Consumer medicine information

Cisatracurium-AFT Injection

Cisatracurium

BRAND INFORMATION

Brand name

Cisatracurium-AFT

Active ingredient

Cisatracurium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cisatracurium-AFT Injection.

What is in this leaflet

This leaflet answers some common questions about CISATRACURIUM-AFT. It does not contain all of the available information.

Reading this leaflet does not take the place of talking to your doctor or pharmacist.

Taking any medicine involves some risk. It is possible that all risks associated with this medicine might not have been detected, despite proper testing. Only your doctor or pharmacist is able to weigh up all of the relevant facts, and you should consult them if you have any queries.

If you have any concerns about the use of CISATRACURIUM-AFT ask your doctor or pharmacist.

Keep this information. You may want to read it again.

This leaflet provides information about CISATRACURIUM-AFT. This information should not be applied to any other medicine, even those that are similar or appear to contain the same ingredients.

What CISATRACURIUM-AFT is used for

CISATRACURIUM-AFT is used to relax the body's muscles. CISATRACURIUM-AFT will normally be given to you when you are in surgery, or during other medical procedures. CISATRACURIUM-AFT is only used in conjunction with an anaesthetic, so you will be asleep during the procedure.

If you have any questions about why CISATRACURIUM-AFT is used ask your doctor.

How does CISATRACURIUM-AFT work?

Cisatracurium besilate (the active ingredient in CISATRACURIUM-AFT) belongs to a group of medicines called "neuromuscular blockers".

CISATRACURIUM-AFT works by blocking the effects of one of the body's chemical messengers called acetylcholine. Acetylcholine is involved in muscle contraction.

By relaxing your body's muscles CISATRACURIUM-AFT makes it easier for you to be kept asleep (under anaesthesia) or sedation.

Your doctor will be able to provide you with more information.

Before you are given CISATRACURIUM-AFT

CISATRACURIUM-AFT is not suitable for everyone.

Before CISATRACURIUM-AFT is used make sure that your doctor knows if:

  1. You are allergic to:
  • cisatracurium besilate, atracurium or benzenesulfonic acid.
  • any other muscle relaxants.
  1. You are pregnant or breastfeeding.
  2. You suffer from myasthenia gravis, or any other form of neuromuscular disease.
  3. You or a relative have had previous difficulties with anaesthetics.
  4. You are allergic to any other muscle relaxant medicine.
  5. You are taking any other medication, including:
  • Antibiotics.
  • Anti-arrhythmics, which are used to control irregular or rapid heart beat.
  • Diuretics, used to increase your volume of urine. These may be taken to reduce oedema (swelling).
  • Magnesium or lithium salts.
  • Phenytoin or carbamazepine (for fits).
  • Any other medicine that you are taking including any you may buy without a prescription from a pharmacy, supermarket or health food shop.

Your doctor will have a complete list of the medicines that may cause problems when taken with CISATRACURIUM-AFT.

When CISATRACURIUM-AFT must not be used

CISATRACURIUM-AFT should not be used after the expiry date printed on the pack.

Using CISATRACURIUM-AFT

CISATRACURIUM-AFT is a medicine that is given by injection. CISATRACURIUM-AFT will be administered by an anaesthetist or other highly trained doctor, usually during surgery or other medical procedures. The dosage will vary according to many factors such as your body weight and how long the procedure will take.

If you have any questions about the dose that you will receive ask your doctor.

In case of overdose

Overdoses of CISATRACURIUM-AFT lead to prolonged relaxation of the body's muscles. This can be readily treated, however, this situation is unlikely to occur because CISATRACURIUM-AFT is only administered by an anaesthetist or other highly trained doctor who will closely monitor your progress.

After being treated with CISATRACURIUM-AFT

Your doctor will be able to tell you whether there are any special instructions after you have been treated with CISATRACURIUM-AFT.

Side Effects

All medicines can have side effects. Sometimes they are serious. Most of the time they are not.

Tell your doctor or pharmacist as soon as possible if you do not feel well after you have been given CISATRACURIUM-AFT.

