Zemuron (Rocuronium Bromide)

ZEMURON™

Organon

Rocuronium Bromide

Nondepolarizing Skeletal Neuromuscular Blocking Agent

Action And Clinical Pharmacology: Rocuronium is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and an intermediate duration of action. The drug acts by binding competitively to cholinergic receptors at the motor end-plate to antagonize the action of acetylcholine, an effect which is reversible in the presence of acetylcholinesterase inhibitors, such as neostigmine and edrophonium.

Pharmacodynamics: The ED95 (dose required to produce 95% suppression of the first [T1] mechanomyographic [MMG] response of the thumb to indirect supramaximal train-of-four stimulation of the ulnar nerve) is approximately 0.3 mg/kg (300 g/kg) in adults receiving opioid/N2O/O2 anesthesia. At equipotent doses, rocuronium has approximately the same clinically effective duration of action as vecuronium. However, the onset of action is approximately 40% shorter for rocuronium than for vecuronium at doses of 2 to 3 times the ED95.

Intubation Conditions: A dose of 0.6 mg/kg (2 ED95) rocuronium administered following the induction of thiopental/ narcotic anesthesia in adults or halothane anesthesia in children generally produces good or excellent conditions for tracheal intubation initiated at 60 to 70 seconds postadministration.

Intubating conditions were assessed in 230 patients in 6 clinical trials 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 g/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 rocuronium injection 0.6 mg/kg or succinylcholine 1 to 1.5 mg/kg. Excellent or good intubating conditions were achieved in 119/120 (99%[95% CI 95 to 99.9%]) patients receiving rocuronium and in 108/110 (98%[95% CI 94 to 99.8%]) patients receiving succinylcholine. The duration of action of rocuronium 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.

Maintenance Doses: In adult patients under opioid/N2O/O2 anesthesia, the median (range of individual values) clinical duration (time from injection of the maintenance dose at a T1 of 25% of control to a return to 25% of the control T1) of maintenance doses of 0.1, 0.15 and 0.2 mg/kg (100, 150 and 200 g/kg) of rocuronium is 12 minutes (range 2 to 31 minutes), 17 minutes (range 6 to 50 minutes), and 24 minutes (range 7 to 69 minutes), respectively. Repetitive maintenance dosing results in clinically insignificant median increases of 2 to 4 minutes in clinical duration between the first and fifth consecutive dose.

The median (range) rate of spontaneous recovery of T1 from 25 to 75% (n=182), following the final maintenance dose of rocuronium, is 13 minutes (4 to 84 minutes).

Anticholinesterase Antagonism: Once spontaneous recovery has started, the neuromuscular block produced by rocuronium is readily reversed with various anticholinesterase agents, e.g., edrophonium or neostigmine. The deeper the level of neuromuscular blockade at reversal, the longer the time required for recovery of neuromuscular function and the greater the dose of anticholinesterase agent required.

Reversal data were analyzed for 320 patients who received neostigmine or edrophonium in the North American clinical trials. When neuromuscular block was reversed at a T1 of 22 to 28% in 36 adults, recovery to a T1 of 89(50 to 132)% and T4/T1 of 69(38 to 92)% was achieved within 5 minutes. Only 5 of the 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) mg/kg.

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

Children (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. Children (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.

Inhalation Anesthetics: The duration of the neuromuscular blocking action of rocuronium may be enhanced by approximately 30% in the presence of potent inhalation anesthetics. The median clinical duration of a dose of 0.6 mg/kg was 30, 38, and 42 minutes under opioid/N2O/O2, enflurane and isoflurane maintenance anesthesia, respectively. During 1 to 2 h of infusion, the infusion rate of rocuronium required to maintain about 95% block was decreased by as much as 40% under enflurane and isoflurane anesthesia (see Precautions, Inhalation Anesthetics).

Children: Children (1 to 13 yr) under halothane anesthesia are less sensitive to rocuronium (ED50 approximately 0.18 mg/kg [180 g/kg], ED95 0.35 to 0.4 mg/kg [350 to 400 g/kg]) than adults on a mg/kg (g/kg) basis. The onset time and duration of block are shorter in children (1 to 13 yr) than in adults. During halothane anesthesia, at doses of 0.6 mg/kg (600 g/kg) of rocuronium, the median onset time is 60 seconds (30 to 200 sec) and the clinical duration is 26 min (17 to 39 min). Maintenance doses of 0.1 or 0.125 mg/kg (100 or 125 g/kg) rocuronium in children under halothane anesthesia provided a median clinical duration of 7 and 10 minutes, respectively. The median rate of spontaneous recovery of T1 from 25 to 75% was 9.5 minutes (4 to 29 minutes).

The clinical durations of action of 0.6 and 0.8 mg/kg doses of rocuronium are approximately 30-60% longer in infants aged 3 months to 1 year than in children aged 1 to 13 yrs.

