You may need several different medicines to keep you asleep or sleepy, free from pain, breathing in a healthy way and to keep your blood pressure steady. The doctor will decide which medicines you need and when you need them.

4. Possible side effects

Like all medicines, Diprivan may cause side effects although not everybody gets them.

Side effects that can happen during anaesthesia

The following side effects can happen during anaesthesia (while the injection is being given to you or when you are sleepy or asleep). Your doctor will be looking out for these. If they happen, your doctor will give you appropriate treatment.

Very common (affects more than 1 in 10 people)

•    A feeling of pain at the site of the injection (while the injection is being given, before you fall asleep).

Common (affects less than 1 in 10 people)

•    Low blood pressure.

•    Changes in your breathing pattern.

•    Slow heart beat.

Rare (affects less than 1 in 1,000 people)

•    Twitching and shaking of your body, or a fit (may also happen when you wake up).

•    Unusual colour of urine (may also happen when you wake up).

Very rare (affects less than 1 in 10,000 people)

•    Allergic reactions.

•    Stopping of your heart beat.

•    Build up of fluid in the lungs which can make you very breathless (may also happen when you wake up).

Side effects that can happen after anaesthesia

The following side effects can happen after anaesthesia (when you are waking up or after you have woken up).

Common (affects less than 1 in 10 people)

•    Feeling sick (nausea).

•    Being sick (vomiting).

•    Headache.

Uncommon (affects less than 1 in 100 people)

•    Swelling and redness along a vein or blood clots.

Very rare (affects less than 1 in 10,000 people)

•    Feeling sexually aroused.

•    High temperature (fever).

•    Redness or soreness where the injection was given.

•    Being unconscious after the operation. (When this has happened, the patients have recovered without problems.)

Other possible side effects

The following side effects have been seen when Diprivan is used in intensive care at higher doses than recommended.

Very rare (affects less than 1 in 10,000 people)

•    Heart failure.

•    Inflamed pancreas (pancreatitis) which causes severe stomach pain.

•    Too much acid in your blood. This may make you breathe more quickly.

•    Increased amount of potassium in your blood.

•    High blood level of a type of fat called lipids.

•    Abnormal heart beat.

•    Enlargement of the liver.

•    Kidney failure.

5. How to store Diprivan

•    The doctor and hospital pharmacist are responsible for storing, using and disposing of Diprivan correctly.

•    Store Diprivan between 2°C and 25°C. Do not freeze.

•    Do not use Diprivan after the expiry date which is stated on the carton.

6. Further information

Leaflet prepared: January 2012

Diprivan is a trade mark of the AstraZeneca group of companies.

© AstraZeneca 2012

UK PAI 11 0054b

AstraZeneca

Overdose

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. Pharmacological Properties Pharmacodynamic properties

Propofol (2, 6-diisopropylphenol) 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, like all general anaesthetics, is poorly understood. However, propofol is thought to produce its sedative/anaesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligandgated GABA_a receptors.

In general, falls in mean arterial blood pressure and slight changes in heart rate are observed when Diprivan 2% is administered for induction and maintenance of anaesthesia. 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 Diprivan 2%, any effects are qualitatively similar to those of other intravenous anaesthetic agents and are readily manageable in clinical practice.

Diprivan 2% reduces cerebral blood flow, intracranial pressure and cerebral metabolism. The reduction in intracranial pressure is greater in patients with an elevated baseline intracranial pressure.

Recovery from anaesthesia is usually rapid and clear-headed with a low incidence of headache and postoperative nausea and vomiting.

In general, there is less postoperative nausea and vomiting following anaesthesia with Diprivan 2% than following anaesthesia with inhalational agents. There is evidence that this may be related to a reduced emetic potential of propofol.

Diprivan 2%, at the concentrations likely to occur clinically, does not inhibit the synthesis of adrenocortical hormones.

Limited studies on the duration of propofol based anaesthesia in children indicate safety and efficacy is unchanged up to duration of 4 hours. Literature evidence of use in children documents use for prolonged procedures without changes in safety or efficacy.

Pharmacokinetic properties

The decline in propofol concentrations following a bolus dose or following the termination of an infusion can be described by a three-compartment open model with very rapid distribution (half-life 2-4 minutes), rapid elimination (half-life 30-60 minutes), and a slower final phase, representative of redistribution of propofol from poorly perfused tissue. Propofol is extensively distributed and rapidly cleared from the body (total body clearance 1.5-2 litres/minute). Clearance occurs by metabolic processes, mainly in the liver where it is blood flow dependent, to form inactive conjugates of propofol and its corresponding quinol, which are excreted in urine.