It is possible that CISATRACURIUM-AFT may cause the following side effects:

  • Flushing of the face and upper body.
  • Skin rashes.
  • Slow heart beat.
  • Low blood pressure.
  • Difficulty breathing.

During studies using cisatracurium less than one patient in every 200 treated experienced these side effects.

Ask your doctor or pharmacist to answer any questions you may have.

There is no evidence that CISATRACURIUM-AFT is addictive.

Storage

CISATRACURIUM-AFT will be stored by the hospital's pharmacy at between 2 °C and 8 °C (in the refrigerator. Do not freeze. Protect from light.

CISATRACURIUM-AFT does not contain any antimicrobial preservative. When diluted, the preparation should be used immediately and any remaining solution must be discarded within 24 hours following dilution.

Product description

What CISATRACURIUM-AFT looks like

CISATRACURIUM-AFT is a colourless to pale yellow or greenish yellow solution.

CISATRACURIUM-AFT is available as:

5 mg/2.5 mL in glass ampoules: AUST R 191832

10 mg/ 5mL in glass ampoules: AUST R 191831

20 mg/10 mL in glass ampoules: AUST R 191833

150 mg/30 mL in glass vials: AUST R 191834

Ingredients

CISATRACURIUM-AFT 5 mg/2.5 mL, 10 mg/5 mL, and 20 mg/10 mL contains cisatracurium besilate equivalent to 2 mg cistracurium in every mL.

CISATRACURIUM-AFT 150 mg/30 mL contains cisatracurium besilate equivalent to 5 mg cisatracuriumin every mL.

CISATRACURIUM-AFT also contains:

  • Benzene sulfonic acid, and
  • Water for Injections.

Manufacturer

CISATRACURIUM-AFT is supplied in Australia by:

AFT Pharmaceuticals Pty Ltd
113 Wicks Road
North Ryde NSW 2113

10 December 2019

Published by MIMS February 2020

BRAND INFORMATION

Brand name

Cisatracurium-AFT

Active ingredient

Cisatracurium

Schedule

S4

 

1 Name of Medicine

Cisatracurium besilate.

2 Qualitative and Quantitative Composition

Cisatracurium-AFT is supplied in two strengths, either 2 mg or 5 mg (as the besilate salt) of cisatracurium besilate per mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cisatracurium-AFT is a colourless to pale yellow or greenish yellow solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Cisatracurium-AFT is indicated for use during surgical and other procedures and in intensive care to relax skeletal muscles, and to facilitate tracheal intubation and mechanical ventilation. It is used as an adjunct to general anaesthesia, or sedation in the intensive care unit.

4.2 Dose and Method of Administration

Cisatracurium-AFT contains no antimicrobial preservative and is intended for single use in one patient only. Discard any residue.

Use by intravenous bolus injection.

Dosage in adults.

Tracheal intubation.

The recommended intubation dose of Cisatracurium-AFT for adults is 0.15 mg/kg bodyweight. 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. Table 1 summarises mean pharmacodynamic data when cisatracurium was administered at doses of 0.1 to 0.4 mg/kg bodyweight to healthy adult patients during opioid (thiopentone/ fentanyl/ midazolam) or propofol anaesthesia.
Enflurane or isoflurane anaesthesia may extend the clinically effective duration of an initial dose of Cisatracurium-AFT by as much as 15%.

Maintenance.

Neuromuscular block can be extended with maintenance doses of Cisatracurium-AFT. A dose of 0.03 mg/kg bodyweight 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 administered dose of Cisatracurium-AFT. 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 the administration of Cisatracurium-AFT is readily reversible with standard doses of anticholinesterase agents. Following the administration of the reversal agent at an average of 10% T1 recovery, 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.
Dosage in paediatric patients ages 1 month to 12 years.

Tracheal intubation.

