pediatric patients (n=28; age 3 to 12 months, n=47; age 1 to 12 years) in three studies using halothane (1% to 5%) and nitrous oxide (60% to 70%) in oxygen. Doses of 0.6 mg/kg provided a median (range) time to maximum block of 1 (0.5 to 3.3) minute(s). This dose provided a median (range) time of clinical relaxation of 41 (24 to 68) minutes in 3 month to 1 year-old infants and 26 (17 to 39) minutes in 1 to 12 year-old pediatric patients [ see Dosage and Administration (2.5) and Use in Specific Populations (8.4) ].

16 HOW SUPPLIED/STORAGE AND HANDLING

Rocunium is available in the following:

• Rocunium 5 mL multiple dose vials containing 50 mg Rocunium injection (10 mg/mL)
  

  Box of 10 NDC 0409-9558-05

• Rocunium 10 mL multiple dose vials containing 100 mg Rocunium injection (10 mg/mL)
  

  Box of 10 NDC 0409-9558-10

This container closure is not made with natural rubber latex.

Rocunium should be stored in a refrigerator, 2° to 8°C (36° to 46°F). DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use Rocunium within 60 days. Use opened vials of Rocunium within 30 days.

Safety and Handling

There is no specific work exposure limit for Rocunium. In case of eye contact, flush with water for at least 10 minutes.

17 PATIENT COUNSELING INFORMATION

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

In addition, inform your patient that severe anaphylactic reactions to neuromuscular blocking agents, including Rocunium, 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.

EN-3451

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira logo

5 mL

Multiple dose vial

Rocuronium

Bromide Inj.

10 mg/mL

For IV use only

Rx only

Peel off &

apply to syringe

Rocunium pharmaceutical active ingredients containing related brand and generic drugs:

• Rocuronium Bromide

Rocunium available forms, composition, doses:

• Injectable; Injection; Rocuronium Bromide 10 mg / ml

Rocunium destination | category:

• Human:
• Muscle relaxants
• Neuromuscular blocking agents
• Skeletal muscle relaxants

Rocunium Anatomical Therapeutic Chemical codes:

• N/A

Rocunium pharmaceutical companies:

• Neon Laboratories

References

1. Dailymed."ROCURONIUM BROMIDE INJECTION, SOLUTION [HOSPIRA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. "Rocuronium". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
3. "Rocuronium". http://www.drugbank.ca/drugs/DB0072... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Rocunium?

Depending on the reaction of the Rocunium after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Rocunium not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Rocunium addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Rocunium, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Rocunium consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology