General anaesthetics.

Propofol

Diprivan 20 mg/ml (2%) emulsion for injection or infusion

Emulsion for injection or infusion. White aqueous isotonic oil-in-water emulsion.

Diprivan 2% is a short-acting intravenous anaesthetic agent suitable for induction and maintenance of general anaesthesia. Diprivan 2% may also be used for sedation of ventilated patients receiving intensive care.

Induction of General Anaesthesia

Adults

Diprivan 2% may be used to induce anaesthesia by infusion.

Administration of Diprivan 2% by bolus injection is not recommended.

Diprivan 2% may be used to induce anaesthesia by infusion but only in those patients who will receive Diprivan 2% for maintenance of anaesthesia.

In unpremedicated and premedicated patients, it is recommended that Diprivan 2% should be titrated (approximately 2 ml [40 mg] every 10 seconds in an average healthy adult by infusion) 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 1.5 to 2.5 mg/kg of Diprivan 2%. The total dose required can be reduced by lower rates of administration (1 to 2.5 ml/min [20 to 50 mg/min]). Over this age, the requirement will generally be less. In patients of ASA Grades 3 and 4, lower rates of administration should be used (approximately 1 ml [20 mg] every 10 seconds).

Maintenance of General Anaesthesia

Anaesthesia can be maintained by administering Diprivan 2% by continuous infusion to prevent the clinical signs of light anaesthesia. Administration of Diprivan 2% by bolus injection is not recommended. Recovery from anaesthesia is typically rapid and it is therefore important to maintain Diprivan 2% administration until the end of the procedure.

The required rate of administration varies considerably between patients, but rates in the region of 4 to 12 mg/kg/h usually maintain satisfactory anaesthesia.

Sedation During Intensive Care

For sedation during intensive care it is advised that Diprivan 2% should be administered by continuous infusion. The infusion rate should be determined by the desired depth of sedation. In most patients sufficient sedation can be obtained with a dosage of 0.3 - 4 mg/kg/h of Diprivan 2%. Diprivan 2% is not indicated for sedation in intensive care of patients of 16 years of age or younger.

It is recommended that blood lipid levels be monitored should Diprivan 2% be administered to patients thought to be at particular risk of fat overload.

Administration of Diprivan 2% should be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from the body. If the patient is receiving other intravenous lipid concurrently, a reduction in quantity should be made in order to take account of the amount of lipid infused as part of the Diprivan 2% formulation: 1.0 ml of Diprivan 2% contains approximately 0.1 g of fat.

If the duration of sedation is in excess of 3 days, lipids should be monitored in all patients.

Administration

Diprivan 2% has no analgesic properties and therefore supplementary analgesic agents are generally required in addition to Diprivan 2%.

Diprivan has been used in association with spinal and epidural anaesthesia and with commonly used premedicants, neuromuscular blocking drugs, inhalational agents and analgesic agents; no pharmacological incompatibility has been encountered. Lower doses of Diprivan 2% may be required where general anaesthesia is used as an adjunct to regional anaesthetic techniques.

Diprivan 2% should not be diluted.

When Diprivan 2% is used to maintain anaesthesia, it is recommended that equipment such as syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

Diprivan 2% should not be mixed prior to administration with injections or infusion fluids. However, Diprivan 2% may be co-administered via a Y-piece connector close to the injection site with the following:

- Dextrose 5% Intravenous Infusion B.P.

- Sodium Chloride 0.9% Intravenous Infusion B.P.

- Dextrose 4% with Sodium Chloride 0.18% Intravenous Infusion B.P.

Induction of General Anaesthesia

Diprivan 2% is not recommended for induction of anaesthesia in children less than 3 years of age.

When used to induce anaesthesia in children, it is recommended that Diprivan 2% be given by slow infusion 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 of Diprivan 2% for induction of anaesthesia. Under this age the requirement may be more. Lower dosage is recommended for children of ASA grades 3 and 4.

Maintenance of General Anaesthesia

Diprivan 2% is not recommended for maintenance of anaesthesia in children less than 3 years of age.

The required rate of administration varies considerably between patients but rates in the region of 9 to 15 mg/kg/h usually achieve satisfactory anaesthesia.

Sedation During Intensive Care

Diprivan 2% is contra-indicated for the sedation of ventilated children aged 16 years or younger receiving intensive care.

Induction of General Anaesthesia

In elderly patients the dose requirement for induction of anaesthesia with Diprivan 2% is reduced. The reduction should take into 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.

Maintenance of General Anaesthesia

When Diprivan 2% is used for maintenance of anaesthesia the rate of infusion should also be reduced. Patients of ASA grades 3 and 4 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.

Sedation During Intensive Care

When Diprivan 2% is used for sedation of anaesthesia the rate of infusion should also be reduced. Patients of ASA grades 3 and 4 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.

Diprivan is contraindicated in patients with a known hypersensitivity to propofol or any of the excipients.

Diprivan 2% is contra-indicated for sedation in intensive care of patients of 16 years of age or younger.