As in adults, the recommended intubation dose of Cisatracurium-AFT is 0.15 mg/kg bodyweight administered rapidly over 5 to 10 seconds. This dose produces good to excellent conditions for tracheal intubation 120 seconds following injection of Cisatracurium-AFT. Pharmacodynamic data for this dose are presented in Tables 3 and 4. If a shorter clinical duration is required, pharmacodynamic data suggest that a dose of 0.1 mg/kg bodyweight may produce similar intubation conditions at 120 to 150 seconds.
In paediatric patients aged 1 month to 12 years, Cisatracurium-AFT has a shorter clinically effective duration and a faster spontaneous recovery profile than those observed with 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 Tables 2 and 3. Younger children (1-11 months old) demonstrated a longer mean clinical effective duration, as compared to the older children. However, there was no significant difference in the mean 25-75% recovery indices between the age groups.
Data in the above tables are derived from study 139-027, an open label study in ASA I/II paediatric patients aged 1 month to 12 years. For data presented, patients were randomised to N2O/O2/ halothane (n = 90) or N2O/O2/ opioid (n = 89) anaesthesia. Within each anaesthetic group patients were stratified into three age groups; 1-11 months, 12-59 months or 60-155 months. Neuromuscular blocking profile was assessed at the adductor pollicis by electromyography.

When Cisatracurium-AFT 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 Table 4.
Data in the above table are derived from an open-label study in ASA I/II paediatric patients aged 2-12 years. Neuromuscular block was assessed at the adductor pollicis by electromyography.
Halothane may be expected to extend the clinically effective duration of a dose of Cisatracurium-AFT by up to 20%. No information is available on the use of Cisatracurium-AFT in children during isoflurane or enflurane anaesthesia but these agents may also be expected to extend the clinically effective duration of a dose of Cisatracurium-AFT by up to 20%.

Maintenance.

Neuromuscular block can be extended with maintenance doses of Cisatracurium-AFT. A dose of 0.02 mg/kg bodyweight 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.

During opioid anaesthesia the median times from 25 to 75% and from 5 to 95% recovery are approximately 10 and 25 minutes respectively.

Reversal.

Neuromuscular block following the administration of Cisatracurium-AFT is readily reversible with standard doses of anticholinesterase agents. Following the administration of the reversal agent at an average of 13% T1 recovery, 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.

Use by intravenous infusion.

Dosage in adults and paediatric patients aged 1 month to 12 years.

Maintenance of neuromuscular block may be achieved by infusion of Cisatracurium- AFT. An initial infusion rate of 3 microgram/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 microgram/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 Cisatracurium-AFT is administered during isoflurane or enflurane anaesthesia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The infusion rate will depend upon the concentration of cisatracurium besilate in the infusion solution, the desired degree of neuromuscular block and the patient's weight. Table 5 provides guidance for delivery of undiluted Cisatracurium-AFT 2 mg/mL.
Continuous infusion of Cisatracurium-AFT is not associated with a progressive increase or decrease in neuromuscular blocking effect.
Following discontinuation of infusion of Cisatracurium-AFT spontaneous recovery from neuromuscular block proceeds at a rate comparable to that following administration of a single bolus injection.

Dosage in neonates aged less than 1 month.

No dosage recommendation for neonates can be made as administration of cisatracurium has not been studied in this patient population.

Dosage in intensive care unit (ICU) patients.

Cisatracurium-AFT may be administered by bolus dose and/or infusion to adult patients in the ICU.
An initial infusion rate of Cisatracurium-AFT of 3 microgram/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 microgram/kg/min (range 0.5 to 10.2 microgram/kg/min or 0.03 to 0.6 mg/kg/hr). (See Table 6).
The median time to full spontaneous recovery following long-term (up to 6 days) infusion of cisatracurium in ICU patients was approximately 50 minutes.
The recovery profile after infusion of Cisatracurium-AFT to ICU patients is independent of the duration of infusion.

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, however 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.

Patients with cardiovascular disease.

Cisatracurium has been used effectively 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, cisatracurium has not been associated with clinically significant cardiovascular effects at any dose studied (up to and including 0.4 mg/kg (8 x ED95)).

Dosage in patients undergoing hypothermic cardiac surgery.

There have been no studies of Cisatracurium-AFT 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.
Monitoring. As with other neuromuscular blocking agents, monitoring of neuromuscular function is recommended during the use of Cisatracurium-AFT in order to individualise dosage requirements.

