SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Propoven 1% emulsion for injection/infusion in pre-filled syringe

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml emulsion contains 10 mg propofol.

Each 10 ml pre-filled syringe contains 100 mg propofol.

Each 20 ml pre-filled syringe contains 200 mg propofol.

Each 50 ml pre-filled syringe contains 500 mg propofol.

Excipients with known effects:

Each ml emulsion contains: soya-bean oil, refined    50 mg

sodium    max. 0.06 mg

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Emulsion for injection/infusion in pre-filled syringe White oil-in-water emulsion

pH of emulsion: 7.5 - 8.5 Osmolality of emulsion: 300 mosmol/kg

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Propoven 1%is a short-acting intravenous general anaesthetic for

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

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

-    sedation of ventilated patients > 16 years of age in the intensive care unit

4.2 Posology and method of administration

Propoven 1% must only be given in hospitals or adequately equipped day therapy units by physicians trained in anaesthesia or in the care of patients in intensive care.

Circulatory and respiratory functions should be constantly monitored (e.g. ECG, pulse oxymetry) and facilities for maintenance of patient airways, artificial ventilation, and other resuscitation facilities should be immediately available at all times.

For sedation during surgical and diagnostic procedures Propoven 1% should not be administered by the same person conducting the surgical or diagnostic procedure.

The dose of Propoven 1% should be individualised based on the response of the patient and premedications used.

Supplementary analgesic agents are generally required in addition to Propoven 1%.

Propoven 1% may be administered by a Target Controlled Infusion system for induction and maintenance of general anaesthesia in adults only. Administration of Propoven 1% by a Target Controlled Infusion system is not recommended for any indication in children. Administration of Propoven 1% by a Target Controlled Infusion system is not recommended for intensive care sedation.

Posology

General anaesthesia in adults

Induction of anaesthesia:

For induction of anaesthesia Propoven 1% should be titrated (approximately 20 - 40 mg propofol every 10 seconds) against the response of the patient until 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 propofol/kg bodyweight.

In patients over this age and in patients of ASA grades III and IV, especially those with impaired cardiac function, the requirements will generally be less and the total dose of Propoven 1% may be reduced to a minimum of 1 mg propofol/kg bodyweight. Lower rates of administration of Propoven 1% should be used (approximately 2 ml of the 10 mg/ml emulsion (20 mg propofol) every 10 seconds).

Maintenance of anaesthesia:

Anaesthesia can be maintained by administering Propoven 1% either by continuous infusion or repeat bolus injections.

For maintenance of anaesthesia generally doses of 4 to 12 mg propofol/kg bodyweight/h should be given. A reduced maintenance dose of approximately 4 mg propofol/kg bodyweight/h may be sufficient during less stressful surgical procedures such as minimal invasive surgery.

In elderly patients, patients in unstable general conditions, patients with impaired cardiac function or hypovolaemic patients and patients of ASA grades III and IV the dosage of Propoven 1% may be reduced further depending on the severity of the patient’s condition and on the performed anaesthetic technique.

For maintenance of anaesthesia with Propoven 1% 10mg/ml using repeat bolus injections dose increments of 25 to 50 mg propofol (= 2.5 - 5 ml Propoven 1%) should be given according to clinical requirements.

Rapid bolus administration (single or repeated) with Propoven 1% 10mg/ml should not be used in the elderly as this may lead to cardiopulmonary depression.

General anaesthesia in children over 1 month of age

Administration of Propoven 1% by a Target Controlled Infusion system is not recommended for any indication in children.

Induction of anaesthesia:

For induction of anaesthesia Propoven 1% should be titrated slowly until clinical signs show the onset of anaesthesia.

The dose should be adjusted according to age and/or bodyweight. Most patients over 8 years of age require approximately 2.5 mg/kg bodyweight Propoven 1% 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 bodyweight).

Maintenance of general anaesthesia:

Anaesthesia can be maintained by administering Propoven 1% 10mg/ml 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 III and IV patients lower doses are recommended (see also section 4.4).

Sedation for diagnostic and surgical procedures in adult patients

To provide sedation during surgical and diagnostic procedures, doses and administration rates should be adjusted according to the clinical response. Most patients will require 0.5 - 1 mg propofol/kg bodyweight over 1 to 5 minutes for onset of sedation. Maintenance of sedation may be accomplished by titrating Propoven 1% infusion to the desired level of sedation. Most patients will require 1.5 - 4.5 mg propofol/kg bodyweight/h. The infusion may be supplemented by bolus administration of 10 - 20 mg propofol (1 - 2 ml Propoven 1%) if a rapid increase of the depth of sedation is required.

In patients older than 55 years and in patients of ASA grades III and IV lower doses of Propoven 1% may be required and the rate of administration may need to be reduced.

