Cisatracurium besylate

Overdose

Symptoms and signs

Prolonged muscle paralysis and its consequences are expected to be the main signs of overdosage with Cisatracurium Besylate.

Management

It is essential to maintain pulmonary ventilation and arterial oxygenation until adequate spontaneous respiration returns. Full sedation will be required since consciousness is not impaired by Cisatracurium Besylate. Recovery may be accelerated by the administration of anti- cholinesterase agents once evidence of spontaneous recovery is present.

Contraindications

Cisatracurium Besylate is contra-indicated in patients known to be hypersensitive to cisatracurium, atracurium, or benzenesulfonic acid.

Incompatibilities

Therefore it is recommended that lactated Ringer's Injection and 5% Dextrose and lactated Ringer's Injection are not used as the diluent in preparing solutions of Cisatracurium Besylate for infusion.

Since Cisatracurium Besylate is stable only in acidic solutions it should not be mixed in the same syringe or administered simultaneously through the same needle with alkaline solutions, e.g., sodium thiopentone. It is not compatible with ketorolac trometamol or propofol injectable emulsion.

Pharmaceutical form

Undesirable effects

Data from pooled internal clinical trials were used to determine the frequency of very common to uncommon adverse reactions.

The following convention has been used for the classification of frequency:- very common (> 1/10), common( > 1/100 to <1/10), uncommon (> 1/1000 to <1/100), rare (> 1/10,000 to <1/1000), very rare (< 1/10,000).

Clinical Trial Data

There have been some reports of muscle/weakness and/or myopathy following prolonged use of muscle relaxants in severely ill patients in the ICU. Most patients were receiving concomitant corticosteroids. These events have been reported infrequently in association with Cisatracurium Besylate and a causal relationship has not been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Preclinical safety data

Acute toxicity

Subacute Toxicity:

Studies with repeated administration for three weeks in dogs and monkeys showed no compound specific toxic signs.

Mutagenicity

Cisatracurium was not mutagenic in an in vitro microbial mutagenicity test at concentrations up to 5000μg/plate.

In an in vivo cytogenetic study in rats, no significant chromosomal abnormalities were seen at s.c doses up to 4mg/kg.

Cisatracurium was mutagenic in an in vitro mouse lymphoma cell mutagenicity assay, at concentrations of 40μg/ml and higher.

A single positive mutagenic response for a drug used infrequently and/or briefly is of questionable clinical relevance.

Carcinogenicity

Carcinogenicity studies have not been performed.

Reproductive toxicology

Fertility studies have not been performed. Reproductive studies in rats have not revealed any adverse effects of cisatracurium on foetal development.

Local tolerance

The result of an intra-arterial study in rabbits showed that Cisatracurium Besylate injection is well tolerated and no drug related changes were seen.

Therapeutic indications

Cisatracurium Besylate is indicated for use during surgical and other procedures in adults and children aged 1 month and over. Cisatracurium Besylate is also indicated for use in adults requiring intensive care. Cisatracurium Besylate can be used as an adjunct to general anaesthesia, or sedation in the Intensive Care Unit (ICU) to relax skeletal muscles, and to facilitate tracheal intubation and mechanical ventilation.

Pharmacodynamic properties

Mechanism of action

Cisatracurium is a neuromuscular blocking agent, ATC code: M03A C11.

Cisatracurium is an intermediate-duration, non-depolarising benzylisoquinolinium skeletal muscle relaxant.

Pharmacodynamic effects

Clinical studies in man indicated that Cisatracurium Besylate is not associated with dose dependent histamine release even at doses up to and including 8 x ED95.

Cisatracurium binds to cholinergic receptors on the motor end-plate to antagonise the action of acetylcholine, resulting in a competitive block of neuromuscular transmission. This action is readily reversed by anti-cholinesterase agents such as neostigmine or edrophonium.

The ED95 (dose required to produce 95% depression of the twitch response of the adductor pollicis muscle to stimulation of the ulnar nerve) of cisatracurium is estimated to be 0.05 mg/kg bodyweight during opioid anaesthesia (thiopentone/fentanyl/midazolam).