Instructions for use.

Physical compatibilities.

Diluted Cisatracurium-AFT is chemically and physically stable for at least 12 hours, when stored in either polyvinyl chloride or polypropylene containers, at concentrations between 0.1 and 2.0 mg/mL in the following infusion solutions:
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.
The product contains no antimicrobial preservative and therefore should be used immediately on dilution, or failing this should be stored at 2 to 8°C for no more than 24 hours, after which time unused solution should be discarded. Dilution should, therefore, be carried out immediately prior to use. Administration should commence as soon as possible thereafter and any remaining solution should be discarded. Containers of Cisatracurium-AFT and any syringe containing Cisatracurium-AFT are for single use in individual patients. At the end of the procedure or at 24 hours following preparation, whichever is the sooner, both the reservoir of Cisatracurium-AFT and the infusion line must be discarded and replaced as appropriate.
Cisatracurium has been shown to be compatible with the following commonly used perioperative 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.
Where other drugs are administered through the same indwelling needle or cannula as Cisatracurium-AFT, 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).

4.3 Contraindications

Cisatracurium-AFT is contraindicated in patients known to be hypersensitive to cisatracurium besilate, atracurium or benzenesulfonic acid.

4.4 Special Warnings and Precautions for Use

Cisatracurium besilate paralyses the respiratory muscles as well as other skeletal muscles but has no effect on consciousness or pain threshold. Cisatracurium-AFT 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 should be available.
Little information is available on the plasma levels and clinical consequences of cisatracurium metabolites that may accumulate during days to weeks of cisatracurium administration in ICU patients. Laudanosine, a major biologically active metabolite of atracurium and cisatracurium without neuromuscular blocking activity, produces transient hypotension and, in higher doses, cerebral excitatory effects (generalised muscle twitching and seizures) when administered to several species of animals. Consistent with the decreased infusion rate requirements of cisatracurium, plasma laudanosine concentrations are approximately one third those following atracurium infusion. There have been rare spontaneous reports of seizures in ICU patients who have received atracurium and other agents. These patients usually had predisposing causes (such as cranial trauma, cerebral oedema, hypoxic encephalopathy, viral encephalitis, uraemia). There are insufficient data to determine whether or not laudanosine contributes to seizures in ICU patients.
Caution should be exercised when administering Cisatracurium-AFT to patients who have shown allergic hypersensitivity to other neuromuscular blocking agents since a high rate of cross sensitivity (greater than 50%) between neuromuscular agents has been reported.
Cisatracurium besilate does not have significant vagolytic or ganglion blocking properties. Consequently, Cisatracurium-AFT 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 nondepolarising blocking agents. An initial dose of not more than 0.02 mg/kg bodyweight cisatracurium besilate is recommended in these patients.
Rarely, certain drugs may aggravate or unmask latent myasthenia gravis or actually induce a myasthenic syndrome. Increased sensitivity to nondepolarising neuromuscular blocking agents might result (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Severe acid-base and/or serum electrolyte abnormalities may increase or decrease the sensitivity of patients to neuromuscular blocking agents.
Cisatracurium besilate has not been studied in patients with a history of malignant hyperthermia. Studies in malignant hyperthermia susceptible pigs indicated that cisatracurium besilate does not trigger this syndrome.
Patients with burns have been shown to develop resistance to nondepolarising neuromuscular blocking agents, including atracurium. The extent of altered response depends upon the size of the burn and the time elapsed since the burn injury. Cisatracurium has not been studied in patients with burns, however, based on its structural similarity to atracurium, the possibility of increased dosing requirements and shortened duration of action must be considered if Cisatracurium-AFT is administered to burn patients.
As with other neuromuscular blocking agents, monitoring of neuromuscular function is recommended during the use of Cisatracurium-AFT in order to individualise dosage requirements.
As with other drugs administered intravenously, when a small vein is selected as the injection site, Cisatracurium-AFT should be flushed through the vein with a suitable intravenous fluid (e.g. sodium chloride intravenous solution 0.9% w/v).
Cisatracurium-AFT does not contain an antimicrobial preservative. Dilution should, therefore, be carried out immediately prior to use. Administration should commence as soon as possible thereafter and any remaining solution should be discarded (see Section 4.2 Dose and Method of Administration, Instructions for use).
Cisatracurium-AFT is hypotonic and must not be administered into the infusion line of a blood transfusion.
Enflurane or isoflurane anaesthesia may extend the clinically effective duration of an initial dose of Cisatracurium-AFT by as much as 15% in adults. In children, halothane may be expected to extend the clinically effective duration of a dose of Cisatracurium-AFT by up to 20%. No information is available on the use of Cisatracurium-AFT in children during isoflurane or enflurane anaesthesia but these agents may also be expected to extend the clinically effective duration of a dose of Cisatracurium-AFT by up to 20%.

