MILSIA Emulsion for injection/infusion Ref.[115187] Active ingredients: Propofol

MILSIA should be given by those trained in anaesthesia (or, where appropriate, doctors trained in the care of patients in intensive care).

Respiration will be depressed and patients should be constantly monitored and facilities for maintenance of a patient airway, artificial ventilation, oxygen enrichment and other resuscitative facilities should be readily available at all times. MILSIA should not be administered by the person conducting the diagnostic or surgical procedure.

A generalised systemic reaction which may be anaphylactic in nature (including angioedema, bronchospasm, erythema and hypotension) may occur following MILSIA administration – estimated as 1 in 15 000.

EDTA is a chelator of metal ions, including zinc. The need for supplemental zinc should be considered during prolonged administration of MILSIA, particularly in patients who are predisposed to zinc deficiency, such as those with burns, diarrhoea and/or major sepsis.

MILSIA contains soya bean oil and egg lecithin and must not be used in patients with an allergy to peanuts, egg or soya protein (see section 4.3).

Abuse of, and dependence on MILSIA, predominantly by health care providers, have been reported (see section 4.8).

Administration of MILSIA

The administration of MILSIA without airway care may result in fatal respiratory complications.

When MILSIA is administered for conscious sedation, for surgical and diagnostic procedures, patients should be continually monitored for early signs of hypotension, airway obstruction and oxygen desaturation.

MILSIA lacks vagolytic activity and has been associated with reports of bradycardia (occasionally profound) and also asystole. The intravenous administration of an anticholinergic medicine before induction, or during maintenance of anaesthesia should be considered, especially in situations where vagal tone is likely to predominate, or when MILSIA is used in conjunction with other medicines likely to cause a bradycardia.

During bolus administration for operative procedures, extreme caution should be exercised in patients with acute pulmonary insufficiency or respiratory depression.

As with other sedative medicines, when MILSIA is used for sedation during operative procedures, involuntarily patient movements may occur. During procedures requiring immobility these movements may be hazardous to the operative site.

During induction of anaesthesia, hypotension and transient apnoea may occur depending on the dose and use of premedicants and other medicines. Occasionally, hypotension may require use of intravenous fluids and reduction of the rate of administration of MILSIA during the period of anaesthetic maintenance.

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

When MILSIA is to be aspirated, it must be drawn aseptically into a sterile syringe or giving set immediately after breaking the vial seal. Administration must commence without delay. Asepsis must be maintained for both MILSIA and infusion equipment throughout the infusion period. Any infusion fluids added to the MILSIA line must be administered close to the cannula site. MILSIA must not be administered via a microbiological filter.

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

Clearance of MILSIA

Caution should be applied in patients with cardiac, respiratory, renal or hepatic impairment or in hypovolaemic or debilitated patients. MILSIA clearance is blood flow dependent, therefore, concomitant medication that reduces cardiac output will also reduce MILSIA clearance.

Concomitant use

Concomitant use of central nervous system depressants e.g., alcohol, general anaesthetics, narcotic analgesics will result in accentuation of their sedative effects. When MILSIA is combined with centrally depressant medicines administered parentally, severe respiratory and cardiovascular depression may occur. It is recommended that MILSIA is administered following the analgesic and the dose should be carefully titrated to the patient’s response.

Patients should be instructed to avoid alcohol before and for at least 8 hours after administration of MILSIA.

Postoperative recovery from MILSIA

An adequate period is needed prior to discharge of the patient to ensure full recovery after use of MILSIA. Very rarely the use of MILSIA may be associated with the development of a period of postoperative unconsciousness, which may be accompanied by an increase in muscle tone. This may or may not be preceded by a period of wakefulness. Although recovery is spontaneous, appropriate care of an unconscious patient should be administered.

MILSIA induced impairment is not generally detectable beyond 12 hours. The effects of MILSIA, the procedure, concomitant medications, the age and the condition of the patient should be considered when advising patients on:

• The advisability of being accompanied on leaving the place of administration
• The timing of recommencement of skilled or hazardous tasks such as driving
• The use of other medicines that may sedate (e.g. benzodiazepines, opiates, alcohol)

As with other anaesthetics, sexual disinhibition may occur during recovery.

Epileptic patients

When MILSIA is administered to an epileptic patient, there may be a risk of convulsion.

Electroconvulsive treatment

The use of MILSIA is not recommended with electroconvulsive treatment.

Mitochondrial disease

Caution should be taken when treating patients with mitochondrial disease. These patients may be susceptible to exacerbations of their disorder when undergoing anaesthesia, surgery and ICU care. Maintenance of normothermia, provision of carbohydrates and good hydration are recommended for such patients. The early presentation of mitochondrial disease exacerbation and of the “propofol infusion syndrome” may be similar.

