SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Propofol 10 mg/ml, emulsion for injection and infusion.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml contains 10 mg propofol. One 20 ml ampoule contains 200 mg propofol. One 50 ml vial contains 500 mg propofol. One 100 ml vial contains 1000 mg propofol. Excipient(s) with known effect:

Soya-bean oil, refined Ph.Eur.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Emulsion for injection or infusion.

Isotonic, white oil-in-water emulsion for intravenous administration.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Propofol is a short-acting intravenous general anaesthetic for:

-    induction and maintenance of general anaesthesia in adults and children > 1 month.

-    sedation for diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia in adults and children > 1 month

-    sedation of ventilated patients >16 years of age in the Intensive Care Unit.

4.2    Posology and method of administration

Posology

The dose of Propofol 10 mg/ml should be individualised by an experienced anaesthetist based on body weight, sensitiveness of the patient and other concomitant medications. Propofol is a short-acting intravenous anaesthetic agent and it has been used in association with spinal and epidural anaesthesia.

It is recommended that propofol should be titrated against the response of the patient until clinical signs show the onset of anaesthesia.

The contents of one ampoule or one vial of Propofol 10 mg/ml are for single use in one patient.

4.2.1    Induction of general anaesthesia Adults:

In unpremedicated and premedicated patients, it is recommended that Propofol 10 mg/ml should be titrated (approximately 4 ml [40 mg] every 10 seconds in an average healthy adult by bolus injection or 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 Propofol 10 mg/ml. The total dose required can be reduced by lower rates of administration (2-5 ml/min [20-50 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 2 ml [20 mg] every 10 seconds).

Elderly:

In elderly the dose requirement for induction of anaesthesia with propofol 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.

Paediatric population:

Propofol 10 mg/ml is not recommended for induction of anaesthesia in children aged less than 1 month.

For induction of anaesthesia in children over 1 month of age, propofol 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 paediatric patients require 1 - 2 mg/kg body weight propofol for onset of sedation. Maintenance of sedation may be accomplished by titrating propofol infusion to the desired level of sedation. Most patients require 1.5-9 mg/kg/h propofol. The infusion may be supplemented by bolus administration of up to 1 mg/kg b.w. if a rapid increase of depth of sedation is required.

Most patients over 8 years of age require approximately 2.5 mg/kg body weight propofol for induction of anaesthesia. In younger children, especially between the age of 1 month and 3 years, dose requirements may be higher (2.5 - 4 mg/kg body weight).

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

4.2.2    Maintenance of general anaesthesia Adults:

Anaesthesia can be maintained by administering Propofol 10 mg/ml either by continuous infusion or by repeated bolus injections to prevent the clinical signs of light anaesthesia. Recovery from anaesthesia is typically rapid and it is therefore important to maintain Propofol 10 mg/ml administration until the end of the procedure.

Continuous Infusion:

The required rate of administration varies considerably between patients, but rates in the region of 4-12 mg/kg/h 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 (5.0 ml) may be given according to clinical need.

Elderly:

When Propofol 10 mg/ml 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 elderly as this may lead to cardiorespiratory depression.

Paediatric population:

Propofol 10 mg/ml is not recommended for maintenance of anaesthesia in children aged less than 1 month.

Anaesthesia can be maintained in children over 1 month of age by administering propofol by infusion or repeated 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/h usually achieve satisfactory anaesthesia. In younger children, especially between the age of 1 month and 3 years, dose requirements may be higher.

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

4.2.3 Sedation during Intensive Care Adults:

For sedation during Intensive Care it is advised that propofol is 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 propofol (See 4.4 Special warnings and precautions for use). Propofol 10 mg/ml is not indicated for sedation in intensive care of patients of 16 years of age or younger (see 4.3 Contraindications). Administration of propofol by volumetric infusion pump is not advised for sedation in the intensive care unit.

Propofol 10 mg/ml may be diluted with 5% Dextrose (see "Dilution and Coadministration" table below).

