Diprivan

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Propofol 20 mg/mL
Available from:
Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics
INN (International Name):
Propofol 20 mg/mL
Dosage:
2% w/v
Pharmaceutical form:
Emulsion for injection
Composition:
Active: Propofol 20 mg/mL Excipient: Disodium edetate Egg lecithin Glycerol Lecithin Nitrogen Sodium hydroxide Soya oil Water for injection
Units in package:
Syringe, glass, prefilled, 10 mL
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Bachem SA
Therapeutic indications:
· DIPRIVAN is a short-acting intravenous anaesthetic agent suitable for induction and maintenance of general anaesthesia in adults and children >1 month. · DIPRIVAN may also be used for sedation of ventilated adult and paediatric patients >1 month receiving intensive care. · DIPRIVAN may also be used for monitored anaesthesia care sedation for surgical and diagnostic procedures in adults and children >1 month.
Product summary:
Package - Contents - Shelf Life: Syringe, glass, prefilled - 10 mL - 2 years from date of manufacture stored at or below 25°C - Syringe, glass, prefilled - 50 mL - 2 years from date of manufacture stored at or below 25°C - Vial, glass, - 50 mL - 2 years from date of manufacture stored at or below 25°C
Authorization number:
TT50-3341/3
Authorization date:
1999-02-17

IPRIVAN

Data Sheet

NEW ZEALAND DATA SHEET

1. PRODUCT NAME

IPRIVAN

Propofol Injection 10 mg/mL (Diprivan 1%).

Propofol Injection 20 mg/mL (Diprivan 2%).

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Diprivan contains 10 mg or 20 mg propofol per 1 mL.

For full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Diprivan is a white, aqueous and isotonic emulsion for intravenous injection.

4. CLINICAL PARTICULARS

Therapeutic indications

IPRIVAN

short-acting

intravenous

anaesthetic

agent

suitable

induction

maintenance of general anaesthesia in adults and children >1 month.

IPRIVAN

may also be used for sedation of ventilated adult and paediatric patients >1 month

receiving intensive care.

IPRIVAN

may also be used for monitored anaesthesia care sedation for surgical and diagnostic

procedures in adults and children >1 month.

Dose and method of administration

For general anaesthesia or monitored anaesthesia care (MAC) sedation, D

IPRIVAN

should be administered only by persons trained in the administration of general

anaesthesia and not involved in the conduct of the surgical/diagnostic procedure.

Patients should be continuously monitored, and facilities for maintenance of a patent

airway, artificial ventilation, and oxygen enrichment and circulatory resuscitation must

be immediately available.

For sedation of intubated, mechanically ventilated adult patients in the Intensive Care

Unit (ICU), D

IPRIVAN

should be administered only by persons skilled in the management

of

critically

ill

patients

and

trained

in

cardiovascular

resuscitation

and

airway

management.

IPRIVAN

has been used in association with spinal and epidural anaesthesia and with

commonly used premedicants, neuromuscular blocking medicines, inhalational agents and

analgesic agents; no pharmacological incompatibility has been encountered. Lower doses of

IPRIVAN

may be required where general anaesthesia is used as an adjunct to regional

anaesthetic techniques.

IPRIVAN

Data Sheet

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For specific guidance relating to the administration of D

IPRIVAN

using the D

IPRIFUSOR

target

controlled infusion (TCI) system, which incorporates D

IPRIFUSOR

TCI software, see section E.

Such use is restricted to induction and maintenance of anaesthesia, conscious sedation for

surgical and diagnostic procedures and for the sedation of ventilated adult patients receiving

intensive care. The D

IPRIFUSOR

TCI system is not recommended for use in children.

A) ADULTS

Induction of General Anaesthesia

IPRIVAN

1% may be used to induce anaesthesia by slow bolus injection or infusion.

IPRIVAN

2% should be used to induce anaesthesia by infusion and only in those patients who

will receive D

IPRIVAN

2% for maintenance of anaesthesia.

In unpremedicated and in premedicated patients, it is recommended that D

IPRIVAN

should be

titrated (approximately 40 mg every 10 seconds in an average healthy adult by bolus injection

or infusion) against the response of the patient until the clinical signs show the onset of

anaesthesia.

Most adult patients aged less than 55 years are likely to require 1.5 to 2.5 mg/kg of D

IPRIVAN

The total dose required can be reduced by lower rates of administration (20 to 50 mg/min).

Over this age, the requirement will generally be less. In patients of ASA Grades 3 and 4, lower

rates of administration should be used (approximately 20 mg every 10 seconds).

Maintenance of General Anaesthesia

Anaesthesia can be maintained by administering D

IPRIVAN

either by continuous infusion or by

repeat bolus injections to maintain the depth of anaesthesia required.

Continuous Infusion: D

IPRIVAN

1% or D

IPRIVAN

2% may be used. The required rate of

administration varies considerably between patients but rates in the region of 4 to 12 mg/kg/h

usually maintain satisfactory anaesthesia.