When Diprivan 2% is used to maintain anaesthesia, blood concentrations asymptotically approach the steady-state value for the given administration rate. The pharmacokinetics are linear over the recommended range of infusion rates of Diprivan 2%.

After a single dose of 3 mg/kg intravenously, propofol clearance/kg body weight increased with age as follows: Median clearance was considerably lower in neonates <1 month old (n=25) (20 ml/kg/min) compared to older children (n= 36, age range 4 months-7 years). Additionally inter-individual variability was considerable in neonates (range 3.7-78 ml/kg/min). Due to this limited trial data that indicates a large variability, no dose recommendations can be given for this age group.

Median propofol clearance in older aged children after a single 3 mg/kg bolus was 37.5 ml/min/kg (4-24 months) (n=8), 38.7 ml/min/kg (11-43 months) (n=6), 48 ml/min/kg (1-3 years)(n=12), 28.2 ml/min/kg (4-7 years)(n=10) as compared with 23.6 ml/min/kg in adults (n=6). Preclinical safety data

Propofol is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in this document.

Pharmaceutical Particulars List of excipients Glycerol Ph. Eur.

Purified Egg Phosphatide Sodium Hydroxide Ph. Eur.

Soya Bean Oil, Refined Ph. Eur.

Water for Injections Ph. Eur.

Nitrogen Ph. Eur.

Disodium Edetate Ph. Eur.

Incompatibilities

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 into infusions of 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.

The neuromuscular blocking agents, atracurium and mivacurium should not be given through the same intravenous line as Diprivan 2% without prior flushing.

6.3    Shelf life

6.3.1    Shelf life of the product as packaged for sale

2 years.

6.3.2    Shelf life after dilution

Diprivan 2% should not be diluted.

6.4    Special precautions for storage

Store between 2°C and 25°C.

Do not freeze.

6.5    Nature and contents of container

a) 10 ml pre-filled syringe containing propofol 20 mg/ml.

b) 50 ml pre-filled syringe containing propofol 20 mg/ml.

c)    50 ml vial containing propofol 20 mg/ml.

6.6    Instructions for use/handling In-use precautions

Containers should be shaken before use. Any portion of the contents remaining after use should be discarded.

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 into infusions of 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. When the pre-filled syringe presentation is used in a syringe pump, appropriate compatibility should be ensured. In particular, the pump should be designed to prevent syphoning and should have an occlusion alarm set no greater than 1000 mm Hg. If using a programmable or equivalent pump that offers options for use of different syringes then choose only the B-D 50/60 ml PLASTIPAK setting when using the Diprivan pre-filled syringe.

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.

7. Marketing Authorisation Holder AstraZeneca UK Limited,

600 Capability Green,

Luton, LU1 3LU, UK.

Leaflet updated: January 2012 © AstraZeneca 2012

Diprivan is a trade mark of the AstraZeneca group of companies.

PAI 11 0054b

AstraZeneca

Medical Information Leaflet

Diprivan 2%

(Issued to the    Medical Professions Only)

1.    Tradename of the Medicinal    Product

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

2.    Qualitative and Quantitative    Composition

Propofol 20 mg/ml

3.    Pharmaceutical Form Emulsion for injection or infusion

White aqueous isotonic oil-in-water emulsion

4.    Clinical Particulars

4.1    Therapeutic indications

Diprivan 2% is a short-acting intravenous general anaesthetic for:

•    Induction and maintenance of general anaesthesia in adults and children >3 years.

•    Sedation for diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia in adults and children >3 years.

•    Sedation of ventilated patients >16 years of age in the intensive care unit.

4.2    Posology and method of administration

For specific guidance relating to the administration of Diprivan 2% with a target controlled infusion (TCI) device, which incorporates Diprifusor TCI software, (see Section 4.2.5). Such use is restricted to induction and maintenance of anaesthesia in adults. The Diprifusor TCI system is not recommended for use in ICU sedation or in children.

4.2.1    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 1.5-2.5 mg/kg of Diprivan 2%. The total dose required can be reduced by lower rates of administration (1-2.5 ml/min [20-50 mg/minj). 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).

Elderly patients

In elderly patients the dose requirement for induction of anaesthesia with Diprivan 2% is reduced. The reduction should take into account the physical status and age of the patient. The reduced dose should be given at a slower rate and titrated against the response.