It is recommended that blood lipid levels be monitored should Propofol 10 mg/ml be administered to patients thought to be at particular risk of fat overload.

Administration of Propofol 10 mg/ml 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 10 mg/ml formulation; 1.0 ml of Propofol 10 mg/ml contains approximately 0.1g of fat.

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

Elderly:

When Propofol 10 mg/ml is used for sedation 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 elderly as this may lead to cardiorespiratory depression.

Paediatric population:

Propofol is contraindicated for the sedation of ventilated children of 16 years of age or younger receiving intensive care.

Dilution and co-administration of Propofol 10 mg/ml with other drugs or infusion fluids (see also 'AdditionalPrecautions' Section).

connector
	Sodium chloride 0.9% intravenous infusion	As above	As above
	Dextrose 4% with sodium chloride 0.18% intravenous infusion	As above	As above

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 Propofol 10 mg/ml 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.

Elderly:

When Propofol 10 mg/ml 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 elderly as this may lead to cardiorespiratory depression.

Paediatric population:

Propofol 10 mg/ml is not recommended for surgical and diagnostic procedures in children aged less than 1 month.

In children over 1 month 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 Propofol 10 mg/ml for onset of sedation. Maintenance of sedation may be accomplished by titrating Propofol 10 mg/ml infusion to the desired level of sedation. Most patients require 1.5-9 mg/kg/h. The infusion may be supplemented by bolus administration of up to 1 mg/kg body weight if a rapid increase of depth of sedation is required.

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

4.2.5    Method of Administration

Propofol has no analgesic properties and therefore supplementary analgesic agents are generally required in addition to Propofol.

Propofol can be used for infusion undiluted from glass containers, plastic syringes or diluted with 5% Dextrose (Intravenous Infusion BP) only, in PVC infusion bags or glass infusion bottles. Dilutions, which must not exceed 1 in 5 (2 mg propofol per ml) should be prepared aseptically immediately before administration and must be used within 6 hours of preparation.

It is recommended that, when using diluted Propofol 10 mg/ml, the volume of 5% Dextrose removed from the infusion bag during the dilution process is totally replaced in volume by Propofol 10 mg/ml emulsion. (see "Dilution and Co-administration" table below).

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 Propofol 10 mg/ml. 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 Propofol 10 mg/ml in the burette.

When Propofol 10 mg/ml is used undiluted to maintain anaesthesia, it is recommended that equipment such as syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

Propofol 10 mg/ml may be administered via a Y-piece 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.

Propofol 10 mg/ml may be premixed with alfentanil injection containing 500 micrograms/ml alfentanil in the ratio of 20:1 to 50:1 v/v. Mixtures should be prepared using sterile technique and used within 6 hours of preparation.

In order to reduce pain on initial injection, Propofol 10 mg/ml may be mixed with preservative-free Lidocaine Injection 0.5% or 1%; (see "Dilution and Coadministration" table below).

Induction and Maintenance of General Anaesthesia

In adult patients under 55 years of age anaesthesia can usually be induced with target propofol concentrations in the region of 4-8 microgram/ml. An initial target of 4 microgram/ml is recommended in premedicated patients and in unpremedicated patients an initial target of 6 microgram/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 0.5-1.0 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 microgram/ml usually maintain satisfactory anaesthesia.

The predicted propofol concentration on waking is generally in the region of 1.0-2.0 microgram/ml and will be influenced by the amount of analgesia given during maintenance.

4.3    Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Propofol 10 mg/ml contains soya-bean oil and should not be used in patients who are hypersensitive to peanut or soya.

Propofol must not be used in patients of 16 years of age or younger for sedation in intensive care (see section 4.4).

Special warnings and precautions for use

Propofol 10 mg/ml 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. Propofol 10 mg/ml should not be administered by the person conducting the diagnostic or surgical procedure.