Repeat Bolus Injections: It is recommended that only D

IPRIVAN

1% is used. If a technique

involving repeat bolus injections is used, increments of 25 mg to 50 mg may be given according

to clinical need.

Sedation During Intensive Care

Titration to clinical response and daily evaluation of sedation levels are important during use

of D

IPRIVAN

for ICU sedation, especially of long duration.

When used to provide sedation for ventilated adult patients undergoing intensive care, it is

recommended that D

IPRIVAN

be given by continuous infusion. Infusion rates of 0.3 and 4.0

mg/kg/h achieve satisfactory sedation in most adult patients. Administration of D

IPRIVAN

ICU sedation in adult patients should not exceed 4mg/k/hour unless the benefit for the patient

outweigh the risks (See Special warnings and precautions for use).

Continuous Sedation for Surgical and Diagnostic Procedures

To provide sedation for surgical and diagnostic procedures, rates of administration should be

individualised and titrated to clinical response.

Most patients will require 0.5 to 1 mg/kg over 1 to 5 minutes for onset of sedation.

IPRIVAN

Data Sheet

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Maintenance of sedation may be accomplished by titrating D

IPRIVAN

infusion to the desired

level of sedation - most patients will require 1.5 to 4.5 mg/kg/h. In addition to the infusion,

bolus administration of 10 to 20 mg may be used if a rapid increase in the depth of sedation is

required. In patients in ASA grades 3 and 4 the rate of administration and dosage may need

to be reduced.

B) ELDERLY PATIENTS

In elderly patients the dose requirement for induction of anaesthesia with D

IPRIVAN

is reduced.

The reduction should take account of the physical status and age of the patient. The reduced

dose should be given at a slower rate and titrated against the response. Where D

IPRIVAN

used for maintenance of anaesthesia or sedation the rate of infusion or ‘target concentration’

should also be reduced. Patients of ASA grades 3 & 4 will require further reductions in dose

and dose rate. Rapid bolus administration (single or repeated) should not be used in the

elderly as this may lead to cardiorespiratory depression.

C) CHILDREN

All Indications

Administration of D

IPRIVAN

by a D

IPRIFUSOR

TCI system is not recommended for any indication

in children.

Induction of General Anaesthesia

IPRIVAN

is not recommended for use in infants less than 1 month old (see Special warnings

and precautions for use and Undesirable effects).

When used to induce anaesthesia in children, it is recommended that D

IPRIVAN

be given slowly

until the clinical signs show the onset of anaesthesia. The dose should be adjusted for age

and/or weight. Most patients over 8 years of age are likely to require approximately 2.5 mg/kg

of D

IPRIVAN

for induction of anaesthesia. Between the ages of one month and eight years the

requirement may be more. Lower dosage is recommended for children of ASA Grades 3 and

Maintenance of General Anaesthesia

IPRIVAN

is not recommended for use in infants less than 1 month old.

Anaesthesia can be maintained by administering D

IPRIVAN

by infusion or repeat bolus injection

to maintain the depth of anaesthesia required. It is recommended that only D

IPRIVAN

1% is

used

repeat

bolus

injections

used.

required

rate of administration

varies

considerably between patients but rates in the region of 9 to 15 mg/kg/h usually achieve

satisfactory anaesthesia.

Short Term Sedation for Diagnostic and Therapeutic Procedures

IPRIVAN

is not recommended for use in infants less than 1 month old.

In infants and children over 1 month of age D

IPRIVAN

1% may be used. In children over 3

years of age D

IPRIVAN

1% or D

IPRIVAN

2% may be used.

provide

short-term

sedation

diagnostic

therapeutic

procedures

rates

administration should be individualised and titrated to clinical response. Most patients will

require 1 to 2 mg/kg over at least 1 minute to initiate sedation. Maintenance of sedation may

be accomplished by titrating D

IPRIVAN

to the desired level of sedation. Most paediatric patients

require 1.5 to 9 mg/kg/h for satisfactory sedation.

IPRIVAN

Data Sheet

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The infusion of D

IPRIVAN

1% may be supplemented by bolus administration of up to 1 mg/kg if

a rapid increase of depth of sedation is required. Administration of D

IPRIVAN

2% by bolus

injection is not recommended.

In patients of ASA grades 3 and 4 the rate of administration and dosage may need to be

reduced.

Sedation During Intensive Care

When used to provide sedation for ventilated paediatric patients undergoing intensive care, it

is recommended that D

IPRIVAN

be given by continuous infusion. The depth of sedation should

be regularly monitored and the rate of infusion adjusted to the minimum required to achieve

and maintain a satisfactory level of sedation. The maximum dose of propofol for paediatric

ICU sedation should be 4 mg/kg/hr. If 4 mg/kg/h does not provide adequate sedation, the

addition of other agents should be considered. Propofol should not be used for more than 48

hours in paediatric patients. Propofol should only be used for >24 hrs in patients who are

assessed as having adequate oxygen delivery (Do

)* and oxygen uptake (Vo

)* parameters.

