Nimbex 2ml. 5ml. 10ml Injection

NIMBEX is used during surgical procedures to relax skeletal muscles and to facilitate controlled ventilation. NIMBEX is suitable for endotracheal intubation especially where subsequent muscle relaxation is required.

Posology
Use by intravenous bolus injection:
Tracheal Intubation : The recommended intubation dose of NIMBEX for adults is 0,15 mg/kg. This dose produces good to excellent conditions for tracheal intubation 120 seconds following injection. Higher doses will shorten the time to onset of neuromuscular block. The following table summarises mean pharmacodynamic data when NIMBEX was administered at doses of 0,1 to 0,4 mg/kg to healthy adult patients during opioid (thiopentone/fentanyl/midazolam) or propofol anaesthesia.

Initial NIMBEX Injection Dose (mg/kg) Anaesthetic Background Time to 90 % T1a Suppression (min) Time to Maximum T1a Suppression (min) Time to 25 % Spontaneous T1a Recovery (min)
0,1 Opioid 3,4 4,8 45
0,15 Propofol 2,6 3,5 55
0,2 Opioid 2,4 2,9 65
0,4 Opioid 1,5 1,9 91
a 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.

Maintenance : Neuromuscular block can be extended with maintenance doses of NIMBEX. A dose of 0,03 mg/kg 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. 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 reversible with standard doses of anticholinesterase medicines. The mean times from 25 to 75 % recovery and to full clinical recovery (T4:T1 ratio u2265 0,7) are approximately 4 and 9 minutes respectively, following administration of the reversal medicine at an average of 10 % T1 recovery.
Paediatric population aged 1 month to 12 years
Tracheal Intubation: As in adults, the recommended intubation dose of NIMBEX is 0,15 mg/kg 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. If a shorter clinical duration is required, pharmacodynamic data suggest that a dose of 0,1 mg/kg may produce similar intubation conditions at 120 to 150 seconds.

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 below.
Paediatric population aged 1 to 11 months
Initial NIMBEX Dose (mg/kg) Anaesthetic Background Time to 90 % Suppression (min) Time to Maximum Suppression (min) Time to 25 % Spontaneous T1 Recovery (min)
0,15 Halothane 1,4 2,0 52
0,15 Opioid 1,4 2,0 47
Paediatric population aged 1 to 12 years
Initial NIMBEX Dose (mg/kg) Anaesthetic Background Time to 90 % Suppression (min) Time to Maximum Suppression (min) Time to 25 % Spontaneous T1 Recovery (min)
0,08 Halothane 1,7 2,5 31
0,1 Opioid 1,7 2,8 28
0,15 Halothane 2,3 3,0 43
0,15 Opioid 2,6 3,6 38
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 isoflurane anaesthesia but these medicines may also be expected to extend the clinically effective duration of a dose of NIMBEX by up to 20 %.
Maintenance : Neuromuscular block can be extended with maintenance doses of NIMBEX. A dose of 0,02 mg/kg provides approximately 9 minutes of additional clinically effective neuromuscular block during halothane anaesthesia. Consecutive maintenance doses do not result in progressive prolongation of effect.
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 reversible with standard doses of anticholinesterase medicines. The mean times from 25 to 75% recovery and to full clinical recovery (T4:T1 ratio u2265 0,7) are approximately 2 and 5 minutes respectively, following administration of the reversal medicine at an average of 13% T1 recovery.
Use by intravenous infusion:
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 u03bcg/kg/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 u03bcg/kg/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. The following table provides guidelines for delivery of undiluted NIMBEX.
Infusion Delivery Rate of NIMBEX 2 mg/ml Patient Weight (kg) Dose (u03bcg/kg/min) Infusion Rate 1,0 1,5 2,0 3,0
20 0,6 0,9 1,2 1,8 ml/hr
70 2,1 3,2 4,2 6,3 ml/hr
100 3,0 4,5 6,0 9,0 ml/hr
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.
Neonates aged less than 1 month: No dosage recommendation for neonates can be made until further information becomes available.
Special populations
Elderly population
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 medicines, it may have a slightly slower onset.
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.
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.
Cardiovascular disease
NIMBEX has been used to provide neuromuscular block in patients undergoing cardiac surgery. When administered by rapid bolus injection (over 5 to 10 seconds) to patients with serious cardiovascular disease, NIMBEX has not been associated with clinically significant cardiovascular effects in any dose studied (up to and including 0,4 mg/kg (8x ED95).
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 u03bcg/kg/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 u03bcg/kg/min range 0,5 to 10,2 u03bcg/kg/min (0,03 to 0,6 mg/kg/h). The median time to full spontaneous recovery following long-term (up to 6 days) infusion of NIMBEX in ICU patients was approximately 50 minutes.
Infusion Delivery Rate of NIMBEX 5 mg/ml Patient Weight (kg) Dose (u03bcg/kg/min) Infusion Rate 1,0 1,5 2,0 3,0
70 0,8 1,2 1,7 2,5 ml/hr
100 1,2 1,8 2,4 3,6 ml/hr
The recovery profile after infusions of NIMBEX to ICU patients is independent of duration of infusion.
Patients undergoing hypothermic cardiac surgery
There have been no studies of NIMBEX in patients undergoing surgery with induced hypothermia (25 to 28 u00b0C). The rate of infusion required to maintain adequate surgical relaxation under these conditions may be expected to be significantly reduced.

NIMBEX is contraindicated in:
u2022 Patients with hypersensitivity to cisatracurium, atracurium, or benzenesulphonic acid or to any excipients in NIMBEX (see section 6.1).
u2022 Pregnancy and lactation, as the use and safety of NIMBEX has not been established in women who are pregnant and breastfeeding.
u2022 Neonates, as NIMBEX has not been studied in this patient population.

Hypersensitivity
CISATRACURIUM, AS IN NIMBEX, PARALYSES THE RESPIRATORY MUSCLES AS WELL AS OTHER SKELETAL MUSCLES BUT HAS NO EFFECT ON CONSCIOUSNESS OR PAIN THRESHOLD. NIMBEX SHOULD ONLY BE ADMINISTERED BY OR UNDER THE SUPERVISION OF AN ANAESTHETIST OR OTHER CLINICIANS WHO ARE FAMILIAR WITH THE USE AND ACTION OF NEUROMUSCULAR BLOCKING MEDICINES. FACILITIES FOR TRACHEAL INTUBATION, AND MAINTENANCE OF PULMONARY VENTILATION AND ADEQUATE ARTERIAL OXYGENATION MUST BE AVAILABLE. MONITORING OF NEUROMUSCULAR FUNCTION IS RECOMMENDED DURING THE USE OF NIMBEX IN ORDER TO INDIVIDUALISE DOSAGE REQUIREMENTS.

Great caution should be exercised when administering NIMBEX to patients who have shown allergic hypersensitivity to other neuromuscular blocking medicines since a high rate of cross-reactivity (greater than 50%) between neuromuscular blocking medicines has been reported (see section 4.3).

Product specific topics
Cisatracurium, as NIMBEX, does not have significant vagolytic or ganglion-blocking properties. Consequently, NIMBEX has no clinically significant effect on heart rate and will not counteract the bradycardia produced by many anaesthetic medicines 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 medicines. An initial dose of not more than 0,02 mg/kg NIMBEX is recommended in these patients.

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

NIMBEX 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.

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

NIMBEX is hypotonic and must not be administered into the infusion line of a blood transfusion.

Many medicines have been shown to influence the magnitude and/or duration of action of non-depolarising neuromuscular blocking medicines, including the following:

Increased effect:
Anaesthetics: Volatile medicines such as enflurane, isoflurane and halothane; Ketamine.
Other non-depolarising neuromuscular blocking medicines.
Other medicines:
Antibiotics, including the aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin and clindamycin.
Antidysrhythmic medicines, including propranolol, calcium channel blockers, lignocaine, procainamide, and quinidine.
Diuretics, including furosemide and possibly thiazides, mannitol and acetazolamide.
Magnesium salts.
Lithium salts.
Ganglion blocking medicines: trimetaphan, hexamethonium.

