Cisatracurium-AFT

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Cisatracurium besilate 0.268% w/v equivalent to cisatracurium 0.2% w/v
Available from:
AFT Pharmaceuticals Ltd
INN (International Name):
Cisatracurium besilate 0.268% w/v (equivalent to cisatracurium 0.2% w/v)
Dosage:
2 mg/mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Cisatracurium besilate 0.268% w/v equivalent to cisatracurium 0.2% w/v Excipient: Benzenesulfonic acid Water for injection
Prescription type:
Prescription
Manufactured by:
Yonsung Fine Chemicals Co. Limited
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.
Product summary:
Package - Contents - Shelf Life: Ampoule, Type I glass - 10 ml - 1 dose units - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light - Ampoule, Type I glass - 5 ml - 1 dose units - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light - Ampoule, Type I glass - 2.5 ml - 1 dose units - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light - Ampoule, Type I glass - 10 ml - 5 dose units - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light - Ampoule, Type I glass - 5 ml - 5 dose units - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light - Ampoule, Type I glass - 2.5 ml - 5 dose units - 24 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light
Authorization number:
TT50-9293
Authorization date:
2013-05-13

Read the complete document

PRODUCT INFORMATION

Cisatracurium-AFT

AFT Pharmaceuticals Pty Ltd

NAME OF THE DRUG

Cisatracurium-AFT contains Cisatracurium besylate

The chemical name of cisatracurium besylate 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) dibenzenesulfonate. The molecular formula of cisatracurium

besylate is C

and it has a molecular weight of 1243.5. The structural

formula is given below:

CAS Number: 96946-42-8

DESCRIPTION

Cisatracurium besylate is a white to yellowish powder.

Cisatracurium-AFT is supplied in two strengths, either 2 mg or 5 mg (as the besylate

salt) of cisatracurium besylate per mL. Cisatracurium-AFT also contains Water for

Injections

benzenesulfonic

acid.

Cisatracurium-AFT

does

contain

antimicrobial preservative and is intended for single patient use on one occasion only.

Discard any residue.

PHARMACOLOGY

Pharmacodynamics

Cisatracurium besylate, a stereoisomer of atracurium, is an intermediate duration, non-

depolarising benzylisoquinolinium skeletal muscle relaxant. Cisatracurium besylate 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 ED

(dose required to produce 95% depression of the twitch response of the

adductor pollicis muscle to stimulation of the ulnar nerve) of cisatracurium besylate 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 ED

which has a longer clinically effective duration than the recommended intubation dose of

atracurium (2 x ED

) (see DOSAGE AND ADMINISTRATION).

The ED

of cisatracurium besylate in children during halothane anaesthesia is 0.04

mg/kg bodyweight.

Cisatracurium besylate 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 non-specific

plasma

esterases

form

monoquaternary

alcohol

metabolite.

Elimination

cisatracurium besylate 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 besylate are independent of dose

in the range studied (0.1 to 0.2 mg/kg bodyweight; i.e.. 2 to 4 x ED

). Population

pharmacokinetic

modelling

confirms

extends

these

findings

mg/kg

bodyweight (8 x ED

). Pharmacokinetic parameters after doses of 0.1 and 0.2 mg/kg

bodyweight cisatracurium Injection administered to healthy adult surgical patients are

summarised below:

Parameter

Range of mean values

Clearance

4.7 to 5.7 mL/min/kg

Volume of distribution at steady state

121 to 161 mL/kg

Elimination half-life

22 to 29 min

Pharmacokinetics during infusions

The pharmacokinetics of cisatracurium besylate following infusion of Cisatracurium-AFT

is similar to those following a single bolus injection. Pharmacokinetics were studied in

healthy

adult

surgical

patients

received

initial

mg/kg

bolus

dose

cisatracurium injection followed by a maintenance infusion of cisatracurium to maintain

89 to 99% T

suppression. Mean clearance of cisatracurium besylate was 6.9 mL/kg/min

and the elimination half-life was 28 minutes. During infusion of cisatracurium besylate

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 besylate in ICU patients receiving prolonged

infusion is similar to those in healthy surgical adults receiving infusion or single bolus

injection.

Mean

clearance

cisatracurium

besylate

mL/kg/min

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

PRECAUTIONS).

These

metabolites

contribute

neuromuscular block.

Pharmacokinetics in elderly patients

There are no clinically important differences in the pharmacokinetics of cisatracurium

besylate 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.

rate

equilibration

between

plasma

concentrations

neuromuscular block, as indicated by k

, was faster in healthy paediatric patients

receiving

halothane

anaesthesia

(0.1330

minutes

than

healthy

adult

patients

receiving opioid anaesthesia (0.0575 minutes

). The EC

in healthy paediatric patients

(125 ng/mL) was similar to the value in healthy adult patients (141 ng/mL) during opioid

anaesthesia.

minor

differences

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

besylate 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 besylate. The recovery profile of cisatracurium besylate 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

besylate 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 besylate. The recovery profile was unchanged.

