Consumer medicine information

Provive 1%

Propofol

BRAND INFORMATION

Brand name

Provive 1%

Active ingredient

Propofol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Provive 1%.

What is in this leaflet

This leaflet answers some common questions about this medicine.

It does not contain all the available information. It does not take the place of talking to your doctor or anaesthetist.

All medicines have risks and benefits. Your doctor or anaesthetist has weighed the risks of you being given Provive 1% against the benefits it is expected to have for you.

If you have any concerns about being given this medicine, ask your doctor or anaesthetist. Keep this leaflet. You may need to read it again.

If you have any concerns about being administered this medicine, ask your doctor or pharmacist.

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

What PROVIVE 1% is used for and how it works

General anaesthesia

Provive 1 % contains propofol, which is used as a short-acting general anaesthetic in adults, and children aged 3 years or older.

A general anaesthetic is a medicine which produces general anaesthesia. Provive MCT- LCT 1 % is short-acting, which means that patients go to sleep quickly, usually within 30 seconds of receiving the medication, but then wake up quickly as it wears off.

Provive 1% can be used for very short operations when only one injection is needed. Provive 1% can be used throughout longer operations if more is given as repeated doses. Provive 1% can also be used to start off anaesthesia (induction anaesthesia). This means the anaesthetist may change over to another anaesthetic once sleep is induced.

Sedation

Provive 1% can be given to adults and adolescents over 16 years of age in lower doses if they need to be sedated or sleepy, but do not need the heavy sleep of anaesthesia. This type of sedation may be required during certain tests or procedures.

Provive 1% can also be used in intensive care wards for adults and adolescents over 16 years of age who are being ventilated (on a breathing machine) to keep them sedated.

Ask your doctor or anaesthetist if you have any questions about why this medicine has been prescribed for you. Your doctor or anaesthetist may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

There is not enough information to recommend the use of this medicine for children under the age of 3 years for general anaesthesia. This medicine must not be used for children 16 years of age and under for sedation during tests or procedures, or for sedation in the intensive care ward.

Before you are given PROVIVE 1%

When you must not be given PROVIVE 1%

You must not be given Provive 1 % if you have an allergy to:

  • any medicine containing propofol;
  • any of the other ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Before up are given PROVIVE 1%

Tell your doctor or anaesthetist if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor or anaesthetist if you have or have had any of the following medical conditions:

  • epilepsy (fits or convulsions)
  • heart-disease
  • respiratory (breathing) problems
  • liver or kidney disease
  • very high blood fat levels or disorders of fat metabolism (this warning applies to very rare conditions, not the more common high blood cholesterol)
  • general debility for some time (feebleness, weakness or loss of strength).

Tell your doctor or anaesthetist if you are pregnant or if you intend to become pregnant or are breast-feeding.

Provive 1 % is not recommended for use during pregnancy or breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor or anaesthetist about any of the above, tell them before you are given Provive 1 %.

Taking other medicines

Tell your doctor, anaesthetist or pharmacist if you are taking or using any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and propofol may interfere with each other. These include:

  • strong pain relievers;
  • medicines used to produce calmness or to help you to sleep;
  • some medicines used to treat anxiety;
  • some medicines used to treat epilepsy such as barbiturates.

Your doctor, anaesthetist or pharmacist may have information on medicines to be careful with or avoid when you are given this medicine.

How is PROVIVE 1% to be given

How much will be given:

Your doctor or anaesthetist will decide how much Provive 1% you are to be given. This will depend on your age and other factors such as your weight and the duration of your procedure. The dose will be adjusted to keep you at the right depth of sleep or sedation. The dose of Provive 1% needed for sedation is less than that needed for anaesthesia.

How will it be given?

Provive 1% is given by an injection into a vein, usually in the forearm or the back of the hand. It must only be given by a doctor or anaesthetist. Each vial is used for one dose in one patient only. Any remaining contents must be discarded after each dose.

Overdose

As Provive 1% is given to you under the supervision of your doctor or anaesthetist, it is very unlikely that you will receive too much. Your doctor or anaesthetist has information on how to recognise and treat an overdose.

Ask your doctor or anaesthetist if you have any concerns.

While you are being given PROVIVE 1%

Things to be careful of

Do not drive a car or operate machinery for at least one day after you have been given Provive 1%.

As with other anaesthetics, Provive 1% may cause impairment of skilled tasks, such as driving or operating machinery, for some time after you have been given it Make sure you know how you react to Provive 1% before you drive a car, operate machinery, or do anything else that could be dangerous if you are drowsy or dizzy.

Ask your doctor when you can return to work involving driving, or operating machinery or heavy equipment.

Side Effects

This medicine helps provide anaesthesia or sedation for most people, but it may have unwanted side effects in a few people. Tell your doctor or anaesthetist as soon as possible if you do not feel well after you have been given Provive 1%.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

Tell your doctor if you notice any of the following and they worry you:

  • pain, heat or tingling at the injection site;
  • flushing of the skin;
  • dizziness;
  • nausea or vomiting, cough, headache, shivering, restlessness or mood changes when you are waking up from the anaesthetic;
  • hiccuping or stopping breathing very briefly.

The above list includes the more common side effects of your medicine. They are usually mild and short lived.

Tell your doctor as soon as possible if you notice any of the following:

  • slow, fast or irregular heart beat;
  • convulsions (fitting);
  • signs of an allergic reaction, such as shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin;
  • severe pain in the upper stomach;
  • temporary paralysis or weakness of the muscles.

The above list includes serious side effects. These side effects are rare. Some of the side effects of Provive 1% may occur whilst you are asleep or sedated. Your doctor or anaesthetist is trained to manage these reactions in the unlikely event that they occur. For example, if you are sleeping too deeply and your blood pressure is too low or you need help breathing, your anaesthetist may reduce the dose of Provive 1%. If your sleep is too light and you move or wriggle a bit, the dose may be increased. If your heart rate becomes too slow or irregular other medicines may be needed. Tell your doctor or anaesthetist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some patients.

After using Provive 1%

Storage

Provive 1% will be stored in the pharmacy or on the ward. Provive 1% is kept in a cool dry place where the temperature stays below 30°C. Do not freeze. Protect from light.

Any unused Provive 1% from the opened vial will be discarded.

Product Description

What does PROVIVE 1% look like?

Provive 1 % is a milky, white liquid in a clear glass vial with an aluminium and violet plastic cap.

It is available in 20 mL, 50 mL and 100 mL vials.

Ingredients

Active ingredients:

  • propofol 10 mg/mL.

Inactive ingredients:

  • Soya oil
  • Glycerol
  • Lecithin egg
  • Sodium oleate
  • Sodium hydroxide
  • Water for injections

Provive 1% does not contain lactose, sucrose, gluten, tartrazine or other azo dyes.

Name and Address of Sponsor

Baxter Healthcare Pty Ltd
1 Baxter Drive Old
Toongabbie, NSW 2146
Australia

Australian Registration numbers:

Provive 1% 20 mL: AUST R 118938

Provive 1% 50 mL: AUST R 118939

Provive 1% 100 mL: AUST R 118940

Date of preparation of this leaflet: January 2019

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Provive 1%

Active ingredient

Propofol

Schedule

S4

 

1 Name of Medicine

Propofol.

6.7 Physicochemical Properties

Chemical name: 2, 6-diisopropylphenol. Molecular formula: C12H18O. Molecular Weight: 178.

Chemical structure.


CAS number.

2078-54-8.

2 Qualitative and Quantitative Composition

Active Ingredient: Propofol (10 mg/mL).

List of excipients with known effect.

Soya oil (100 mg/mL), egg lecithin (12 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Emulsion for intravenous injection, or infusion.
Provive 1% is a white, oil in water emulsion in a clear glass vial.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Propofol 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, as for other 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.
It has been reported that in patients with normal intraocular pressure 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.
It has been stated that limited experience in susceptible patients does not indicate any propensity of propofol to induce malignant hyperthermia.
Propofol does not suppress the adrenal response to adrenocorticotrophic hormone (ACTH).

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

The pharmacokinetics of propofol show a three compartment open model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues. Following an intravenous (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 two and four minutes, followed by a rapid elimination phase with a half-life of 30 to 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.
In the adult, propofol clearance ranges from 1.5 to 2 L/minute (21 to 29 mL/kg/minute). Propofol is primarily metabolised by the liver to predominantly glucuronide conjugates and their corresponding quinols, which are inactive. These are excreted via the kidney. The pharmacokinetics of propofol are linear over the recommended range of infusion rates of the product. Moderate hepatic or renal impairment do not alter these pharmacokinetics.
In children, the distribution and clearance down to the age of 3 years are similar to those of adults.
In older patients for a given dose, a higher peak plasma concentration is observed. The volume of distribution (VD) and clearance are also decreased, which 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 intensive care unit (ICU) sedation for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening, usually within five minutes. Longer infusions (ten 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

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.

