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Pharmacology: Pharmacodynamics: Pharmacodynamic effects: Rocuronium bromide is an intermediate acting, non-depolarising neuromuscular blocking agent with a fast onset, possessing all of the characteristic pharmacological actions of this class of medicinal products (curariform). It acts by competing for nicotinic cholinoceptors at the motor end-plate.
The ED90 (dose required to produce 90 % depression of the twitch response of the thumb to stimulation of the ulnar nerve) during balanced anaesthesia is approximately 0.3 mg per kg body weight.
Clinical efficacy and safety: Routine practice: Within 60 seconds after intravenous administration of a dose of 0.6 mg rocuronium bromide per kg body weight (2 x ED90 under balanced anaesthesia), adequate intubation conditions can be achieved in nearly all patients. In 80 % of these patients intubation conditions are rated excellent. Within 2 minutes general muscle paralysis adequate for any type of procedure is established. The clinical duration (the duration until spontaneous recovery to 25% of control twitch height with this dose is 30 - 40 minutes. The total duration (time until spontaneous recovery to 90% of control twitch height) is 50 minutes. The mean time of spontaneous recovery of twitch response from 25 to 75 % (recovery index) after a bolus dose of 0.6 mg rocuronium bromide per kg body weight is 14 minutes.
With lower dosages of 0.3 - 0.45 mg rocuronium bromide per kg body weight (1 - 1 ½ x 2 x ED90), the onset of the effect is slower and the duration of action is shorter (13 - 26 min). After administration of 0.45 mg rocuronium bromide per kg body weight, acceptable intubation conditions are reached after 90 seconds.
Emergency intubation: During rapid sequence induction of anaesthesia under propofol or fentanyl/thiopental anaesthesia, adequate intubation conditions are achieved within 60 seconds in 93 % and 96 % of the patients respectively, after administration of a dose of 1.0 mg rocuronium bromide per kg body weight. Of these, 70 % are rated excellent. The clinical duration with this dose approaches 1 hour, at which time the neuromuscular block can be safely reversed. After administration of a dose of 0.6 mg rocuronium bromide per kg body weight, adequate intubation conditions are achieved within 60 seconds in 81 % and 75 % of the patients during a rapid sequence induction technique with propofol or fentanyl/thiopental, respectively.
Doses higher than 1.0 mg rocuronium bromide per kg body weight will not improve the intubation conditions appreciably; the duration of the effect, however, will be prolonged. Doses higher than 4 x ED90 have not been studied.
Intensive care: The use of rocuronium in the Intensive Care Unit was studied in two open-label trials. A total of 95 adult patients were treated with an initial dose of 0.6 mg rocuronium bromide per kg body weight, followed by a continuous infusion of 0.2 - 0.5mg/kg/h during the first hour of administration as soon as twitch height recovers to 10 % or upon reappearance of 1 to 2 twitches to train-of-four (TOF) stimulation. The dosages were individually titrated. In the following hours, doses were decreased under regular monitoring of the TOF stimulation. Administration for a time period of up to 7 days has been investigated.
Adequate neuromuscular blockade was achieved, but a high variability in hourly infusion rates between patients and a prolonged recovery from neuromuscular blockade was observed.
The time to recover of the train of four ratio to 0.7 is not significantly correlated to the total duration of rocuronium infusion. After a continuous infusion for 20 hours or more the median (range) time between return of T2 to train of four stimulation and recovery of the train of four ratio to 0.7 varied between 0.8 and 12.5 hours in patients without multiple organ failure and 1.2 - 25.5 hours in patients with multiple organ failure.
Paediatric population: Mean onset time in infants, toddlers and children at an intubation dose of 0.6 mg/kg is slightly shorter than in adults. Comparison within paediatric age groups showed that the mean onset time in neonates and adolescents (1 min) is slightly longer than in infants, toddlers and children (0.4, 0.6 and 0.8 min, respectively).