Rarely, certain medicines may aggravate or unmask latent myasthenia gravis or actually induce a myasthenic syndrome; increased sensitivity to non-depolarising neuromuscular blocking medicines might result. Such medicines include various antibiotics, beta-blockers (propranolol, oxprenolol), antidysrhythmic medicines (procainamide, quinidine), anti-rheumatic medicines (chloroquine, D-penicillamine), trimetaphan, chlorpromazine, steroids, phenytoin and lithium.

Administration of suxamethonium to prolong the effects of non-depolarising neuromuscular blocking medicines may result in a prolonged and complex block which can be difficult to reverse with anticholinesterases.

Decreased effect:
Phenytoin, carbamazepine: a decreased effect is seen after prior chronic administration of phenytoin or carbamazepine.
Anticholinesterases: Treatment with anticholinesterases such as donepezil, commonly used in the treatment of Alzheimer's disease may shorten the duration and diminish the magnitude of neuromuscular blockade with cisatracurium, as in NIMBEX.

No effect:
Suxamethonium: Prior administration of suxamethonium has no effect on the duration of neuromuscular block following bolus doses of NIMBEX or on infusion rate requirements.

The use of NIMBEX is contraindicated in pregnancy and lactation (see section 4.3.)
Pregnancy
There are no adequate data from the use of NIMBEX in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition, and postnatal development. The potential risk for humans is unknown. NIMBEX should not be used during pregnancy (see section 4.3).
Breastfeeding
It is not known whether cisatracurium, as in NIMBEX, or its metabolites are excreted in human milk. A risk to the breastfed infant cannot be excluded. As a precaution breastfeeding should be discontinued during treatment with NIMBEX.
Fertility
Fertility studies have not been performed.

This precaution is not relevant to the use of NIMBEX. NIMBEX will always be used in combination with a general anaesthetic and therefore the usual precautions relating to performance of tasks following general anaesthesia apply. NIMBEX has minor influence on the ability to drive or operate machinery.
Patients should not drive, use machinery or perform any tasks that require concentration until they are certain that NIMBEX does not adversely affect their ability to do so safely (see section 4.8).

a) Summary of the safety profile
No adverse experiences occurred during the clinical development programme that were considered to be reasonably attributable to NIMBEX. Adverse experiences, considered possibly attributable, occurred with a frequency of less than 0,5 %. These were cutaneous flushing or rash, bradycardia, hypotension and bronchospasm.

b) Tabulated list of adverse reactions
System organ class Common Uncommon Very Rare
Immune system disorders Anaphylactic reaction, anaphylactic shock
Cardiac disorders Bradycardia
Vascular disorders Hypotension Cutaneous flushing
Respiratory, thoracic and mediastinal disorders Bronchospasm
Skin and subcutaneous tissue disorders Rash
Musculoskeletal and connective tissue disorders Myopathy, muscle weakness

c) Description of selected adverse reactions
Immune system disorders
Anaphylactic reactions of varying degrees of severity have been observed after the administration of neuromuscular blocking medicines, including anaphylactic shock.

Severe anaphylactic reactions have been reported in patients receiving NIMBEX in conjunction with one or more anaesthetics.

Musculoskeletal and connective tissue disorders
There have been some reports of persistent muscle weakness and/or myopathy following prolonged use of NIMBEX in severely ill patients in the ICU. Most patients were receiving concomitant corticosteroids. These events have been reported infrequently in association with cisatracurium, as in NIMBEX, and a causal relationship has not been established.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to: SAHPRA: https://www.sahpra.org.za/health-products-vigilance/ Aspen Pharmacare: E-mail: [email protected] Tel: 0800 118 088/ +27 (0)11 239-6200

Symptoms
Prolonged muscle paralysis and its consequences are expected to be the main signs of overdosage with NIMBEX.
Treatment
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 anticholinesterase medicines once evidence of spontaneous recovery is present.