DIPRIVAN Emulsion for injection or infusion Ref.[8033] Active ingredients: Propofol

Diprivan 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 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. Diprivan 1% should not be administered by the person conducting the diagnostic or surgical procedure.

Abuse of, and dependence on Diprivan 1%, predominantly by health care professionals, have been reported. As with other general anaesthetics, the administration of Diprivan 1% without airway care may result in fatal respiratory complications.

When Diprivan 1% 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.

As with other sedative agents, when Diprivan 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.

An adequate period is needed prior to discharge of the patient to ensure full recovery after use of Diprivan 1%. Very rarely the use of Diprivan 1% 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.

Diprivan 1% induced impairment is not generally detectable beyond 12 hours. The effects of Diprivan 1%, 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 agents that may sedate (Eg, benzodiazepines, opiates, alcohol.)

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. Diprivan 1% clearance is blood flow dependent, therefore, concomitant medication that reduces cardiac output will also reduce Diprivan 1% clearance.

Diprivan 1% 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 Diprivan 1% is used in conjunction with other agents likely to cause a bradycardia.

As with other intravenous anaesthetic and sedative agents, patients should be instructed to avoid alcohol before and for at least 8 hours after administration of Diprivan 1%.

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

Concomitant use of central nervous system depressants e.g. alcohol, general anaesthetics, narcotic analgesics will result in accentuation of their sedative effects. When Diprivan 1% is combined with centrally depressant drugs administered parenterally, severe respiratory and cardiovascular depression may occur. It is recommended that Diprivan 1% is administered following the analgesic and the dose should be carefully titrated to the patient’s response (see Section 4.5).

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 1% during the period of anaesthetic maintenance.

When Diprivan 1% is administered to an epileptic patient, there may be a risk of convulsion.

Appropriate care should be applied in patients with disorders of fat metabolism and in other conditions where lipid emulsions must be used cautiously (see section 4.2).

Use is not recommended with electroconvulsive treatment.

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

The benefits and risks of the proposed procedure should be considered prior to proceeding with repeated or prolonged use (>3 hours) of propofol in young children (<3 years) and in pregnant women as there have been reports of neurotoxicity in preclinical studies, see Section 5.3.

Paediatric population

The use of Diprivan is not recommended in newborn infants as this patient population has not been fully investigated. Pharmacokinetic data (see section 5.2) indicate that clearance is considerably reduced in neonates and has a very high inter-individual variability. Relative overdose could occur on administering doses recommended for older children and result in severe cardiovascular depression.

Diprivan 2% is not recommended for use in children < 3 years of age due to difficulty in titrating small volumes.

Propofol must not be used in patients of 16 years of age or younger for sedation for intensive care as the safety and efficacy of propofol for sedation in this age group have not been demonstrated (see section 4.3).

Advisory statements concerning Intensive Care Unit 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 were 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 intensive care unit.

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 Diprivan 1% (usually at dose rates greater than 4mg/kg/h for more than 48 hours).

Prescribers should be alert to these events in patients with the above risk factors and immediately discontinue propofol – when the above signs develop. All sedative and therapeutic agents used in the intensive care unit (ICU), should be titrated to maintain optimal oxygen delivery and haemodynamic parameters. Patients with raised intra-cranial pressure (ICP) should be given appropriate treatment to support the cerebral perfusion pressure during these treatment modifications.

Treating physicians 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 and in other conditions where lipid emulsions must be used cautiously.

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. Administration of propofol 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 propofol formulation; 1.0 mL of Diprivan contains approximately 0.1 g of fat.

Diprivan 1% contains 0.0018 mmol sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Additional Precautions

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 presentations of mitochondrial disease exacerbation and of the ‘propofol infusion syndrome’ may be similar.

Diprivan 1% contains no antimicrobial preservatives and supports growth of micro-organisms.

EDTA chelates metal ions, including zinc, and reduces microbial growth rates. The need for supplemental zinc should be considered during prolonged administration of Diprivan 1%, particularly in patients who are predisposed to zinc deficiency, such as those with burns, diarrhoea and/or major sepsis.

When Diprivan 1% is to be aspirated, it must be drawn aseptically into a sterile syringe or giving set immediately after opening the ampoule or breaking the vial seal. Administration must commence without delay. Asepsis must be maintained for both Diprivan 1% and infusion equipment throughout the infusion period. Any infusion fluids added to the Diprivan 1% line must be administered close to the cannula site. Diprivan 1% must not be administered via a microbiological filter.

Diprivan 1% and any syringe containing Diprivan 1% are for single use in an individual patient. In accordance with established guidelines for other lipid emulsions, a single infusion of 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.

Diprivan 1% 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 1% may be required where general anaesthesia is used as an adjunct to regional anaesthetic techniques. Profound hypotension has been reported following anaesthetic with propofol in patients treated with rifampicin.

The concurrent administration of other CNS depressants such as pre-medication drugs, inhalation agents, analgesic agents may add to the sedative, anaesthetic and cardiorespiratory depressant effects of Diprivan 1% (see Section 4.4).

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

Pregnancy

The safety of Diprivan 1% during pregnancy has not been established. Studies in animals have shown reproductive toxicity (see section 5.3). Diprivan 1% should not be given to pregnant women except when absolutely necessary. Diprivan 1% can, however, be used during an induced abortion.

Obstetrics

Diprivan 1% crosses the placenta and can cause neonatal depression. It should not be used for obstetric anaesthesia unless clearly necessary.

Breast-feeding

Studies of breastfeeding mothers showed that small quantities of Diprivan 1% are excreted in human milk. Women should therefore not breast-feed for 24 hours after administration of Diprivan 1%. Milk produced during this period should be discarded.

Diprivan 1% has moderate influence on the 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.

Diprivan 1% induced impairment is not generally detectable beyond 12 hours (Section 4.4).

General

Induction and maintenance of anaesthesia or sedation is generally smooth with minimal evidence of excitation. The most commonly reported ADRs are pharmacologically predictable side effects of an anaesthetic/sedative agent, such as hypotension. The nature, severity and incidence of adverse events observed in patients receiving Diprivan 1% may be related to the condition of the recipients and the operative or therapeutic procedures being undertaken.

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).

Table of Adverse Drug Reactions

Immune system disorders

Very rare: Anaphylaxis – may include angioedema, bronchospasm, erythema and hypotension

Metabolism and nutrition disorders

Not known⁹: Metabolic acidosis⁵, hyperkalaemia⁵, hyperlipidaemia⁵

Psychiatric disorders

Not known⁹: Euphoric mood. Drug abuse and drug dependence⁸

Nervous system disorders

Common: Headache during recovery phase

Rare: Epileptiform movements, including convulsions and opisthotonus during induction, maintenance and recovery

Very rare: Postoperative unconsciousness

Not known⁹: Involuntary movements

Cardiac disorders

Common: Bradycardia¹

Very rare: Pulmonary oedema

Not known⁹: Cardiac arrhythmia⁵, cardiac failure^5,7

Vascular disorders

Common: Hypotension²

Uncommon: Thrombosis and phlebitis

Respiratory, thoracic and mediastinal disorders

Common: Transient apnoea during induction

Not known⁹: Respiratory depression (dose dependent)

Gastrointestinal disorders

Common: Nausea and vomiting during recovery phase

Very rare: Pancreatitis

Hepatobiliary disorders

Not known⁹: Hepatomegaly⁵

Musculoskeletal and connective tissue disorders

Not known⁹: Rhabdomyolysis^3,5

Renal and urinary disorders

Very rare: Discolouration of urine following prolonged administration

Not known⁹: Renal failure⁵

Reproductive system and breast disorders

Very rare: Sexual disinhibition

General disorders and administration site conditions

Very common: Local pain on induction⁴

Very rare: Tissue necrosis (10) following accidental extravascular administration

Not known⁹: Local pain, swelling, following accidental extravascular administration

Investigations

Not known⁹: Brugada type ECG^5,6

Injury, poisoning and procedural complications

Very rare: Postoperative fever

¹ Serious bradycardias are rare. There have been isolated reports of progression to asystole.
² Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of Diprivan.
³ Very rare reports of rhabdomyolysis have been received where Diprivan has been given at doses greater than 4 mg/kg/hr for ICU sedation.
⁴ 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.
⁵ 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.
⁶ Brugada-type ECG – elevated ST-segment and coved T-wave in ECG.
⁷ Rapidly progressive cardiac failure (in some cases with fatal outcome) in adults. The cardiac failure in such cases was usually unresponsive to inotropic supportive treatment.
⁸ Abuse of and drug dependence on propofol, predominantly by health care professionals.
⁹ Not known as it cannot be estimated from the available clinical trial data.
¹⁰ Necrosis has been reported where tissue viability has been impaired.

Dystonia/dyskinesia have been reported.

Local

The local pain which may occur during the induction phase of Diprivan 1% anaesthesia can be minimised by the co-administration of lidocaine (see “Dosage and Administration”) and 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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