Sedation for diagnostic and surgical procedures 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 bodyweight propofol for onset of sedation. Maintenance of sedation may be accomplished by titrating Propoven 1% infusion to the desired level of sedation. Most patients require 1.5 - 9 mg/kg/h propofol. With Propoven 1% 10mg/ml, the infusion may be supplemented by bolus administration of up to 1 mg/kg bodyweight if a rapid increase of depth of sedation is required.

In ASA III and IV patients lower doses may be required.

Sedation in patients over 16 years of age in the intensive care unit

When used to provide sedation for ventilated patients under intensive care conditions, it is recommended that Propoven 1% should be given by continuous infusion. The dose should be adjusted according to the depth of sedation required. Usually satisfactory sedation is achieved with administration rates in the range of 0.3 to 4.0 mg propofol/kg bodyweight/h. Rates of infusion greater than 4.0 mg propofol/kg bodyweight/h are not recommended (see section 4.4).

Administration of Propoven 1% by a target controlled infusion system is not recommended for sedation in the intensive care unit (ICU).

The duration of administration must not exceed 7 days.

Method of administration

For intravenous use.

For single use only. Any unused emulsion must be discarded.

Pre-filled syringes should be shaken before use.

If two layers can be seen after shaking the emulsion should not be used.

Use only homogeneous preparations and undamaged pre-filled syringes.

Propoven 1% can be used for infusion undiluted or diluted (for dilution see section 6.6).

When Propoven 1% is infused , it is recommended that equipment such as burettes, drop counter, syringe pumps (including TCI systems) or volumetric infusion pumps should always be used to control infusion rates.

Propoven 1% is a lipid containing emulsion without antimicrobial preservatives and may support rapid growth of micro-organisms.

The emulsion must be drawn aseptically and giving immediately after opening the syringe. Administration must commence without delay.

Asepsis must be maintained for both Propoven 1% and infusion equipment throughout the infusion period. Co-administration of other medicinal products or fluids added to the Propoven 1% infusion line must occur close to the cannula site using a Y-piece connector or a three-way valve. For instructions on co-administration of the medicinal product, see section 6.6.

Propoven 1% must not be administered via a microbiological filter.

Propoven 1% and any infusion equipment containing Propoven 1% are for single administration in an individual patient. After use remaining solution of Propoven 1% has to be discarded.

Infusion of undiluted Propoven 1%:

As usual for fat emulsions, the infusion of undiluted Propoven 1% via one infusion system must not exceed 12 hours. After 12 hours, the infusion system and reservoir of Propoven 1% must be discarded or replaced if necessary.

Infusion of diluted Propoven 1%:

For administering infusion of diluted Propoven 1%, burettes, drop counters or infusion pumps should always be used to control infusion rates and to avoid the risk of accidentally uncontrolled infusion of large volumes of diluted Propoven 1%. This risk has to be taken into account when the decision for the maximum dilution in the burette is made.

To reduce pain on the injection site, lidocaine may be injected immediately before the use of Propoven 1% (see section 4.4). Alternatively, Propoven 1% may be mixed, immediately for use, with preservative free lidocaine injection (20 parts of Propoven 1% with up to 1 part of 1% lidocaine injection solution under controlled and validated aseptical conditions. The mixture has to be administered within 6 hours after preparation.

Muscle relaxants like atracurium and mivacurium should only be administered after flush of the same infusion site used for Propoven 1%.

Propoven 1% will be injected into a vein either manually or by electric pumps. In case of using electronic pumps, appropriate compatibility should be ensured.

10 ml and 20 ml glass syringes and 10 ml plastic syringes are suitable for manual use only and must not be used with a pump.

10 ml and 20 ml glass syringes must also not be used with needle-free connectors, except standard tubing or 3-way stopcocks to avoid breakage or clogging of the connector.

If breakage/clogging are observed, the pre-filled syringe must be disposed and a new one must be used.

Application of pre-filled syringes (for pre-assembled syringes step 2 can be omitted):

Sterility has to be ensured. The outer surface of the syringe and the plunger rod are not sterile!

1)    Take out the syringe from the packaging and shake it.

2)    Insert the plunger rod by screwing it clock-wise into the syringe.

3)    Remove the tip cap from the syringe and connect the infusion line, needle or cannula to the syringe. Get rid of the air bubble (a small bubble can remain) and the ready-to-use syringe will be installed in the pump or administered manually.

Target Controlled Infusion - Administration of Propoven 1% by pumps (for 50 ml syringe only):

Administration of Propoven 1% by a Target Controlled Infusion system is restricted to induction and maintenance of general anaesthesia in adults. It is not recommended for use in ICU sedation or sedation for surgical and diagnostic procedures, or in children.

Propoven 1% may be administered by a Target Controlled Infusion system incorporating appropriate Target Controlled Infusion software. Users must be familiar with the infusion pump users' manual, and with the administration of Propoven 1% by Target Controlled Infusion.