The duration of relaxation and the time to recovery tend to be shorter in children compared to infants and adults. Comparing within paediatric age groups demonstrated that mean time to reappearance of T3 was prolonged in neonates and infants (56.7 and 60.7 min, respectively) when compared to toddlers, children and adolescents (45.3, 37.6 and 42.9 min, respectively). (See Table 1.)
Click on icon to see table/diagram/imageSpecial populations: The duration of the effect of maintenance doses of 0.15 mg rocuronium bromide per kg body weight might be somewhat longer under enflurane and isoflurane anaesthesia in geriatric patients and in patients with hepatic or renal disease (approximately 20 minutes) than in patients without impairment of excretory organ functions under intravenous anaesthesia (approximately 13 minutes). No cumulation of effect (progressive increase in duration of action) with repetitive maintenance doses at the recommended level has been observed.
Cardiovascular surgery: In patients scheduled for cardiovascular surgery the most common cardiovascular changes during the onset of maximum blockage after receiving a dose of 0.6 - 0.9 mg rocuronium bromide per kg body weight are a slight and clinically insignificant increase in heart rate up to 9% and an increase in mean arterial blood pressure up to 16% from the control values.
Antagonists: Administration of acetylcholinesterase inhibitors, such as neostigmine, pyridostigmine or edrophonium, antagonises the action of rocuronium bromide.
Pharmacokinetics: Distribution and elimination: After intravenous administration of a single bolus dose of rocuronium bromide, the time course of the plasma concentration runs in three exponential phases. In normal adults, the mean (95%Cl) elimination half-life is 73 (66-80) minutes, the (apparent) volume of distribution at steady state conditions is 203 (193-214) ml/kg and the plasma clearance is 3.7 (3.5-3.9) ml/kg/min.
When administered as a continuous infusion to facilitate mechanical ventilation for a time period of 20 hours or more, the mean elimination half-life and the mean (apparent) volume of distribution at steady state are increased. A high variability between patients was found in controlled clinical studies, related to the nature and extent of (multiple) organ failure and individual patient characteristics. In patients with multiple organ failure a mean (±SD) elimination half-life of 21.5 (±3.3) hours, an (apparent) volume of distribution at steady state of 1.5 (±0.8) l·kg-1 and a plasma clearance of 2.1 (±0.8) ml/kg/min were found.
Rocuronium bromide is excreted in urine and bile. Excretion in urine approaches 40 % within 12 - 24 hours. After injection of a radiolabeled dose of rocuronium bromide, excretion of the radiolabel is on average 47 % in urine and 43 % in faeces after 9 days. Approximately 50 % is recovered as rocuronium bromide.
Biotransformation: No metabolites are detected in the plasma.
Paediatric population: The apparent volume of distribution in infants (3-12 months) is higher compared to older children (1-8 years) and adults. In children aged 3-8 years, clearance is higher and the elimination half-life is approximately 20 minutes shorter compared to adults and children < 3 years.
Pharmacokinetics (PK) of rocuronium bromide in paediatric patients (n=146) with ages ranging from 0 to 17 years were evaluated using a population analysis of the pooled pharmacokinetic datasets from two clinical trials under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. All pharmacokinetic parameters were found to be linearly proportional to body weight illustrated by a similar clearance (CL; l/kg/h). The volume of distribution (l/kg) and elimination half-life (h) decrease with age (years). The pharmacokinetic parameters of typical paediatrics within each age group are summarized as follows: See Table 2.
Click on icon to see table/diagram/imageGeriatric patients and patients with renal dysfunction: The plasma clearance in geriatric patients and in patients with renal dysfunction is slightly reduced compared to younger patients with normal renal function. In patients with hepatic diseases, the mean elimination half-life is prolonged by 30 minutes and the mean plasma clearance is reduced by 1 ml/kg/min. (See also Dosage & Administration.)
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development.
Carcinogenicity studies have not been performed with rocuronium bromide.