4 Clinical Particulars

4.1 Therapeutic Indications

Short acting IV anaesthetic agent suitable for induction and maintenance of general anaesthesia in adults and in children aged 3 years and older. Provive 1% has no analgesic properties.
Although the safety and efficacy of propofol in paediatric day surgery have not been demonstrated, it may be a useful agent in this setting and its use should not be precluded.
Provive 1% may also be used in adults for sedation of ventilated patients receiving intensive care. Provive 1% may also be used in adults for monitored conscious sedation for surgical and diagnostic procedures.

4.3 Contraindications

Known allergy to propofol or any of the other ingredients contained in Provive 1%: namely egg lecithin, glycerol, soya oil and sodium oleate.
Provive 1% is contraindicated 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

Each 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 Glucose 5% Intravenous Infusion BP. The final concentration of propofol should not be less than 2 mg/mL to preserve the emulsion base.
The neuromuscular blocking agents, atracurium and mivacurium should not be given through the same intravenous line as Provive 1% without prior flushing.

Identified precautions.

Monitoring and facilities.

As with all anaesthetic procedures, Provive 1% 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 resuscitation facilities should be readily available at all times. Provive 1% should not be administered by the person conducting the diagnostic or surgical procedure. When Provive 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 surgical/ diagnostic procedures. When propofol 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. 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) bolus doses or during supplemental maintenance bolus doses, especially in the elderly, debilitated and American Society of Anesthesiologists (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.
When Provive 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.

During induction of anaesthesia, hypotension and apnoea, similar to effects with other IV anaesthetic agents, commonly occur and may be influenced by the rate of administration, the use of premedication and other agents including benzodiazepines.
Propofol lacks vagolytic activity and has been associated with reports of bradycardia (occasionally profound) and also asystole. The IV 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 Provive 1% is used in conjunction with other agents likely to cause bradycardia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Induction, maintenance and recovery.

Occasionally hypotension may require use of IV fluids and reduction in the rate of administration of Provive 1% during the period of anaesthetic maintenance. Ventilatory depression can occur following administration of propofol. 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. 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.

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. As Provive 1% is formulated as an oil in water emulsion, elevations in serum triglycerides may occur when the product 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 Provive 1% 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 Provive 1% formulation. One mL of Provive 1% contains approximately 0.1 g of fat. The calorific value of Provive 1% is similar to that of Intralipid 10%. That is, 1.0 mL of Provive 1% provides 1.1 kcals.

Epilepsy.

Propofol has been found to have no effect on electroshock seizure threshold in animals. When propofol is administered to an epileptic patient, there may be a risk of seizure during the recovery phase. Perioperative myoclonia, less frequently including convulsions and opisthotonos, has occurred in temporal relationship in cases to 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 adrenocortical hormones. At concentrations of propofol likely to be encountered in anaesthetic practice, no clinically significant effect on adrenocortical hormones 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.

Life threatening adverse events, occurring together or in combinations of cardiac failure, arrhythmias, metabolic acidosis, rhabdomyolysis and renal failure have been associated with propofol when used for sedation during intensive care.
There have been very rare reports of metabolic acidosis, rhabdomyolysis, 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).

Aseptic technique.

(See Section 4.4 Special Warnings and Precautions for Use and Section 6.4 Special Precautions for Storage.) Strict aseptic technique must always be maintained during handling. Provive 1% is for single use in one patient only. Provive 1% can support the growth of microorganisms as it is not an antimicrobially preserved product.
There have been reports in which failure to use aseptic technique when handling propofol injection was associated with microbial contamination of the product and with fever, infection/ sepsis, other life threatening illness, and/or death. Accordingly, strict aseptic technique must be adhered to. Do not use if contamination is suspected. Discard unused portions as directed within the required time limits (see below).
When Provive 1% is to be aspirated, it must be drawn aseptically into a sterile syringe or giving set immediately after breaking the vial seal. To reduce microbiological hazard, use as soon as practicable after reconstitution. If storage is required, hold at 2 to 8°C for not more than 12 hours. Asepsis must be maintained for both Provive 1% and the infusion equipment throughout the infusion period. Any drugs or fluids added to the Provive 1% line must be administered close to the cannula site. Provive 1% must not be administered via a microbial filter. Containers of Provive 1% and any syringe containing Provive 1% are for single use in an individual patient. In accordance with established guidelines for other lipid emulsions, a single infusion of Provive 1% must not exceed 12 hours. At the end of the procedure or at 12 hours, whichever is the sooner, both the reservoir of Provive 1% and the infusion line must be discarded and replaced as appropriate.

Use in hepatic impairment.

Patients with severe hepatic impairment have not been adequately studied.

Use in renal impairment.

Patients with severe renal impairment have not been adequately studied.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

Use in children.