Use in elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

None known.

4.5 Interactions with Other Medicines and Other Forms of Interactions

A number of drugs have been shown to influence the magnitude and/or duration of action of nondepolarising neuromuscular blocking agents.
The following drugs have been shown to increase the effects of nondepolarising neuromuscular blocking agents.
Anaesthetics: volatile anaesthetics such as enflurane, isoflurane and halothane (see Section 4.4 Special Warnings and Precautions for Use).
Ketamine.
Other nondepolarising neuromuscular blocking agents.
Antibiotics, including: the aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin and clindamycin.
Antiarrhythmic drugs, including: propranolol, calcium channel blockers, lignocaine, procainamide and quinidine.
Diuretics, including: frusemide and possibly thiazides, mannitol and acetazolamide.
Magnesium salts.
Lithium salts.
Ganglion blocking drugs (trimetaphan, hexamethonium).
Prior chronic administration of phenytoin or carbamazepine has been shown to decrease the effects of nondepolarising neuromuscular blocking agents.
Prior administration of suxamethonium has no effect on the duration of neuromuscular block following bolus doses of cisatracurium or on infusion rate requirements.
Administration of suxamethonium to prolong the effects of nondepolarising neuromuscular blocking agents may result in a prolonged and complex block which can be difficult to reverse with anticholinesterases.
Rarely, certain drugs may aggravate or unmask latent myasthenia gravis or actually induce a myasthenic syndrome. Increased sensitivity to nondepolarising neuromuscular blocking agents might result. Such drugs include various antibiotics, beta-blockers (propranolol, oxprenolol), antiarrhythmic drugs (procainamide, quinidine), antirheumatic drugs (chloroquine, penicillamine), trimetaphan, chlorpromazine, steroids, phenytoin and lithium.
Treatment with anticholinesterases, commonly used in the treatment of Alzheimer's disease, e.g. donepezil, may shorten the duration and diminish the magnitude of neuromuscular blockade with cisatracurium.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
Teratology studies in nonventilated pregnant rats treated subcutaneously with maximum subparalysing doses (4 mg/kg daily) and in ventilated rats treated intravenously with paralysing doses of cisatracurium (1.0 mg/kg), respectively, revealed no foetal toxicity or teratogenic effects. There are no adequate and well controlled studies of cisatracurium in pregnant women. Because animal studies are not always predictive of human response, cisatracurium should be used during pregnancy only if clearly needed.
Doses of 0.2 or 0.4 mg/kg cisatracurium given to female beagles undergoing caesarean section resulted in negligible levels of cisatracurium in umbilical vessel blood of neonates and no deleterious effects on the puppies.
 Studies have not been conducted to determine whether cisatracurium or its metabolites are excreted in human or animal milk.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Observed in clinical trials of surgical patients.

No adverse experiences considered to be reasonably attributable to cisatracurium were reported amongst 937 surgical patients studied during the clinical development programme. The following adverse experiences were judged by investigators during the clinical trials to have a possible causal relationship to administration of cisatracurium.

Incidence greater than 1%.

None.

Incidence less than 1%.

Cardiovascular: bradycardia (0.4%), hypotension (0.2%), flushing (0.2%).
Respiratory: bronchospasm (0.2%).
Dermatological: rash (0.1%).

