NEW ZEALAND DATA SHEET

1 PRODUCT NAME
Fresofol 1% emulsion for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Propofol 1% w/v (10 mg/mL) supplied as:
 Propofol 200 mg/20 mL
 Propofol 500 mg/50 mL
 Propofol 1000 mg/100 mL

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM
Injection, emulsion

Fresofol 1% is a sterile, white, isotonic, oil-in water emulsion; designed for intravenous
injection (bolus or infusion).

4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Fresofol 1% is a short-acting intravenous anaesthetic agent suitable for the induction and
maintenance of general anaesthesia in adults and children aged three years and older.

Although the safety and efficacy of Fresofol 1% in paediatric day surgery have not been
demonstrated, it may be a useful agent in this setting and its use should not be precluded.

Fresofol 1% may also be used in adults for the sedation of ventilated patients receiving
intensive care.

Fresofol 1% may also be used in adults for monitored conscious sedation for surgical and
diagnostic procedures.

4.2 Dose and method of administration

(see also section 4.4 Special warnings and precautions for use – Aseptic Technique)
Strict aseptic technique must always be maintained during handling. Fresofol 1% injection is a
single patient use only parenteral product which does not contain any antimicrobial
preservative. Accordingly, strict aseptic technique must still be adhered to. Do not use if
contamination is suspected. Discard unused portions as directed within the required time
limits. There have been reports in which failure to use aseptic technique when handling
Fresofol 1% injection was associated with microbial contamination of the product and with
fever, infection/sepsis, other life-threatening illness, and/or death.

Adults
a) Induction of general anaesthesia
Fresofol 1% may be used to induce anaesthesia by slow bolus injection or infusion. In
unpremedicated and in premedicated patients, it is recommended that Fresofol 1% should

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be titrated [approximately 4 mL (40 mg) every 10 seconds in an average healthy adult]

against the response of the patient until clinical signs show the onset of anaesthesia.

Most adult patients aged less than 55 years are likely to require 2.0–2.5 mg propofol/kg
body weight.

Over this age, the requirement will be generally less (see Use in the elderly, below). In
general, slower rates of infusion at induction results in a lower induction dose requirement
and greater haemodynamic stability. In patients of ASA grades III and IV (according to the
classification of the American Society of Anaesthiologists), lower rates of administration of
Fresofol 1% should be used [approximately 2 mL (20 mg) every 10 seconds].

b) Maintenance of general anaesthesia

Anaesthesia can be maintained by administering Fresofol 1% either by continuous infusion
or repeat bolus injections to maintain the depth of anaesthesia required. Experience in
procedures lasting more than one hour is limited.

 Continuous infusion
For maintenance of anaesthesia using continuous infusion doses, the required rate of
administration varies considerably between patients, but rates in the region of
0.067–0.2 mg/kg/min (4–12 mg propofol/kg body weight per hour) usually maintain
satisfactory anaesthesia. A reduced maintenance dose of approximately 4 mg
propofol/kg/ bodyweight per hour may be sufficient during less stressful surgical
procedures such as minimal invasive surgery.

 Repeat bolus injections

For maintenance of anaesthesia using repeat bolus injections dose increments of
25–50 mg propofol (2.5–5 mL Fresofol 1%) may be given according to clinical need.

 Time to recovery
Recovery from induction doses usually occurs within 5–10 minutes. Recovery from
induction doses (2–2.5 mg of propofol per kg) and maintenance (with 0.1–0.2 mg
propofol per kg per minute) for up to 2 hours occurs in most patients within eight
minutes. If an opioid has been used, recovery may take up to 19 minutes.

c) Sedation in adults during intensive care

When used to provide sedation for ventilated adult patients undergoing intensive care, it is
recommended that Fresofol 1% be given by continuous infusion. The infusion rate should
be adjusted according to the depth of sedation required but rates in the region of
1.0–3.0mg/kg/h should achieve satisfactory sedation. Infusion rates greater than
4.0 mg/kg/h are not recommended.

d) Monitored conscious 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 0.5–1 mg/kg over 1–5 minutes for onset of sedation.

Maintenance of sedation may be accomplished by titrating Fresofol 1% infusion to the

desired level of sedation – most patients will require 1.5–3.0 mg/kg/h. In addition to the
infusion, bolus administration of 10–20 mg may be used if a rapid increase in the depth of
sedation is required. In patients in ASA grades III or IV and in the elderly, the rate of

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administration and dosage may need to be reduced. Patients should not be discharged for
at least three hours after the procedure.