CLINICAL TRIALS

The cisatracurium clinical development programme was constructed to provide for

systematic

collection

efficacy

safety

data

ensure

exposure

therapeutically

relevant

doses

cisatracurium

various

populations

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.

major

populations

patients

were

classified

American

Society

Anesthesiologists

(ASA)

Classification

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

estimated

from

dose-response

studies

adult

patients

receiving

opioid

anaesthesia

0.05

mg/kg.

1295

patients

whom

cisatracurium was administered in clinical trials, 102 (8%) received initial bolus doses <

, 649 (50%) received initial bolus doses in the ED

to 2 x ED

range, and 515

(40%) received initial doses that exceeded 2 x ED

. ICU patients had neuromuscular

block initiated with an infusion and/or bolus dose.

Following

initial

dose

cisatracurium,

many

patients

received

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.

INDICATIONS

Cisatracurium-AFT is indicated for use during surgical and other procedures and in

intensive

care

relax

skeletal

muscles,

facilitate

tracheal

intubation

mechanical ventilation. It is used as an adjunct to general anaesthesia, or sedation in the

intensive care unit.

CONTRAINDICATIONS

Cisatracurium-AFT

contraindicated

patients

known

hypersensitive

cisatracurium besylate, atracurium or benzenesulfonic acid.

PRECAUTIONS

Cisatracurium besylate 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

available

plasma

levels

clinical

consequences

cisatracurium metabolites that may accumulate during days to weeks of cisatracurium

administration in ICU patients. Laudanosine, a major biologically active metabolite of

atracurium

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

cranial

trauma,

cerebral

oedema,

hypoxic

encephalopathy,

viral

encephalitis,

uraemia).

There

insufficient

data

determine

whether

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

besylate

does

have

significant

vagolytic

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 non-depolarising blocking agents. An initial dose of not

more than 0.02 mg/kg bodyweight cisatracurium besylate is recommended in these

patients.

Rarely, certain drugs may aggravate or unmask latent myasthenia gravis or actually

induce a myasthenic syndrome. Increased sensitivity to non-depolarising neuromuscular

blocking agents might result (see INTERACTIONS WITH OTHER MEDICINES).

Severe acid-base and/or serum electrolyte abnormalities may increase or decrease the

sensitivity of patients to neuromuscular blocking agents.

Cisatracurium besylate has not been studied in patients with a history of malignant

hyperthermia.

Studies

malignant

hyperthermia

susceptible

pigs

indicated

that

cisatracurium besylate does not trigger this syndrome.

Patients

with

burns

have

been

shown

develop

resistance

non-depolarising

neuromuscular blocking agents, including atracurium. The extent of altered response

depends

upon

size

of the

burn

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

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%.

Mutagenicity / Carcinogenicity

Carcinogenesis

fertility

studies

have

been

performed.

Cisatracurium

evaluated for genotoxic potential in a battery of four tests. It was non-genotoxic 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.

Use in Pregnancy

Pregnancy Category: C

Teratology studies in non-ventilated 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

negligible

levels

cisatracurium

umbilical

vessel

blood

neonates and no deleterious effects on the puppies.

Use in lactation

Studies have not been conducted to determine whether cisatracurium or its metabolites

are excreted in human or animal milk.

Effects on laboratory tests

None known

INTERACTIONS WITH OTHER MEDICINES

A number of drugs have been shown to influence the magnitude and/or duration of

action of non-depolarising neuromuscular blocking agents.

The following drugs have been shown to increase the effects of non-depolarising

neuromuscular blocking agents.

Anaesthetics:

Volatile

anaesthetics

such

enflurane,

isoflurane

halothane

(see

PRECAUTIONS).

Ketamine.

Other non-depolarising neuromuscular blocking agents.

Antibiotics, including:

the aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin and

clindamycin.

Anti-arrhythmic drugs, including:

propanolol, 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 non-depolarising 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

suxamethonium

prolong

effects

non-depolarising

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 non-depolarising neuromuscular

blocking agents might result. Such drugs include various antibiotics, beta-blockers

(propanolol, oxprenolol), anti-arrhythmic drugs (procainamide, quinidine), anti-rheumatic

drugs (chloroquine, penicillamine), trimetaphan, chlorpromazine, steroids, phenytoin and

lithium.

Treatment with anticholinesterases, commonly used in the treatment of Alzheimer’s

disease

e.g.

donepezil,

shorten

duration

diminish

magnitude

neuromuscular blockade with cisatracurium.

