Consumer medicine information

Propofol-Lipuro 1% and 2%

Propofol

BRAND INFORMATION

Brand name

Propofol-Lipuro 1% and 2%

Active ingredient

Propofol

Schedule

1. What is in this leaflet

This leaflet contains some common questions about Propofol-Lipuro.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risk of you taking this medicine against the benefits they expect it will have for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

2. What is Propofol-Lipuro used for?

It is a short-acting sleep inducing medicinal product used to start and sustain a general anaesthesia.

It is used to induce sleep or lower your level of consciousness (as a sedative) during intensive care or during diagnostic or surgical procedures.

3. Before you are given Propofol-Lipuro

When you must not be given Propofol-Lipuro

Do not use Propofol-Lipuro:

if you are allergic (hypersensitive) to Propofol or any of the other ingredients of Propofol-Lipuro
if you are allergic (hypersensitive) to soya or peanut

Take special care with Propofol-Lipuro if:

you have a disorder in which your body does not handle fat properly
you have any other health problems which require much caution in the use of fat emulsions
you are very overweight
your blood volume is too low (hypovolaemia)
you are very weak or have heart, circulatory, kidney or liver problems
you have high pressure within in the skull and low blood pressure in the arteries
you have problems with your breathing
you have epilepsy
you are undergoing some procedures where spontaneous movements are particularly, undesirable.

Please tell your doctor if you have one of these diseases or conditions.

Do not give Propofol-Lipuro in children of one month of age or younger as a general anaesthetic.

Do not give Propofol-Lipuro 2% in children under 3 years of age.

Do not give Propofol-Lipuro in children 16 years or younger as a sedation during intensive care.

The use of Propofol-Lipuro is not recommended in newborn infants

It will not be used when you are receiving electroconvulsive therapy (electric shock treatment in cases of severe long lasting epileptic attacks.

If you are receiving other lipids by a drip into your vein at the same time your doctor will pay attention to your total daily fat intake.

Propofol will be administered to you by a physician trained in anaesthesia or intensive care. You will be constantly monitored during anaesthesia and waking-up time.

If you experience signs of the so called ‘propofol infusion syndrome’ (a doctor must be called if the following happen) your doctor will decrease the dosage of propofol or will switch to an alternative drug.

Taking or using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Some medicines may depress your breathing or your blood circulation when combined with Propofol or prolong the effect of Propofol:

Painkillers, benzodiazepine tranquillisers, narcotic gases, some local anaesthetics, fentanyl, other medicinal products usually given before operations.

On the other hand, the sedative effect of some of these medicinal products may become stronger.

When given together with Propofol, certain medicines used for muscle relaxation (suxamethonium) or as antidote (neostigmin) may depress heart function.

Occurrence of a specific organic changes in the brain (leucoencephalopathy) has been reported in patients having received fat emulsions such as Propofol-Lipuro together with ciclosporin (a medicine used to suppress rejection reactions after organ transplantation and to suppress overreactions of the immune system).

Make sure that your doctor knows if you are taking any of these medicinal products.

Using Propofol-Lipuro with food and drink

Alcohol and Propofol make the sedative effects of each other stronger. Therefore you should not drink alcohol just before or just after you have Propofol-Lipuro.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

Propofol-Lipuro should not be used during pregnancy.

If you are breast-feeding your child you should stop nursing and discard breast milk for 24 hours after you have received Propofol-Lipuro. Studies in breast-feeding women showed that Propofol is excreted in small amounts into the milk.

Driving and using machines

You should not drive or operate machinery for a while after you have had an injection or infusion of Propofol-Lipuro. Your doctor will tell you how long you must wait before you drive or use machinery again.

Your doctor will advise you

if you should be accompanied when you are leaving.
when you can drive and use machinery again.
on the use of other tranquillizing drugs (e.g. tranquillizers, strong pain killers, alcohol).

Important information about some of the ingredients of Propofol-Lipuro

This medicinal product contains less than 1 mmol (23 mg) sodium in 100 mL, that is, it is essentially ‘sodium free’.

4. How to use Propofol-Lipuro

Propofol-Lipuro will only be given by anaesthetists or by specially trained doctors in an intensive care unit.

Dosage

The dose you are given will vary depending on your age, body weight and physical condition.

The doctor will give the correct dose to start and to sustain anaesthesia or to achieve the required level of sedation, by carefully watching your responses and vital signs (pulse, blood pressure, breathing, etc).

The doctor will also observe limits of the time of application, if necessary.

Propofol-Lipuro will usually be given by injection when used to induce general anaesthesia and by continuous infusion (a slower, longer injection) when used to maintain general anaesthesia. It may given as an infusion either diluted or undiluted. When used as a sedative it will usually be given by infusion.