The dose rates of D

IPRIVAN

for ICU sedation in paediatric patients should not exceed this

guidance unless the benefit for the patient outweigh the risks (See Special warnings and

precautions for use).

= cardiac output (CO in L/min) x haemoglobin concentration (Hb in g/L) x arterial oxygen

saturation (Sao

as fraction ) x 1.39 mL/g. Results are in mL min

= CO x Hb x (Sao

-Svo

) x 1.39

Children are at particular risk of fat overload. Therefore serum lipids should be monitored and

adequate carbohydrate intake maintained in children receiving D

IPRIVAN

(see Special warnings

and precautions for use).

Supplementary analgesic agents are generally required in addition to D

IPRIVAN

Following infusion of D

IPRIVAN

, discontinuation should be gradual to minimise the risk of

withdrawal symptoms.

D) ADMINISTRATION

Administration of D

IPRIVAN

2% by bolus injection is not recommended.

Supplementary analgesic agents are generally required in addition to D

IPRIVAN

IPRIVAN

can be used for infusion undiluted from plastic syringes or glass infusion bottles or

IPRIVAN

pre-filled syringes. When D

IPRIVAN

is used undiluted to maintain anaesthesia, it is

recommended that equipment such as syringe pumps or volumetric infusion pumps should

always be used to control infusion rates.

IPRIVAN

1% may also be used diluted with 5% Dextrose Intravenous Infusion only, in PVC

infusion bags or glass infusion bottles. Dilutions, which must not exceed 1 in 5 (2 mg

propofol/mL) should be prepared aseptically immediately before administration. The mixture

is stable for up to 6 hours.

The dilution may be used with a variety of infusion control techniques but a giving set used

alone will not avoid the risk of accidental, uncontrolled infusion of large volumes of diluted

IPRIVAN

. A burette, drop counter or volumetric pump must be included in the infusion line.

The risk of uncontrolled infusion must be taken into account when deciding the maximum

amount of dilution in the burette.

IPRIVAN

Data Sheet

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IPRIVAN

may be administered via a Y-piece close to the injection site, into infusions of

Dextrose 5% Intravenous Infusion, Sodium Chloride 0.9% Intravenous Infusion or Dextrose

4% with Sodium Chloride 0.18% Intravenous Infusion.

The glass pre-filled syringe (PFS) has a lower frictional resistance than plastic disposable

syringes and operates more easily. Therefore, if D

IPRIVAN

is administered using a hand held

pre-filled syringe, the line between the syringe and the patient must not be left open if

unattended.

When the pre-filled syringe presentation is used in a syringe pump appropriate compatibility

should be ensured. In particular, the pump should be designed to prevent syphoning and

should have an occlusion alarm set no greater than 1000 mmHg. If using a programmable or

equivalent pump that offers options for use of different syringes then choose only the ‘B - D’

50/60 mL ‘PLASTIPAK’ setting when using the D

IPRIVAN

pre-filled syringe.

IPRIVAN

1% may be premixed with alfentanil injection containing 500 µg/mL alfentanil

(RAPIFEN; Janssen Pharmaceuticals Ltd.) in the ratio of 20:1 to 50:1 v/v. Mixtures should be

prepared using sterile technique and used within 6 hours of preparation.

To reduce pain on initial injection, that part of the D

IPRIVAN

1% used for induction may be mixed

with lignocaine injection in a plastic syringe in the ratio of 20 parts D

IPRIVAN

1% with up to one

part of 0.5% or 1% lignocaine injection immediately prior to administration.

DILUTION AND CO-ADMINISTRATION OF D

IPRIVAN

WITH OTHER MEDICINES OR

INFUSION FLUIDS

(See also "Additional Precautions" section)

Co-Administration

Technique

Additive or

Diluent

Preparation

Precautions

Pre-mixing

Dextrose 5%

Intravenous Infusion

Mix 1 part of D

IPRIVAN

with up to 4 parts of Dextrose

5% Intravenous Infusion in

either PVC infusion bags or

glass infusion bottles. When

diluted

bags

recommended that the bag

should be full and that the

dilution

prepared

withdrawing

volume

infusion fluid and replacing it

with

equal

volume

IPRIVAN

Prepare aseptically

immediately before

administration. The mixture

is stable for up to 6 hours.

Lignocaine

Hydrochloride

Injection (0.5% or

1% without

preservatives).

Mix 20 parts of D

IPRIVAN

with up to 1 part of either

0.5% or 1% Lignocaine

Hydrochloride Injection.

Prepare mixture aseptically

immediately prior to

administration. Use for

induction only.

Alfentanil Injection

(500 µg/mL).

Mix D

IPRIVAN

1% with

Alfentanil injection in a ratio

of 20:1 to 50:1 v/v.

Prepare mixture aseptically;

use within 6 hours of

preparation

Co-administration via a Y-

piece connector

Dextrose 5%

Intravenous

Infusion.