ADVERSE REACTIONS

Observed in clinical trials of surgical patients

No adverse experiences considered to be reasonably attributable to cisatracurium were

reported

amongst

surgical

patients

studied

during

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

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 besylate 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 besylate.

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

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.

DOSAGE AND ADMINISTRATION

Cisatracurium-AFT contains no antimicrobial preservative and is intended for single use

in one patient only.

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. The following table

summarises mean pharmacodynamic data when cisatracurium was administered at

doses

mg/kg

bodyweight

healthy

adult

patients

during

opioid

(thiopentone/fentanyl/midazolam) or propofol anaesthesia.

Initial

cisatracurium

dose (mg/kg

body weight)

Anaesthetic

background

Time to 90% T

suppression

(min)

Time to

maximum T

suppression

(min)

Time to

spontaneous T

recovery (min)

Opioid

0.15

Propofol

Opioid

Opioid

Single twitch response as well as the first component of the Train-of-Four response of the

adductor pollicis muscle following the supramaximal electrical stimulation of the ulnar nerve

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

propofol

anaesthesia.

Consecutive

maintenance doses do not result in progressive prolongation of effect.

Spontaneous recovery

Once

spontaneous

recovery

from

neuromuscular

block

underway,

rate

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

administration

Cisatracurium-AFT

readily

reversible with standard doses of anticholinesterase agents. Following the administration

of the reversal agent at an average of 10% T

recovery, the mean times from 25 to 75%

recovery and to full clinical recovery (T

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

tracheal

intubation

seconds

following

injection

Cisatracurium-AFT. 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 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

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 the tables below. 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.

Paediatric Patients aged 1 to 11 months

Initial

cisatracurium

dose (mg/kg

bodyweight)

Number of

patients

studied

Anaesthetic

background

Time to 90%

suppression

(min)

Time to

maximum

suppression

(min)

Time to 25%

spontaneous

recovery

(min)

0.15

Halothane

0.15

Opioid

Paediatric Patients aged 1 to 12 years

Initial

cisatracurium

dose (mg/kg

bodyweight)

Number of

patients

studied

Anaesthetic

background

Time to 90%

suppression

(min)

Time to

maximum

suppression

(min)

Time to 25%

spontaneous

recovery

(min)

0.15

Halothane

0.15

Opioid

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 N

/halothane (n=90) or N

/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 the table

below:

Initial

cisatracurium

dose (mg/kg

bodyweight)

Number of

patients

studied

Anaesthetic

background

Time to 90%

suppression

(min)

Time to

maximum

suppression

(min)

Time to 25%

spontaneous

recovery

(min)

0.08

Halothane

Opioid

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

20%.

information

available

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

administration

Cisatracurium-AFT

readily

reversible with standard doses of anticholinesterase agents. Following the administration

of the reversal agent at an average of 13% T

recovery, the mean times from 25 to 75%

recovery and to full clinical recovery (T

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 μg/kg/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/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 INTERACTIONS WITH

OTHER MEDICINES).

The infusion rate will depend upon the concentration of cisatracurium besylate in the

infusion solution, the desired degree of neuromuscular block and the patient’s weight.

The following table provides guidance for delivery of undiluted Cisatracurium-AFT 2

mg/mL.

Infusion delivery rate of Cisatracurium-AFT 2 mg/mL

Patient

weight (kg)

Dose (μg/kg/min)

Infusion rate

mL/hour

mL/hour

mL/hour

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

dosage

recommendation

neonates

made

administration

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.

initial

infusion

rate

Cisatracurium-AFT

μg/kg/min

(0.18

mg/kg/hr)

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/min or 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-AFT 5 mg/mL

Patient

weight (kg)

Dose (μg/kg/min)

Infusion rate

mL/hour

mL/hour

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

similar

pharmacodynamic

profile

that

observed

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 ED

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

product

contains no

antimicrobial

preservative

therefore

should

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 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

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).

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

compatible

with

ketorolac,

trometamol or propofol injection emulsion.

OVERDOSAGE

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.

PRESENTATION AND STORAGE CONDITIONS

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

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

Protect from light.

NAME AND ADDRESS OF THE SPONSOR

Australia

AFT Pharmaceuticals Pty Ltd

Level 1, 296 Burns Bay Rd

Lane Cove

Sydney

NSW 2066

New Zealand

AFT Pharmaceuticals Ltd

Auckland

POISON SCHEDULE OF THE MEDICINE

Prescription Only Medicine

DATE OF FIRST INCLUSION IN THE ARTG

25 January 2013

DATE OF THIS AMENDMENT

12 December 2013

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