Observed in clinical trials of intensive care unit patients.

Three adverse experiences were reported among 68 ICU patients administered cisatracurium in conjunction with other drugs in clinical studies. One patient experienced bronchospasm, considered possibly attributable to cisatracurium. In one of the two ICU studies, a randomised and double blind study of ICU patients using TOF neuromuscular monitoring, there were two reports of prolonged recovery (167 and 270 minutes) among 28 patients administered cisatracurium and 13 reports of prolonged recovery (range: 90 minutes to 33 hours) among 30 patients administered vecuronium.

Observed during clinical practice.

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of cisatracurium besilate in conjunction with one or more anaesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to cisatracurium besilate.

Hypersensitivity.

Very rarely: severe anaphylactic reactions have been reported in patients receiving cisatracurium in conjunction with one or more anaesthetic agents.
Anaphylactic reactions of varying degrees of severity have been observed after the administration of neuromuscular blocking agents.

Other reported reactions.

There have been some reports of muscle weakness and/or myopathy following prolonged use of muscle relaxants, including cisatracurium, in severely ill patients in the ICU. Most patients were receiving concomitant corticosteroids.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms and signs.

Prolonged muscle paralysis and its consequences are expected to be the main signs of overdose with Cisatracurium-AFT.

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-AFT. Recovery may be accelerated by the administration of anticholinesterase agents once evidence of spontaneous recovery is present.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Cisatracurium besilate, a stereoisomer of atracurium, is an intermediate duration, nondepolarising benzylisoquinolinium skeletal muscle relaxant. Cisatracurium besilate 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 anticholinesterase agents such as neostigmine.
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 besilate is estimated to be 0.05 mg/kg bodyweight during opioid anaesthesia (thiopentone, fentanyl, midazolam). The recommended intubation dose for cisatracurium in adults is 3 x ED95, which has a longer clinically effective duration than the recommended intubation dose of atracurium (2 x ED95) (see Section 4.2 Dose and Method of Administration).
The ED95 of cisatracurium besilate in children during halothane anaesthesia is 0.04 mg/kg bodyweight.
Cisatracurium besilate undergoes degradation in the body at physiological pH and temperature by Hofmann elimination to form laudanosine and the monoquaternary acrylate metabolite. The monoquaternary acrylate undergoes hydrolysis by nonspecific plasma esterases to form the monoquaternary alcohol metabolite. Elimination of cisatracurium besilate 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.

Clinical trials.