Co-administer via a Y-piece

connector.

Place the Y- piece connector

close to the injection site.

Sodium Chloride

0.9% Intravenous

Infusion.

As above

As above

Dextrose 4% with

Sodium Chloride

0.18% Intravenous

Infusion.

As above

As above

IPRIVAN

Data Sheet

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E)

TARGET

CONTROLLED

INFUSION

-

ADMINISTRATION

OF

DIPRIVAN

BY

DIPRIFUSOR TCI SYSTEM IN ADULTS

IPRIVAN

may be administered by TCI with the D

IPRIFUSOR

TCI system incorporating

IPRIFUSOR

TCI software. This system will operate only on recognition of electronically tagged

pre-filled syringes containing D

IPRIVAN

1% or 2% injection. The D

IPRIFUSOR

TCI system will

automatically adjust the infusion rate to achieve the concentration of D

IPRIVAN

selected by the

operator.

Users

must

be familiar

with

infusion pump

user

manual

with

administration of D

IPRIVAN

by TCI and with the correct use of the syringe identification system,

all of which are set out in the D

IPRIFUSOR

user manual.

The D

IPRIFUSOR

TCI system can provide two modes of target controlled infusion: target blood

concentration and target effect-site (brain) concentration. Earlier models provide only the

target blood concentration mode.

Administration of D

IPRIVAN

by a D

IPRIFUSOR

TCI system is restricted to adults for the induction

and maintenance of general anaesthesia, conscious sedation for surgical and diagnostic

procedures and for the sedation of ventilated patients receiving intensive care. It is not

recommended for use in children.

The system allows control of induction and depth of anaesthesia or sedation by setting and

adjusting target (predicted) blood or effect-site concentrations of propofol. Use of the target

effect-site concentration mode achieves a more rapid induction of sedation or anaesthesia

than use of the target blood concentration mode.

The D

IPRIFUSOR

TCI system assumes that the initial target concentrations in the patient are

zero. Therefore, in patients who have recently received prior propofol, there may be a need

to select a lower initial target concentration when commencing D

IPRIFUSOR

TCI. Similarly, the

immediate recommencement of D

IPRIFUSOR

TCI is not recommended if the pump has been

switched off.

If the D

IPRIFUSOR

TCI system has been used for anaesthesia, it can be continued into the

postoperative period to provide sedation during intensive care, with appropriate selection of a

target concentration.

Guidance on propofol target concentrations is given below. In view of inter-patient variability

propofol

pharmacokinetics

pharmacodynamics,

both

premedicated

unpremedicated patients, the target propofol concentration should be titrated against the

response of the patient in order to achieve the depth of anaesthesia or sedation required.

Induction and Maintenance of General Anaesthesia

In adult patients under 55 years of age anaesthesia can usually be induced with target blood

propofol concentrations in the region of 4 to 8 µg/mL or target effect-site concentrations of 2.5

to 4 µg/mL. An initial target blood concentration of 4 µg/mL or target effect-site concentration

of 2.5 µg/mL is recommended in premedicated patients and in unpremedicated patients an

initial target blood concentration of 6 µg/mL or target effect-site concentration of 4 µg/mL is

advised. Induction time with target blood concentrations is generally within the range of 60 to

120 seconds. Higher target blood concentrations will allow more rapid induction of anaesthesia

but may be associated with more pronounced haemodynamic and respiratory depression.

When using target effect-site concentrations the use of higher targets to achieve more rapid

induction of anaesthesia is not necessary and not recommended.

IPRIVAN

Data Sheet

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Lower initial target concentrations should be used in patients over the age of about 55 years

and in patients of ASA grades 3 and 4 (use of effect-site mode in patients of ASA grade 4 is

not recommended). For the effect-site mode an initial target of 0.5 to 1.0 μg/mL should be

used. For both target concentration modes, the target can then be increased in steps of 0.5

to 1.0 µg/mL at intervals of 1 minute to achieve a gradual induction of anaesthesia.

Supplementary

analgesia

will

generally

required

extent

which

target

concentrations for maintenance of anaesthesia can be reduced will be influenced by the

amount of concomitant analgesia administered. Target propofol blood concentrations in the

region of 3 to 6 µg/mL and target effect-site concentrations of 2.5 to 4.0 µg/mL usually induce

and maintain satisfactory anaesthesia. In the absence of supplementary analgesia, higher

effect-site targets of 5 to 6 μg/mL may be required to facilitate laryngoscopy or to abolish

responses to painful stimuli.

For both target concentration modes, the predicted propofol concentration (blood or effect-site)

on waking is generally in the region of 1.0 to 2.0 µg/mL and will be influenced by the amount

of analgesia given during maintenance. When target concentrations are reduced, the

IPRIFUSOR

transiently stops the infusion to allow concentrations to fall and achieve a new

target more quickly.