Abuse of, and dependence on propofol, predominantly by health care professionals, have been reported. As with other general anaesthetics, the administration of Propofol 10 mg/ml without airway care may result in fatal respiratory complications.

When Propofol 10 mg/ml 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 Propofol 10 mg/ml 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 Propofol 10 mg/ml. Very rarely the use of Propofol 10 mg/ml 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.

Propofol 10 mg/ml induced impairment is not generally detectable beyond 12 hours. The effects of Propofol 10 mg/ml, 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. Propofol 10 mg/ml clearance is blood flow dependent, therefore, concomitant medication that reduces cardiac output will also reduce Propofol 10 mg/ml clearance.

Propofol 10 mg/ml 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 Propofol 10 mg/ml 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 Propofol 10 mg/ml.

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 Propofol 10 mg/ml is combined with centrally depressant drugs administered parenterally, severe respiratory and cardiovascular depression may occur. It is recommended that Propofol 10 mg/ml 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 Propofol 10 mg/ml during the period of anaesthetic maintenance.

When Propofol 10 mg/ml 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.

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 Propofol 10 mg/ml (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 promptly consider decreasing or stopping the Propofol 10 mg/ml dosage 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 Propofol 10 mg/ml contains approximately 0.1 g of fat.

Propofol 10 mg/ml contains 0.0026 mmol sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Paediatric population:

The use of propofol 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.

Propofol 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).

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.

Propofol 10 mg/ml 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

Propofol 10 mg/ml, particularly in patients who are predisposed to zinc deficiency, such as those with burns, diarrhoea and/or major sepsis.

When Propofol 10 mg/ml 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 Propofol 10 mg/ml and infusion equipment throughout the infusion period. Any infusion fluids added to the Propofol 10 mg/ml line must be administered close to the cannula site. Propofol 10 mg/ml must not be administered via a microbiological filter.

Propofol 10 mg/ml and any syringe containing Propofol 10 mg/ml 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.

Propofol 10 mg/ml 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 Propofol 10 mg/ml may be required where general anaesthesia is used as an adjunct to regional anaesthetic techniques.

Profound hypertension 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 Propofol 10 mg/ml (see Section 4.4).

Pregnancy

The safety of propofol during pregnancy has not been established. Propofol 10 mg/ml should not be given to pregnant women except when absolutely necessary. Propofol 10 mg/ml can, however, be used during an induced abortion.

Obstetrics

Propofol 10 mg/ml crosses the placenta and can cause neonatal depression. It should not be used for obstetric anaesthesia unless clearly necessary.

Breast-feeding

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

Effects on ability to drive and use machines

Propofol 10 mg/ml 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. Propofol 10 mg/ml induced impairment is not generally detectable beyond 12 hours (Section 4.4).

4.8    Undesirable effects

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 propofol 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

System Organ Class	Frequency	Undesirable Effects
Immune system disorders:	Very rare	Anaphylaxis - may include angioedema, bronchospasm, erythema and hypotension
Metabolism and Nutrition disorders:	Not known (9)	Metabolic acidosis (5), hyperkalaemia (5), hyperlipidaemia (5)
Psychiatric disorders:	Not known (9)	Euphoric mood, drug abuse and drug dependence (8)
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 known (9)	Involuntary movements
Cardiac disorders:	Common	Bradycardia (1)

	Very rare	Pulmonary oedema
	Not known (9)	Cardiac arrhythmia (5), cardiac failure (5), (7)
Vascular disorders:	Common	Hypotension (2)
	Uncommon	Thrombosis and phlebitis
Respiratory, thoracic and mediastinal disorders:	Common	Transient apnoea during induction
	Not known (9)	Respiratory depression (dose dependent)
Gastrointestinal disorders:	Common	Nausea and vomiting during recovery phase
	Very rare	Pancreatitis
Hepatobiliary disorders	Not known (9)	Hepatomegaly (5)
Musculoskeletal and connective tissue disorders:	Not known (9)	Rhabdomyolysis (3), (5)
Renal and urinary disorders	Very rare	Discolouration of urine following prolonged administration
	Not known (9)	Renal failure (5)
Reproductive system and breast disorders	Very rare	Sexual disinhibition
General disorders and administration site conditions:	Very common	Local pain on induction (4)
	Very rare	Tissue necrosis (10) following accidental extravascular administration
	Not known (9)	Local pain, swelling, following accidental extravascular administration
Investigations	Not known (9)	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 Propofol 10 mg/ml.