Propofol-Lipuro will only be given for a maximum of 7 days.

Method of administration

You will receive Propofol-Lipuro by intravenous injection or infusion, that is, through a needle or small tube placed in one of your veins.

Because Propofol-Lipuro does not contain preservatives, an infusion from one vial or bottle of Propofol-Lipuro will not last longer than 12 hours..

Your circulation and breathing will be constantly monitored while you are being given the injection or infusion.

Overdose

If you received more Propofol-Lipuro then you should

It is unlikely that this occurs because the doses you receive are very carefully controlled.

If you accidentally got an overdose, this could lead to depression of heart function, circulation and breathing. In this case your doctor will employ any necessary treatment immediately.

If you have any further questions on the use of this product, ask your doctor or pharmacist

5. Possible Side Effects

Like all medicines, Propofol-Lipuro emulsion for injection or infusion can cause side effects, although not everybody gets them.

Common (may affect up to 1 in 10 people):

Low blood pressure that might occasionally need infusion of fluids and reduction of the speed of administration of propofol.
Too low heartbeat that might be serious in rare cases.

Rare (may affect up to 1 in 1,000 people):

Convulsions like in epilepsy

Very rare (may affect up to 1 in 10,000 people):

Allergic reactions including swelling of the face, tongue or throat, wheezing breath, skin redness and low blood pressure
There have been cases of unconsciousness occurring after operations. You will therefore be carefully observed during the waking-up time.
Water on lungs (lung oedema) after administration of propofol
Inflammation of the pancreas.

Not known (frequency cannot be estimated from the available data):

There have been reports of isolated cases of severe adverse reactions presenting as a combination of the following symptoms: breakdown of muscle tissue, accumulation of acidic (sour) substances in the blood, abnormally high blood potassium level, high blood fat levels, abnormalities in the electrocardiogram (Brugada-type ECG), liver enlargement, irregular heart-beat, kidney failure and heart failure. This has been called the “propofol infusion syndrome”. Some of the affected patients eventually died. These effects have only been seen in patients in intensive care with doses higher than 4 mg of propofol per kg body weight per hour. See also section 2, ‘Warnings and precautions’.

Other side effects are:

Very common (affects more than 1 treated patient of 10):

Pain at the injection site occurring during the first injection. The pain may be reduced by injecting propofol into larger veins of the forearm. Injection of lidocaine (a local anaesthetic) and propofol at the same time also helps to reduce the pain at the injection site.

Common (may affect up to 1 in 10 people):

Short interruption of breathing
Headache during the time of recovery
Sickness or vomiting during the time of recovery

Uncommon (may affect up to 1 in 100 people):

Blood clots in veins or inflammation of veins

Very rare (may affect up to 1 in 10,000 people):

Loss of sexual control during the time of recovery
Abnormal colour of urine after longer lasting administration of propofol
Cases of fever after an operation

Not known (frequency cannot be estimated from the available data):

Involuntary movements
Abnormally good mood
Drug abuse
Failure of the heart
Breakdown of muscle tissue has been reported very rarely in cases where propofol has been given at greater doses than recommended for sedation in intensive care units

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

6. Storage

Keep out of the reach and sight of children.

Do not use Propofol-Lipuro after the expiry date which is stated on the label and the carton after EXP. The expiry date refers to the last day of that month.

Keep ampoules in the outer carton in order to protect from light. Store below 25°C. Do not freeze.

Propofol-Lipuro must be used immediately after opening the ampoule, vial or bottle.

Do not use Propofol-Lipuro if two separate layers can be seen after shaking the product.

The following information is intended for medical or healthcare professionals only:

The containers are for single use in one patient only.

Any unused emulsion must be thrown away at the end of administration.

The containers must be shaken before use.

7. Product Description

What Propofol-Lipuro looks like

It is a milky-white oil-in water emulsion which comes in the following:

Propofol-Lipuro 1%:

20mL glass ampoule

20mL colourless glass vial, sealed with a grey rubber stopper and aluminium seal with a blue polypropylene flip-off insert

50mL colourless glass infusion bottles, sealed with a grey rubber stopper and aluminium seal with a blue polypropylene flip-off insert

100mL colourless glass infusion bottles, sealed with a grey rubber stopper and aluminium seal with a blue polypropylene flip-off insert

Propofol-Lipuro 2%:

50mL colourless glass infusion bottles, sealed with a grey rubber stopper and aluminium seal with a red polypropylene flip-off insert

Ingredients:

Propofol-Lipuro 1%

Active ingredient:

Propofol

1 mL contains 10 mg of Propofol.