Conscious Sedation for Surgical and Diagnostic Procedures

The target concentration setting should be titrated against the response of the patient to

achieve the depth of conscious sedation required.

An initial target blood propofol concentration in the range of 0.5 to 2.5 µg/mL will generally be

required. Initial target blood concentrations towards the upper end of the recommended

range will allow more rapid induction of conscious sedation. In elderly patients and in patients

of ASA grades 3 and 4, initial blood target concentrations towards the lower end of the range

should be used.

In young, healthy patients, an effect-site target of 1.5 to 2.0 μg/mL generally achieves

satisfactory sedation, which is achieved more rapidly than when the target blood concentration

control mode is used. When using target effect-site concentrations the use of higher targets

to achieve more rapid induction of sedation is not necessary and not recommended. There is

insufficient evidence to recommend use of effect-site mode for conscious sedation in elderly

patients or patients of ASA grades 3 or 4.

Sedation During Intensive Care

An initial target blood propofol concentration setting in the range of 0.2 to 2.0 µg/mL will

generally be required. Administration should begin at low target settings which should be

titrated against the response of the patient to achieve the depth of sedation desired. There

are no data on the target effect-site concentration mode for the sedation of ventilated ICU

patients; thus, such use is not recommended.

Contraindications

IPRIVAN

is contraindicated:

In patients with a known allergy to propofol or any of the other ingredients of D

IPRIVAN

injection including egg and soy bean protein.

For the sedation of children under the age of 3 years with serious viral respiratory tract

infections receiving intensive care.

For the sedation of children of all ages with croup or epiglottitis receiving intensive care

(see Special warnings and precautions for use)

IPRIVAN

Data Sheet

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Special warnings and precautions for use

IPRIVAN

should be given by those trained in anaesthesia (or, where appropriate, doctors

trained in the care of patients in Intensive Care).

Patients should be constantly monitored and facilities for maintenance of a patent airway,

artificial ventilation, oxygen enrichment and other resuscitative facilities should be readily

available at all times. D

IPRIVAN

should not be administered by the person conducting the

diagnostic or surgical procedure.

When D

IPRIVAN

is administered for monitored anaesthesia care sedation for surgical and

diagnostic

procedures

patients

should

continually

monitored

early

signs

hypotension, airway obstruction and oxygen desaturation.

As with other sedative agents, when D

IPRIVAN

is used for sedation during operative

procedures, involuntary movements may occur. During procedures requiring immobility

these movements may be hazardous to the operative site.

An adequate period is needed prior to discharge of the patient to ensure full recovery after

general anaesthesia. Very rarely the use of D

IPRIVAN

may be associated with the

development of a period of post-operative unconsciousness, which may be accompanied

by an increase in muscle tone. This may or may not be preceded by a period of

wakefulness. Although recovery is spontaneous, appropriate care of an unconscious

patient should be administered.

As with other intravenous anaesthetic agents, caution should be applied in patients with

cardiac, respiratory, renal or hepatic impairment or in hypovolaemic or debilitated patients.

IPRIVAN

lacks vagolytic activity and has been associated with reports of bradycardia

(occasionally

profound)

also

asystole.

intravenous

administration

anticholinergic agent before induction, or during maintenance of anaesthesia should be

considered, especially in situations where vagal tone is likely to predominate or when

IPRIVAN

is used in conjunction with other agents likely to cause a bradycardia.

When D

IPRIVAN

is administered to an epileptic patient, there may be an increased risk of

convulsion.

Appropriate care should be applied in patients with disorders of fat metabolism and in other

conditions where lipid emulsions must be used cautiously.

It is recommended that blood lipid levels be monitored should D

IPRIVAN

be administered to

patients thought to be at particular risk of fat overload. Administration of D

IPRIVAN

should

be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared

from the body. If the patient is receiving other intravenous lipid concurrently, a reduction

in quantity should be made in order to take account of the amount of lipid infused as part

of the D

IPRIVAN

formulation; 1.0 mL of D

IPRIVAN

contains approximately 0.1 g of fat.

IPRIVAN

is not recommended for use in neonates for induction and maintenance of

anaesthesia. Data from off-label use have indicated that if the paediatric (1 month to 16

years of age) dose regimen is applied to neonates, a relative overdose could occur which

may result in cardio-pulmonary depression.

There are no data to support the use of D

IPRIVAN

for the sedation of premature neonates

receiving intensive care.

IPRIVAN

Data Sheet

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There are no clinical trials data to support the use of D

IPRIVAN

for the sedation of children

with croup or epiglottitis receiving intensive care.

Paediatric neurotoxicity

Published juvenile animal studies demonstrate that the administration of anaesthetic and

sedative agents that block NMDA receptors and/or potentiate GABA activity increase

neuronal apoptosis in the developing brain and result in long-term cognitive defects when

used for longer than 3 hours. The clinical significance of these findings is not clear.

However, based on the available data across species, the window of vulnerability to these

changes is believed to correlate with exposures in the third trimester of gestation through

the first several months of life, but may extend out to approximately three years of age in

humans.

Some published studies in children suggest that similar deficits may occur after repeated or

prolonged exposures to anaesthetic agents early in life and may result in adverse cognitive

or behavioural effects. These studies have substantial limitations and it is not clear if the

observed effects are due to the anaesthetic/sedative agent administration or other factors

such as the surgery or underlying illness.

Anaesthetic and sedative agents are a necessary part of the care of children and pregnant

women needing surgery, other procedures or tests that cannot be delayed, and no specific

medicines have been shown to be safer than any other. Decisions regarding the timing of

any elective procedures requiring anaesthesia should take into consideration the benefits

of the procedure weighed against the potential risks (see also Fertility, pregnancy and

lactation).

ADVISORY STATEMENT CONCERNING INTENSIVE CARE UNIT MANAGEMENT

Propofol Infusion Syndrome (PRIS)

Use of D

IPRIVAN

Injectable Emulsion infusions for both adult and paediatric ICU sedation has

been associated with a constellation of metabolic derangements and organ system failures,

referred to as ‘propofol infusion syndrome’, that in some cases have resulted in death.

The syndrome is characterised by severe metabolic acidosis, rhabdomyolysis, hyperkalaemia,

ECG changes* and/or cardiac failure. The syndrome is most often associated with prolonged,

high-dose infusions (>5 mg/kg/h for >48h). The following appear to be the major risk factors

development

these

events:

decreased

oxygen

delivery

tissues;

serious

neurological injury and/or sepsis; high dosages of one or more of the following pharmacological

agents – vasoconstrictors, steroids, inotropes and/or propofol. All sedative and therapeutic

agents used in the ICU (including D

IPRIVAN

) should be titrated to maintain optimal oxygen

delivery and haemodynamic parameters.

Propofol should only be used for >24 hrs in patients who have adequate oxygen delivery and

uptake parameters.

The maximum dose of propofol for ICU sedation should be 4mg/kg/h. If 4mg/kg/h does not

provide adequate sedation, the addition of other agents should be considered. Propofol should

not be used for prolonged sedation (>48 hours) or at infusion rates of > 4 mg/kg/h, particularly

in severely head injured patients also receiving incremental inotropic support.

If the cause of a new onset metabolic acidosis cannot be determined, the possibility of it being

due to a propofol infusion syndrome should be considered. As a precaution, the adequacy of

oxygen delivery/uptake should be reassessed, the use of vasoconstrictors should be reviewed

IPRIVAN

Data Sheet

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and cessation of propofol should be considered. Fluorescent green urine may indicate that

the patient is acidotic.

Patients with mitochondrial disease may be susceptible to exacerbations when undergoing

anaesthesia/surgery. Provision of carbohydrates and good hydration is recommended for

such patients.

* Coved ST segment elevation (similar to ECG changes of the Brugada syndrome)

ADDITIONAL PRECAUTIONS

IPRIVAN

contains no antimicrobial preservatives and supports growth of micro-organisms.

IPRIVAN

contains disodium edetate 0.005% w/v (EDTA) as a microbial inhibitor. EDTA is

a chelator of metal ions, including zinc; during prolonged administration of D

IPRIVAN

need for supplemental zinc should be considered in patients predisposed to zinc deficiency,

such as those with burns, diarrhoea and /or sepsis.

When D

IPRIVAN

is to be aspirated, it must be drawn aseptically into a sterile syringe or

giving set immediately after opening the ampoule or breaking the vial seal. Administration

must commence without delay. Asepsis must be maintained for both D

IPRIVAN

and the

infusion equipment throughout the infusion period. Any medicines or fluids added to the

IPRIVAN

line must be administered close to the cannula site. D

IPRIVAN

must not be

administered via a microbiological filter.

IPRIVAN

and any syringe containing D

IPRIVAN

are for single use in an individual patient.

In accordance with established guidelines for other lipid emulsions, a single infusion of

IPRIVAN

must not exceed 12 hours. At the end of the procedure or at 12 hours, whichever

is the sooner, both the reservoir of D

IPRIVAN

and the infusion line must be discarded and

replaced as appropriate.

Interaction with other medicines and other forms of interaction

IPRIVAN

has been used in association with spinal and epidural anaesthesia and with

commonly used premedicants, neuromuscular blocking drugs, inhalational agents and

analgesic agents; no pharmacological incompatibility has been encountered. Lower doses

of D

IPRIVAN

may be required where general anaesthesia is used as an adjunct to regional

anaesthetic techniques.

Fertility, pregnancy and lactation

Pregnancy

IPRIVAN

should not be used in pregnancy. D

IPRIVAN

has been used during termination of

pregnancy in the first trimester.

IPRIVAN

crosses the placenta and may be associated with neonatal depression. It should

not be used for obstetric anaesthesia.

Anaesthetic and sedative agents are a necessary part of the care of children and pregnant

women needing surgery, other procedures or tests that cannot be delayed, and no specific

medicines have been shown to be safer than any other. Decisions regarding the timing of

any elective procedures requiring anaesthesia should take into consideration the benefits of

the procedure weighed against the potential risks.

Preclinical data

Published studies in pregnant primates demonstrate that the administration of anaesthetic

and sedative agents that block NMDA receptors and/or potentiate GABA activity during the

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Data Sheet

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period of peak brain development increases neuronal apoptosis in the developing brain of

the offspring when used for longer than 3 hours. There are no data on pregnancy exposures

in primates corresponding to periods prior to the third trimester in humans (see also

Preclinical safety data).

Lactation

Safety to the neonate following the use of D

IPRIVAN

in mothers who are breast-feeding has

not been established.

Effects on ability to drive and use machines

Patients should be advised that performance at skilled tasks, such as driving and operating

machinery, may be impaired for some time after use of D

IPRIVAN

Undesirable effects

Induction of anaesthesia with D

IPRIVAN

is generally smooth with minimal evidence of

excitation. The most commonly reported ADRs are pharmacologically predictable side

effects of an anaesthetic agent, such as hypotension. Given the nature of anaesthesia and

those patients receiving intensive care, events reported in association with anaesthesia

and intensive care may also be related to the procedures being undertaken or the

recipient’s condition.

Tabulated summary of adverse reactions

The following convention has been utilised for the classification of frequency: Very common

(≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000

and <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available

data).

Frequency

System Organ Class

Event

Very common

(>1/10)

General

disorders

and

administration

site

conditions:

Local pain on induction

Common

(>1/100, <1/10)

Vascular disorders:

Cardiac disorders:

Respiratory,

thoracic

and

mediastinal disorders:

Gastrointestinal disorders:

Nervous system disorders:

General

disorders

and

administration

site

conditions:

Vascular disorders:

Hypotension

Bradycardia

Transient apnoea during

induction

Nausea and vomiting

during recovery phase

Headache during

recovery phase

Withdrawal symptoms in

children

Flushing in children

Uncommon

Vascular disorders:

Thrombosis and phlebitis

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(>1/1 000, <1/100)

Rare

(>1/10 000, <1/1 000)

Nervous

system:

Psychiatric disorders

Epileptiform movements,

including convulsions

and opisthotonus during

induction, maintenance

and recovery

Euphoric mood

Very rare

(<1/10 000)

Musculoskeletal

and

connective

tissue

disorders:

Gastrointestinal disorders:

Injury,

poisoning

and

procedural complications:

Renal

and

urinary

disorders:

Immune system disorders:

Reproductive system and

breast:

Cardiac disorders:

Nervous system disorders:

Rhabdomyolysis

Pancreatitis

Post-operative fever

Discolouration of urine

following prolonged

administration

Anaphylaxis – may

include angioedema,

bronchospasm, erythema

and hypotension

Sexual disinhibition

Pulmonary oedema

Post-operative

unconsciousness

Not known (cannot be

estimated from the

available data)

Reproductive system and

breast disorders:

Priapism

May be minimised by using the larger veins of the forearm and antecubital fossa. With D

IPRIVAN

local pain can also be minimised by the co-administration of lignocaine (see Dose and method of

administraton, Part D).

Occasionally, hypotension may require use of intravenous fluids and reduction of the administration

rate of D

IPRIVAN

Serious bradycardias are rare. There have been isolated reports of progression to asystole.

Following abrupt discontinuations of D

IPRIVAN

during intensive care.

Very rare reports of rhabdomyolysis have been received where D

IPRIVAN

has been given at doses of

greater than 4 mg/kg/hr for ICU sedation. Also there have been rare reports of metabolic acidosis and

cardiac failure associated with Diprivan administered at rates >5 mg/kg/h for >58 hours. A causal

relationship has not been established.

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Data Sheet

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Reports from off-label use of D

IPRIVAN

for induction of anaesthesia in neonates indicates

that cardio-respiratory depression may occur if the paediatric dose regimen is applied (see

Dose and method of administration and Special warnings and precautions for use).

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows

continued

monitoring

benefit/risk

balance

medicine.

Healthcare

professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/

Overdose

Accidental overdosage is likely to cause cardio-respiratory depression. Respiratory

depression

should

treated

artificial

ventilation

with

oxygen.

Cardiovascular

depression would require lowering of the patient's head and, if severe, use of plasma

expanders and pressor agents.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766)

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anaesthetics, general.

Propofol (2, 6-diisopropylphenol) is a short-acting general anaesthetic agent with a rapid onset

of action of approximately 30 seconds. Recovery from anaesthesia is usually rapid. The

mechanism of action, like all general anaesthetics, is poorly understood. However, propofol is

thought to produce its sedative/anaesthetic effects by the positive modulation of the inhibitory

function of the neurotransmitter GABA through the ligand-gated GABA

receptors.