Monitored conscious sedation in patients should be continuously monitored by persons not

involved in the conduct of the surgical or diagnostic procedure. Oxygen supplementation
should be immediately available and provided where clinically indicated; oxygen saturation
should be monitored in all patients. Patients should be continuously monitored for early
signs of hypotension, apnoea, airway obstruction and/or oxygen desaturation. These
cardiorespiratory effects are more likely to occur following rapid initiation (loading) boluses
or during supplemental maintenance boluses, especially in the elderly, debilitated or ASA
grades III or IV patients. Patients should be monitored during sedation and recovered
according to the standards of the Australian and New Zealand College of Anaesthetists.

Use in the elderly

In elderly patients the dose requirement for induction of anaesthesia with Fresofol 1% 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. Induction
infusion rates of 300 mL/hour (50 mg/min) are associated with less hypertension and apnoea
in elderly patients. Where Fresofol 1% is used for maintenance of anaesthesia or sedation the
rate of infusion or ‘target concentration’ should also be reduced. Patients of ASA grades III and
IV will require further reductions in dose and dose rate. Rapid bolus administration (single or
repeated) should not be used in the elderly unventilated patient as this may lead to apnoea.

A rapid bolus may also depress cardiac function.

Use in children (over 3 years of age)

Children are at particular risk of fat overload. Therefore serum lipids should be monitored in
children receiving propofol.

Supplementary analgesic agents are generally required in addition to propofol. Following

infusion of propofol, discontinuation of these analgesic agents should be gradual to minimise
the risk of withdrawal symptoms.

a) Induction of anaesthesia
Due to lack of experience, Fresofol 1% must not be used in children under 3 years of age.

When used to induce anaesthesia, it is recommended that Fresofol 1% should be titrated

slowly until the clinical signs show the onset of anaesthesia.

The dose should be adjusted for age and/or weight.

Children over 8 years of age are likely to require approximately 2.5 mg propofol/kg body
weight for induction of anaesthesia. Under this age the requirements may be more. Lower
dosage is recommended for children in children of ASA grades III and IV.

b) Maintenance of anaesthesia
Fresofol 1% is not recommended for use in children less than three years of age.
Anaesthesia can be maintained by administering Fresofol 1% by infusion or repeat bolus
injection to maintain the depth of anaesthesia required. The required rate of
administration varies considerably between patients but rates in the region of
9–15mg/kg/h usually achieve satisfactory anaesthesia.

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c) Sedation during intensive care

Fresofol 1% is contraindicated for sedation in children as safety and efficacy have not been
demonstrated.

Although no causal relationship has been established, serious adverse events (including
fatalities) have been observed from spontaneous reports of unregistered use. These events
were seen more frequently in children with respiratory tract infections (including croup)
given doses in excess of those recommended for adults. Lipaemia and an evolving
metabolic acidosis may be precursors of fatal outcomes.

d) Monitored conscious sedation for surgical and diagnostic procedures

Fresofol 1% is contraindicated for sedation in children as safety and efficacy have not been
demonstrated.

Administration
(see also section 4.4 Special warnings and precautions for use)
Fresofol 1% is a lipid containing emulsion without an antimicrobial preservative and may
support rapid growth of micro-organisms. Ampoules and vials of Fresofol 1% are to be shaken
before use. The emulsion 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 Fresofol 1% and infusion equipment throughout the
infusion period. Fresofol 1% must not be administered via a microbiological filter.

Fresofol 1% and any infusion equipment containing Fresofol 1% are for single administration in
an individual patient. Any portion of the contents remaining after use should be discarded.

Changes to the haemodynamic parameters such as systolic arterial pressure, diastolic arterial
pressure, cardiac output and systemic vascular resistance appear to be independent to
changes to rate of infusion of propofol.

Infusion of undiluted Fresofol 1%

When Fresofol 1% is infused undiluted to maintain anaesthesia, it is recommended that
equipment such as drop counter, syringe pumps or volumetric infusion pumps should always
be used in control infusion rates.

As usual for fat emulsions, the infusion of Fresofol 1% via one infusion system must not exceed
12 hours. After 12 hours, the infusion system and reservoir of Fresofol 1% must be discarded
or replaced if necessary.

