Presentation

Provive MCT-LCT 1%(r) (Propofol 10 mg/mL) is a white, oil in water emulsion for injection in a clear Type II glass vial with a grey butyl rubber closure and aluminium and plastic violet flip- off seal.

Actions

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. It is thought that propofol produces its sedative/anaesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated 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 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).

Pharmacokinetics

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 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 30-60 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 - 2 L/minute (21 - 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. Patients with severe hepatic or renal impairment have not been adequately studied. In older patients for a given dose, a higher peak plasma concentration is observed. The VD (volume of distribution) 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.

Dosage and Administration

Aseptic technique (refer also to Precautions):

Strict aseptic technique must always be maintained during the handling of Provive MCT-LCT 1%(r). Provive MCT-LCT 1%(r) is for single use in one patient only. Provive MCT-LCT 1%(r) can support the growth of micro-organisms 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 Warnings and Precautions, Aseptic technique). 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 MCT-LCT 1%(r) may be used to induce anaesthesia by slow bolus injection or infusion. In both unpremedicated and premedicated patients, it is recommended that Provive MCT-LCT 1%(r) should be titrated (approximately 4 mL (40 mg) every 10 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 MCT-LCT 1%(r) at 1.5 - 2.5 mg/kg. In elderly patients, requirements will be generally less (see Elderly patients, below). In general, slower rates of infusion at induction results in a lower induction dose requirement and greater haemodynamic stability. In patients of ASA grades III and IV, lower rates of administration should be used (approximately 2 mL (20 mg) every ten seconds). Recovery from induction doses usually occurs within 5 - 10 minutes.

Maintenance of general anaesthesia:

Anaesthesia can be maintained by administering Provive MCT-LCT 1%(r) either by continuous infusion or by repeat bolus injections to maintain the depth of anaesthesia required.

Continuous infusion

- The required rate of administration varies considerably between patients, but rates in the region of 4 - 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 MCT-LCT 1%(r) be given by continuous infusion. The infusion rate should be adjusted according to the depth of sedation required but rates in the region of 0.3 - 4.0 mg/kg/hour should achieve satisfactory sedation. Infusion rates greater than 4.0 mg/kg/hour should not be used unless the benefit to the patient outweighs the possible risks.

Monitored conscious sedation for surgical and diagnostic procedures:

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 - 1 mg/kg over 1 - 5 minutes for onset of sedation. Maintenance of sedation may be accomplished by titrating Provive MCT-LCT 1%(r) infusion to the desired level of sedation; most patients will require 1.5 - 4.5 mg/kg/hour. In addition to the infusion, bolus administration of 10 - 20 mg may be used if a rapid increase in the depth of sedation is required. In patients in ASA grades III or IV, the rate of administration and dosage may need to be reduced.

Use in the elderly:

In elderly patients the dose requirement for induction of anaesthesia with Provive MCT-LCT 1%(r) 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 MCT-LCT 1%(r) 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 as this may lead to cardiorespiratory depression.

Paediatric usage

Induction of general anaesthesia:

Provive MCT-LCT 1%(r) is not recommended for use in infants less than 1 month old When used to induce anaesthesia in children, it is recommended that Provive MCT-LCT 1%(r) 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 eight years of age are likely to require approximately 2.5 mg/kg Provive MCT-LCT 1%(r) for induction of anaesthesia. Under this age the requirement may be more. Lower dosage is recommended for children of ASA grades III or IV.

Maintenance of general anaesthesia:

Provive MCT-LCT 1%(r) is not recommended for use in infants less than 1 month old Anaesthesia can be maintained by administering Provive MCT-LCT 1%(r) 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 - 15 mg/kg/hour usually achieve satisfactory anaesthesia.

Sedation during intensive care:

The use of propofol for sedation in children 16 years of age and younger during intensive care is contraindicated.

Monitored conscious sedation for surgical and diagnostic procedures:

Provive MCT-LCT 1%(r) is not recommended for sedation in children as safety and efficacy have not been demonstrated.

Administration:

See also Warnings and Precautions, Pharmaceutical precautions. Supplementary analgesic agents are generally required in addition to Provive MCT-LCT 1%(r). No pharmacological incompatibility has been noted when Provive MCT-LCT 1%(r) has been used in association with spinal and epidural anaesthesia and commonly used pre- medicants, neuromuscular blocking agents, inhalational agents and analgesics. Lower doses of Provive MCT-LCT 1%(r) may be required where general anaesthesia is used as an adduct to regional anaesthetic techniques. Provive MCT-LCT 1%(r) can be infused undiluted from plastic syringes or glass infusion bottles. When Provive MCT-LCT 1%(r) is used undiluted to maintain anaesthesia, it is recommended that drop counters, syringe pumps or volumetric infusion pumps be used to control infusion rates. Provive MCT-LCT 1%(r) can be diluted with Glucose 5% Intravenous Infusion, and used from glass infusion bottles or PVC infusion bags. Dilutions should be prepared aseptically immediately before administration and must be used within 6 hours of preparation. Such dilutions must not be more dilute than one volume of Provive LCT-LCT 1% to four volumes of diluent (Propofol 2 mg/mL). It is recommended that in order to prepare diluted Provive MCT- LCT 1%(r), the volume of Glucose 5% Intravenous Infusion BP removed from the infusion bag during the dilution process be totally replaced in volume by Provive MCT-LCT 1%(r) 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 MCT-LCT 1%(r). 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. Provive MCT-LCT 1%(r) 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 MCT-LCT 1%(r) may be premixed with alfentanil injection (500 mcg/mL alfentanil) in ratios of 20:1 - 50:1 v/v. Mixtures should be prepared using aseptic techniques and used within 6 hours. To reduce pain on initial injection, the part of Provive MCT-LCT 1%(r) used for induction may be mixed with Lignocaine Injection.