Inactive ingredients:

Soya oil,

Medium-chain triglycerides,

Egg lecithin,

Glycerol,

Sodium oleate,

Water for injections

Propofol-Lipuro 2%

Active ingredient:

Propofol

1 mL contains 20 mg of Propofol.

Inactive ingredients:

Soya oil,

Medium-chain triglycerides,

Egg lecithin,

Glycerol,

Sodium oleate,

Water for injections

Australian registration number:

Propofol-Lipuro 1%:

20mL ampoule AUST R 142906

20mL vial AUST R 220082

50mL bottle AUST R 220083

100mL bottle AUST R 220081

Propofol-Lipuro 2%:

50mL bottle AUST R 220084

8. Sponsor Details

B. Braun Australia Pty Ltd
Level 5, 7-9 Irvine Place
Bella Vista NSW 2156
Australia

Toll Free Number: 1800 251 705

9. Date of Information

This leaflet was updated in July 2019

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Propofol-Lipuro 1% and 2%

Active ingredient

Propofol

Schedule

1 Name of Medicine

Propofol.

2 Qualitative and Quantitative Composition

Propofol-Lipuro contains (see Table 1):
Contains egg lecithin and soya oil. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sterile, milky white, isotonic, oil in water emulsion for intravenous infusion or injection containing 10 mg propofol per 1 mL (Propofol-Lipuro 1%) or 20 mg propofol per 1 mL (Propofol-Lipuro 2%).

4 Clinical Particulars

4.1 Therapeutic Indications

Because of the difficulty in titrating small volumes, Propofol-Lipuro 2% should not be used in children aged from one month to 3 years.

Induction of general anaesthesia in children and adults.

Propofol-Lipuro is a short acting intravenous anaesthetic agent suitable for induction of general anaesthesia in adults and children aged one month and older.

Maintenance of general anaesthesia in children and adults.

Propofol-Lipuro is a short acting intravenous anaesthetic agent suitable for maintenance of general anaesthesia in adults and children aged 3 years and older.
Propofol-Lipuro 1% may also be used for maintenance of general anaesthesia in children aged from one month to 3 years for procedures not exceeding 60 minutes, unless alternative anaesthetic agents should be avoided.
Propofol has no analgesic properties.

Sedation during intensive care in adults.

Propofol-Lipuro may also be used in patients > 16 years for sedation of ventilated patients receiving intensive care.

Conscious sedation for surgical and diagnostic procedures.

Propofol-Lipuro may also be used for monitored conscious sedation for surgical and diagnostic procedures in the following.
Propofol-Lipuro 1%: adults and children aged one month and older.
Propofol-Lipuro 2%: adults and children aged 3 years and older.

4.2 Dose and Method of Administration

Aseptic technique (see Section 4.4 Special Warnings and Precautions for Use, In-use precautions and Aseptic technique).

Strict aseptic technique must always be maintained during handling. Do not use if contamination is suspected. Discard unused portions as directed within the required time limits.

Adults.

Induction of general anaesthesia. Propofol-Lipuro may be used to induce anaesthesia by slow bolus injection or infusion.
In unpremedicated and premedicated patients it is recommended that propofol should be titrated (20-40 mg of propofol every 10 seconds) against response of the patient until the clinical signs show the onset of anaesthesia. Most adult patients less than 55 years are likely to require 1.5 to 2.5 mg of propofol per kg bodyweight.
In elderly patients, requirements will be generally less (see Elderly patients). 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 or IV, lower rates of administration should be used (approximately 2 mL Propofol-Lipuro 1% or 1 mL Propofol-Lipuro 2%, corresponding to 20 mg of propofol every 10 seconds).
Recovery from induction doses usually occur within 5 to 10 minutes.
Maintenance of general anaesthesia. Anaesthesia can be maintained by administering propofol either by continuous infusion or by repeat bolus injections to maintain the depth of anaesthesia required. Experience in procedures lasting more than one hour is limited.

Continuous infusion.

The required rate of administration varies considerably between patients but rates in the region of 0.067 to 0.2 mg/kg b.w./min (4 to 12 mg/kg b.w./h) usually maintain satisfactory anaesthesia.

Repeat bolus injection.