Infusion of diluted Fresofol 1%

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
Fresofol 1%. 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 dilution in the burette.

Dilutions, which must not exceed 1 part of Fresofol 1% and 4 parts of Glucose 5% intravenous
infusion solution (at least 2 mg Fresofol 1% per mL) should be prepared aseptically
immediately before administration. It is recommended that in order to prepare diluted
Fresofol 1%, the volume of 5% Glucose (Intravenous Infusion BP) removed from the infusion

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bag during the dilution process be totally replaced in volume by Fresofol 1%. Unused portions
of the injection as well as reservoirs, IV lines or solutions containing propofol injection, must
be discarded at the end of the procedure or within 6 hours, whichever occurs sooner.

Fresofol 1% may be administered via a Y-piece close to the injection site, into infusions of
Glucose 5% (Intravenous Infusion BP), Sodium Chloride 0.9% (Intravenous Infusion BP), or
Glucose 4% with Sodium Chloride 0.18% (Intravenous Infusion BP).

Fresofol 1% should not be mixed prior to administration with other therapeutic agents or
infusion fluids other than 5% glucose (Intravenous Infusion BP). Muscle relaxants like
atracurium and mivacurium should not be given through the same intravenous line as
Fresofol 1% without prior flushing.

4.3 Contraindications
Fresofol 1% is contraindicated:
 in patients with hypersensitivity to egg, soya or peanut protein or to any of the other
ingredients contained in Fresofol 1% (see section 6.1 List of excipients).
 during pregnancy, breast-feeding and obstetrics (except abortion).
 for general anaesthesia in children less than 3 years of age.
 in children 16 years of age or younger for sedation during intensive care and for monitored
conscious sedation for surgical and diagnostic procedures.

4.4 Special warnings and precautions for use

Monitoring facilities
Fresofol 1% should be given by a physician trained in anaesthesia (or where appropriate,
physicians trained in the care of patients in Intensive Care). Fresofol 1% should not be
administered by the person conducting the diagnostic or surgical procedure. When
Fresofol 1% is administered as a sedative for surgical or diagnostic procedures, patients should
be continuously monitored by persons not involved in the conduct of the diagnostic or surgical
procedure. Oxygen supplementation should be immediately available and provided when
clinically indicated; oxygen saturation should be monitored in all patients. Patients should be
continuously monitored for early signs of hypotension, apnoea, airway obstruction and/or
oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid
initiation (loading) boluses or during supplemental maintenance boluses, especially in the
elderly, debilitated and ASA grades III or IV patients and with co-administration of other
sedatives and opioid agents. Monitoring during the procedure and during the recovery period
should be in accordance with the needs of the patient. Facilities for maintenance of a patent
airway, artificial oxygen enrichment and other resuscitation facilities should be readily
available at all times.

When Fresofol 1% is used for sedation during operative procedures, involuntary patient
movements may occur. During procedures requiring immobility these movements may be
hazardous to the operative site.

Premedication
As with other intravenous anaesthetic agents, hypotension and apnoea during induction of
anaesthesia commonly occur and may be influenced by the rate of administration, use of other
premedications and other agents including benzodiazepines.

Fresofol 1% lacks vagolytic activity and has been associated with bradycardia (occasionally
profound) (see section 4.8 Undesirable effects) and also asystole. The intravenous

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administration of an anticholinergic agent before induction or during maintenance of

anaesthesia should be considered, especially in situations where vagal tone is likely to
predominate or when Fresofol 1% is used in conjunction with other agents likely to cause
bradycardia (see section 4.5 Interaction with other medicines and other forms of interaction).

Induction, maintenance and recovery

Occasionally hypotension may require use of intravenous fluids and reduction of the rate of
administration of Fresofol 1% during the period of anaesthetic maintenance.

Ventilatory depression can occur following administration of Fresofol 1%.

Fresofol 1% reduces cerebral blood flow, intracranial pressure and cerebral metabolism. This
reduction in intracranial pressure is greater in patients with an elevated baseline intracranial
pressure.

An adequate period is needed prior to discharge of the patient to ensure full recovery after
general anaesthesia. Very rarely the use of Fresofol 1% may be associated with the
development of unconsciousness after the period when recovery from anaesthesia should
have occurred. This may be accompanied by an increase in muscle tone and may or may not
be preceded by a period of wakefulness. Although recovery is spontaneous, appropriate care
of an unconscious patient should be administered.