Geriatrics: Geriatric patients (³65 yrs) under opioid/N2O/O2 anesthesia show a longer onset time and duration of block than adults (18 to 65 yrs) at equivalent doses. At doses of 0.6, 0.9 and 1.2 mg/kg (600, 900 and 1 200 g/kg) of rocuronium, median onset times of 3.7 (1.3 to 11.3), 2.5 (1.2 to 5), and 1.3 (1.2 to 4.7) minutes, respectively, have been reported for geriatric patients compared with 1.8 (0.6 to 13), 1.4 (0.8 to 6.2), and 1.0 (0.6 to 4.7) minutes, respectively for adults. Thus, rocuronium is not recommended for rapid sequence tracheal intubation in geriatric patients. Median clinical duration times at these doses were 46 (22 to 73), 62 (49 to 75), and 94 (64 to 138) minutes, respectively for geriatric patients versus 31 (15 to 85), 58 (27 to 111), and 67 (38 to 160) minutes, respectively for adults. The median rate of spontaneous recovery of T1 from 25 to 75% after a dose of 0.6 mg/kg (600 g/kg) was 21 (11 to 56) minutes in geriatric patients (70 to 90 yrs) compared with 12 (5 to 36) minutes in young adults (18 to 60 yrs).

Hepatic Impairment: The influence of hepatic impairment on the pharmacodynamics of a 0.6 mg/kg dose of rocuronium was investigated in a study in which 9 patients with alcoholic cirrhosis were compared to 10 patients with normal hepatic function. Relative to the normal group, the patients with hepatic impairment exhibited an increased clinical duration of action (60 versus 42 min). The recovery index (time for recovery from 25 to 75% T1 suppression) was also prolonged in the cirrhotic patients (53 versus 20 min).

Renal Failure: Three single centre clinical trials have been performed to compare the pharmacodynamic characteristics of a 0.6 mg/kg dose of rocuronium in patients having normal renal function (n=31) to those for patients having renal impairment (n=30) undergoing kidney transplantation or AV shunt/peritoneal catheter implantation surgery for hemodialysis while receiving steady-state isoflurane anesthesia. The pharmacodynamic characteristics of rocuronium were not altered in a consistent manner in the patients with renal impairment although clinical duration and recovery times were more variable than in patients with normal renal function. Dosage adjustments are not recommended for patients with renal impairment receiving rocuronium.

Hemodynamics: In most clinical trials, the monitoring of hemodynamic parameters during the period immediately following the administration of rocuronium was confounded by laryngoscopy and intubation, events in themselves associated with elevations of heart rate and mean arterial blood pressure. In 1 study in which a 6 minute period was permitted to elapse between the administration of rocuronium at 0.6, 0.9 and 1.2 mg/kg doses and subsequent intubation, no dose-dependent changes in heart rate or mean arterial pressure were observed.

Histamine Release: In studies of histamine release, a clinically significant elevation of plasma histamine concentration occurred in 1 of 88 patients. Clinical signs of histamine release (flushing, rash, or bronchospasm) associated with the administration of rocuronium injection were assessed in clinical trials and reported in 9 of 1 137 (0.8%) patients.

Pharmacokinetics: The pharmacokinetic characteristics of i.v. administered rocuronium are best described by a 3 compartment open model.

Geriatrics: In a study of the comparative pharmacokinetics of a 0.6 mg/kg dose of rocuronium in 22 adult (27 to 58 yrs) and 20 geriatric (70 to 78 yrs) patients, advanced age was associated with a significant decrease in clearance and steady-state volume of distribution, although the elimination half-life remained unaltered.

In pediatric patients receiving a single 0.8 mg/kg bolus dose of rocuronium, the observed half-life values were in the same order of magnitude as those reported for adult patients. The half-life values for rocuronium decreased with advancing pediatric age. Clearance tended to be somewhat higher in the 3 to 8 year olds than in the younger patients. The steady-state volume of distribution was significantly higher in the 3 to 12 month age group than in the 3 to 8 year age group. No statistically significant differences were observed between the 3 age groups in terms of the plasma levels of rocuronium at 25, 75, and 90% recovery.

Hepatic and Renal Impairment: The steady-state volume of distribution was increased by about 30% in patients undergoing cadaver renal transplantation (n=10) and 100% in patients with hepatic dysfunction associated with alcoholic cirrhosis (n=9) relative to patients with normal renal and hepatic function (n=10). The beta elimination half-life was increased by approximately 80% in patients with hepatic impairment, but was unaffected in the renally impaired patient group.

Inhalational Anesthesia: Plasma levels of rocuronium during continuous infusion were determined in patients receiving steady-state opioid/N2O/O2 (n=10), enflurane (n=9), or isoflurane (n=9) anesthesia. At the end of the second hour of continuous infusion, lower mean plasma concentrations were required to maintain 90 to 95% neuromuscular blockade during steady-state isoflurane (1 223 ng/mL) and enflurane (1 117 ng/mL) anesthesia than during opioid/N2O/O2 (1 358 ng/mL) anesthesia.