The cisatracurium clinical development programme was constructed to provide for systematic collection of efficacy and safety data and to ensure exposure to therapeutically relevant doses of cisatracurium in various populations of patients undergoing a diversity of surgical procedures during opioid, propofol or inhalation anaesthesia as well as ICU patients who require neuromuscular blocking agents to facilitate mechanical ventilation. The result was 23 clinical trials conducted in 1295 surgical and ICU patients administered cisatracurium and 255 patients administered control neuromuscular blocking agents (atracurium or vecuronium). A total of 20 of these studies contributed efficacy data and included 1206 patients administered cisatracurium. All studies contributed safety data.
The major populations of patients were classified by the American Society of Anesthesiologists (ASA) classification or New York Heart Association (NYHA) classification as:
Healthy (ASA class 1 or 2) young adult (aged 18-50 years), elderly adult (aged 65-89) and paediatric patients (aged 1 month-12 years);
Seriously ill (ASA class 3 or 4) elderly patients or patients with end-stage renal or hepatic disease;
Seriously ill (NYHA class I to IV) adult patients with serious cardiovascular disease scheduled for coronary artery bypass graft (CABG) surgery;
Critically ill adult ICU patients requiring neuromuscular blocking agents to facilitate mechanical ventilation.
The studies included 660 healthy adult patients, 236 paediatric patients (aged 2-12 years), 110 paediatric patients (aged 1-23 months), 15 patients with end-stage liver disease (ESLD), 17 patients with end-stage renal failure (ESRF), 182 patients with serious cardiovascular disease (undergoing coronary artery bypass graft surgery) and 68 critically ill patients in the ICU. Forty eight elderly patients (> 65 years) were specifically studied in two studies. Overall, 172 (13%) of the patients administered cisatracurium were ≥ 65 years.
The most common types of surgical procedures were urological (28% of cisatracurium patients) and CABG (14% of cisatracurium patients). Other types of procedures included general surgery (11%), gynaecological (7%), neurosurgical (5%), orthopaedic (8%), oral (3%), plastic (2%), ear, nose and throat (3%) and vascular (1%). ICU patients accounted for 5% of patients administered cisatracurium. There were no obstetric studies.
The clinical development programme acquired substantive data in regard to efficacy and safety of large bolus doses of cisatracurium. The mean clinically effective dose of cisatracurium (ED95) estimated from two dose response studies of adult patients receiving opioid anaesthesia was 0.05 mg/kg. Of the 1295 patients to whom cisatracurium was administered in clinical trials, 102 (8%) received initial bolus doses < ED95, 649 (50%) received initial bolus doses in the ED95 to 2 x ED95 range, and 515 (40%) received initial doses that exceeded 2 x ED95. ICU patients had neuromuscular block initiated with an infusion and/or bolus dose.
Following the initial dose of cisatracurium, many patients received one or more additional bolus doses, continuous intravenous (iv) infusion, or both to maintain an adequate level of neuromuscular block. The use of cisatracurium by continuous infusion during surgical procedures requiring extended neuromuscular block was investigated in healthy (ASA class 1 or 2) adult patients in 7 studies. The majority of patients received cisatracurium by infusion during opioid anaesthesia, the duration of infusion ranging from 11-261 minutes. Maintenance dose data for cisatracurium were captured in 6 studies, a total of 154 adult surgical patients being administered 1-21 maintenance doses of 0.03 mg/kg.
The adequacy of intubation conditions following cisatracurium was assessed in 5 studies in a total of 480 patients (aged 1 month to 87 years) administered cisatracurium.

5.2 Pharmacokinetic Properties

Pharmacokinetics in adult patients.

Noncompartmental pharmacokinetics of cisatracurium besilate are independent of dose in the range studied (0.1 to 0.2 mg/kg bodyweight; i.e. 2 to 4 x ED95). Population pharmacokinetic modelling confirms and extends these findings up to 0.4 mg/kg bodyweight (8 x ED95). Pharmacokinetic parameters after doses of 0.1 and 0.2 mg/kg bodyweight cisatracurium injection administered to healthy adult surgical patients are summarised in Table 7.

Pharmacokinetics during infusions.

The pharmacokinetics of cisatracurium besilate following infusion of Cisatracurium-AFT is similar to those following a single bolus injection. Pharmacokinetics were studied in healthy adult surgical patients who received an initial 0.1 mg/kg bolus dose of cisatracurium injection followed by a maintenance infusion of cisatracurium to maintain 89 to 99% T1 suppression. Mean clearance of cisatracurium besilate was 6.9 mL/kg/min and the elimination half-life was 28 minutes. During infusion of cisatracurium besilate peak plasma concentrations of laudanosine and the monoquaternary alcohol metabolites are approximately 6% and 11% of the parent compound, respectively.
The recovery profile after infusion of cisatracurium is independent of the duration of infusion and is similar to that after single bolus injection.

Pharmacokinetics in intensive care unit (ICU) patients.

The pharmacokinetics of cisatracurium besilate in ICU patients receiving prolonged infusion is similar to those in healthy surgical adults receiving infusion or single bolus injection. Mean clearance of cisatracurium besilate was 7.5 mL/kg/min and the elimination half-life was 27 minutes. The recovery profile after infusions of cisatracurium in ICU patients is independent of duration of infusion.
Concentrations of metabolites are higher in ICU patients with abnormal renal and/or hepatic functions (see Section 4.4 Special Warnings and Precautions for Use). These metabolites do not contribute to neuromuscular block.

Pharmacokinetics in elderly patients.