Concomitant disease states

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.

Elevation of serum triglycerides

Appropriate care should be applied in patients with disorders of fat metabolism and in other
conditions where lipid emulsions must be used cautiously.

Because Fresofol 1% injection is formulated in an oil-in-water emulsion, elevations in serum

triglycerides may occur when Fresofol 1% injection is administered for extended periods of
time. Patients at risk of hyperlipidaemia should be monitored for increases in serum
triglycerides or serum turbidity. Administration of Fresofol 1% injection should be adjusted if
lipids are being cleared inadequately from the body. A reduction in the quantity of
concurrently administered lipids is indicated to compensate for the amount of lipid infused as
part of the Fresofol 1% injection formulation; 1.0 mL of Fresofol 1% injection contains
approximately 0.1 g of lipid (see also Use for sedation during intensive care, below).

The calorific value of Fresofol 1% is similar to that of “Intralipid” 10% i.e. 1.0 mL of Fresofol 1%
provides 1.1 kcals.

Epilepsy
Propofol has been found to have no effect on electroshock seizure threshold in animals. When
Fresofol 1% injection is administered to an epileptic patient, there may be a risk of seizure
during the recovery phase. Perioperative myoclonia less frequently including convulsions and
opisthotonus, has occurred in temporal relationship in cases in which Fresofol 1% injection has
been administered.

As with thiopentone, in vitro studies have shown that propofol is much less potent than
etomidate in the inhibition of synthesis of adrenocorticohormones. At concentrations of

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Fresofol 1% likely to be encountered in anaesthetic practice, no clinically significant effect on

adrenocorticohormones has been noted in studies to date.

Anaphylactoid reactions
Fresofol 1% has been reported to occasionally cause clinical anaphylactic/anaphylactoid type
of reactions with angioedema, bronchospasm, erythema and hypotension. These reactions
have been reported to respond to adrenaline.

Use for sedation during intensive care

Life threatening adverse events, occurring together or in combinations, of cardiac failure,
arrhythmias, metabolic acidosis, rhabdomyolysis and renal failure associated with propofol
when used in sedation during intensive care.

There have been very rare reports of metabolic acidosis, rhabdomyolsis, hyperkalaemia,
and/or rapidly progressive cardiac failure (in some cases with a fatal outcome) in adults
treated for more than 48 hours with propofol infusions in excess of 5 mg/kg/hour. These
reports have mainly (but not exclusively) been in patients with serious head injuries treated
with high doses of propofol, inotropes and vasoconstrictors. These reports also indicated that
a failure of oxygen delivery to the tissues was likely to have occurred. If these adverse events
occur unexpectedly in the presence of high infusion rates of propofol, or hypertriglyceridaemia
/lipidaemia is detected, consideration should be given to decreasing the propofol dosage or
switching to an alternative sedative. In the event of propofol dosage modification patients
with raised intracranial pressure should continue to be monitored and treated appropriately as
should patients with metabolic, respiratory and/or haemodynamic disturbances. The risk of
these life-threatening events occurring may be increased in the presence of persistent low
cardiac output. The maximum dose of propofol for adult sedation during intensive care should
not exceed 4.0 mg/kg/hour [see section 4.2 Dose and method of administration]. The use of
propofol for sedation in children 16 years of age and younger during intensive care and for
monitored conscious sedation for surgical and diagnostic procedures is contraindicated (see
section 4.3 Contraindications).

Obstetrics
Fresofol 1% crosses the placenta and may be associated with neonatal depression. It should
not be used for obstetric anaesthesia.

Paediatric population
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 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

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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 section 4.6 Fertility, pregnancy and
lactation).

Aseptic technique (see also Pharmaceutical precautions, below)

Strict aseptic technique must always be maintained during handling. Fresofol 1% injection is a
single patient use only parenteral product which does not contain any antimicrobial
preservative. Accordingly, strict aseptic technique must still be adhered to. Do not use if
contamination is suspected. Discard unused portions. There have been reports in which
failure to use aseptic technique when handling Fresofol 1% injection was associated with
microbial contamination of the product and with fever, infection/sepsis, other life-threatening
illness, and/or death.