The ED95 of cisatracurium in children during halothane anaesthesia is 0.04 mg/kg.

Pharmacokinetic properties

Biotransformation/Elimination

Cisatracurium undergoes degradation in the body at physiological pH and temperature by Hofmann elimination (a chemical process) to form laudanosine and the monoquaternary acrylate metabolite. The monoquaternary acrylate undergoes hydrolysis by non-specific plasma esterases to form the monoquaternary alcohol metabolite. Elimination of cisatracurium is largely organ independent but the liver and kidneys are primary pathways for the clearance of its metabolites.

These metabolites do not possess neuromuscular blocking activity.

Pharmacokinetics in adult patients

Non-compartmental pharmacokinetics of cisatracurium are independent of dose in the range studied (0.1 to 0.2 mg/kg, i.e. 2 to 4 x ED95).

Population pharmacokinetic modelling confirms and extends these findings up to 0.4 mg/kg (8 x ED95). Pharmacokinetic parameters after doses of 0.1 and 0.2 mg/kg Cisatracurium Besylate administered to healthy adult surgical patients are summarised in the table below:

Pharmacokinetics in elderly patients

There are no clinically important differences in the pharmacokinetics of cisatracurium in elderly and young adult patients. The recovery profile is also unchanged.

Pharmacokinetics in patients with renal/hepatic impairment

There are no clinically important differences in the pharmacokinetics of cisatracurium in patients with end-stage renal failure or end stage liver disease and in healthy adult patients. Their recovery profiles are also unchanged.

Pharmacokinetics during infusions

The pharmacokinetics of cisatracurium after infusions of Cisatracurium Besylate are similar to those after single bolus injection. The recovery profile after infusion of Cisatracurium Besylate is independent of duration of infusion and is similar to that after single bolus injection.

Pharmacokinetics in Intensive Care Unit (ICU) patients

The pharmacokinetics of cisatracurium in ICU patients receiving prolonged infusions are similar to those in healthy surgical adults receiving infusions or single bolus injections. The recovery profile after infusions of Cisatracurium Besylate in ICU patients is independent of duration of infusion.

Concentrations of metabolites are higher in ICU patients with abnormal renal and/or hepatic function. These metabolites do not contribute to neuromuscular block.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Product specific topics

Cisatracurium paralyses the respiratory muscles as well as other skeletal muscles but has no known effect on consciousness or pain threshold. Cisatracurium Besylate should be only administered by or under the supervision of anaesthetists or other clinicians who are familiar with the use and action of neuromuscular blocking agents. Facilities for tracheal intubation, and maintenance of pulmonary ventilation and adequate arterial oxygenation have to be available.

Caution should be exercised when administering Cisatracurium Besylate to patients who have shown hypersensitivity to other neuromuscular blocking agents since a high rate of cross-sensitivity (greater than 50%) between neuromuscular blocking agents has been reported.

Cisatracurium does not have significant vagolytic or ganglion- blocking properties. Consequently, Cisatracurium Besylate has no clinically significant effect on heart rate and will not counteract the bradycardia produced by many anaesthetic agents or by vagal stimulation during surgery.

Patients with myasthenia gravis and other forms of neuromuscular disease have shown greatly increased sensitivity to non-depolarising blocking agents. An initial dose of not more than 0.02 mg/kg Cisatracurium Besylate is recommended in these patients.

Severe acid-base and/or serum electrolyte abnormalities may increase or decrease the sensitivity of patients to neuromuscular blocking agents.

There is no information on the use of Cisatracurium Besylate in neonates aged less than one month since it has not been studied in this patient population.

Cisatracurium has not been studied in patients with a history of malignant hyperthermia. Studies in malignant hyperthermia- susceptible pigs indicated that cisatracurium does not trigger this syndrome.

There have been no studies of cisatracurium in patients undergoing surgery with induced hypothermia (25 to 28°C). As with other neuromuscular blocking agents the rate of infusion required to maintain adequate surgical relaxation under these conditions may be expected to be significantly reduced.

Cisatracurium has not been studied in patients with burns; however, as with other non-depolarising neuromuscular blocking agents, the possibility of increased dosing requirements and shortened duration of action must be considered if Cisatracurium Besylate injection is administered to these patients.

