Zemuron

rocuronium bromide

Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Zemuron

Zemuron® (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.

Zemuron Dosage and Administration

Zemuron 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 Zemuron 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 Zemuron.

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 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)].

Dose for Tracheal Intubation

The recommended initial dose of Zemuron, regardless of anesthetic technique, is 0.6 mg/kg. Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1 (0.4–6) minute(s) and most patients have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 3 minutes. This dose may be expected to provide 31 (15–85) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Under halothane, isoflurane, and enflurane anesthesia, some extension of the period of clinical relaxation should be expected [see Drug Interactions (7.3)].

A lower dose of Zemuron (0.45 mg/kg) may be used. Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1.3 (0.8–6.2) minute(s), and most patients have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 4 minutes. This dose may be expected to provide 22 (12–31) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Patients receiving this low dose of 0.45 mg/kg who achieve less than 90% block (about 16% of these patients) may have a more rapid time to 25% recovery, 12 to 15 minutes.

A large bolus dose of 0.9 or 1.2 mg/kg can be administered under opioid/nitrous oxide/oxygen anesthesia without adverse effects to the cardiovascular system [see Clinical Pharmacology (12.2)].

Rapid Sequence Intubation

In appropriately premedicated and adequately anesthetized patients, Zemuron 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 Zemuron, administered at 25% recovery of control T1 (defined as 3 twitches of train-of-four), provide a median (range) of 12 (2–31), 17 (6–50), and 24 (7–69) 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 Zemuron 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 Zemuron 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 Zemuron 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 Zemuron can be prepared by mixing Zemuron 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 Zemuron can be individualized for each patient using the following tables for 3 different concentrations of Zemuron solution as guidelines:

TABLE 1: Infusion Rates Using Zemuron Injection (0.5 mg/mL)*

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)
* 50 mg Zemuron in 100 mL solution
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 Zemuron Injection (1 mg/mL)*

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)
* 100 mg Zemuron 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 Zemuron Injection (5 mg/mL)*

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)
* 500 mg Zemuron 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 Zemuron 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) Zemuron 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 Zemuron 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 Zemuron 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 Zemuron 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 Zemuron 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 Zemuron 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 Zemuron infusion may be expected to proceed at rates comparable to that following similar total exposure to single bolus doses [see Clinical Pharmacology (12.2)].

Zemuron 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 (22–73), 62 (49–75), and 94 (64–138) 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 Zemuron 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 Zemuron. 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 Zemuron 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 Zemuron 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 Zemuron 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 Zemuron is potentiated by isoflurane and enflurane anesthesia. Potentiation is minimal when administration of the recommended dose of Zemuron 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 Zemuron 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 Zemuron

Diluent Compatibility: Zemuron is compatible in solution with:

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

Zemuron 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: Zemuron is physically incompatible when mixed with the following drugs:

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

If Zemuron 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 Zemuron and drugs for which incompatibility with Zemuron has been demonstrated or for which compatibility with Zemuron has not been established.

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

Zemuron 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

Zemuron (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

Zemuron 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

Zemuron 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 Zemuron 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 Zemuron, have been reported. These reactions have, in some cases (including cases with Zemuron), 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 non depolarizing, has been reported.

Need for Adequate Anesthesia

Zemuron 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 the post-operative phase (such as drug interactions or patient condition) should also be considered. If not used as part of standard clinical practice the use of a reversal agent should be considered, especially in those cases where residual paralysis is more likely to occur.

Long-Term Use in an Intensive Care Unit

Zemuron has not been studied for long-term use in the intensive care unit (ICU). As with other nondepolarizing neuromuscular blocking drugs, apparent tolerance to Zemuron 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 Zemuron or any other neuromuscular blocking agent should not be given until there is a definite response (one twitch of the train-of-four) to nerve stimulation. Prolonged paralysis and/or skeletal muscle weakness may be noted during initial attempts to wean from the ventilator patients who have chronically received neuromuscular blocking drugs in the ICU.

Myopathy after long-term administration of other nondepolarizing neuromuscular blocking agents in the ICU alone or in combination with corticosteroid therapy has been reported. Therefore, for patients receiving both neuromuscular blocking agents 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.

Malignant Hyperthermia (MH)

Zemuron has not been studied in MH-susceptible patients. Because Zemuron 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 Zemuron Injection did not appear to trigger malignant hyperthermia.

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 (2.5)].

QT Interval Prolongation

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

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

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

Certain inhalation anesthetics, particularly enflurane and isoflurane, antibiotics, magnesium salts, lithium, local anesthetics, procainamide, and quinidine have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Drug Interactions (7.3)].

In these or other patients in whom potentiation of neuromuscular block or difficulty with reversal may be anticipated, a decrease from the recommended initial dose of Zemuron 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 Zemuron 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 Zemuron. No data are available in such patients and no dosing recommendations can be made.

Zemuron-induced neuromuscular blockade was modified by alkalosis and acidosis in experimental pigs. Both respiratory and metabolic acidosis prolonged the recovery time. The potency of Zemuron 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.

Incompatibility with Alkaline Solutions

Zemuron, 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.

Increase in Pulmonary Vascular Resistance

Zemuron may be associated with increased pulmonary vascular resistance, so caution is appropriate in patients with pulmonary hypertension or valvular heart disease [see Clinical Studies (14.1)].

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.

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.

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 (5.4)]


• Myopathy [see Warnings and Precautions (5.5)]


• Increased pulmonary vascular resistance [see Warnings and Precautions (5.11)]

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 US (n=1137) an