When Fresofol 1% 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 Fresofol 1% and the
infusion equipment throughout the infusion period. Any drugs or fluids added to the Fresofol
1% line must be administered close to the cannular site. Fresofol 1% must not be
administered via a microbiological filter.

Containers of Fresofol 1% are for single use in an individual patient. In accordance with
established guidelines for other lipid emulsions, a single infusion of Fresofol 1% must not
exceed 12 hours. At the end of the procedure or at 12 hours, whichever is the sooner, both
the reservoir of Fresofol 1% and the infusion line must be discarded and replaced as
appropriate.

Pharmaceutical precautions (see also Aseptic technique, above)

In-use precautions:
Each ampoule or vial should be shaken before use. Do not use if the emulsion is separated or
discoloured.

Any portion of the contents remaining after use should be discarded.

The emulsion should not be mixed prior to administration with other therapeutic agents or
infusion fluids other than 5% Glucose (Intravenous Infusion BP).

The neuromuscular blocking agents, atracurium and mivacurium, should not be given through
the same i.v. line as Fresofol 1% without prior flushing.

Special warnings and precautions for use

Use of Fresofol 1% is not recommended with electroconvulsive therapy.

The safety and efficacy of Fresofol 1% for (background) sedation in children younger than 16
years of age have not been demonstrated. Although no causal relationship has been
established, serious undesirable effects with (background) sedation in patients younger than
16 years of age (including cases with fatal outcome) have been reported during unlicensed use.
In particular these effects concerned occurrence of metabolic acidosis, hyperlipidemia,
rhabdomyolysis and /or cardiac failure. These effects were most frequently seen in children
with respiratory tract infections who received dosages in excess of those advised in adults for
sedation in ICU. Similarly very rare reports have been received of occurrence of metabolic
acidosis, rhabdomyolysis, hyperkalaemia and/or rapidly progressive cardiac failure (in some

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cases with fatal outcome) in adults treated for more than 58 hours with dosages in excess of
5 mg/kg/hr. These exceeds the maximum dosage of 4 mg/kg/hr currently advised for sedation
in the ICU. The cardiac failure in such cases was usually unresponsive to inotropic supportive
treatment.

Prescribers are reminded if possible not to exceed the dosage of 4 mg/kg/hr which is usually
sufficient for sedation of mechanically ventilated patients in the ICU situation (treatment
durations in excess of 1 day). Prescribers should be alert to these possible undesirable effects
and decrease the dosage or switch to an alternative sedative at the first sign of occurrence of
symptoms.

Fresofol 1% contains soya oil and egg lecithin which may rarely cause severe allergic reactions.
Cross allergic reactions have been observed between soya-bean and peanut.

4.5 Interaction with other medicines and other forms of interaction

Fresofol 1% has been used with commonly used premedications or drugs used during
anaesthesia or sedation (including a range of inhalational anaesthetics, analgesics, muscle
relaxants or local anaesthetics). No significant adverse interactions have been observed.

Bradycardia and cardiac arrest may occur after treatment with suxamethonium or neostigmin.

Leucoencephalopathy has been reported with administration of lipid emulsions such as

propofol in patients receiving cyclosporine.

When Fresofol 1% is given with CNS depressants (e.g. potent analgesics), the sedative effect
may be intensified and the possibility of severe respiratory or cardiovascular depression should
be considered.

Fresofol 1% injection does not cause a clinically significant change in onset, intensity or
duration of action of the commonly used neuromuscular blocking agents (e.g. succinylcholine
and nondepolarizing muscle relaxants).

Induction Phase
At induction, the dose requirements of Fresofol 1% injection may be reduced in patients with
intramuscluar or intravenous premedications (see section 4.4 Special warnings and
precautions for use, Premedication), particularly with narcotics (e.g. morphine, meperidine
and fentanyl) and combinations of opoids and sedatives (e.g. benzodiazepines, barbiturates,
chloral hydrate, droperidol). These agents may increase the anaesthetic or sedative effects of
Fresofol 1% injection and may also result in more pronounced decreases in systolic, diastolic
and mean arterial pressures and cardiac output. Decreased oxygen saturation has been
reported when Fresofol 1% is administered with fentanyl; therefore oxygen supplementation
should be used.

Maintenance Phase
During maintenance of anaesthesia or sedation, the rate of Fresofol 1% injection
administration should be adjusted to the desired level of anaesthesia or sedation and may be
reduced in the presence of supplemental analgesic agents (e.g. nitrous oxide or opioids).