There are no clinically important differences in the pharmacokinetics of cisatracurium besilate in elderly patients. In a comparative study plasma clearance was unaffected by age. Minor differences in volume of distribution (+17%) and half-life (+4 min) did not affect the recovery profile.

Pharmacokinetics in paediatric patients.

No full study has been performed to assess the pharmacokinetics of cisatracurium in paediatric patients.
The population pharmacokinetics/ pharmacodynamics of cisatracurium was described in 20 healthy paediatric patients during halothane anaesthesia, using the same model developed for healthy adult patients. The clearance was higher in healthy paediatric patients (5.89 mL/min/kg) than in healthy adult patients (4.57 mL/min/kg) during opioid anaesthesia. The rate of equilibration between plasma concentrations and neuromuscular block, as indicated by keo, was faster in healthy paediatric patients receiving halothane anaesthesia (0.1330 minutes-1) than in healthy adult patients receiving opioid anaesthesia (0.0575 minutes-1). The EC50 in healthy paediatric patients (125 nanogram/mL) was similar to the value in healthy adult patients (141 nanogram/mL) during opioid anaesthesia. The minor differences in the pharmacokinetic/ pharmacodynamic parameters of cisatracurium were associated with a faster time to onset and a shorter duration of cisatracurium induced neuromuscular block in paediatric patients.

Pharmacokinetics in patients with renal impairment.

There are no clinically important differences in the pharmacokinetics of cisatracurium besilate in patients with end-stage renal failure. In a comparative study there were no statistically significant or clinically important differences in pharmacokinetic parameters of cisatracurium besilate. The recovery profile of cisatracurium besilate is unchanged in the presence of renal failure.

Pharmacokinetics in patients with hepatic impairment.

There are no clinically important differences in the pharmacokinetics of cisatracurium besilate in patients with end-stage liver disease. In a comparative study of patients undergoing liver transplantation and healthy adults there were small differences in volume of distribution (+21%) and clearance (+16%). There were no differences in the elimination half-life of cisatracurium besilate. The recovery profile was unchanged.

5.3 Preclinical Safety Data

Genotoxicity.

Cisatracurium was evaluated for genotoxic potential in a battery of four tests. It was nongenotoxic in assays for clastogenic activity (in vitro human lymphocyte cytogenetics assay and a rat bone marrow cytogenetics assay) and an Ames Salmonella assay for gene mutations. As was the case with atracurium, the mouse lymphoma assay was positive.

Carcinogenicity.

Carcinogenesis and fertility studies have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Cisatracurium-AFT also contains Water for Injections and benzenesulfonic acid.
Cisatracurium-AFT does not contain any antimicrobial preservative and is intended for single patient use on one occasion only.

6.2 Incompatibilities

Physical incompatibilities.

Cisatracurium-AFT is not chemically stable when diluted in Lactated Ringer's Injection.
Since Cisatracurium-AFT 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. thiopentone). Cisatracurium-AFT is not compatible with ketorolac, trometamol or propofol injection emulsion.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Cisatracurium-AFT should be stored between 2° and 8°C. Refrigerate. Do not freeze. Protect from light.

6.5 Nature and Contents of Container

Cisatracurium-AFT is available in the following strengths and pack sizes:
5 mg/2.5 mL: packs of 1 or 5 ampoules: AUST R 191832;
10 mg/5 mL: packs of 1 or 5 ampoules: AUST R 191831;
20 mg/10 mL: packs of 1 or 5 ampoules: AUST R 191833;
150 mg/30 mL: packs of 1 vial: AUST R 191834.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Cisatracurium besilate is a white to yellowish powder. The chemical name of cisatracurium besilate is (1R,1'R,2R,2'R,) -2,2'-(3,11-dioxo-4, 10- dioxatridecamethylene) bis(1,2,3,4-tetrahydro- 6,7-dimethoxy-2-methyl- 1-veratrylisoquinolinium) dibenzene- sulfonate. The molecular formula of cisatracurium besilate is C65H82N2O18S2 and it has a molecular weight of 1243.5.

Chemical structure.


CAS number.

96946-42-8.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes