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rocuronium bromide injection Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

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

Table 4: Percent of Excellent or Good Intubating Conditions and Median (Range) Time to Completion of Intubation in Patients with Intubation Initiated at 60 to 70 Seconds
*             Excludes patients undergoing Cesarean section
**           Pediatric patients were under halothane anesthesia
               Excellent intubating conditions = jaw relaxed, vocal cords apart and immobile, no diaphragmatic movement
               Good intubating conditions = same as excellent but with some diaphragmatic movement

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

0.45 (n=43)

0.6 (n=51)

86%

96%

1.6 (1.0 to 7.0)

1.6 (1.0 to 3.2)

Infants** 3 mo to 1 yr

0.6 (n=18)

Pediatric** 1 to 12 yrs

0.6 (n=12)

100%

 

100%

1.0 (1.0 to 1.5)

 

1.0 (0.5 to 2.3)

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

Table 5: Median (Range) Time to Onset and Clinical Duration Following Initial (Intubating) Dose During Opioid/Nitrous Oxide/Oxygen Anesthesia (Adults) and Halothane Anesthesia (Pediatric Patients)
n = the number of patients who had time to maximum block recorded
Clinical duration = time until return to 25% of control T1. Patients receiving doses of 0.45 mg/kg who achieved less than 90% block (16% of these patients) had about 12 to 15 minutes to 25% recovery.

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

 

 

 

0.45 (n=50)

1.3 (0.8 to 6.2)

3.0 (1.3 to 8.2)

22 (12 to 31)

0.6 (n=142)

1.0 (0.4 to 6.0)

1.8 (0.6 to 13.0)

31 (15 to 85)

0.9 (n=20)

1.1 (0.3 to 3.8)

1.4 (0.8 to 6.2)

58 (27 to 111)

1.2 (n=18)

0.7 (0.4 to 1.7)

1.0 (0.6 to 4.7)

67 (38 to 160)

Geriatric ≥65 yrs

 

 

 

0.6 (n=31)

2.3 (1.0 to 8.3)

3.7 (1.3 to 11.3)

46 (22 to 73)

0.9 (n=5)

2.0 (1.0 to 3.0)

2.5 (1.2 to 5.0)

62 (49 to 75)

1.2 (n=7)

1.0 (0.8 to 3.5)

1.3 (1.2 to 4.7)

94 (64 to 138)

Infants 3 mo to 1 yr

 

 

 

0.6 (n=17)

0.8 (0.3 to 3.0)

41 (24 to 68)

0.8 (n=9)

0.7 (0.5 to 0.8)

40 (27 to 70)

Pediatric 1 to 12 yrs

 

 

 

0.6 (n=27)

0.8 (0.4 to 2.0)

1.0 (0.5 to 3.3)

26 (17 to 39)

0.8 (n=18)

0.5 (0.3 to 1.0)

30 (17 to 56)

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

Table 6: Median (Range) Time to Onset and Clinical Duration Following Initial (Intubating) Dose During Sevoflurane (induction) and Isoflurane/Nitrous Oxide (maintenance) Anesthesia (Pediatric Patients)
n=the number of patients with the highest number of observations for time to maximum block or reappearance T3.

Rocuronium Bromide
Dose (mg/kg)
Administered over 5 sec

Time to
Maximum Block
(min)

Time to
Reappearance T3 
(min)

Neonates birth to <28 days
0.45 (n=5)
0.6 (n=10)
1 (n=6)

 1.1 (0.6-2.2)
1.0 (0.2-2.1)
0.6 (0.3-1.8)

40.3 (32.5-62.6)
49.7 (16.6-119.0)
114.4 (92.6-136.3)

Infants 28 days to ≤3 mo
0.45 (n=9)
0.6 (n=11)
1 (n=5)

0.5 (0.4-1.3)
0.4 (0.2-0.8)
0.3 (0.2-0.7)

49.1 (13.5-79.9)
59.8 (32.3-87.8)
103.3 (90.8-155.4)

Toddlers >3 mo to ≤2 yrs
0.45 (n=17)
0.6 (n=29)
1 (n=15)