Cisatracurium Besylate is hypotonic and must not be applied into the infusion line of a blood transfusion.

Intensive Care Unit (ICU) Patients: -

When administered to laboratory animals in high doses, laudanosine, a metabolite of cisatracurium and atracurium, has been associated with transient hypotension and in some species, cerebral excitatory effects. In the most sensitive animal species, these effects occurred at laudanosine plasma concentrations similar to those that have been observed in some ICU patients following prolonged infusion of atracurium.

Consistent with the decreased infusion rate requirements of cisatracurium, plasma laudanosine concentrations are approximately one third those following atracurium infusion.

There have been rare reports of seizures in ICU patients who have received atracurium and other agents. These patients usually had one or more medical conditions predisposing to seizures (eg. cranial trauma, hypoxic encephalopathy, cerebral oedema, viral encephalitis, uraemia). A causal relationship to laudanosine has not been established.

Effects on ability to drive and use machines

This precaution is not relevant to the use of Cisatracurium Besylate. Cisatracurium Besylate will always be used in combination with a general anaesthetic and therefore the usual precautions relating to performance of tasks following general anaesthesia apply.

Dosage (Posology) and method of administration

Cisatracurium Besylate should only be administered by or under the supervision of anaesthetists or other clinicians who are familiar with the use and action of neuromuscular blocking agents. Facilities for tracheal intubation, and maintenance of pulmonary ventilation and adequate arterial oxygenation have to be available.

Please note that Cisatracurium Besylate should not be mixed in the same syringe or administered simultaneously through the same needle as propofol injectable emulsion or with alkaline solutions such as sodium thiopentone..

Cisatracurium Besylate contains no antimicrobial preservative and is intended for single patient use.

Monitoring advice

As with other neuromuscular blocking agents, monitoring of neuromuscular function is recommended during the use of Cisatracurium Besylate in order to individualise dosage requirements.

Use by intravenous bolus injection

Dosage in adults

Tracheal Intubation. The recommended intubation dose of Cisatracurium Besylate for adults is 0.15mg/kg (body weight). This dose produced good to excellent conditions for tracheal intubation 120 seconds after administration of Cisatracurium Besylate, following induction of anaesthesia with propofol.

Higher doses will shorten the time to onset of neuromuscular block.

Table 1 summarises mean pharmacodynamic data when Cisatracurium Besylate was administered at doses of 0.1 to 0.4mg/kg (body weight) to healthy adult patients during opioid (thiopentone/fentanyl/midazolam) or propofol anaesthesia.

Table 1: Mean Pharmacodynamic Data Following a Range of Cisatracurium Doses

* T1 Single twitch response as well as the first component of the Train-of-four response of the adductor pollicis muscle following supramaximal electrical stimulation of the ulnar nerve.

Enflurane or isoflurane anaesthesia may extend the clinically effective duration of an initial dose of Cisatracurium Besylate by as much as 15%.

Maintenance. Neuromuscular block can be extended with maintenance doses of Cisatracurium Besylate. A dose of 0.03 mg/kg (body weight) provides approximately 20 minutes of additional clinically effective neuromuscular block during opioid or propofol anaesthesia.

Consecutive maintenance doses do not result in progressive prolongation of effect.

Spontaneous Recovery. Once spontaneous recovery from neuromuscular block is underway, the rate is independent of the Cisatracurium Besylate dose administered. During opioid or propofol anaesthesia, the median times from 25 to 75% and from 5 to 95% recovery are approximately 13 and 30 minutes, respectively.

Reversal. Neuromuscular block following Cisatracurium Besylate administration is readily reversible with standard doses of anticholinesterase agents. The mean times from 25 to 75% recovery and to full clinical recovery (T4:T1 ratio > 0.7) are approximately 4 and 9 minutes respectively, following administration of the reversal agent at an average of 10% T1 recovery.

