Rocuronium Bromide Injection - Scientific Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Class:||Neuromuscular blocking agents|
|Form:||Liquid solution, Intravenous (IV)|
|Ingredients:||Rocuronium bromide, Sodium acetate, Sodium chloride, Sodium hydroxide, Acetic acid|
Rocuronium Bromide Injection is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. Rocuronium bromide is chemically designated as 1-[17β-(acetyloxy)-3α-hydroxy-2β-(4-morpholinyl)-5α-androstan-16β-yl]-1-(2-propenyl)pyrrolidinium bromide.
The structural formula is:
The partition coefficient of rocuronium bromide in n-octanol/water is 0.5 at 20°C.
Rocuronium bromide injection is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellow/orange, for intravenous injection only. Each mL contains 10 mg rocuronium bromide and 2 mg sodium acetate. The aqueous solution is adjusted to isotonicity with sodium chloride and to a pH of 4 with acetic acid and/or sodium hydroxide.
Mechanism of Action
Rocuronium bromide 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.
The ED95 (dose required to produce 95% suppression of the first [T1] mechanomyographic [MMG] response of the adductor pollicis muscle [thumb] to indirect supramaximal train- of-four stimulation of the ulnar nerve) 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 1 presents intubating conditions in patients with intubation initiated at 60 to 70 seconds.
|Rocuronium Bromide 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
1.6 (1 to 7)
1.6 (1 to 3.2)
3 mo to 1 yr
1 (1 to 1.5)
|Pediatric† 1 to 12 yrs
1 (0.5 to 2.3)
* 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.
Table 2 presents the time to onset and clinical duration for the initial dose of Rocuronium Bromide Injection under opioid/nitrous oxide/oxygen anesthesia in adults and geriatric patients, and under halothane anesthesia in pediatric patients.
|Rocuronium Bromide 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
1.3 (0.8 to 6.2)
1 (0.4 to 6)
1.1 (0.3 to 3.8)
0.7 (0.4 to 1.7)
3 (1.3 to 8.2)
1.8 (0.6 to 13)
1.4 (0.8 to 6.2)
1 (0.6 to 4.7)
22 (12 to 31)
31 (15 to 85)
58 (27 to 111)
67 (38 to 160)
|Geriatric ≥65 yrs
2.3 (1 to 8.3)
2 (1 to 3)
1 (0.8 to 3.5)
3.7 (1.3 to 11.3)
2.5 (1.2 to 5)
1.3 (1.2 to 4.7
46 (22 to 73)
62 (49 to 75)
94 (64 to 138)
|Infants 3 mo to 1 yr
0.8 (0.3 to 3)
0.7 (0.5 to 0.8)
41 (24 to 68)
40 (27 to 70)
|Pediatric 1 to 12 yrs
0.8 (0.4 to 2)
1 (0.5 to 3.3)
0.5 (0.3 to 1)
26 (17 to 39)
30 (17 to 56)
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.
Table 3 presents the time to onset and clinical duration for the initial dose of Rocuronium Bromide Injection under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia in pediatric patients.
|Rocuronium Bromide Dose (mg/kg) Administered over 5 sec||Time to Maximum Block (min)||Time to Reappearance T 3 (min)|
|Neonates birth to <28 days|
|0.45 (n=5)||1.1 (0.6 to 2.2)||40.3 (32.5 to 62.6)|
|0.6 (n=10)||1 (0.2 to 2.1)||49.716.6 to 119)|
|1 (n=6)||0.6 (0.3 to 1.8)||114.4 (92.6 to 136.3)|
|Infants 28 days to ≤3 mo|
|0.45 (n=9)||0.5 (0.4 to 1.3)||49.1 (13.5 to 79.9)|
|0.6 (n=11)||0.4 (0.2 to 0.8)||59.8 (32.3 to 87.8)|
|1 (n=5)||0.3(0.2 to 0.7)||103.3 (90.8 to 155.4)|
|Toddlers >3 mo to ≤2 yrs|
|0.45 (n=17)||0.8 (0.3 to 1.9)||39.2 (16.9 to 59.4)|
|0.6 (n=29)||0.6 (0.2 to 1.6)||44.2 (18.9 to 68.8)|
|1 (n=15)||0.50.2 to 1.5)||72 (36.2 to 128.2)|
|Children >2 yrs to ≤11 yrs|
|0.45 (n=14)||0.9 (0.4 to 1.9)||21.5 (17.5 to 38)|
|0.6 (n=37)||0.8 (0.3 to 1.7)||36.7 (20.1 to 65.9)|
|1 (n=16)||0.7 (0.4 to 1.2)||53.1 (31.2 to 89.9)|
|Adolescents >11 to ≤17 yrs|
|0.45 (n=18)||1 (0.5 to 1.7)||37.5 (18.3 to 65.7)|
|0.6 (n=31)||0.9 (0.2 to 2.1)||41.4 (16.3 to 91.2)|
|1 (n=14)||0.7 (0.5 to 1.2)||67.1 (25.6 to 93.8)|
n=the number of patients with the highest number of observations for time to maximum block or reappearance T3.