Metabolism: Following administration of a single 1 mg/kg bolus dose to 10 adult patients, metabolites in the plasma or urine were either absent or below the limit of detection (5 ng/mL).

Excretion: Following administration of a single 1 mg/kg bolus dose to 10 adult patients, total urinary excretion was 33% over a 24 hour period. Of this, 65% was recovered during the first 2 hours and 94% over the first 6 hours.

Placental Transfer: The placental transfer of rocuronium was investigated in 2 studies involving a total of 17 neonates born to women receiving 0.6 mg/kg rocuronium during Cesarean section. The mean umbilical venous to maternal venous plasma ratio ranged from 16 to 22% in these studies.

Reduced Plasma Cholinesterase Activity: No differences from patients with normal plasma cholinesterase activity are expected since rocuronium metabolism does not depend on plasma cholinesterase.

Indications And Clinical Uses: Rocuronium is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration of action. Rocuronium is indicated as an adjunct to general anesthesia to facilitate both rapid sequence (initiated at 60 to 90 seconds post-administration) and routine endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

Contra-Indications: In patients known to have an allergic hypersensitivity to the drug or any component of its formulation.

Manufacturers’ Warnings In Clinical States: General: Rocuronium should be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are familiar with its actions and the possible complications of its use. The drug should not be administered unless facilities for intubation, artificial respiration, oxygen therapy, and an antagonist are within immediate reach. It is recommended that clinicians administering neuromuscular blocking agents such as rocuronium employ a peripheral nerve stimulator to monitor drug response, need for additional relaxant, and adequacy of spontaneous recovery or antagonism.

Intensive Care Unit: To reduce the possibility of prolonged neuromuscular blockade and other complications that might occur following long-term use in the ICU, rocuronium or any other neuromuscular relaxant should be administered in carefully adjusted doses by or under the supervision of experienced clinicians who are familiar with its actions and with appropriate peripheral nerve stimulator muscle monitoring techniques.

Neuromuscular Disease: 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. For patients having conditions in which prolonged neuromuscular blockade is a possibility (e.g., neuromuscular disease, carcinomatosis, severe cachexia, or debilitation), a peripheral nerve stimulator and use of a small test dose may be of particular value in assessing and monitoring dosage requirements.

Compatibility: Rocuronium injection, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during i.v. infusion through the same needle.

Precautions: Rapid Sequence Tracheal Intubation: Rapid sequence tracheal intubation has not been adequately studied at time points of less than 60 seconds post-administration of rocuronium. As the onset of action of rocuronium is delayed in geriatric patients relative to other adults, the use of rocuronium for rapid sequence intubation is not recommended in patients over 65 years of age.

Cardiovascular Effects: Rocuronium was associated with a slight elevation of heart rate and blood pressure in some studies (mean increase 10% over baseline) in which hemodynamic measurements were performed prior to intubation and initiation of surgery. The increase in heart rate and mean arterial pressure which occurs during endotracheal intubation may be accentuated in the presence of rocuronium. In the North American studies, laryngoscopy and tracheal intubation following rocuronium administration were accompanied by transient tachycardia (³30% increases) in about one-third of adult patients under opioid/N2O/O2 anesthesia. Experience with rocuronium in patients undergoing cardiovascular surgery is limited to 2 small clinical trials.

In one of these, 17 patients scheduled for aortic surgery were anesthetized with fentanyl and flunitrazepam, then intubated prior to receiving single bolus doses of 0.6 or 0.9 mg/kg rocuronium. Mean arterial pressure was significantly increased over baseline levels at 2, 5 and 10 minute time points in the 0.6 mg/kg (15 to 24% increases over baseline) but not the 0.9 mg/kg (3 to 7% increases over baseline group). In another study, the hemodynamic effects of single bolus doses of 0.9 mg/kg rocuronium and 0.15 mg/kg vecuronium were studied in ASA 3 and 4 patients scheduled for coronary artery bypass grafting in whom anesthesia had been induced with midazolam and sufentanil. Rocuronium (n=11) was associated with statistically significant increases in mean arterial blood pressure at 5 minutes post-administration (13% increase over baseline) and 10 minutes post-intubation (9% increase over baseline) which were not seen in the vecuronium group (n=10). These increases did not, however, represent an elevation over mean arterial blood pressure values prior to the induction of anesthesia. In both of these studies, mean increases in heart rate of 6 to 8% over post-induction baseline values were observed.

Tachycardia (³30%) occurred in 12 of 127 children. Most of the children developing tachycardia were from a single study in which the patients were anesthetized with halothane and did not receive atropine for induction.