If a technique involving repeat bolus injections is used, increments of 25 to 50 mg of propofol (2.5 to 5.0 mL Propofol-Lipuro 1%, 1.25 to 2.5 mL Propofol-Lipuro 2%) may be given according to clinical need.
Sedation during intensive care. When used to provide sedation for ventilated adult patients undergoing intensive care, it is recommended that propofol should be given by continuous infusion. The infusion rate should be adjusted according to the required depth of sedation. Usually satisfactory sedation is achieved with dosages in the range of 0.3-4.0 mg of propofol per kg bodyweight per hour. Infusion rates greater than 4.0 mg/kg/h are not recommended.
Propofol-Lipuro 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.
Administration of Propofol-Lipuro by target controlled infusion (TCI) system is not recommended for sedation during intensive care.
Monitored conscious sedation for surgical and diagnostic procedures. Propofol-Lipuro is contraindicated for sedation in children as safety and efficacy have not been demonstrated.
To provide sedation for surgical and diagnostic procedures, doses and rates of administration should be individualised and titrated to clinical response.
Most patients will require 0.5-1 mg of propofol per kg bodyweight over 1 to 5 minutes for onset of sedation.
Maintenance of sedation may be accomplished by titrating propofol infusion to the desired level of sedation; most patients will require 1.5-4.5 mg of propofol per kg bodyweight per hour. In addition to the infusion, bolus administration of 10-20 mg of propofol (1-2 mL of Propofol-Lipuro 1% or 0.5-1 mL of Propofol-Lipuro 2%) may be used if a rapid increase of the depth of sedation is required. In patients in ASA grades III or IV (according to the classification of the American Society of Anaesthesiologists) and in the elderly, the rate of 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 which is also endorsed by the Gastroenterological Society of Australia; Royal Australasian College of Surgeons; Australasian College for Emergency Medicine; College of Intensive Care Medicine of Australia and New Zealand; Royal Australian and New Zealand College of Radiologists; Royal Australian and New Zealand College of Psychiatrists.
Administration of propofol by target controlled infusion (TCI) system is not recommended for monitored conscious sedation.

Elderly patients.

In elderly patients the dose requirement for induction of anaesthesia with Propofol-Lipuro 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 hypotension and apnoea in elderly patients. Where Propofol-Lipuro 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.

Paediatric use.

Induction of general anaesthesia. Propofol-Lipuro 1% is suitable for induction of general anaesthesia in children aged one month and older. Propofol-Lipuro is contraindicated for use in infants less than 1 month old.
When used to induce anaesthesia in children, it is recommended that Propofol-Lipuro be given slowly until 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 of propofol per kg bodyweight for induction of anaesthesia. Under this age the requirement may be more. Lower dosage is recommended for children of ASA grades III and IV.
Maintenance of general anaesthesia. Propofol-Lipuro 1% may also be used for maintenance of general anaesthesia in children aged from one month to 3 years. Propofol-Lipuro 2% may be technically difficult to use in children under 3 years of age. Duration of use in maintenance studies in children under 3 years of age was mostly approx. 20 minutes, with a maximum duration of 75 minutes. A maximum duration of use of approximately 60 minutes should therefore not be exceeded except where there is a specific indication for longer use e.g. malignant hyperthermia where volatile agents must be avoided. Propofol-Lipuro is not recommended for use in infants less than 1 month old. For maintenance of general anaesthesia, a satisfactory level of anaesthesia is usually achieved by continuous infusion with a dosage regimen in the range of 9-15 mg of propofol per kg bodyweight per hour. Younger children, less than 3 years, may need higher dosages, within the range of recommended dosages, when compared with older paediatric patients. Dosage should be adjusted individually and particular attention paid to the need for adequate analgesia.
Sedation during intensive care. Propofol-Lipuro is contraindicated for sedation in children ≤ 16 years 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.
Children are at particular risk of fat overload. Therefore serum lipids should be monitored in children receiving Propofol-Lipuro.
Supplementary analgesic agents are generally required in addition to Propofol-Lipuro. Following infusion of Propofol-Lipuro, discontinuation of these analgesic agents should be gradual to minimise the risk of withdrawal symptoms.
Monitored conscious sedation for surgical and diagnostic procedures. As safety and efficacy have not been demonstrated. Propofol-Lipuro is contraindicated for sedation in infants less than 1 month old.

Administration (also see Section 4.4 Special Warnings and Precautions for Use, Aseptic technique).

Propofol must only be given in hospitals or adequately equipped day therapy units by physicians trained in anaesthesia or in the care of patients in intensive care. Circulatory and respiratory functions should be constantly monitored (e.g. ECG, pulse oxymeter) and facilities for maintenance of patient airways, artificial ventilation, and other resuscitation facilities should be immediately available at all times. For sedation during surgical or diagnostic procedures propofol should not be given by the same person that carries out the surgical or diagnostic procedure.
Supplementary analgesic drugs are generally required in addition to propofol.

Infusion of undiluted Propofol-Lipuro.