The time to 80% or greater block and clinical duration as a function of dose are presented in Figures 1 and 2.
FIGURE 1: Time to 80% or Greater Block vs . Initial Dose of Rocuronium Bromide by Age Group (Median, 25th and 75th Percentile, and Individual Values)
FIGURE 2: Duration of Clinical Effect vs . Initial Dose of Rocuronium Bromide by Age Group (Median, 25th and 75th Percentile, and Individual Values)
The clinical durations for the first 5 maintenance doses, in patients receiving 5 or more maintenance doses are represented in Figure 3 [see Dosage and Administration].
FIGURE 3: Duration of Clinical Effect vs . Number of Rocuronium Bromide Maintenance Doses, by Dose
Once spontaneous recovery has reached 25% of control T1, the neuromuscular block produced by rocuronium bromide is readily reversed with anticholinesterase agents, e.g., edrophonium or neostigmine.
The median spontaneous recovery from 25% to 75% T 1 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 5 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) 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 rocuronium bromide may be enhanced in the presence of potent inhalation anesthetics [see Drug Interactions].
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 rocuronium bromide administration over the dose range of 0.12 to 1.2 mg/kg (4 x ED95) within 5 minutes after rocuronium bromide 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. In US studies, laryngoscopy and tracheal intubation following rocuronium bromide 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 rocuronium bromide administration is less than vecuronium but greater than pancuronium. The tachycardia observed in some patients may result from this vagal blocking activity.
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 rocuronium bromide were assessed in clinical trials and reported in 9 of 1,137 (0.8%) patients.
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 rocuronium bromide, 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 [see Dosage and Administration].
|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 Distributionat Steady State (L/kg)||0.25 (0.04)||0.22 (0.03)|
|t1/2 ß 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 5 shows the pharmacokinetic parameters in subjects with either impaired renal or hepatic function.
|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 ß Elimination (hr)||2.4 (0.8)*||2.4 (1.1)||4.3 (2.6)|
* 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.
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].
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.
Under halothane anesthesia, the clinical duration of effects of rocuronium bromide 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 6.
|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 rocuronium bromide 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 rocuronium bromide decreases with increasing age from 1.1 hour to 0.7 to 0.8 hour. Table 7 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)|
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies in animals have not been performed with rocuronium bromide to evaluate carcinogenic potential or impairment of fertility. Mutagenicity studies (Ames test, analysis of chromosomal aberrations in mammalian cells, and micronucleus test) conducted with rocuronium bromide did not suggest mutagenic potential.
In US clinical studies, a total of 1,137 patients received rocuronium bromide, including 176 pediatric, 140 geriatric, 55 obstetric, and 766 other adults. Most patients (90%) 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 1,394 patients received rocuronium bromide, including 52 pediatric, 128 geriatric (65 years or greater), and 1,214 other adults.
Intubation using doses of rocuronium bromide 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 2 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.
In 1 clinical study, 10 patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft received an initial dose of 0.6 mg/kg rocuronium bromide. Neuromuscular block was maintained during surgery with bolus maintenance doses of 0.3 mg/kg. Following induction, continuous 8 mcg/kg/min infusion of rocuronium bromide 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 6 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 rocuronium bromide 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 rocuronium bromide and in 108/110 (98% [94% to 99.8%]) patients receiving succinylcholine. The duration of action of rocuronium bromide 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.
Rocuronium bromide was dosed according to actual body weight (ABW) in most clinical studies. The administration of rocuronium bromide 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 1 clinical study in obese patients, rocuronium bromide 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.
Rocuronium bromide 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, rocuronium bromide is not recommended for rapid sequence induction in Cesarean section patients.
Rocuronium bromide was evaluated in 55 geriatric patients (ages 65 to 80 years) in 6 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.
Rocuronium bromide 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 to 65.9) minutes] and longest in infants [59.8 (32.3 to 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.
Rocuronium bromide 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 3 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.