Pulmonary Vascular Resistance: Caution is appropriate in patients with pulmonary hypertension or valvular heart disease. In one clinical trial, 10 patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft surgery received an initial dose of 0.6 mg/kg rocuronium injection. Neuromuscular block was maintained during surgery with bolus maintenance doses of 0.3 mg/kg. Following induction, continuous 0.008 mg/kg/min infusion of rocuronium 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. Hypertension and tachycardia were reported in some patients but these occurrences were less frequent in patients receiving beta or calcium channel blocking drugs. In 7 of these 10 patients rocuronium was associated with transient increases (³30%) in pulmonary vascular resistance. In another clinical trial of 17 patients undergoing abdominal aortic surgery, transient increases (³30%) in pulmonary vascular resistance were observed in 4 of 17 patients receiving rocuronium 0.6 or 0.9 mg/kg.

Long-term Use in ICU: No information is available concerning the efficacy and safety of long-term (days to weeks) i.v. rocuronium infusion to facilitate mechanical ventilation in the intensive care unit. In rare cases, long-term use of neuromuscular blocking drugs to facilitate mechanical ventilation in ICU settings has been associated with prolonged paralysis and/or skeletal muscle weakness that is first noted during attempts to wean patients from the ventilator. In these patients, the actions of the neuromuscular blocking agent may be enhanced by other drugs (e.g., broad spectrum antibiotics, narcotics and/or steroids) or by conditions such as acid-base or electrolyte imbalance, hypoxic episodes of varying duration, or extreme debilitation. Additionally, patients immobilized for extended periods frequently develop symptoms consistent with disuse muscle atrophy. The recovery picture may vary from regaining movement and strength in all muscles to initial recovery of movement of the facial muscles and small muscles of the extremities then to the remaining muscles. In rare cases, recovery may involve an extended period of time or even require rehabilitation. Therefore, when there is a need for long-term mechanical ventilation, the benefits-to-risk ratio of neuromuscular blockade must be considered. The syndrome of critical illness polyneuropathy associated with sepsis and multiorgan failure may be associated with prolonged skeletal muscle paralysis, but can also occur without the use of muscle relaxants. Thus, the role of muscle relaxants in the etiology of prolonged paralysis in the ICU is not known with certainty. Continuous infusion or intermittent bolus dosing to support long term mechanical ventilation has not been studied sufficiently to support dosage recommendations.

Whenever the use of rocuronium or any neuromuscular blocking agent is contemplated in the ICU, it is recommended that neuromuscular transmission be monitored continuously during administration and recovery with the help of a nerve stimulator. Additional doses of rocuronium or any other neuromuscular blocking agent should not be given before there is a definite response to T1 or to the first twitch. If no response is elicited, infusion administration should be discontinued until a response returns.

Pregnancy: A teratogenicity study has been conducted in rats using i.v. administered doses of rocuronium up to 0.3 mg/kg. No teratogenic effects were observed at the sub-paralyzing doses used in this study. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies have not been performed under conditions that would approximate those of clinical use, rocuronium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Obstetrics (Cesarean section): Rocuronium injection 0.6 mg/kg (600 g/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. The umbilical venous plasma concentrations were 18% of maternal concentrations at delivery.
Lactation: It is not known whether rocuronium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when rocuronium is administered to a nursing woman.

Children: The use of rocuronium in children less than 3 months of age has not been investigated. See Pharmacology and Dosage, Pediatrics for clinical experience and recommendations for use in infants and children 3 months to 14 years of age. Although the potency of rocuronium is similar in infants and older children (estimated ED95 values of 0.39 mg/kg for infants 1 to 12 months, 0.35 mg/kg for children 1 to 4 yrs, 0.4 mg/kg for children 4 to 13 yrs under halothane anesthesia), the duration of clinically effective blockade tends to be longer in infants less than 12 months in age. Of the children anesthetized with halothane who did not receive atropine with induction, about 80% experienced a transient increase (³30%) in heart rate after intubation.

Geriatrics: Rocuronium has been administered to 43 elderly patients (65 to 78 yrs) in clinical trials. The duration of neuromuscular blockade tends to be slightly longer in elderly patients (see Pharmacology). As the onset of action of rocuronium is delayed in geriatric patients relative to other adults, the use of rocuronium for rapid sequence intubation is not recommended in patients over 65 years of age.

Hepatic Disease: Rocuronium has been studied in a limited number of patients (n=38) with clinically significant hepatic disease. In 9 patients with alcoholic cirrhosis receiving stable isoflurane anesthesia, the median clinical duration of a 0.6 mg/kg (600 g/kg) dose was moderately prolonged (60 min) compared to that observed in 10 patients with normal hepatic function (42 min). The median recovery rate (25 to 75% recovery of twitch suppression) was also prolonged in patients with cirrhosis (53 min) compared to patients with normal hepatic function (20 min). Because rocuronium is primarily excreted by the liver, it should be used with caution in patients having clinically significant hepatic disease. Four of eight patients with cirrhosis, who received rocuronium 0.6 mg/kg under opioid/N2O/O2 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 disease. 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 single bolus doses higher than 0.6 mg/kg has not been studied in patients with hepatic impairment.

Renal Failure: Rocuronium has been studied at the dose of 0.6 mg/kg (600 g/kg) in a limited number of patients (n=10) undergoing renal transplant surgery, recently dialyzed in preparation for cadaver renal transplant. The median clinical duration was not considered to be prolonged relative to patients with normal renal function (53 min versus 42 min), however there was substantial variation within the renal transplant group (range: 22 to 90 minutes). The median spontaneous recovery rate from 25 to 75% of control in renal transplant patients was similar to that in normal patients (30 [7 to 35] min vs. 20 [12 to 67]min). Two additional studies have been performed in which rocuronium was administered to a total of 20 patients undergoing nephrectomy, AV shunt surgery, or implantation of peritoneal catheters. These studies did not demonstrate a consistent trend for prolongation of recovery time. Due to the limited role of the kidney in the excretion of rocuronium, usual dosing guidelines should generally be suitable for patients with renal failure.

Concomitant Disease States: As with other neuromuscular blocking agents, rocuronium may have profound neuromuscular blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with carcinomatosis. 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 should be considered. Resistance to nondepolarizing neuromuscular blocking agents may be associated with burns, disuse atrophy, denervation, cerebral palsy, and direct muscle trauma.

Obesity: Rocuronium injection 0.6 mg/kg has been administered according to actual body weight (ABW) (n=12) or ideal body weight (IBW) (n=11) in a clinical trial in obese patients. Obese patients dosed according to IBW had a longer time to maximum block (median 135 s [73 to 203] vs. 83 s [57 to 102]) and a shorter clinical duration (median 25 min [14 to 29] vs. 34 min [24 to 52]) than obese patients dosed according to ABW. Patients dosed according to IBW did not achieve intubating conditions comparable to those dosed based on ABW. A third group consisting of nonobese patients receiving 0.6 mg/kg rocuronium, exhibited a time to maximum block of 116 (61 to 165) seconds and a clinical duration of 28 (19 to 38) minutes. These results support the recommendation that obese patients be dosed based on actual body weight.

Hypothermia: Hypothermia (25 to 28°C) has been associated with a decreased requirement for nondepolarizing neuromuscular blocking agents.

Malignant Hyperthermia (MH): Malignant hyperthermia has not been reported in association with the administration of rocuronium. Because rocuronium is always used with other agents, and because 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 rocuronium was not associated with the development of malignant hyperthermia.

Burns: Resistance to nondepolarizing neuromuscular blocking agents may develop in patients with burns, depending on the time elapsed since the injury and the size of the burn.

Delayed Onset of Action: The onset of action of nondepolarizing neuromuscular blockers may be delayed in patients having conditions associated with slower circulation time (e.g., cardiovascular disease or advanced age) or an increased volume of distribution (e.g., edematous states). Because higher doses of rocuronium produce a longer duration of action, the initial dosage should not usually be increased in these patients to enhance onset time; instead, more time should be allowed for the drug to achieve its maximum effect.

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

Acid-Base or Electrolyte Abnormalities: Electrolyte and/or acid-base imbalances may enhance or inhibit neuromuscular blockade. For example, hyperkalemia has been reported to antagonize nondepolarizing agents while hypokalemia has been associated with an enhancement of their activity.

I.M. Use: No data are available to support the use of rocuronium by i.m. injection.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies in animals have not been performed to evaluate carcinogenic potential or impairment of fertility. Mutagenicity studies (Ames test, mammalian cell, and micronucleus test) conducted with rocuronium revealed no mutagenic potential.

Drug Interactions: Succinylcholine: The use of rocuronium before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been sufficiently studied. If rocuronium is administered following succinylcholine, it should not be given until recovery from succinylcholine has been observed. When a 0.6 mg/kg (600 g/kg) dose of rocuronium was administered after a 1 mg/kg dose of succinylcholine following recovery of T1 to 75% of control, the mean clinical duration of action was slightly prolonged relative to that observed without succinylcholine (mean 36 vs. 30 minutes).

Other Nondepolarizing Muscle Relaxants: There are no controlled studies documenting the use of rocuronium before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession.

Inhalation Anesthetics: The ED50 of rocuronium in adult patients determined under stable end-tidal concentrations of isoflurane, halothane, and enflurane was reduced by 20%, 41% and 46% respectively, as compared with that determined under opioid/N2O/O2 anesthesia. ED95 doses were, however, similar for patients receiving opioid/N2O/O2, halothane, and isoflurane anesthesia. The ED95 under conditions of enflurane anesthesia was approximately 40% lower than that determined for other types of anesthesia.