Advisory statements concerning intensive care unit (ICU) management

Use of propofol emulsion infusions for ICU sedation has been associated with a constellation of metabolic derangements and organ system failures that may result in death. Reports have been received of combinations of the following: metabolic acidosis, rhabdomyolysis, hyperkalaemia, hepatomegaly, renal failure, hyperlipidaemia, cardiac arrhythmia, brugada-type ECG (elevated ST-segment and coved T-wave) and rapidly progressive cardiac failure usually unresponsive to inotropic supportive treatment. Combinations of these events have been referred to as the “propofol infusion syndrome”. These events are mostly seen in patients with serious head injuries and children with respiratory tract infections who received dosages in excess of those advised in adults for sedation in the ICU.

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 medicines – vasoconstrictors, steroids, inotropes and/or MILSIA (usually at dose rates greater than 4 mg/kg/h for more than 48 hours).

Prescribers should be alert to these events in patients with the above risk factors and promptly consider decreasing or stopping the MILSIA dosage when the above signs develop. All sedative and therapeutic medicines used in the ICU, should be titrated to maintain optimal oxygen delivery and haemodynamic parameters. Patients with raised intra-cranial pressure should be given appropriate treatment to support the cerebral perfusion pressure during these treatment modifications.

Anaesthetists are reminded if possible, not to exceed the dosage of 4 mg/kg/h.

Appropriate care should be applied in patients with disorders of fat metabolism, patients predisposed of fat embolism and in other conditions where lipid emulsions must be used cautiously. Fat metabolism may be affected in conditions such as renal insufficiency, uncompensated diabetes mellitus, certain forms of liver insufficiency, metabolic disorders, severe trauma including long bone and multiple fractures, and sepsis.

It is recommended that blood lipid levels should be monitored if propofol is administered to patients thought to be at particular risk of fat overload (see section 4.2, “Method of administration”). Lipids should be monitored in all patients if the duration of sedation is in excess of 3 days.

In the elderly, debilitated or ASA Ill or IV patients, rapid single or repeated bolus administration should not be used in order to minimise undesirable cardiorespiratory side effects.

Information on excipients of MILSIA

MILSIA contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

Concomitant use of benzodiazepines, parasympatholytic medicines or inhalational anaesthetics has been reported to prolong the anaesthesia and to reduce the respiratory rate.

It is recommended that MILSIA be given after opioids so that the dose of MILSIA can be carefully titrated against the response.

After supplementary pre-medication of opiates, apnoea may occur with increasing frequency and over a prolonged period.

After administration of fentanyl, the blood level of MILSIA may be temporarily increased, with an increase in rate of apnoea.

The dosage of MILSIA should be reduced if used with nitrous oxide or halogenated anaesthetics. Although MILSIA does not potentiate the effects of neuromuscular blockers, bradycardia and asystole have occurred after use of MILSIA with atracurium or suxamethonium.

When MILSIA is combined with centrally depressant medicines administered parenterally, severe respiratory and cardiovascular depression may occur.

Leucoencephalopathy has been reported with administration of lipid emulsions such as MILSIA in patients receiving ciclosporin.

Profound hypotension has been reported following anaesthetic with propofol in patients treated with rifampicin.

A need for lower doses has been observed in patients taking valproate. When used concomitantly, a dose reduction of MILSIA may be considered.

Pregnancy

The safety of MILSIA during pregnancy has not been established. MILSIA should not be used in pregnant women except when absolutely necessary. MILSIA crosses the placenta and may be associated with neonatal depression. MILSIA should not be used for obstetric anaesthesia unless clearly necessary.

Lactation

MILSIA should not be used in mothers who are breastfeeding as it is distributed in breast milk for the first 24 hours after administration of MILSIA. Milk produced during this period should be discarded.

Patients should be advised that performance at skilled tasks, such as driving and operating machinery, may be impaired for some time after general anaesthesia. MILSIA induced impairment is not generally detectable beyond 12 hours.

¹ Local pain at the injection site may be minimised by injection into a large vein and antecubital fossa or by co-administration of intravenous lignocaine (lidocaine). After co-administration of lignocaine (lidocaine) the following undesirable effects may occur: giddiness, vomiting, drowsiness, convulsions, bradycardia, cardiac dysrhythmia and shock.
² Combinations of these events, reported as “propofol infusion syndrome”, may be seen in seriously ill patients who often have multiple risk factors for the development of the events, see section 4.4).
³ Reports of rhabdomyolysis have been received when MILSIA has been given at doses greater than 4 mg/kg/hr for ICU sedation.
⁴ Brugada-type ECG – elevated ST-segment and coved T-wave in ECG.
⁵ Marked hypotension may require use of intravenous fluids and a reduction in the rate of administration of MILSIA. Account should be taken of the possibility of severe drop in blood pressure in patients with impaired coronary or cerebral perfusion or those with hypovolaemia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of MILSIA is important. It allows continued monitoring of the benefit/risk balance of MILSIA. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

MILSIA should not be mixed prior to administration with injections or infusion fluids other than 5% dextrose or lignocaine (lidocaine) injection or alfentanil injection (see above).

The neuromuscular blocking medicines atracurium and mivacurium should not be given through the same intravenous line as MILSIA without prior flushing.