CISATRACURIUM Solution for injection/infusion Ref.[6709] Active ingredients: Cisatracurium

Cisatracurium 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.

Cisatracurium 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 (see section 6.2).

This medicinal product 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 in order to individualise dosage requirements.

Use by intravenous bolus injection

Dosage in adults

Tracheal Intubation

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

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

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

* T 1 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 by as much as 15%.

Maintenance

Neuromuscular block can be extended with maintenance doses of cisatracurium. 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 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 administration is readily reversible with standard doses of anticholinesterase agents. The mean times from 25 to 75% recovery and to full clinical recovery (T^T ratio >0.7) are approximately 4 and 9 minutes respectively, following administration of the reversal agent at an average of 10% T recovery.

Dosage in paediatric patients

Tracheal Intubation (paediatric patients aged 1 month to 12 years)

As in adults, the recommended intubation dose of cisatracurium 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. Pharmacodynamic data for this dose are presented in the tables below.

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

In paediatric patients aged 1 month to 12 years, cisatracurium 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 below.

Paediatric Patients aged 1 to 11 months:

Paediatric Patients aged 1 to 12 years:

When cisatracurium is not required for intubation: A dose of less than 0.15 mg/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 below:

Administration of cisatracurium following suxamethonium has not been studied in paediatric patients (see section 4.5).

Halothane may be expected to extend the clinically effective duration of a dose of cisatracurium by up to 20%. No information is available on the use of cisatracurium 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.

Maintenance (paediatric patients aged 2-12 years)

Neuromuscular block can be extended with maintenance doses of cisatracurium. 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 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 administration is readily reversible with standard doses of anti-cholinesterase agents. The mean times from 25 to 75% recovery and to full clinical recovery (T4T1 ratio >0.7) are approximately 2 and 5 minutes respectively, following administration of the reversal agent at an average of 13% T 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. An initial infusion rate of 3 μg/kg (body weight)/min (0.18 mg/kg/hr) is recommended to restore 89 to 99% T 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 is administered during isoflurane or enflurane anaesthesia (see section 4.5).

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. The following table provides guidelines for delivery of undiluted cisatracurium.

Infusion Delivery Rate of Cisatracurium injection 2 mg/ml:

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

Following discontinuation of infusion of cisatracurium, 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 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 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 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 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 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 has not been studied in children undergoing cardiac surgery.

Dosage in Intensive Care Unit (ICU) patients

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

An initial infusion rate of cisatracurium 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 0.6 mg/kg/hr)]

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

Infusion Delivery Rate of Cisatracurium injection 5 mg/ml:

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

Prolonged muscle paralysis and its consequences are expected to be the main signs of overdosage with this medicinal product.

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 this medicinal product. Recovery may be accelerated by the administration of anti-cholinesterase agents once evidence of spontaneous recovery is present.

Shelf life

As packaged for sale: 24 months.

Shelf life after dilution: Chemical and physical in-use stability has been demonstrated for 24 hours at 5°C and 25°C at concentrations of 0.1 and 2 mg/ml in PVC infusion bags.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C-8°C). Do not freeze. Keep vials in the outer carton in order to protect from light.

For storage conditions for the diluted solution, see section 6.3.

Clear Type I glass vials with rubber stopper; packs of 1 and 5 vials.

Not all pack sizes may be marketed.

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 differs from the above description or if the container is damaged, the product must be discarded.

This medicinal product may be diluted to concentrations between 0.1 and 2 mg/ml with the following infusion solutions:

Sodium Chloride (0.9% w/v) IV Infusion
Glucose (5% w/v) IV Infusion
Sodium Chloride (0.18% w/v) and Glucose (4% w/v) IV infusion
Sodium Chloride (0.45% w/v) and Glucose (2.5% w/v) IV infusion

Since the product contains no antimicrobial preservative, dilution should be carried out immediately prior to use, or failing this, the diluted solution should be stored as directed in section 6.3.

Cisatracurium 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 this medicinal product, 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 should be flushed through the vein with a suitable intravenous fluid, e.g., sodium chloride intravenous infusion (0.9% w/v).