Dosage in paediatric patients

Tracheal Intubation (paediatric patients aged 1 month to 12 years): As in adults, the recommended intubation dose of Cisatracurium Besylate is 0.15 mg/kg (body weight) administered rapidly over 5 to 10 seconds. This dose produces good to excellent conditions for tracheal intubation 120 seconds following injection of Cisatracurium Besylate. Pharmacodynamic data for this dose are presented in the tables 2, 3 and 4.

Cisatracurium Besylate has not been studied for intubation in ASA Class III-IV paediatric patients. There are limited data on the use of Cisatracurium Besylate in paediatric patients under 2 years of age undergoing prolonged or major surgery.

In paediatric patients aged 1 month to 12 years, Cisatracurium Besylate has a shorter clinically effective duration and a faster spontaneous recovery profile than those observed in adults under similar anaesthetic conditions. Small differences in the pharmacodynamic profile were observed between the age ranges 1 to 11 months and 1 to 12 years which are summarised in the tables 2 and 3:

Table 2: Paediatric Patients aged 1 to 11 months

Table 3: Paediatric Patients aged 1 to 12 years

When Cisatracurium Besylate is not required for intubation: A dose of less than 0.15mg/kg can be used. Pharmacodynamic data for doses of 0.08 and 0.1 mg/kg for paediatric patients aged 2 to 12 years are presented in the table 4:

Table 4: Paediatric patients aged 2 to 12 years

Administration of Cisatracurium Besylate following suxamethonium has not been studied in paediatric patients.

Halothane may be expected to extend the clinically effective duration of a dose of Cisatracurium Besylate by up to 20%. No information is available on the use of Cisatracurium Besylate in children during anaesthesia with other halogenated fluorocarbon anaesthetic agents, but these agents may also be expected to extend the clinically effective duration of a dose of Cisatracurium Besylate.

Maintenance (paediatric patients aged 2-12 years). Neuromuscular block can be extended with maintenance doses of Cisatracurium Besylate. In paediatric patients aged 2 to 12 years, a dose of 0.02 mg/kg (body weight) provides approximately 9 minutes of additional clinically effective neuromuscular block during halothane anaesthesia. Consecutive maintenance doses do not result in progressive prolongation of effect.

There are insufficient data to make a specific recommendation for maintenance dosing in paediatric patients under 2 years of age. However, very limited data from clinical studies in paediatric patients under 2 years of age suggest that a maintenance dose of 0.03mg/kg may extend clinically effective neuromuscular block for a period of up to 25 minutes during opioid anaesthesia.

Spontaneous Recovery. Once recovery from neuromuscular block is underway, the rate is independent of the Cisatracurium Besylate dose administered. During opioid or halothane anaesthesia, the median times from 25 to 75% and from 5 to 95% recovery are approximately 11 and 28 minutes, respectively.

Reversal. Neuromuscular block following Cisatracurium Besylate administration is readily reversible with standard doses of anti-cholinesterase agents. The mean times from 25 to 75% recovery and to full clinical recovery (T4:T1 ratio > 0.7) are approximately 2 and 5 minutes respectively, following administration of the reversal agent at an average of 13% T1 recovery.

Use by intravenous infusion

Dosage in adults and children aged 2 to 12 years

Maintenance of neuromuscular block may be achieved by infusion of Cisatracurium Besylate. An initial infusion rate of 3 μg/kg (body weight)/min (0.18 mg/kg/hr) is recommended to restore 89 to 99% T1 suppression following evidence of spontaneous recovery. After an initial period of stabilisation of neuromuscular block, a rate of 1 to 2 μg/kg (body weight)/min (0.06 to 0.12 mg/kg/hr) should be adequate to maintain block in this range in most patients.

Reduction of the infusion rate by up to 40% may be required when Cisatracurium Besylate is administered during isoflurane or enflurane anaesthesia..

The infusion rate will depend upon the concentration of cisatracurium in the infusion solution, the desired degree of neuromuscular block, and the patient's weight. Table 5 provides guidelines for delivery of undiluted Cisatracurium Besylate.

Table 5: Infusion Delivery Rate of Cisatracurium Besylate injection 2mg/ml

Steady rate continuous infusion of Cisatracurium Besylate is not associated with a progressive increase or decrease in neuromuscular blocking effect.