The concurrent administration of potent inhalational agents (e.g. isoflurane, enflurane and
halothane) during maintenance with Fresofol 1% injection has not been extensively evaluated.
These inhalational agents can also be expected to increase the anaesthetic or sedative and
cardiorespiratory effects of Fresofol 1% injection.

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4.6 Fertility, pregnancy and lactation

Pregnancy
Risk summary statement
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
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 section 5.3
Preclinical safety data).

Breast-feeding
Propofol is reportedly distributed into breast milk. Safety to the child has not been
established, therefore Fresofol 1% is contraindicated in mothers who are breast-feeding.

4.7 Effects on ability to drive and use machines

After administration of Fresofol 1%, the patient should be kept under observation for an
appropriate period of time. The patient should be instructed not to drive, operate machinery,
or work in potentially hazardous situations. The patient should not be allowed to go home
unaccompanied, and should be instructed to avoid consumption of alcohol.

4.8 Undesirable effects

During induction of propofol in clinical trials, hypotension and transient apnoea occurred in up
to 75% of patients. Excitation phenomena such as involuntary movements, twitches, tremors,
hypertonus and hiccup occurred in 14% of patients. Bradycardia responsive to atropine has
been reported.

During the recovery phase vomiting, headache and shivering occurred in about 2% of the
patients with nausea occurring more frequently.

Very common (> 1/10)

Body as a whole: pain during injection (burning, tingling/stinging)

Common (> 1/100, < 1/10)

Body as a whole: elation/euphoria, headache, shivering.
Cardiovascular: hypotension, hypertension, bradycardia.
Gastrointestinal: nausea, vomiting.
Respiratory: transient apnoea, cough.
Skin: flush/rash

Uncommon (> 1/1000, < 1/100)

Cardiovascular: arrhythmias - tachycardia, extrasystole.

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Rare (< 1/1000)

Body as a whole: fever.
Blood: thrombosis, phlebitis.
CNS: convulsions and seizures of the epileptic type.
Urogenital: discolouration of the urine on prolonged use.
Other: anaphylactoid reactions, in some cases with angio-oedema, bronchospasm,
erythema and hypotension. (These reactions have been reported to
respond to adrenaline).

Very Rare (< 1/10000)

Muscoskeletal and
connective tissue: rhabdomyolysis (when propofol has been administered at doses greater
than 4 mg/kg/hr for ICU sedation).
Gastrointestinal: pancreatitis, abdominal cramps.
CNS: pulmonary oedema, post-operative unconsciousness.
Other: cough, hiccup.

Very rare reports of cardiac failure, metabolic acidosis, renal failure and hyperkalaemia have
been reported.

Occasionally, hypotension may require use of intravenous fluids and reduction of the rate of
administration of Fresofol 1% during the period of anaesthetic maintenance or sedation.

Epileptiform movements, including convulsions and opisthotonus, have occurred. As with

other anaesthetic agents, depression of cardiac output may occur. As with other anaesthetics,
sexual disinhibition may occur during recovery. Depression, crying, confusion, restlessness,
broncho or laryngospasm were also observed.

Following abrupt discontinuation of Fresofol 1% in children receiving intensive care,

withdrawal symptoms and flushing have been noted. Cardio-respiratory depression may
occur in neonates if paediatric dosage regimen is used for induction of anaesthesia.

Following paravenous application severe tissue responses may occur very rarely.

Intra-arterial injection in animals did not induce local tissue effects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It
allows continued monitoring of the benefit/risk balance of the medicine. Healthcare
professionals are asked to report any suspected adverse reactions
https://nzphvc.otago.ac.nz/reporting/

4.9 Overdose
Accidental overdosage may cause cardiorespiratory depression. Respiratory depression should
be treated by artificial ventilation with oxygen. Cardiovascular depression requires lowering of
the patient’s head, and, in severe cases, the 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).

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5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anaesthetics, general; other general anaesthetics
ATC codes: N01AX10

Propofol is a short-acting general anaesthetic agent with a rapid onset of action of

approximately 30 seconds. The mechanism of action, like all general anaesthetics, is poorly
understood. The majority of pharmacodynamic properties exhibited by propofol are
proportional to the dose or concentration in the blood. These dose or dose-rate dependent
properties include the desired therapeutic effects of mild sedation through to anaesthesia, but
also include the increasing incidence of cardiac and respiratory depression seen with
increasing dose.