When administering Propofol-Lipuro by continuous infusion, it is recommended that burettes, drop counters, syringe pumps or volumetric infusion pumps, should always be used to control the infusion rates. As established for the parenteral administration of all kinds of fat emulsions, the duration of continuous infusion of Propofol-Lipuro from one infusion system must not exceed 12 hours. The infusion line and the reservoir of Propofol-Lipuro must be discarded and replaced after 12 hours at the latest. Any portion of Propofol-Lipuro remaining after the end of infusion or after replacement of the infusion system must be discarded.

Infusion of diluted Propofol-Lipuro.

For administering infusion of diluted Propofol-Lipuro, burettes, drop counters, syringe pumps, or volumetric infusion pumps should always be used to control infusion rates and to avoid the risk of accidentally uncontrolled infusion of large volumes of diluted Propofol-Lipuro.
The maximum dilution must not exceed 1 part of Propofol-Lipuro with 4 parts of 5% w/v glucose solution or 0.9% w/v sodium chloride solution, or 0.18% w/v sodium chloride and 4% w/v glucose solution (minimum concentration 2 mg propofol/mL). The mixture should be prepared aseptically immediately prior to administration. The duration of infusion should not exceed 6 hours.
Propofol-Lipuro must not be mixed with other solutions for injection or infusion. However, coadministration of Propofol-Lipuro together with 5% w/v glucose solution or 0.9% w/v sodium chloride solution, or 0.18% w/v sodium chloride and 4% w/v glucose solution via a Y connector close to the injection site is possible.
In order to reduce pain on initial injection, Propofol-Lipuro 1% may be mixed with preservative free lidocaine injection (mix 20 parts of Propofol-Lipuro 1% with up to 1 part of lidocaine injection 1%). For Propofol-Lipuro 2% lidocaine may be injected immediately prior to the injection of Propofol-Lipuro 2%. Before giving the muscle relaxants atracurium or mivacurium subsequent to Propofol-Lipuro through the same intravenous line, it is recommended that the line be rinsed prior to administration.

Duration of use.

Propofol-Lipuro can be administered for a maximum period of 7 days.

4.3 Contraindications

Propofol-Lipuro is contraindicated:
in patients with a known hypersensitivity to propofol or to any of the other ingredients contained in Propofol-Lipuro, namely soya oil, medium chain triglycerides, glycerol, egg lecithin, and sodium oleate;
in patients who are allergic to soya or peanut;
for induction and maintenance of general anaesthesia in children younger than 1 month.

4.4 Special Warnings and Precautions for Use

In-use precautions.

Propofol-Lipuro is administered intravenously by injection or continuous infusion either undiluted or diluted with 5% w/v glucose solution or 0.9% w/v sodium chloride solution as well as in a 0.18% w/v sodium chloride and 4% w/v glucose solution in PVC infusion bags or glass infusion bottles.
Containers should be shaken before use.
If two layers can be seen after shaking the product should not be used.
Before use, the neck of the ampoule should be cleaned with medicinal alcohol (spray or swabs). After use, tapped containers must be discarded.
Propofol-Lipuro contains no antimicrobial preservatives and supports growth of microorganisms. Therefore, Propofol-Lipuro is to be drawn up aseptically into a sterile syringe or an infusion set immediately after opening the ampoule. Administration must commence without delay. Asepsis must be maintained for both Propofol-Lipuro and the infusion equipment throughout the infusion period.
Any drugs or fluids added to a running Propofol-Lipuro infusion must be administered close to the cannula site. Propofol-Lipuro must not be administered via infusion sets with microbiological filters.
The neuromuscular blocking agents, atracurium and mivacurium should not be given through the same i.v. line as Propofol-Lipuro without prior flushing.

Monitoring, facilities.

As with all anaesthetic procedures, propofol should be given by those trained in anaesthesia (or where appropriate, doctors trained in the care of patients in intensive care). Patients should be continuously monitored and facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment and other resuscitative facilities should be readily available at all times. Propofol should not be administered by the person conducting the diagnostic or surgical procedure.
As with other general anaesthetics, the administration of propofol without airway care may result in fatal respiratory complications. When propofol is administered as a sedative for surgical or diagnostic procedures, patients should be continuously monitored by persons not involved in the conduct of the surgical/ diagnostic procedures. 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 coadministration 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.
Propofol should be administered with caution when propofol is used for sedation during operative procedures, since involuntary patient movements may occur. During procedures requiring immobility, such as ophthalmic surgery, these movements may be hazardous to the operative site.

Abuse potential.

The abuse of propofol, predominantly by healthcare professionals, has been reported.