⁽³⁾    Very rare reports of rhabdomyolysis have been received where Propofol 10 mg/ml 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 Propofol 10 mg/ml 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 Propofol 10 mg/ml 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 national reporting system listed in Appendix V.

4.9    Overdose

Accidental overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression requires lowering of the patient's head and, if severe, use of plasma expanders and pressor agents.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: other general anaesthetics ATC code: N01AX10

Mechanism of action

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 ligand-gated GABA_a receptors.

Pharmacodynamic properties

In general, falls in mean arterial blood pressure and slight changes in heart rate are observed when Propofol 10 mg/ml 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 Propofol 10 mg/ml, any effects are qualitatively similar to those of other intravenous anaesthetic agents and are readily manageable in clinical practice.

Propofol 10 mg/ml reduces cerebral blood flow, intracranial pressure and cerebral metabolism. The reduction in intracranial pressure is greater in patients with an elevated baseline intracranial pressure.

Clinical efficacy and safety

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

In general, there is less post-operative nausea and vomiting following anaesthesia with Propofol 10 mg/ml than following anaesthesia with inhalational agents. There is evidence that this may be related to a reduced emetic potential of propofol.

Propofol 10 mg/ml, at the concentrations likely to occur clinically, does not inhibit the synthesis of adrenocortical hormones.

Paediatric population

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.

Absorption

When Propofol 10 mg/ml is used to maintain anaesthesia, blood concentrations asymptotically approach the steady-state value for the given administration rate.

Distribution

Propofol is extensively distributed and rapidly cleared from the body (total body clearance 1.5-2 litres/minute).

Elimination

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.

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.

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).

Linearity

The pharmacokinetics are linear over the recommended range of infusion rates of Propofol 10 mg/ml.

Propofol is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Glycerol, purified egg-lecithin, refined soybean oil, oleic acid, sodium hydroxide and Water for Injections.

The neuromuscular blocking agents atracurium and mivacurium should not be given through the same intravenous line as Propofol 10 mg/ml without prior flushing.

Shelf life

3 years (ampoules and vials).

Dilutions should be prepared aseptically immediately before administration and must be used within 6 hours of preparation.

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package.

Do not freeze.

6.5    Nature and contents of container

Glass ampoules of 20 ml containing 200 mg propofol packaged per 1, 5 or 10 pieces. Glass vials of 50 ml containing 500 mg propofol packaged per 1, 5 or 10 pieces. Glass vials of 100 ml containing 1,000 mg propofol packaged per 1, 5 or 10 pieces. The ampoules (colourless glass Type I) and vials (colourless glass Type II) are packaged in carton boxes together with a patient information leaflet.

Not all pack sizes may be marketed

6.6    Special precautions for disposal

For single use only.

Finger protection should be used when ampoules are opened.

In order to eliminate the risk of infection from bacterial contamination strict aseptic techniques must be used when handling propofol emulsion.

Please inspect the product visually before using.

Shake before use.

When two layers can be seen in the ampoule or vial after shaking then the product should not be used.

If other visual appearances have changed or if the container is damaged the product should not be used.

Any portion of the contents remaining after first use should be discarded.

7. MARKETING AUTHORISATION HOLDER

Genthon BV Microweg 22 6545 CM Nijmegen

The Netherlands

8. MARKETING AUTHORISATION NUMBER

PL 15919/0023

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/11/2007

10    DATE OF REVISION OF THE TEXT

19/09/2016