The cardiovascular effects of propofol range from a minimal reduction in blood pressure
through to arterial hypotension, and a decrease in heart rate. 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 propofol, any effects are
qualitatively similar to those of other intravenous anaesthetic agents and are readily
manageable in clinical practice.

Preliminary findings in patients with normal intraocular pressure indicate that propofol
anaesthesia produces a decrease in intra-ocular pressure, which may be associated with a
concomitant decrease in systemic vascular resistance.

In combination with hypocarbia, propofol increases cerebro-vascular resistance, decreases

cerebral blood flow, cerebral metabolic oxygen consumption and intra-cranial pressure; but
does not affect cerebro-vascular reactivity to changes in arterial carbon dioxide tension.

Limited experience in susceptible patients does not indicate any propensity of propofol to
induce malignant hyperthermia.

Propofol does not suppress the adrenal response to adrenocorticotropic hormone (ACTH).

5.2 Pharmacokinetic properties

The pharmacokinetics of propofol follow a three compartment open model with
compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating
tissues.

Absorption
Following an IV bolus dose, there is rapid equilibration between the plasma and the highly
perfused tissue of the brain, thus accounting for the rapid onset of anaesthesia.

Distribution
Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance.
The initial (distribution) half-life is between 2–4 minutes, followed by a rapid elimination phase
with a half-life of 30–60 minutes and followed by a slower final phase, representative of
redistribution of propofol from poorly perfused tissue. Accumulation may occur if higher than
necessary infusion rates are used.

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Metabolism
Propofol is primarily metabolised by the liver to predominately glucuronide conjugates and
their corresponding quinols, which are inactive. These are excreted renally. The
pharmacokinetics of propofol are linear over the recommended range of infusion rates of
propofol. Moderate hepatic or renal impairment do not alter these pharmacokinetics.
Patients with severe hepatic or renal impairment have not been adequately studied.

Excretion
Adult propofol clearance ranges from 1.5–2 L/minute (21–29 mL/kg/min).

The distribution and clearance in children down to the age of three years are similar to those
of adults.

In older patients for a given dose, a higher peak plasma concentration is observed. The VD and
clearance are also decreased; this may explain the decreasing dose requirement with
increasing age and the sensitivity of older patients to the other dose related effects of
propofol.

Discontinuation of propofol after the maintenance of anaesthesia for approximately one hour,
or of ICU sedation for one day, results in a prompt decrease in blood propofol concentrations
and rapid awakening, usually within 5 minutes. Longer infusions (10 days of ICU sedation)
result in accumulation of significant tissue stores of propofol, such that the reduction in
circulating propofol is slowed and the time to awakening may be increased by up to 15
minutes.

5.3 Preclinical safety data

Animal toxicology and/or pharmacology
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.

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6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Soya oil
Glycerol
Egg lecithin
Water for Injections
Oleic acid (pH adjustment)
Sodium hydroxide (pH adjustment)

6.2 Incompatibilities
Fresofol 1% should not be mixed prior to administration with injections or infusion solutions
other than 5% glucose intravenous infusion solution, sodium chloride 0.9% intravenous
infusion solution.

6.3 Shelf life

24 months

6.4 Special precautions for storage

Store below 25C. Do not freeze.

6.5 Nature and contents of container

 Pack containing 5 × 20 mL ampoules (type 1 glass), 10 x 20mL ampoules (type 1 glass)
 Packs containing *1 × 50 mL, 10 × 50 mL, *1 × 100 mL or 10 × 100 mL vials (type 1 glass,
rubber closure, aluminium cap)

* Pack sizes not marketed

6.6 Special precautions for disposal

No special requirements for disposal.

7 MEDICINE SCHEDULE
Prescription Medicine

8 SPONSOR
Fresenius Kabi New Zealand Limited
60 Pavilion Drive
Airport Oaks, Auckland
New Zealand

Freecall: 0800 144 892

9 DATE OF FIRST APPROVAL

Date of publication in the New Zealand Gazette of consent to distribute the medicine:
2 May 2002

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 NEW ZEALAND DATA SHEET

10 DATE OF REVISION OF THE TEXT

14th June 2017

SUMMARY TABLE OF CHANGES

Section changed Summary of new information

n.a. New data sheet format

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