Children

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

For induction of anaesthesia in children over 3 years of age, Diprivan 2% should be titrated slowly until clinical signs show the onset of anaesthesia. The dose should be adjusted according to age and/or body weight. Most patients over 8 years of age require approximately 2.5 mg/kg body weight of Diprivan 2% for induction of anaesthesia. In younger children, dose requirements may be higher (2.5^1 mg/kg body weight).

For ASA 3 and 4 patients lower doses are recommended (see also Section 4.4)

Administration of Diprivan 2% by a Diprifusor TCI system is not recommended for induction of general anaesthesia in children.

4.2.2    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.

P032396

II

Adults

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

Elderly patients

When Diprivan 2% is used for maintenance of anaesthesia the rate of infusion or 'target concentration' 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.    ——

Children

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

Anaesthesia can be maintained in children over 3 years of age by administering Diprivan 2% by infusion 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/h usually achieve satisfactory anaesthesia. In younger children, dose requirements may be higher.

For ASA 3 and 4 patients lower doses are recommended (see also Section 4.4).

Administration of Diprivan 2% by a Diprifusor TCI system is not recommended for maintenance of general anaesthesia in children.

4.2.3    Sedation during intensive care Adults

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^t mg/kg/h of Diprivan 2% (see 4.4 Special warnings and special precautions for use). Diprivan 2% is not indicated for sedation in intensive care of patients of 16 years of age or younger (see

4.3 Contraindications). Administration of Diprivan 2% by Diprifusor TCI system is not advised for sedation in the intensive care unit.

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 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.

Elderly patients

When Diprivan 2% is used for sedation or 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.

Children

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

4.2.4    Sedation for Surgical and Diagnostic Procedures Adults

To provide sedation for surgical and diagnostic procedures, 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 Diprivan 2% infusion to the desired level of sedation - most patients will require 1.5-4.5 mg/kg/h. 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 of ASA Grades 3 and 4 the rate of administration and dosage may need to be reduced.

Administration of Diprivan 2% by a 'Diprifusor' TCI system is not recommended for sedation for surgical and diagnostic procedures.

Elderly Patients

When Diprivan 2% is used for sedation the rate of infusion or 'target concentration' 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.

Children

Diprivan 2% is not recommended for surgical and diagnostic procedures in children aged less than 3 years.

In children over 3 years of age, doses and administration rates should be adjusted according to the required depth of sedation and the clinical response. Most paediatric patients require 1-2 mg/kg body weight of Diprivan 2% for onset of sedation. Maintenance of sedation may be accomplished by titrating Diprivan 2% infusion to the desired level of sedation. Most patients require 1.5-9 mg/kg/h Diprivan 2%.

In ASA 3 and 4 patients lower doses may be required.

4.2.5 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. Diprivan 2% can be used for infusion undiluted from glass containers, plastic syringes or Diprivan 2% pre-filled syringes.

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 into infusions of 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.

The glass pre-filled syringe (PFS) has a lower frictional resistance than plastic disposable syringes and operates more easily. Therefore, if Diprivan 2% is administered using a hand held pre-filled syringe, the line between the syringe and the patient must not be left open if unattended. When the pre-filled syringe presentation is used in a syringe pump appropriate compatibility should be ensured. In particular, the pump should be designed to prevent syphoning and should have an occlusion alarm set no greater than 1000 mm Hg. If using a programmable or equivalent pump that offers options for use of different syringes then choose only the B-D 50/60 ml PLASTIPAK setting when using the Diprivan 2% pre-filled syringe.

Target Controlled Infusion - Administration of Diprivan 2% by a Diprifusor TCI System In adults

Administration of Diprivan 2% by a Diprifusor TCI system is restricted to induction and maintenance of general anaesthesia in adults. It is not recommended for use in ICU sedation or in children.

Diprivan may be administered by TCI only with a Diprifusor TCI system incorporating Diprifusor TCI software.

Such systems will operate only on recognition of electronically tagged pre-filled syringes containing Diprivan 1% or 2% Injection. The Diprifusor TCI system will automatically adjust the infusion rate for the concentration of Diprivan recognised. Users must be familiar with the infusion pump users manual, and with the administration of Diprivan 2% by TCI and with the correct use of the syringe identification system.

The systems allow the anaesthetist or intensivist to achieve and control a desired speed of induction and depth of anaesthesia by setting and adjusting target (predicted) blood concentrations of propofol.

The Diprifusor TCI system assumes that the initial blood propofol concentration in the patient is zero. Therefore, in patients who have received prior propofol, there may be a need to select a lower initial target concentration when commencing Diprifusor TCI. Similarly, the immediate recommencement of Diprifusor TCI is not recommended if the pump has been switched off.