Diprivan 2% contains soya oil and should not be used in patients who are hypersensitive to peanut or soya.

Diprivan 2% should be given by those trained in anaesthesia, or where appropriate, doctors trained in the care of patients in Intensive Care. Facilities for maintenance of a patent airway, artificial ventilation and oxygen enrichment should be available.

During induction of anaesthesia, hypotension and transient apnoea may occur depending on the dose and use of premedicants and other agents.

Occasionally, hypotension may require use of intravenous fluids and reduction of the rate of administration of Diprivan 2% during the period of anaesthetic maintenance.

An adequate period is needed prior to discharge of the patient to ensure full recovery after general anaesthesia. Very rarely, the use of Diprivan may be associated with the development of a period of post-operative 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.

When Diprivan 2% is administered to an epileptic patient, there may be a risk of convulsion.

As with other sedative agents, when Diprivan 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.

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.

The risk of relative vagal overactivity may be increased because Diprivan 2% lacks vagolytic activity. Diprivan 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 Diprivan 2% is used in conjunction with other agents likely to cause a bradycardia.

Appropriate care should be applied in patients with disorders of fat metabolism and in other conditions where lipid emulsions must be used cautiously.

Use is not recommended with electroconvulsive treatment.

As with other anaesthetics sexual disinhibition may occur during recovery.

Diprivan 2% is not advised for general anaesthesia in children younger than 1 month of age. The safety and efficacy of Diprivan 2% for (background) sedation in children younger than 16 years of age have not been demonstrated. Although no causal relationship has been established, serious undesirable effects with (background) sedation in patients younger than 16 years of age (including cases with fatal outcome) have been reported during unlicensed use. In particular these effects concerned occurrence of metabolic acidosis, hyperlipidemia, rhabdomyolysis and/or cardiac failure. These effects were most frequently seen in children with respiratory tract infections who received dosages in excess of those advised in adults for sedation in the intensive care unit.

Similarly very rare reports have been received of occurrence of metabolic acidosis, rhabdomyolysis, hyperkalaemia and/or rapidly progressive cardiac failure (in some cases with fatal outcome) in adults who were treated for more than 58 hours with dosages in excess of 5 mg/kg/h. This exceeds the maximum dosage of 4 mg/kg/h currently advised for sedation in the intensive care unit. The patients affected were mainly (but not only) seriously head-injured patients with raised ICP. The cardiac failure in such cases was usually unresponsive to inotropic supportive treatment. Treating physicians are reminded if possible not to exceed the dosage of 4 mg/kg/h. Prescribers should be alert to these possible undesirable effects and consider decreasing the Diprivan 2% dosage or switching to an alternative sedative at the first sign of occurrence of symptoms. Patients with raised ICP should be given appropriate treatment to support the cerebral perfusion pressure during these treatment modifications.

Diprivan 2% contains 0.0018 mmol sodium per ml.

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

Additional Precautions

Diprivan 2% contains no antimicrobial preservatives and supports growth of micro-organisms. Asepsis must be maintained for both Diprivan 2% and infusion equipment throughout the infusion period. Any drugs or fluids added to the Diprivan 2% infusion line must be administered close to the cannula site. Diprivan 2% must not be administered via a microbiological filter.

Diprivan 2% and any syringe containing Diprivan 2% are for single use in an individual patient. For use in long-term maintenance of anaesthesia or sedation in intensive care it is recommended that the infusion line and reservoir of Diprivan 2% be discarded and replaced at regular intervals.

General

Induction of anaesthesia is generally smooth with minimal evidence of excitation.

Side effects during induction, maintenance and recovery occur uncommonly.

The most commonly reported ADRs 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.

(1) May be minimised by using the larger veins of the forearm and antecubital fossa. With Diprivan 1% local pain can also be minimised by the co-administration of lidocaine.

(2) Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of Diprivan.

(3) Serious bradycardias are rare. There have been isolated reports of progression to asystole.

(4) Following abrupt discontinuation of Diprivan during intensive care.

(5) Very rare reports of rhadbomyolysis have been received where Diprivan has been given at doses greater than 4 mg/kg/hr for ICU sedation.

Pulmonary edema, hypotension, asystole, bradycardia, and convulsions, have been reported. In very rare cases rhabdomyolysis, metabolic acidosis, hyperkalaemia or cardiac failure, sometimes with fatal outcome, have been observed when propofol was administered at dosages in excess of 4 mg/kg/h for sedation in the intensive care unit. Dystonia/dyskinesia have been reported.

Reports from off-label use of Diprivan for induction of anaesthesia in neonates indicates that cardio-respiratory depression may occur if the paediatric dose regimen is applied.

Local

The local pain which may occur during the induction phase can be minimised by the use of the larger veins of the forearm and antecubital fossa. Thrombosis and phlebitis are rare. Accidental clinical extravasation and animal studies showed minimal tissue reaction. Intra-arterial injection in animals did not induce local tissue effects.

AstraZeneca

(POM)

07 May 2009