PROVIVE Emulsion for injection Ref.[50449] Active ingredients: Propofol

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 patient 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.

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) grade III or IV patients, and with co‐administration of other sedatives and opioid agents. Monitoring during the procedure and during the recovery period should be in accordance with the needs of the patient.

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 intravenous 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 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 Provive 1% is used in conjunction with other agents likely to cause bradycardia (see section 4.5).

Induction, maintenance and recovery

Occasionally hypotension may require use of intravenous 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 0.1g of fat. The calorific value of Provive 1% is similar to that of Intralipid 10%. That is, 1.0mL of Provive 1% provides 1.1kcals.

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 an increased risk of seizure during the recovery phase. Perioperative myoclonia, less frequently including convulsions and opisthotonos, has occurred in temporal relationship to 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 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 4mg/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/lipipaemia 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 4.0mg/kg/hour. 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).

Provive 1% is not recommended for use in neonates for the induction or maintenance of anaesthesia. Available data suggest that if the paediatric dose regimen is applied to neonates a relative overdose could occur which may result in cardio‐pulmonary depression. There is no data to support the use of Provive 1% for the sedation of premature neonates receiving intensive care.

Aseptic technique

Strict aseptic technique must always be followed 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. 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. If storage is required, hold at 2–8°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% 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.

The neuromuscular blocking agents atracurium and mivacurium should not be given through the same intravenous line as Provive 1% without prior flushing.

PAEDIATRIC POPULATION

Use in children

There are no data to support the use of propofol for the sedation of premature neonates receiving intensive care. 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

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.

ADVISORY STATEMENT CONCERNING INTENSIVE CARE UNIT MANAGEMENT

Propofol Infusion Syndrome (PRIS)

Use of Provive 1% Injectable Emulsion infusionsfor both adult and paediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as’propofol infusion syndrome', that in some cases have resulted in death.

The syndrome is characterised by severe metabolic acidosis, rhabdomyolysis, hyperkalaemia, ECG changes* and/or cardiac failure. The syndrome is most often associated with prolonged, high‐dose infusions (>5mg/kg/h for >48h). The following appear to be the 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. All sedative and therapeutic agents used in the ICU (including Provive 1%) should be titrated to maintain optimal oxygen delivery and haemodynamic parameters.

Propofol should only be used for >24 hours in patients who have adequate oxygen delivery and uptake parameters.

The maximum dose of propofol for ICU sedation should be 4mg/kg/h. If 4mg/kg/h does not provideadequate sedation,theaddition ofotheragentsshouldbe considered. Propofolshould not be used for prolonged sedation (>48 hours) or at infusion rates of >4mg/kg/h, particularly in severely head injured patients also receiving incremental inotropic support.

If the cause of a new onset metabolic acidosis cannot be determined, the possibility of it being due to a propofol infusion syndrome should be considered. As a precaution, the adequacy of oxygen delivery/uptake shouldbe reassessed,theuse of vasoconstrictorsshould be reviewed and cessation of propofol should be considered. Fluorescent green urine may indicate that the patient is acidotic.

Patients with mitochondrial diseasemaybe susceptible to exacerbationswhen undergoing anaesthesia/surgery. Provision of carbohydrates and good hydration isrecommended for such patients.

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

As with other intravenous 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 intravenous 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; 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.

Pregnancy Category C

All general anaesthetics cross the placenta and carry the potential to produce central nervous system and respiratory depression in the new‐born 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.

Breastfeeding

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.

Fertility

Studies in female rats at intravenous doses up to 15mg/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 15mg/kg/day for five days.

Patients should be advised that performance at skilled tasks, such as driving and operating machinery, may be impaired for some time after general anaesthesia.

Summary of the safety profile

Induction of anaesthesia with propofol is generally smooth with minimal evidence of excitation. The most commonly reported adverse reactions are pharmacologically predictable side effects of an anaesthetic agent, such as hypotension. Given the nature of anaesthesia and those patients receiving intensive care, events reported in association with anaesthesia and intensive care may also be related to the procedures being undertaken or the recipient’s condition.

Tabulated summary of adverse reactions

The following definitions of frequencies are used: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

¹ May be minimised by using the larger veins of the forearm and antecubital fossa. With propofol 1% local pain can also be minimised by the co‐administration of lignocaine (see section 4.2).
² Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of propofol.
³ Serious bradycardias are rare. There have been isolated reports of progression to asystole.
⁴ Following abrupt discontinuations of propofol during intensive care.
⁵ Very rare reports of rhabdomyolysis have been received where propofol has been given at doses of greater than 4mg/kg/hr for ICU sedation. Also there have been rare reports of metabolic acidosis and cardiac failure associated with propofol administered at rates >5mg/kg/h for >58 hours. A causal relationship has not been established.

Reports from off‐label use of propofol for induction of anaesthesia in neonates indicates that cardio‐respiratory depression may occur if the paediatric dose regimen is applied (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions

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

Neuromuscular blocking agents, e.g. atracurium and micacurium, should not be given through the same IV line as Provive 1% without prior flushing.

This medicine must not be mixed with other medicines except those mentioned in section 6.6.