Premedication.

During induction of anaesthesia, hypotension and apnoea, similar to effects with other intravenous anaesthetic agents, commonly occur and may be influenced by the rate of administration, and the use of premedicants and other agents, including benzodiazepines.
Propofol lacks vagolytic activity and has been associated with reports of bradycardia (occasionally profound) and also asystole. The intravenous 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 propofol is used in conjunction with other agents likely to cause a bradycardia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Induction, maintenance and recovery.

Occasionally hypotension may require use of intravenous fluids and reduction of the rate of administration of propofol during the period of anaesthetic maintenance.
Ventilatory depression can occur following administration of propofol. An adequate period is needed prior to discharge of the patient to ensure full recovery after general anaesthesia. Very rarely the use of propofol 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.
Propofol reduces cerebral blood flow, intracranial pressure and cerebral metabolism. This reduction in intracranial pressure is greater in patients with an elevated baseline intracranial pressure.

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, debilitated or epileptic patients. In patients with severe cardiac impairment it is recommended that propofol is given with great caution and under intensive monitoring.
If possible, hypovolaemia, cardiac insufficiency, circulatory depression or impaired respiratory function should be compensated before the administration of propofol.

Elevation of serum triglycerides.

Appropriate care should be paid to disorders of fat metabolism or to diseases requiring particularly restrictive use of lipid emulsions.
Because Propofol-Lipuro is formulated in an oil in water emulsion, elevations in serum triglycerides may occur when Propofol-Lipuro is administered for extended periods of time. Propofol-Lipuro contains medium chain triglycerides (MCT) 50 mg/mL and long chain triglycerides (LCT) 50 mg/mL. Metabolism of medium chain triglycerides (MCTs) differs from that of long chain triglycerides (LCT). Unlike longer chain fatty acids, MCT require little carnitine for mitochondrial entry, and their more rapid breakdown may impart an increased production of ketones. It is recommended that the impact of total fat administration and infusion rate be considered in patients receiving Propofol-Lipuro in conjunction with other fat containing products such as parenteral nutrition agents, especially in patients demonstrating disturbances in normal fat metabolism. Patients at risk of hyperlipidaemia should be monitored for increases in serum triglycerides or serum turbidity. The dosage and infusion rate should be within the ranges recommended. Too rapid infusion of Propofol-Lipuro could lead to metabolic acidosis. Administration of Propofol-Lipuro 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 Propofol-Lipuro formulation; 1.0 mL of Propofol-Lipuro contains 0.1 g of fat (see also Sedation during intensive care).
Lipids should be monitored in ICU treatment after 3 days.
1.0 mL of Propofol-Lipuro provides 1.02 kcals.

Epilepsy.

Propofol has been found to have no effect on electroshock seizure threshold in animals. When propofol injection is administered to an epileptic patient, there may be a risk of seizure during the recovery phase. Before anaesthesia of an epileptic patient, it should be checked that the patient has received the antiepileptic treatment. Perioperative myoclonia less frequently including convulsions and opisthotonus, has occurred in temporal relationship in cases in which propofol 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 propofol likely to be encountered in anaesthetic practice, no clinically significant effect on adrenocorticohormones has been noted in studies to date.

Anaphylactoid reactions.

Propofol 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.

When propofol is used for sedation during intensive care the following life threatening adverse events known as propofol infusion syndrome (PRIS), can occur together or in combinations: cardiac failure, arrhythmias, metabolic acidosis, rhabdomyolysis, ECG changes and/or rapidly progressive cardiac failure (in some cases with a fatal outcome), hyperkalaemia, hepatomegaly, hyperlipidemia and renal failure.
There have been very rare reports of occurrence of PRIS in adults (in some cases with a fatal outcome) 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. The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or propofol. If these adverse events occur unexpectedly in the presence of high infusion rates of propofol, or hypertriglyceridemia/ lipidemia 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 safety and efficacy of propofol 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 the intensive care unit.
The use of propofol for sedation in children 16 years of age and younger during intensive care and for sedation for surgical and diagnostic procedures in children younger than 1 month (Propofol-Lipuro 1%) and in children under 3 years (Propofol-Lipuro 2%), is contraindicated (see Section 4.3 Contraindications).

Aseptic technique (see Section 4.2 Dose and Method of Administration).