Following discontinuation of infusion of Cisatracurium Besylate, spontaneous recovery from neuromuscular block proceeds at a rate comparable to that following administration of a single bolus.

Dosage in neonates (aged less than 1 month)

The use of Cisatracurium Besylate in neonates is not recommended as it has not been studied in this patient population.

Dosage in elderly patients

No dosing alterations are required in elderly patients. In these patients Cisatracurium Besylate has a similar pharmacodynamic profile to that observed in young adult patients but, as with other neuromuscular blocking agents, it may have a slightly slower onset.

Dosage in patients with renal impairment

No dosing alterations are required in patients with renal failure.

In these patients Cisatracurium Besylate has a similar pharmacodynamic profile to that observed in patients with normal renal function but it may have a slightly slower onset.

Dosage in patients with hepatic impairment

No dosing alterations are required in patients with end-stage liver disease. In these patients Cisatracurium Besylate has a similar pharmacodynamic profile to that observed in patients with normal hepatic function but it may have a slightly faster onset.

Dosage in patients with cardiovascular disease

When administered by rapid bolus injection (over 5 to 10 seconds) to adult patients with serious cardiovascular disease (New York Heart Association Class I-III) undergoing coronary artery bypass graft (CABG) surgery, Cisatracurium Besylate has not been associated with clinically significant cardiovascular effects at any dose studied (up to and including 0.4 mg/kg (8x ED95)). However, there are limited data for doses above 0.3 mg/kg in this patient population).

Cisatracurium Besylate has not been studied in children undergoing cardiac surgery.

Dosage in Intensive Care Unit (ICU) patients

Cisatracurium Besylate may be administered by bolus dose and/or infusion to adult patients in the ICU.

An initial infusion rate of Cisatracurium Besylate of 3 μg/kg (body weight)/min (0.18 mg/kg/hr) is recommended for adult ICU patients. There may be wide interpatient variation in dosage requirements and these may increase or decrease with time. In clinical studies the average infusion rate was 3 μg/kg/min [range 0.5 to 10.2 μg/kg (body weight)/min (0.03 to 0.6mg/kg/hr )]. Table 6 provides guidelines for delivery of undiluted Cisatracurium Besylate Forte (5mg/ml) injection.

The median time to full spontaneous recovery following long-term (up to 6 days) infusion of Cisatracurium Besylate in ICU patients was approximately 50 minutes.

Table 6: Infusion Delivery Rate of Cisatracurium Besylate Forte injection 5mg/ml

The recovery profile after infusions of Cisatracurium Besylate to ICU patients is independent of duration of infusion.

Special precautions for disposal and other handling

This product is for single use only. Use only clear and almost colourless up to slightly yellow/greenish yellow coloured solutions. The product should be visually inspected before use, and if the visual appearance has changed or if the container is damaged, the product must be discarded.

Diluted Cisatracurium Besylate is physically and chemically stable for at least 24 hours at 5°C and 25°C at concentrations between 0.1 and 2 mg/mL in the following infusion fluids, in either polyvinyl chloride or polypropylene containers.

Sodium Chloride (0.9% w/v) Intravenous Infusion.

Glucose (5% w/v) Intravenous Infusion.

Sodium Chloride (0.18% w/v) and Glucose (4% w/v) Intravenous Infusion.

Sodium Chloride (0.45% w/v) and Glucose (2.5% w/v) Intravenous Infusion.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Cisatracurium Besylate has been shown to be compatible with the following commonly used peri-operative drugs, when mixed in conditions simulating administration into a running intravenous infusion via a Y-site injection port: alfentanil hydrochloride, droperidol, fentanyl citrate, midazolam hydrochloride and sufentanil citrate. Where other drugs are administered through the same indwelling needle or cannula as Cisatracurium Besylate, it is recommended that each drug be flushed through with an adequate volume of a suitable intravenous fluid, e.g., Sodium Chloride Intravenous Infusion (0.9% w/v).

As with other drugs administered intravenously, when a small vein is selected as the injection site, Cisatracurium Besylate should be flushed through the vein with a suitable intravenous fluid, e.g., sodium chloride intravenous infusion (0.9% w/v).