Guidance on propofol target concentrations is given below. In view of interpatient variability in propofol pharmacokinetics and pharmacodynamics, in both premedicated and unpremedicated patients the target propofol concentration should be titrated against the response of the patient in order to achieve the depth of anaesthesia required.

In adult patients under 55 years of age anaesthesia can usually be induced with target propofol concentrations in the region of 4-8 micrograms/ml.

An initial target of 4 micrograms/ml is recommended in premedicated patients and in unpremedicated patients an initial target of 6 micrograms/ml is advised. Induction time with these targets is generally within the range of 60-120 seconds. Higher targets will allow more rapid induction of anaesthesia but may be associated with more pronounced haemodynamic and respiratory depression.

A lower initial target concentration should be used in patients over the age of about 55 years and in patients of ASA Grades 3 and 4. The target concentration can then be increased in steps of 0.5-1 microgram/ml at intervals of 1 minute to achieve a gradual induction of anaesthesia.

Supplementary analgesia will generally be required and the extent to which target concentrations for maintenance of anaesthesia can be reduced will be influenced by the amount of concomitant analgesia administered. Target propofol concentrations in the region of 3-6 micrograms/ml usually maintain satisfactory anaesthesia.

The predicted propofol concentration on waking is generally in the region of 1-2 microgram/ml and will be influenced by the amount of analgesia given during maintenance.

Sedation during intensive care

Target blood propofol concentration settings in the range of 0.2-2 micrograms/ml will generally be required. Administration should begin at low target setting which should be titrated against the response of the patient to achieve the depth of sedation desired.

4.3    Contraindications

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

Diprivan 2% must not be used in patients of 16 years of age or younger for sedation in intensive care (see 4.4 Special warnings and precautions for use).

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

4.4    Special warnings and precautions for use

Diprivan 2% 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 and oxygen enrichment and other resuscitative facilities should be readily available at all times. Diprivan 2% should not be administered by the person conducting the diagnostic or surgical procedure.

The abuse of Diprivan 2%, predominantly by health care professionals, has been reported. As with other general anaesthetics, the administration of Diprivan 2% without airway care may result in fatal respiratory complications. When Diprivan 2% 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. 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.

As with other sedative agents, when Diprivan 2% 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 2%. Very rarely the use of Diprivan 2% 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.

Diprivan 2% induced impairment is not generally detectable beyond 12 hours. The effects of Diprivan 2%, 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 2% clearance is blood flow dependent, therefore, concomitant medication that reduces cardiac output will also reduce Diprivan 2% clearance.

Diprivan 2% 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 2% is used in conjunction with other agents likely to cause a bradycardia. When Diprivan 2% 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).

It is recommended that blood lipid levels should be monitored if Diprivan 2% is 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 contains approximately 0.1 g of fat.

Use is not recommended with electroconvulsive treatment.

As with other anaesthetics sexual disinhibition may occur during recovery.

The use of Diprivan is not recommended in newborn infants as this    4.t

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.

Advisory statements concerning Intensive Care Unit management

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.

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 (in some cases with fatal outcome) in adults. Combinations of these events have been referred to as the Propofol Infusion Syndrome.

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 2% (usually following extended dosing at dose rates greater than 4mg/kg/h).

Prescribers should be alert to these events and consider decreasing the Diprivan 2% dosage or switching to an alternative sedative at the first sign of occurrence of symptoms. All sedative and therapeutic agents used in the intensive care unit (ICU), including Diprivan 2%, 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.

Diprivan 2% contains 0.0018 mmol sodium per ml.

Additional Precautions

Diprivan 2% 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 2%, particularly in patients who are predisposed to zinc deficiency, such as those with bums, diarrhoea and/or major sepsis.

When Diprivan 2% 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 2% and infusion equipment throughout the infusion period. Any infusion fluids added to the Diprivan 2% 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. In accordance with established guidelines for other lipid emulsions, a single infusion of Diprivan 2% must not exceed 12 hours. At the end of the procedure or at 12 hours, whichever is the sooner, both the reservoir of Diprivan 2% and the infusion line must be discarded and replaced as appropriate.

4.5    Interaction with other medicaments and other forms of interaction

See section 4.2.5 Administration.

4.6    Pregnancy and lactation

Pregnancy Teratology studies in rats and rabbits showed no teratogenic effects.

The safety of Diprivan 2% during pregnancy has not been established.

Diprivan 2% should not be given to pregnant women except when absolutely necessary. Diprivan 2% can, however, be used during an induced abortion.