Since the neuromuscular blocking agents are routinely administered before, or shortly after, the administration of inhalation anesthetics, minimal effects on onset time and peak effect are generally observed. In routine use of neuromuscular blocking agents, only spontaneous recovery is generally affected (prolonged). No definite interaction between rocuronium and halothane, as used clinically, has been demonstrated. In one study use of enflurane in 10 patients, resulted in a 20% increase in the 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/N2O/O2 anesthesia. Potentiation by these agents is also observed with respect to the infusion rates of rocuronium required to maintain approximately 95% neuromuscular block. Under isoflurane and enflurane anesthesia, the infusion rates are approximately 30 to 40% lower than under conditions of opioid/N2O/O2 anesthesia. The median spontaneous recovery time from 25 to 75% of control T1 is prolonged by enflurane and isoflurane by 15% and 62% respectively. Halothane did not prolong the spontaneous recovery rate. Reversal-induced recovery of rocuronium neuromuscular block is similar regardless of anesthetic technique.

I.V. Anesthetics: The use of propofol for induction and maintenance of anesthesia does not alter the clinical duration or recovery characteristics following recommended doses of rocuronium.

Anticonvulsants: There are limited data (4 patients in 4 trials) from clinical trials in which patients received rocuronium during chronic anticonvulsant therapy with phenytoin. In 2 of these patients, apparent resistance to the effects of rocuronium was observed in the form of diminished magnitude of neuromuscular block or shortened clinical duration. In patients receiving chronic treatment with anticonvulsants such as phenytoin and carbamazepine, the possibility of diminished effect or shortened duration should be considered when rocuronium is administered. Infusion rates may need to be increased.

Antibiotics: Parenteral/intraperitoneal administration of high doses of certain antibiotics may produce neuromuscular block or intensify the blockade induced by nondepolarizing neuromuscular relaxants. The following antibiotics have been associated with various degrees of paralysis: aminoglycosides (such as neomycin, streptomycin; kanamycin, gentamicin, and dihydrostreptomycin), vancomycin, tetracyclines, bacitracin, polymyxin B, colistin, and sodium colistimethate.

If these or other newly introduced antibiotics are used in conjunction with rocuronium during surgery, prolongation of neuromuscular block should be considered a possibility.

Three antibiotics, cefuroxime (20 mg/kg i.v.), netilmicin (2 mg/kg i.v.), and metronidazole (7.5 mg/kg i.v.), were studied for their interactive effects with rocuronium. Administration of these antibiotics 5 minutes prior to a 0.6 mg/kg dose of rocuronium has no effect on the onset time to maximum blockade. The mean clinical duration of action tended to be longer in the patients receiving concomitant antibiotic treatment (38 min with saline, 43 min with metronidazole, 44 to 49 min with cefuroxime, and 50 min with netilmicin), although the observed differences were not statistically significant. The duration of maintenance doses of rocuronium was not increased in the presence of the antibiotics.

Other: Experience concerning injection of quinidine during recovery from use of other muscle relaxants suggests that recurrent paralysis may occur. This possibility must also be considered for rocuronium.

Magnesium salts, administered for the management of toxemia of pregnancy, may enhance neuromuscular blockade.

Lithium, local anesthetics, and procainamide have been reported to increase the duration of neuromuscular block with nondepolarizing neuromuscular blocking agents. Infusion requirements may be lower in the presence of these drugs.

Adverse Reactions: Clinical studies in North America (n=1 137) and Europe (n=1 394) included a total of 2 531 patients. The most frequent side effect of nondepolarizing blocking agents, as a class, is an extension of the drug’s pharmacological action beyond the time period needed for surgery and anesthesia (see Pharmacology). Clinical signs may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiratory insufficiency or apnea. This may be due to the drug’s effect or inadequate antagonism.

The patients exposed in North American clinical studies provide the basis for calculation of adverse reaction rates. The following adverse experiences were reported in patients administered rocuronium injection (all events judged by investigators during the clinical trials to have at least a possible causal relationship).

The following adverse events were judged by the investigator to be at least possibly related to rocuronium treatment.

Digestive: nausea, vomiting.

Respiratory: asthma (bronchospasm, wheezing, or rhonchi), hiccup.

Skin and Appendages: rash, injection site edema, pruritus.

The most commonly reported adverse events in the European studies were transient hypotension (2%) and hypertension (2%). These events were reported at a higher frequency than in the North American studies (0.1% and 0.1%, respectively). This apparent discrepancy may be related to the fact that, in the North American studies, changes in heart rate and blood pressure were considered adverse events only if judged by the investigator to be unexpected, clinically significant, or possibly related to histamine release.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No cases of significant accidental or intentional overdose have been reported. The possibility of iatrogenic overdosage can be minimized by carefully monitoring the muscle twitch response to peripheral nerve stimulation. 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 and controlled ventilation until recovery of normal respiration is assured. Upon evidence of spontaneous recovery from neuromuscular blockade, further recovery may be facilitated by administration of an anticholinesterase agent (e.g., neostigmine or edrophonium) in conjunction with an appropriate anticholinergic agent. A peripheral nerve stimulator should be used to monitor recovery.

