Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Ibigen Srl, via Fossignano 2, 04011, Aprilia (LT), Italy
Pharmacotherapeutic group: Muscle relaxants, peripherally acting agents, other quaternary ammonium compounds
ATC code: M03AC09
Rocuronium bromide is a fast onset, intermediate acting non-depolarising neuromuscular blocking agent, possessing all of the characteristic pharmacological actions of this class of medicinal products (curariform agents). It acts by competing for nicotinic cholinoceptors at the motor end-plate. This action is antagonised by acetylcholinesterase inhibitors such as neostigmine, edrophonium and pyridostigmine.
The ED90 (dose required to produce 90% depression of the twitch response of the thumb to stimulation of the ulnar nerve) during intravenous anaesthesia is approximately 0.3 mg/kg rocuronium bromide. The ED95 in infants is lower than in adults and children (0.25, 0.35 and 0.40 mg/kg respectively).
The clinical duration (the duration until spontaneous recovery to 25% of control twitch height) with 0.6 mg/kg rocuronium bromide 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/kg rocuronium bromide is 14 minutes. With lower dosages of 0.3-0.45 mg/kg rocuronium bromide (1-1½ x ED90), onset of action is slower and duration of action is shorter (13–26 min). With high doses of 2 mg/kg, clinical duration is 110 minutes.
Within 60 seconds following intravenous administration of a dose of 0.6 mg/kg rocuronium bromide (2 x ED90 under intravenous anaesthesia), adequate intubation conditions can be achieved in nearly all patients of which in 80% intubation conditions are rated excellent. General muscle paralysis adequate for any type of procedure is established within 2 minutes. After administration of 0.45 mg/kg rocuronium bromide, acceptable intubation conditions are present after 90 seconds.
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, following a dose of 1.0 mg/kg rocuronium bromide. 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. Following a dose of 0.6 mg/kg rocuronium bromide, 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 0.1 mg/kg rocuronium bromide do not improve intubation conditions in a perceptible way, however the duration of action is prolonged. Doses higher than 4 x ED90 were not studied.
Mean onset time in infants and children at an intubation dose of 0.6 mg/kg is slightly shorter than in adults. The duration of relaxation and the time to recovery tend to be shorter in children compared to infants and adults.
The duration of action of maintenance doses of 0.15 mg/kg rocuronium bromide might be somewhat longer under enflurane and isoflurane anaesthesia in geriatric patients and in patients with hepatic and/or renal disease (approximately 20 minutes) than in patients without impairment of excretory organ functions under intravenous anaesthesia (approximately 13 minutes). No accumulation of effect (progressive increase in duration of action) with repetitive maintenance dosing at the recommended level has been observed.
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 0.2-0.5 mg/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.
In patients scheduled for cardiovascular surgery the most common cardiovascular changes during the onset of maximum block following 0.6-0.9 mg/kg rocuronium bromide 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.
Administration of acetylcholinesterase inhibitors, (neostigmine, pyridostigmine or edrophonium) at reappearance of T2 or at the first signs of clinical recovery, antagonises the action of Rocuronium bromide.
After intravenous administration of a single bolus dose of rocuronium bromide the plasma concentration time course runs in three exponential phases. In normal adults, the mean (95%CI) elimination half-life is 73 (66-80) minutes, the (apparent) volume of distribution at steady state conditions is 203 (193-214) ml/kg and plasma clearance is 3.7 (3.5-3.9) ml/kg/min.
In controlled studies the plasma clearance in geriatric patients and in patients with renal dysfunction was reduced, in most studies however without reaching the level of statistical significance. In patients with hepatic disease, the mean elimination half-life is prolonged by 30 minutes and the mean plasma clearance is reduced by 1 ml/kg/min. (See also section 4.2).
In infants (28 days to 23 months), the apparent volume of distribution at steady state conditions is increased compared to adults and children (2-11 years). In older children (3-8 years), a trend is seen towards higher clearance and shorter elimination half-life (approximately 20 minutes) compared to adults, younger children and infants.
When administered as a continuous infusion to facilitate mechanical ventilation for 20 hours or more, the mean elimination half-life and the mean (apparent) volume of distribution at steady state are increased.
A large between patient variability is found in controlled clinical studies, related to 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, a (apparent) volume of distribution at steady state of 1.5 (± 0.8) l/kg and a plasma clearance of 2.1 (± 0.8) ml/kg/min were found. (See also section 4.2).
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 the parent compound. No metabolites are detected in plasma.
No chronic toxicity studies of rocuronium bromide have been conducted.
In vivo and in vitro mutagenicity studies have revealed no mutagenic potential of rocuronium bromide.
No carcinogenicity studies of rocuronium bromide have been conducted.
Studies using sub-pharmacological intravenous doses of rocuronium bromide in rats during organogenesis have produced no evidence of embryolethal effects, teratological alterations or foetal growth inhibition. Rocuronium bromide crosses the placental barrier in rats to a limited extent, and is recovered in milk in small amounts.
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