Strict aseptic technique must always be maintained during handling. Propofol-Lipuro contains no antimicrobial preservatives and supports growth of microorganisms. Therefore, Propofol-Lipuro is to be drawn up aseptically into a sterile syringe or an infusion set immediately after opening the ampoule. Before use, the neck of the ampoule should be cleaned with medicinal alcohol (spray or swabs). After use, tapped containers must be discarded.
Administration must commence without delay. Asepsis must be maintained for both Propofol-Lipuro and the infusion equipment throughout the infusion period.
Any drugs or fluids added to a running Propofol-Lipuro infusion must be administered close to the cannula site. Propofol-Lipuro must not be administered via infusion sets with microbiological filters.
The contents of one ampoule or vial of Propofol-Lipuro and any syringe containing Propofol-Lipuro are for single use in one patient. Any portion of the contents remaining after use must be discarded. As established for the parenteral administration of all kinds of fat emulsions, the duration of continuous infusion of Propofol-Lipuro from one infusion system must not exceed 12 hours. The infusion line and the reservoir of Propofol-Lipuro must be discarded and replaced after 12 hours at the latest. Any portion of Propofol-Lipuro remaining after the end of infusion or after replacement of the infusion system must be discarded.

Use in the elderly.

Please see Section 4.2 Dose and Method of Administration, Elderly patients.

Paediatric use.

Use in children.

There are no clinical trials to support the use of propofol for the sedation of children with croup or epiglottitis receiving intensive care.

Use in neonates (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications).

Propofol-Lipuro is not recommended for induction and maintenance of anaesthesia in neonates.
There are no data to support the use of propofol for sedation of premature neonates receiving intensive care.

Paediatric neurotoxicity.

Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/analgesic/sedation drug administration or other factors such as the surgery or underlying illness.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy. The clinical significance of these nonclinical finding is yet to be determined.
Exposure is longer than the period of infusion. Depending on the drug and patient characteristics, as well as dosage, the elimination phase may be prolonged relative to the period of administration.

Others.

This medicinal product contains less than 1 mmol (23 mg) sodium in 100 mL, i.e. essentially sodium free.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

As with other intravenous sedative agents, when propofol is given with central nervous system depressants, such as potent analgesics, alcohol, or general anaesthetics, the sedative effect may be intensified and the possibility of severe respiratory or cardiovascular depression should be considered. Concomitant use of benzodiazepines, parasympatholytic agents or inhalation anaesthetics has been reported to prolong the anaesthesia and to reduce the respiratory rate.
The induction dose requirements of propofol may be reduced in patients with intramuscular or intravenous premedication (see Premedication), particularly with narcotics (e.g. morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g. benzodiazepines, barbiturates, chloral hydrate, droperidol, etc).
These agents may increase the anaesthetic or sedative effects of propofol 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 propofol is administered with fentanyl; for this reason oxygen supplementation should be used.
After additional premedication with opioids there may be a higher incidence and longer duration of apnoea. After administration of fentanyl, the blood level of propofol may be temporarily increased with an increase in the rate of apnoea.
During maintenance of anaesthesia or sedation, the rate of propofol administration should be adjusted according 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 propofol has not been extensively evaluated.
These inhalational agents can also be expected to increase the anaesthetic or sedative and cardiorespiratory effects of propofol.
Propofol 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).
Bradycardia and cardiac arrest may occur after treatment with suxamethonium or neostigmine.
No significant adverse interactions with commonly used premedications or drugs used during anaesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anaesthetic agents) have been observed.
Lower doses of propofol may be required where general anaesthesia is used as an adjunct to regional anaesthetic techniques.
Leucoencephalopathy has been reported with administration of lipid emulsions such as propofol in patients receiving cyclosporine.
Propofol clearance is blood flow dependent, therefore, concomitant medication that reduces cardiac output will also reduce propofol clearance.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in female rats at intravenous doses up to 15 mg/kg/day for 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility. Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.
(Category C)
All general anaesthetics cross the placenta and carry the potential to produce central nervous system and respiratory depression in the newborn infant. In routine practice this does not appear to be a problem: however, in the compromised fetus, careful consideration should be given to this potential depression, and to the selection of anaesthetic drugs, doses and techniques.
Propofol should not be used in pregnancy. Teratology studies in rats and rabbits show some evidence of delayed ossification or abnormal cranial ossification with an increase in the incidence of subcutaneous haematomas. Reproductive studies in rats suggest that administration of propofol to the dam adversely affects perinatal survival of the offspring.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy.
Published studies in pregnant and juvenile animals demonstrate that the use of anaesthetic/analgesic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes.

Obstetrics.

Propofol crosses the placenta and may be associated with neonatal depression. It should not be used for obstetric anaesthesia.
Studies in breastfeeding women showed that propofol is excreted in small amounts into the milk. Therefore, mothers should stop breastfeeding and discard breast milk for 24 hours after administration of propofol.