In general, falls in mean arterial blood pressure and slight changes in heart rate are observed

when D

IPRIVAN

is administered for induction and maintenance of anaesthesia. However, the

haemodynamic parameters normally remain relatively stable during maintenance and the

incidence of untoward haemodynamic changes is low.

Although ventilatory depression can occur following administration of D

IPRIVAN

, any effects are

qualitatively

similar

those

other

intravenous

anaesthetic

agents

readily

manageable in clinical practice.

IPRIVAN

reduces cerebral blood flow, intracranial pressure and cerebral metabolism. The

reduction in intracranial pressure is greater in patients with an elevated baseline intracranial

pressure.

Recovery from anaesthesia is usually rapid and clear headed with a low incidence of headache

and post-operative nausea and vomiting.

IPRIVAN

at the concentrations likely to occur clinically, does not inhibit the synthesis of

adrenocortical hormones.

5.2

Pharmacokinetic properties

The decline in propofol concentrations following a bolus dose or following the termination of

an infusion can be described by a three compartment open model. The first phase is

characterised by a very rapid distribution (half-life: 2 to 4 minutes) rapid elimination (half-life:

30 to 60 minutes) and a slower final phase, representative of redistribution of propofol from

poorly perfused tissue.

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Propofol is extensively distributed and rapidly cleared from the body (total body clearance 1.5

to 2 L/min). Clearance occurs by metabolic processes, mainly in the liver, to form inactive

conjugates of propofol and its corresponding quinol, which are excreted in urine.

When

IPRIVAN

used

maintain

anaesthesia,

blood

concentrations

asymptotically

approach the steady-state value for the given administration rate. The pharmacokinetics are

linear over the recommended range of infusion rates of D

IPRIVAN

5.3

Preclinical safety data

Published studies in animals demonstrate that the use of anaesthetic and sedative agents

during the period of rapid brain growth or synaptogenesis results in widespread neuronal and

oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and

neurogenesis. Based on comparisons across species, the window of vulnerability to these

changes is believed to correlate with exposures in the third trimester through the first several

months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of an anaesthetic regimen that produced a light surgical

plane of anaesthesia did not increase neuronal cell loss, however, treatment regimens of 5

hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the

neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in

learning and memory.

In a published study conducted on rhesus monkeys, administration of an anaesthetic dose of

ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing

brain of the foetus. In other published studies, administration of either isoflurane or propofol

for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte

apoptosis in the developing brain of the offspring of rhesus macaques. With respect to brain

development, this time period corresponds to the third trimester of gestation in the human. The

clinical significance of these findings is not clear; however, studies in juvenile animals suggest

neuroapoptosis correlates with long-term cognitive deficits. Healthcare providers should

balance the benefits of appropriate anaesthesia in pregnant women, neonates and young

children who require procedures with the potential risks suggested by the nonclinical data.

6. PHARMACEUTICAL PRECAUTIONS

List of excipients

Soya-bean oil, egg lecithin, disodium edetate, glycerol, sodium hydroxide and water for

injections.

Incompatibilities

IPRIVAN

should not be mixed prior to administration with injections or infusion fluids with

the exception of D

IPRIVAN

1% which can be mixed with 5% Dextrose (Intravenous Infusion

BP) in PVC bags or glass infusion bottles or lignocaine injection or alfentanil injection in

plastic syringes (see Dose and method of administration).

The neuromuscular blocking agents, atracurium and mivacurium should not be given

through the same IV line as D

IPRIVAN

without prior flushing.

Shelf life

Vials: 36 months.

Pre-filled syringes: 24 months.

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Data Sheet

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Special precautions for storage

The emulsion should be stored below 25°C; it must not be frozen.

Nature and contents of container

IPRIVAN

50 mL Glass Vials

50 mL Glass Pre-filled syringes

IPRIVAN

50 mL Glass Pre-filled syringes

Special precautions for disposal and other handling

Containers should be shaken before use. Any portion of the contents remaining after use

should be discarded.

The glass pre-filled syringe (PFS) has a lower frictional resistance than plastic disposable

syringes and operates more easily. Therefore, if D

IPRIVAN

is administered using a hand

held pre-filled syringe, the line between the syringe and the patient must not be left open if

unattended.

Asepsis for D

IPRIVAN

and infusion equipment must be maintained.

7. MEDICINE SCHEDULE

Prescription Medicine.

8. SPONSOR

Pharmacy Retailing (NZ) Limited

Trading as Healthcare Logistics

58 Richard Pearse Drive

Airport Oaks

Auckland

New Zealand

9. DATE OF FIRST APPROVAL

19 December 1985

10.

DATE OF PREPARATION

23 January 2020

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Update to the SPC-style format

Additional safety data in 4.4,4.6 and 5.3 due to MARC

request

Introduction of a heading and frequency classification

Addition of headings to table columns

IPRIVAN

Data Sheet

Copyright

Introduction of an adverse event “priapism”

© This data sheet is copyrighted to AstraZeneca Limited and may be reproduced but not altered in any

way.

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