NIMBEX Solution for injection / infusion Ref.[2659] Active ingredients: Cisatracurium

Nimbex 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 Nimbex 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).

Nimbex 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 Nimbex in order to individualise dosage requirements.

Use by intravenous bolus injection

Dosage in adults

Tracheal Intubation

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

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

Table 1 summarises mean pharmacodynamic data when Nimbex 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.

^* 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 Nimbex by as much as 15%.

Maintenance

Neuromuscular block can be extended with maintenance doses of Nimbex. 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 Nimbex 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 Nimbex 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 Nimbex 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 Nimbex. Pharmacodynamic data for this dose are presented in the tables below.

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

In paediatric patients aged 1 month to 12 years, Nimbex 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 Nimbex 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 Nimbex 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 Nimbex by up to 20%. No information is available on the use of Nimbex 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 Nimbex.

Maintenance (paediatric patients aged 2-12 years)

Neuromuscular block can be extended with maintenance doses of Nimbex. 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 Nimbex 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 Nimbex 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 Nimbex. 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 Nimbex 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. Table 5 provides guidelines for delivery of undiluted Nimbex.

Table 5. Infusion Delivery Rate of Nimbex injection 2mg/ml:

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

Following discontinuation of infusion of Nimbex, 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 Nimbex 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 Nimbex 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 Nimbex 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 Nimbex 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, Nimbex 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).

Nimbex has not been studied in children undergoing cardiac surgery.

Dosage in Intensive Care Unit (ICU) patients

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

An initial infusion rate of Nimbex 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 Nimbex Forte (5mg/ml) injection.

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

Table 6. Infusion Delivery Rate of Nimbex Forte injection 5 mg/ml:

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

h3, Symptoms and signs

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

h3, 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 Nimbex. Recovery may be accelerated by the administration of anti-cholinesterase agents once evidence of spontaneous recovery is present.

Shelf life before dilution: 2 years.

Chemical and physical in-use stability has been demonstrated for at least 24 hours at 5°C and 25°C (see section 6.6).

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 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C to 8°C). Do not freeze.

Store in the original package in order to protect from light

For storage conditions of the diluted medicinal product see section 6.3.

Nimbex 2mg/ml solution for injection/infusion:

2.5ml in ampoule (glass): box of 5.
5ml in ampoule (glass): box of 5.
10ml in ampoule (glass): box of 5.
25ml in ampoule (glass: box of 2.

Type I, clear, neutral glass ampoules.

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 has changed or if the container is damaged, the product must be discarded.

Diluted Nimbex 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.

However, since the product contains no antimicrobial preservative, dilution should be carried out immediately prior to use, or failing this be stored as directed under section 6.3.

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

Nimbex 2 mg/ml solution for injection/infusion

Instructions to open the ampoule (only applicable to 2mg/ml ampoule)

Ampoules are equipped with the OPC (One Point Cut) opening system and must be opened following the below instructions:

• Hold with the hand the bottom part of the ampoule as indicated in picture 1.
• Put the other hand on the top of the ampoule positioning the thumb above the coloured point and press as indicated in picture 2.

Picture 1

Picture 2