4.7 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 general anaesthesia. Patients must be accompanied when going home after discharge and must be instructed to avoid drinking alcohol.

4.8 Adverse Effects (Undesirable Effects)

The most commonly observed adverse effects of propofol are hypotension and respiratory depression. These effects depend on the propofol dose administered but also on the type of premedication and other concomitant medication.
During induction in clinical trials with a product containing propofol which is interchangeable with Propofol-Lipuro, hypotension and transient apnoea occurred in up to 75% of patients. Excitatory 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.
Specifically, the following side effects have been observed. (See Table 2.)

Propofol infusion syndrome.

Symptoms of PRIS include: metabolic acidosis, notably lactic acidosis, hyperlipidemia, hyperkalaemia, rhabdomyolysis typically indicated by a marked increase of the blood creatine phosphokinase, renal impairment or failure and cardiac failure not responding to inotropic medication. Cases of fatal outcome have been reported. Of note, the propofol infusion syndrome may present with varying combinations of the symptoms listed here (see Section 4.4 Special Warnings and Precautions for Use, Use for sedation during intensive care).
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 propofol in children receiving intensive care, withdrawal symptoms and flushing have been noted. Cardiorespiratory depression may occur in neonates if paediatric dosage regimen is used for induction of anaesthesia.

Reporting suspected adverse events.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Accidental overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression would require lowering the patient's head and, if severe, use of plasma expanders and pressor agents.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 principally by the positive modulation of the inhibitory function of the neurotransmitter GABA through GABAA receptors. 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 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 intraocular pressure, which may be associated with a concomitant decrease in systemic vascular resistance.
In combination with hypocarbia, propofol increases cerebrovascular resistance, decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure; but does not affect cerebrovascular 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 ACTH.

Clinical trials.

No data available.

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. 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. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. The initial (distribution) half-life is between 2 and 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.
Adult propofol clearance ranges from 1.5-2 litres/minute (21-29 mL/kg/min).
Propofol is primarily metabolised by the liver to, predominately glucuronide conjugates and their corresponding quinols, which are inactive. These are excreted renally. Clearance occurs by metabolism, mainly in the liver, where it is blood flow dependent. 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.
The distribution and clearance in children down to the age of three years are similar to those of adults. In infants from one month to three years, the clearance of propofol has shown to be higher than children three years and older. Infants may require an increased dose but is not significantly greater than the dose for children between 3 and 8 years of age.
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.
Metabolism of medium chain triglycerides (MCTs) differs from that of long chain triglycerides (LCT). Unlike longer chain fatty acids, MCT require little carnitine for mitochondrial entry, and their more rapid breakdown may impart an increased production of ketones.

5.3 Preclinical Safety Data

Genotoxicity.

Propofol was not genotoxic in a series of assays for gene mutation (Salmonella typhimurium, Saccharomyces cerevisiae), chromosomal damage (dominant lethal, micronucleus and cytogenetics assays) and other genotoxic effects (Saccharomyces cerevisiae gene conversion).

Carcinogenicity.

Animal carcinogenicity studies have not been performed with propofol.

6 Pharmaceutical Particulars

6.1 List of Excipients

The vehicle contains soya oil, medium chain triglycerides, glycerol, egg lecithin, sodium oleate and water for injections.

6.2 Incompatibilities

See Section 4.2 Dose and Method of Administration; see Section 4.4 Special Warnings and Precautions for Use.

6.3 Shelf Life

In-use shelf life.

To be used immediately after opening the ampoule or vial.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.
Do not freeze.
Keep container in the outer carton in order to protect from light.

6.5 Nature and Contents of Container

Propofol-Lipuro 1%.

Colourless Type I glass ampoules containing 20 mL of emulsion.
Colourless Type II glass vials, sealed with a grey bromobutyl rubber stopper and aluminium seal with a blue polypropylene flip‐off insert containing 20 mL of emulsion.
Colourless Type II glass bottles, sealed with a grey bromobutyl rubber stopper and aluminium seal with a blue polypropylene flip‐off insert containing 50 or 100 mL of emulsion.

Pack sizes.

Glass ampoules: 5 x 20 mL.
Glass vials: 10 x 20 mL.
Glass bottles: 10 x 50 mL, 10 x 100 mL.

Propofol-Lipuro 2%.

Colourless Type II glass bottles sealed with a grey bromobutyl rubber stopper and aluminium seal with a red polypropylene flip‐off insert containing 50 mL of emulsion.
Glass bottles: 10 x 50 mL.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical name: 2,6-diisopropylphenol.

Chemical structure.

CAS number.

2078-54-8.

7 Medicine Schedule (Poisons Standard)

S4.

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