As overdosage may increase the risk of hemodynamic side effects, intensified monitoring of vital organ function is required for the period of paralysis and during an extended period post recovery.

Antagonism of Neuromuscular Blockade: Antagonists (such as neostigmine) should not be administered prior to the demonstration of some spontaneous recovery from neuromuscular blockade. The use of a nerve stimulator to document recovery and antagonism of neuromuscular blockade is recommended. The time required for anticholinesterase-mediated recovery is longer for reversals attempted at deeper levels of blockade.

Patients should be evaluated for adequate clinical evidence of antagonism, e.g., 5 second head lift, adequate phonation, ventilation and upper airway maintenance. Ventilation must be supported until no longer required.

Antagonism may be delayed in the presence of debilitation, carcinomatosis, and concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular blockade or depress respiratory function. Under such circumstances the management is the same as that of prolonged neuromuscular blockade.

Dosage And Administration: Rocuronium injection is for i.v. use only. This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case.

To avoid distress to the patient, rocuronium should not be administered before unconsciousness has been induced. It should not be mixed in the same syringe or administered simultaneously through the same needle with alkaline solutions (e.g., barbiturate solutions).

The dosage information which follows is derived from studies in which the administration of rocuronium was based upon units of drug/unit of body weight. It is expressed in this section in terms of units of mg/kg (instead of g/kg) to assist the clinician in calculating individual patient dosage requirements relative to the product as supplied for clinical use. It is intended to serve as an initial guide to the use of rocuronium by clinicians familiar with other neuromuscular blocking agents (see Pharmacology and Dosage, Maintenance Dosing).

It is recommended that clinicians administering neuromuscular blocking agents such as rocuronium employ a peripheral nerve stimulator to monitor drug response, determine the need for additional relaxant and adequacy of spontaneous recovery or antagonism.

Adults: For intubating times, onset times, and clinical duration for various doses, see Pharmacology.

Rapid Intubation: In appropriately premedicated and adequately anesthetized patients, doses of 0.6 to 1.2 mg/kg (600 to 1 200 g/kg) rocuronium will provide good or excellent intubating conditions in most patients in 60 to 90 seconds.

At initial doses of 0.6 mg/kg, neuromuscular block sufficient for intubation (³80% block) is attained in a median (range) time of 1 (0.4 to 6) minute(s). Maximum blockade is achieved in most patients in a median (range) of 1.8 (0.6 to 13) minutes. This dose may be expected to provide 31 (15 to 85) minutes of clinical relaxation under opioid/N2O/O2 anesthesia. Under halothane, isoflurane, and enflurane anesthesia, some extension of the period of clinical relaxation should be expected (see Precautions, Inhalation Anesthetics).

Should there be reason for the selection of a larger bolus dose in individual patients, initial doses of 0.9 or 1.2 mg/kg can be administered during surgery under opioid/N2O/O2 anesthesia. These doses will provide ³80% block in most patients in 1.1 and 0.7 minutes, respectively, with maximum blockade occurring in most patients in 1.4 and 1 minute, respectively. Doses of 0.9 and 1.2 mg/kg may be expected to provide 58 (27 to 111) and 67 (38 to 160) minutes, respectively, of clinical relaxation under opioid/N2O/O2 anesthesia.

Doses for Routine Endotracheal Intubation: The recommended initial dose regardless of anesthetic regimen is 0.6 mg/kg (see Rapid Intubation). A lower dose of rocuronium injection (0.45 mg/kg) may be used. Neuromuscular block sufficient for intubation (³80%) is attained in a median (range) time of 1.3 (0.8 to 6.2) minute(s) and most patients have intubation completed within 1.6 (1 to 7) minutes. Maximum blockade is achieved in most patients in 3 (1.3 to 8.2) minutes. This dose may be expected to provide 22 (12 to 31) minutes of clinical relaxation under opioid/N2O/O2 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.

Inhalation Anesthetics: Maximum blockade, onset times, intubation times, and intubation scores are similar whether rocuronium is administered during opioid/N2O/O2 anesthesia or during anesthesia with enflurane, isoflurane, or halothane. The choice of an intubating dose of rocuronium should not, therefore, be reduced below 0.6 mg/kg if rapid intubation is to be performed or below 0.45 mg/kg if routine tracheal intubation is to be performed. Increases in the clinical duration (25 to 35%) and recovery time (20 to 70%) may be apparent, however, in the presence of halogenated inhalation agents.

Maintenance Dosing: Maintenance doses of 0.1, 0.15, and 0.2 mg/kg (100, 150, and 200 g/kg) rocuronium, administered at 25% recovery of control T1, provide a median 12, 17, and 24 minutes of clinically effective neuromuscular blockade during opioid/N2O/O2 anesthesia (see Pharmacology). Smaller or less frequent bolus maintenance doses should be considered during anesthesia with halogenated inhalation agents. In all cases, dosing should be guided based on the clinical duration following initial dose or prior maintenance dose and not administered until signs of neuromuscular function are evident. Cumulation of effect with repetitive maintenance dosing has been observed (see Pharmacology), but it is not of clinical significance.