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

Use in neonates.

Propofol is not recommended for induction and maintenance of anaesthesia in neonates.

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.
With inhalation or infusion of such drugs, exposure is longer than the period of inhalation or infusion. Depending on the drug and patient characteristics, as well as dosage, the elimination phase may be prolonged relative to the period of administration.
See Section 4.2 Dose and Method of Administration and Section 4.3 Contraindications.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

As with other IV sedative agents, when propofol is given with central nervous system depressants, such as potent analgesics, the sedative effect may be intensified and the possibility of severe respiratory or cardiovascular depression should be considered. The induction dose requirements of Provive 1% may be reduced in patients with intramuscular or IV premedication (see Section 4.4 Special Warnings and Precautions for Use, Identified precautions), 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; and for this reason, oxygen supplementation should be used. During maintenance of anaesthesia or sedation, the rate of Provive 1% 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 Provive 1%.
Propofol does not cause a clinically significant change in onset, intensity or duration of action of the commonly used neuromuscular blocking agents (e.g. suxamethonium and nondepolarising muscle relaxants).
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 Provive 1% may be required where general anaesthesia is used as an adjunct to regional anaesthetic techniques.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in female rats at intravenous doses up to 15 mg/kg/day for two 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 five 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 foetus, careful consideration should be given to this potential depression, and to the selection of anaesthetic drugs, doses and techniques.
Provive 1% should not be used in pregnancy. Teratology studies with propofol 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.
Provive 1% should not be used for obstetric anaesthesia as propofol crosses the placenta and may be associated with neonatal depression.
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.
Provive 1% is not recommended for use in women who are breastfeeding because propofol has been reported to be excreted in human milk and the effects of oral absorption of small amounts of propofol are unknown.

4.8 Adverse Effects (Undesirable Effects)

It has been reported that during induction in clinical trials, 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.

Very common (> 1/10).

Body as a whole.

Pain during injection (burning, tingling/ stinging).

Common.

Elation/ euphoria, headache, shivering.

Cardiovascular.

Hypotension, hypertension, bradycardia.

Gastrointestinal.

Nausea, vomiting.

Respiratory.

Transient apnoea, cough.

Skin.

Flush/ rash.

Blood.

Thrombosis, phlebitis.

Uncommon.

Cardiovascular.

Arrhythmias, tachycardia, extrasystole.

Rare.

Body as a whole.

Fever.

Central nervous system.

Convulsions and seizures of the epileptic type.

Urogenital.

Discolouration of the urine on prolonged use.

Other.

Anaphylactoid reactions, in some cases with angioedema, bronchospasm, erythema and hypotension. (These reactions have been reported to respond to adrenaline.)

Very rare.

Musculoskeletal and connective tissue.

Rhabdomyolysis (when propofol has been administered at doses greater than 4 mg/kg/hour for ICU sedation).

Gastrointestinal.

Pancreatitis, abdominal cramps.

Central nervous system.

Pulmonary oedema, postoperative unconsciousness.

Other.

Hiccup.
Very rare reports of cardiac failure, metabolic acidosis, renal failure and hyperkalaemia have been reported.
Occasionally, hypotension may require use of IV fluids and reduction of the rate of administration of Provive 1% during the period of anaesthetic maintenance or sedation.
Epileptiform movements, including convulsions and opisthotonos, 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, bronchospasm 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.
Accidental clinical extravasation and animal studies showed minimal tissue reaction. Intra-arterial injection in animals did not induce local tissue effects.

Reporting suspected adverse effects.

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

4.2 Dose and Method of Administration

Aseptic technique.

(See Section 4.4 Special Warnings and Precautions for Use.) Strict aseptic technique must always be maintained during the handling of Provive 1%. Provive 1% is for single use in one patient only. Provive 1% can support the growth of microorganisms as it is not an antimicrobially preserved product. 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 (see Section 4.4 Special Warnings and Precautions for Use). There have been reports in which failure to use aseptic technique when handling propofol products was associated with microbial contamination of the product and with fever, infection/ sepsis, other life threatening illness, and/or death.

Adults.

Induction of general anaesthesia.

Provive 1% may be used to induce anaesthesia by slow bolus injection or infusion. In unpremedicated and in premedicated patients, it is recommended that Provive 1% should be titrated (approximately 4 mL (40 mg) every ten seconds in an average healthy adult) against the response of the patient until the clinical signs show the onset of anaesthesia. Most adult patients aged less than 55 years are likely to require Provive 1% at 2.0 to 2.5 mg/kg. In elderly patients, requirements will be generally less (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly). 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, lower rates of administration should be used (approximately 2 mL (20 mg) every ten seconds).
Recovery from induction doses usually occurs within five to ten minutes.