Obstetrics Diprivan 2% crosses the placenta and can cause neonatal depression. It should not be used for obstetric anaesthesia.

Lactation Studies of breastfeeding mothers showed that small quantities of Diprivan 2% are excreted in human milk. Women should therefore not breastfeed for 24 hours after administration of Diprivan 2%. Milk produced during this period should be discarded.

4.7    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.

Diprivan 2% induced impairment is not generally detectable beyond 12 hours (please see section 4.4).

For further copies of this leaflet, visit emc.medicines.org.uk or call AstraZeneca on 01582 836836. PACKAGE LEAFLET: INFORMATION FOR THE USER

Diprivan 20 mg/ml (2%)

Emulsion for Injection or Infusion

propofol

Read all of this leaflet carefully before you start

having this medicine.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, ask your doctor or nurse.

•    If you think you have a side effect, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse.

In this leaflet:

1.    What Diprivan is and what it is used for

2.    Before you have Diprivan

3.    How to have Diprivan

4.    Possible side effects

5.    How to store Diprivan

6.    Further information

1. What Diprivan is and what it is used for

Diprivan contains a medicine called propofol. This belongs to a group of medicines called ‘general anaesthetics’. General anaesthetics are used to cause unconsciousness (sleep) so that surgical operations or other procedures can be performed. They can also be used to sedate you (so that you are sleepy but not completely asleep).

Diprivan will be given to you as an injection by a doctor. In adults and children over 3 years of age it is used to:

•    Help put you to sleep before an operation or other procedure.

•    Keep you asleep during an operation or other procedure.

•    Sedate you during diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia.

In people over 16 years of age it is also used to:

•    Sedate you when receiving artificial respiration in an Intensive Care Unit (ICU).

2. Before you have Diprivan

Do not have Diprivan if:

•    You are allergic (hypersensitive) to propofol or any of the other ingredients of Diprivan (listed in Section 6: Further information).

•    You are allergic to peanut or soya. This is because Diprivan contains soya oil.

•    You are pregnant (see the section called ‘Pregnancy and breast-feeding’).

•    You are 16 years of age or younger for sedation in intensive care.

If any of the above apply to you, do not have Diprivan

and tell your doctor, anaesthetist or nurse. If you are not

sure, talk to one of these people before having Diprivan.

Take special care with Diprivan

Diprivan is not recommended in children aged less than

3 years.

Before you have this medicine, tell your doctor, anaesthetist or nurse if:

•    You have ever had a fit or convulsion.

•    You have ever been told that you have very high levels of fat in your blood.

•    You have ever been told that your body has problems using fat.

•    Your body has lost lots of water (you are dehydrated).

•    You have any other health problems, such as problems with your heart, breathing, kidneys or liver.

•    You have been generally unwell for some time.

If you are not sure if any of the above apply to you, talk to your doctor or nurse before having Diprivan.

Taking other medicines

Tell your doctor if you are taking or have recently taken any other medicines. This includes medicines that you buy without a prescription and herbal medicines.

Pregnancy and breast-feeding

•    Do not have Diprivan if you are pregnant.

•    If you are trying to get pregnant or if you are breastfeeding, talk to your doctor or nurse before having this medicine.

Driving and using machines

After having Diprivan, you may still feel sleepy for some time. Do not drive or use any tools or machines until you are sure the effects have worn off.

•    If you are able to go home shortly after having Diprivan, do not drive a car or use any tools or machines.

•    Ask your doctor when you can start doing these activities again and when you can go back to work.

Important information about some of the ingredients of Diprivan

Diprivan contains sodium. If you are on a sodium controlled diet, you will need to take this into account. Diprivan contains soya oil. If you are allergic to peanut or soya, do not use this medicine.

Diprivan contains disodium edetate. During prolonged use of Diprivan for intensive care, you may need to be given a zinc (a mineral) supplement.

3. How to have Diprivan

You will be given Diprivan by a doctor. It will be given to you as an injection into a vein. This is usually in the back of your hand or in your forearm.

•    The doctor will give you the injection through a fine plastic tube called a ‘cannula’.

•    The doctor can also use an electric pump to control how fast the injection is given. This may be done if you are having a long operation or if you are in an Intensive Care Unit.

The dose of Diprivan varies from one patient to another. The amount of Diprivan that you need depends on your age, size, physical fitness and the level of sleepiness or sleep that you need. The doctor will give you the correct dose to start and to sustain anaesthesia or to achieve the required level of sedation, by carefully watching your responses and vital signs (pulse, blood pressure, breathing etc.).    Please turn over =>

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