Continuous Infusion: After evidence of early spontaneous recovery (10% of control T1) from initial doses of 0.45 to 0.6 mg/kg (450 to 600 g/kg), a continuous infusion of 0.01 to 0.012 mg/kg/min (10 to 12 g/kg/min) can be initiated with the rate of infusion being adjusted thereafter to maintain a 90% suppression of twitch response. The infusion of rocuronium should be individualized for each patient. The rate of administration should be adjusted according to the patient’s twitch response as determined by peripheral nerve stimulation. Infusion rates may range from 0.004 to 0.016 mg/kg/min (4 to 16 g/kg/min).

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.

Halogenated 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%.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium infusion may be expected to proceed at rates similar to those following comparable total doses administered by repetitive bolus injections (see Pharmacology).

Infusion solutions of rocuronium can be prepared by mixing rocuronium with an appropriate infusion solution such as 5% Dextrose Injection, USP. Unused portions of infusion solutions should be discarded.

Children: Initial Doses: Initial doses of 0.6 mg/kg (600 g/kg) in children (3 mo to 12 yrs) under halothane anesthesia produce 100% neuromuscular blockade and excellent to good intubating conditions within approximately 60 to 90 seconds. This dose will provide approximately 25 to 30 minutes of clinical relaxation in children aged 1 to 12 years receiving halothane anesthesia. For infants aged 3 to 12 months, the duration of action of a 0.6 mg/kg dose is longer than in older patients, averaging 42 minutes under conditions of halothane anesthesia.

Maintenance Doses: In children aged 4 to 13 yrs maintenance doses of 0.075 to 0.125 mg/kg (75 to 125 g/kg), administered upon return of T1 to 25% of control, provide clinical relaxation for a median of 7 to 10 minutes (see Pharmacology).

Use by Continuous Infusion: A continuous infusion of rocuronium initiated at a rate of 0.012 mg//kg/min (12 g/kg/min) upon return of T1 to 10% of control has been demonstrated to maintain neuromuscular blockade at 89 to 99% in children receiving halothane anesthesia. The infusion of rocuronium must be individualized for each patient. The rate of administration should be adjusted according to the patient’s twitch response as determined by peripheral nerve stimulation. Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium infusion may be expected to proceed at rates comparable to that following similar total exposure to single bolus doses (see Pharmacology).

Geriatrics: Although the potency of rocuronium is similar in geriatric patients and adults, the onset of action is delayed in patients ³65 years. The choice of an intubating dose of rocuronium should not be reduced below 0.6 mg/kg if routine tracheal intubation is to be performed. Rapid sequence tracheal intubation is not recommended in the elderly. Geriatric patients (³65 yrs) exhibit a slightly prolonged median (range) clinical duration of 46 (22 to 73) minutes, 62 (49 to 75) minutes and 94 (64 to 138) minutes under opioid/N2O/O2 anesthesia following doses of 0.6, 0.9, and 1.2 mg/kg, respectively. The median (range) rate of spontaneous recovery of T1 from 25 to 75% in geriatric patients is 16.5 (7 to 56) minutes which is not different from that in adults (see Pharmacology). Maintenance doses of 0.1 and 0.15 mg/kg (100 to 150 g/kg) rocuronium, administered at 25% recovery of T1, provide approximately 13 and 33 minutes of clinical duration under opioid/N2O/O2 anesthesia.

Compatibility: Zemuron is compatible in solution with: 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, 5% Dextrose and 0.9% Sodium Chloride Injection, USP, Sterile Water for Injection, USP and Lactated Ringer’s Solution.

Use within 24 hours of mixing with the above solutions.

Rocuronium injection 10 mg/mL may be added to an appropriate amount of product in i.v. infusion bottles, bags and PCA syringe pumps to yield a final concentration of 0.5 mg/mL and 2 mg/mL. The bottles and bags should be thoroughly mixed.

Parenteral drug products should be inspected visually for particulate matter and clarity prior to administration whenever solution and container permit.

Route of Administration: For i.v. injection only.

Availability And Storage: Each mL of sterile nonpyrogenic solution for i.v. injection only contains: rocuronium bromide 10 mg, sodium acetate, trihydrate 2 mg, sodium chloride approx. 3.3 mg, water for injection q.s. to 1 mL and nitrogen (present). May contain: sodium hydroxide and/or glacial acetic acid to adjust the pH to approximately 4.0. Preservative-free. Single dose vials of 5 mL. Boxes of 10.

Store under refrigeration (2 to 8°C) until ready to use. To facilitate use in the operating room, the unopened container may be stored up to 30 days at room temperature (15 to 30°C).

ZEMURON™ Organon Rocuronium Bromide Nondepolarizing Skeletal Neuromuscular Blocking Agent

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