Maintenance of general anaesthesia.

Anaesthesia can be maintained by administering Provive 1% 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 reported to be 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/minute (4 to 12 mg/kg/hour) usually maintain satisfactory anaesthesia.

Repeat bolus injections.

If a technique involving repeat bolus injections is used, increments of 25 mg (2.5 mL) to 50 mg (5 mL) 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 Provive 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 to 3.0 mg/kg/hour should achieve satisfactory sedation. Infusion rates greater than 4.0 mg/kg/hour are not recommended.
Provive 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.

Monitored conscious sedation for surgical and diagnostic procedures.

Provive 1% is contraindicated for sedation in children as safety and efficacy have not been demonstrated.
To provide sedation for surgical and diagnostic procedures in adult patients, rates of administration should be individualised and titrated to clinical response.Most patients will require 0.5 to 1 mg/kg over one to five minutes for onset of sedation. Maintenance of sedation may be accomplished by titrating Provive 1% infusion to the desired level of sedation; most patients will require 1.5 to 3.0 mg/kg/hour. In addition to the infusion, bolus administration of 10 to 20 mg may be used if a rapid increase in the depth of sedation is required. In patients of ASA grades III or IV (according to the classification of the American Society of Anesthesiologists) 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.

Use in the elderly.

In elderly patients the dose requirement for induction of anaesthesia with Provive 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/minute) are associated with less hypotension and apnoea in elderly patients. Where Provive 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.

Paediatric usage.

Induction of general anaesthesia.

Provive 1% is not recommended for use in children less than three years of age. When used to induce anaesthesia in children, it is recommended that Provive 1% be given slowly until the clinical signs show the onset of anaesthesia. The dose should be adjusted for age and/or weight. Most patients over 8 years of age are likely to require approximately 2.5 mg/kg Provive 1% for induction of anaesthesia. Under this age the requirement may be more. Lower dosage is recommended for children of ASA grades III or IV.
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.

Maintenance of general anaesthesia.

Provive 1% is not recommended for use in children less than 3 years of age. Anaesthesia can be maintained by administering Provive 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 to 15 mg/kg/hour usually achieve satisfactory anaesthesia.

Sedation during intensive care.

Provive 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.

Monitored conscious sedation for surgical and diagnostic procedures.

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

Administration.

See Section 4.4 Special Warnings and Precautions for Use and Section 6.4 Special Precautions for Storage.
Provive 1% can be infused undiluted from plastic syringes or glass infusion bottles. It can be diluted with Glucose 5% Intravenous Infusion BP only, and used from glass or PVC infusion bags/ bottles. Dilutions should be prepared aseptically immediately before administration and must be used within six hours of preparation. Such dilutions must not be more dilute than one volume of Provive to four volumes of diluent (propofol 2 mg/mL). It is recommended that in order to prepare diluted Provive 1%, the volume of Glucose 5% Intravenous Infusion BP removed from the infusion bag during the dilution process be totally replaced in volume by Provive 1% emulsion. 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 Provive 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 amount of dilution in the burette.
When Provive 1% is used undiluted to maintain anaesthesia, it is recommended that drop counters, syringe pumps or volumetric infusion pumps should always be used to control infusion rates.
Changes to the haemodynamic parameters such as systolic arterial pressure, diastolic arterial pressure, cardiac output and systemic vascular resistance appear to be independent of changes to the rate of infusion of propofol.
Provive 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. Provive 1% should not be mixed prior to administration with other therapeutic agents or infusion fluids other than Glucose 5% Intravenous Infusion BP.

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.

4.9 Overdose

Accidental overdosage is likely to cause cardiorespiratory depression.

Treatment.

Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression would require lowering of the patient's head and, if severe, use of plasma expanders and pressor agents.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Soya oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL), sodium oleate (0.3 mg/mL), sodium hydroxide and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Provive 1% in unopened containers should be stored below 30°C. Do not freeze. Keep in carton until use to protect contents from light.

6.5 Nature and Contents of Container

Provive 1% is supplied in a glass vial with a grey butyl rubber closure and aluminium and plastic violet flip-off seal.
Provive 1% is available in three presentations:
200 mg propofol in 20 mL: AUST R 118938 - packs of 5 vials;
500 mg propofol in 50 mL: AUST R 118939 - packs of 1 vial;
1000 mg propofol in 100 mL: AUST R 118940 - packs of 1 vial.

6.6 Special Precautions for Disposal

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

Summary Table of Changes