 0.8 (0.3-1.9)
0.6 (0.2-1.6)
0.5 (0.2-1.5)

39.2 (16.9-59.4)
44.2 (18.9-68.8)
72.0 (36.2-128.2)

Children >2 yrs to ≤11 yrs
0.45 (n=14)
0.6 (n=37)
1 (n=16)

 0.9 (0.4-1.9)
0.8 (0.3-1.7)
0.7 (0.4-1.2)

21.5 (17.5-38.0)
36.7 (20.1-65.9)
53.1 (31.2-89.9)

Adolescents >11 to ≤17 yrs
0.45 (n=18)
0.6 (n=31)
1 (n=14)

1.0 (0.5-1.7)
0.9 (0.2-2.1)
0.7 (0.5-1.2)

37.5 (18.3-65.7)
41.4 (16.3-91.2)
67.1 (25.6-93.8)

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

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 five maintenance doses, in patients receiving five or more maintenance doses are represented in Figure 3 [see Dosage and Administration (2.4)].

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

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

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

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

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

Hemodynamics

There were no dose-related effects on the incidence of changes from baseline (30% or greater) in mean arterial blood pressure (MAP) or heart rate associated with 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 [see Clinical Studies (14.3)]. 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.

Histamine Release

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

12.3 Pharmacokinetics

Adult and Geriatric Patients

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

Following intravenous administration of 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 (2.6)].

Table 7: Mean (SD) Pharmacokinetic Parameters in Adults (n=22; ages 27 to 58 yrs) and Geriatric (n=20; 65 yrs or greater) During Opioid/Nitrous Oxide/Oxygen Anesthesia

PK Parameters

Adults
(Ages 27 to 58 yrs)

Geriatrics
(≥65 yrs)

Clearance (L/kg/hr)

0.25 (0.08)

0.21 (0.06)

Volume of Distribution at Steady State (L/kg)

0.25 (0.04)
   

0.22 (0.03)
   

t1/2 β Elimination (hr)

1.4 (0.4)

1.5 (0.4)

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

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

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

Table 8: Mean (SD) Pharmacokinetic Parameters in Adults with Normal Renal and Hepatic Function (n=10, ages 23 to 65), Renal Transplant Patients (n=10, ages 21 to 45), and Hepatic Dysfunction Patients (n=9, ages 31 to 67) During Isoflurane Anesthesia
*  Differences in the calculated t1/2 β and Cl between this study and the study in young adults vs. geriatrics (≥65 years) is related to the different sample populations and anesthetic techniques.

PK Parameters

Normal Renal and Hepatic Function

Renal Transplant Patients

Hepatic Dysfunction Patients

Clearance (L/kg/hr)

0.16 (0.05)*

0.13 (0.04)

0.13 (0.06)

Volume of
Distribution at
Steady State (L/kg)

0.26 (0.03)
   
   

0.34 (0.11)
   
   

0.53 (0.14)
   
   

t1/2 β Elimination (hr)

2.4 (0.8)*

2.4 (1.1)

4.3 (2.6)

The net result of these findings is that subjects with renal failure have clinical durations that are similar to but somewhat more variable than the duration that one would expect in subjects with normal renal function. Hepatically impaired patients, due to the large increase in volume, may demonstrate clinical durations approaching 1.5 times that of subjects with normal hepatic function. In both populations the clinician should individualize the dose to the needs of the patient [see Dosage and Administration (2.6)].

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

Pediatric Patients

Under halothane anesthesia, the clinical duration of effects of 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 9.

Table 9: Mean (SD) Pharmacokinetic Parameters of Rocuronium in Pediatric Patients (ages 3 to less than 12 mos, n=6; 1 to less than 3 yrs, n=5; 3 to less than 8 yrs, n=7) During Halothane Anesthesia

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 0.7-0.8 hour. Table 10 presents the pharmacokinetic parameters in the different age groups in the studies with sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia.

Table 10: Mean (SD) Pharmacokinetic Parameters of Rocuronium in Pediatric Patients During 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)

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