Dilution and Co-adminstration

Contraindications

Known allergy to propofol or any of the other ingredients contained in Provive MCT-LCT 1%(r), namely egg lecithin, glycerol, soya oil, medium chain triglycerides and sodium oleate. Sedation in children 16 years of age and younger during intensive care. Sedation of children under 3 years of age with serious viral respiratory tract infections receiving intensive care.. Sedation of children of all ages with croup or epiglottitis receiving intensive care.

Warnings and Precautions

Monitoring and facilities: As with all anaesthetic procedures, Provive MCT-LCT 1%(r) 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 MCT-LCT 1%(r) should not be administered by the person conducting the diagnostic or surgical procedure. When Provive MCT-LCT 1%(r) 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.

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 MCT-LCT 1%(r) is used in conjunction with other agents likely to cause bradycardia (see also Interactions). Induction, maintenance and recovery: Occasionally hypotension may require use of intravenous fluids and reduction in the rate of administration of Provive MCT-LCT 1%(r) 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 MCT-LCT 1%(r) 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 MCT-LCT 1%(r) 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 Anesia(r) formulation. One mL of Provive MCT-LCT 1%(r) contains approximately 0.1 g of fat. The calorific value of Provive MCT-LCT 1 %(r) is similar to that of Intralipid 10%. That is, 1.0 mL of Provive MCT-LCT 1%(r) 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 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 4 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/ 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 4.0 mg/kg/hour. Provive MCT-LCT 1%(r) 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 MCT-LCT 1%(r) for the sedation of premature neonates receiving intensive care. Aseptic technique: Strict aseptic technique must always be followed during handling. Provive MCT-LCT 1%(r) is for single use in one patient only. Provive MCT-LCT 1%(r) 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 MCT- LCT 1%(r) 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 2-8degC for not more than 12 hours. Asepsis must be maintained for both Provive MCT-LCT 1%(r) and the infusion equipment throughout the infusion period. Any drugs or fluids added to the Provive MCT-LCT 1%(r) line must be administered close to the cannula site. Anesia(r) must not be administered via a microbial filter. Containers of Provive MCT-LCT 1%(r) are for single use in an individual patient. In accordance with established guidelines for other lipid emulsions, a single infusion of Provive MCT-LCT 1%(r) must not exceed 12 hours. At the end of the procedure or at 12 hours, whichever is the sooner, both the reservoir of Provive MCT-LCT 1%(r) 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 MCT-LCT 1%(r) without prior flushing.

Carcinogenesis, mutagenesis, impairment of fertility:

Animal carcinogenicity studies have not been performed with propofol. 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). 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.

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.

Pregnancy and Lactation

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 MCT-LCT 1%(r) 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 MCT-LCT 1%(r) should not be used for obstetric anaesthesia as propofol crosses the placenta and may be associated with neonatal depression.

Use in lactation:

Provive MCT-LCT 1%(r) 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.

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.

Interactions

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 MCT-LCT 1%(r) 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 MCT-LCT 1%(r) 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 MCT-LCT 1%(r). 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 MCT-LCT 1%(r) may be required where general anaesthesia is used as an adjunct to regional anaesthetic techniques.

Overdosage

Accidental overdosage is likely to cause cardiorespiratory depression. 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.

Pharmaceutical precautions

Store below 30degC. Do not freeze. Keep in carton until use to protect contents from light. 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 2mg/mL to preserve the emulsion base. See Dilution and Co- administration. Neuromuscular blocking agents e.g. atracurium and micacurium should not be given through the same I.V. line as Provive MCT-LCT 1%(r) prior flushing.

Medicine classification

Prescription Medicine.

Package quantities

200 mg/ 20 mL - 5 vials per pack 500 mg/ 50 mL - 1 vial per pack 1000 mg/100 mL - 1 vial per pack

Further information

Provive MCT-LCT 1%(r) also contains soya oil, medium chain triglycerides, glycerol, egg lecithin, sodium oleate and water for injections.

Name and address

AFT Pharmaceuticals Ltd PO Box 33-203 Takapuna, Auckland New Zealand

Date of preparation

03 March 2011 Provive MCT-LCT 1%(r) is a registered trade mark of Claris Lifesciences Limited, used under license.