The system allows the anaesthetist or intensivist to achieve and control a desired speed of induction and depth of anaesthesia by setting and adjusting target (predicted) plasma and/or effect-side concentrations of propofol.

Different modalities of the various pump systems should be considered i.e. the Target Controlled Infusion system might assume 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 Target Controlled Infusion. Similarly, the immediate recommencement of Target Controlled Infusion 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.

Induction and Maintenance of General Anaesthesia during target controlled infusion

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.

Sedation during intensive care (target controlled infusion not advised)

Target blood propofol concentration settings in the range of 0.2 - 2.0 microgram/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

• Hypersensitivity to the active substance, soya, peanut or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

As with other sedative agents, when propofol is used for sedation during operative procedures, involuntary patient movements may occur. During procedures requiring immobility these movements may be hazardous to the operative site.

In isolated cases there may be a phase of postoperative unconsciousness that may be accompanied by an increased muscular tone. The appearance of this period is not dependent whether the patient came out of an anaesthetic or not. Although consciousness is spontaneously regained the unconscious patient should be kept under intensive observation.

Full recovery from general anaesthesia should be confirmed prior to discharge. Paediatric population

The use of Propoven 1% is not recommended for 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 with a very high interindividual variability. Relative overdose could occur administering doses recommended for older children resulting in severe cardiovascular depression. Propoven 1% is not recommended for general anaesthesia in children younger than 1 month of age. In any case, special care should be exercised when propofol is used for anaesthesia in infants and children up to 3 years of age, although currently available data do not suggest significant differences in terms of safety compared with children older than 3 years.

Administration of Propoven 1% by a Target Controlled Infusion system is not recommended for any indication in children.

The safety of propofol for (background) sedation in the intensive care unit in children and adolescents younger than 16 years of age has 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, renal failure 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 ICU.

Special patient groups

Cardiac, circulatory or pulmonary insufficiency and hypovolaemia 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 clearance is blood flow dependent, therefore, concomitant medication which reduces cardiac output will also reduce propofol clearance.

Cardiac, circulatory or pulmonary insufficiency and hypovolaemia should be compensated before administration of Propoven 1%.

Propoven 1% should not be administered in patients with advanced cardiac failure or other severe myocardial disease except with extreme caution and intensive monitoring.

The risk of relative vagotonia may be increased because propofol lacks vagolytic activity. It 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 with Propoven 1% should be considered, especially in situations where vagal tone is likely to predominate or when Propoven 1% is used in conjunction with other agents likely to cause a bradycardia.

Epilepsy

Before anaesthesia of an epileptic patient, it should be checked that the patient has received the antiepileptic treatment. Although several studies have demonstrated efficacy in treating status epilepticus, administration of propofol in epileptic patients may also increase the risk of seizure.

Use of Propoven 1% is not recommended with electroconvulsive therapy.

Patients with disorders of fat metabolism

Special care should be applied in patients with disorders of fat metabolism and in other conditions where lipid emulsions must be used with caution. If patients receive parenteral nutrition it is necessary to take account of the amount of lipid infusion as part of the Propoven 1% formulation: 1.0 ml Propoven 1% contains 0.1 gram of fat. Lipids should be monitored in the Intensive Care Unit treatment every 2 days.

Due to a higher dosage in patients with severe overweight the risk of haemodynamic effects on the cardiovascular system should be taken into consideration.

Patients with a high intracranial pressure

Special care should be recognised in patients with a high intracranial pressure and a low mean arterial pressure as there is a risk of a significant decrease of the intracerebral perfusion pressure.

Similarly very rare reports have been received of occurrence of metabolic acidosis, rhabdomyolysis, hyperkalaemia, arrhythmias and/or rapidly progressive cardiac failure (in some cases with fatal outcome) in adults who were treated for more than 48 hours with dosages in excess of 5 mg propofol/kg bodyweight/h. This exceeds the maximum dosage of 4 mg propofol/kg bodyweight/h currently advised for sedation in the intensive care unit. The patients affected were mainly (but not only) seriously head-injured patients with increased intracranial pressure (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 propofol/kg bodyweight/h. Prescribers should be alert to these possible undesirable effects and consider decreasing the propofol dosage or switching to an alternative sedative at the first sign of occurrence of respective symptoms. Patients with raised ICP should be given appropriate treatment to support the cerebral perfusion pressure during these treatment modifications.

Pain on the injection site

To reduce pain on the injection site during induction of anaesthesia with Propoven 1%, lidocaine can be injected prior to the propofol emulsion.

Intravenous lidocaine must not be used in patients with hereditary acute porphyria.

This medicinal product contains less than 1 mmol (23 mg) sodium per 100 ml, i.e. essentially ‘sodium- free’.

4.5 Interaction with other medicinal products and other forms of interaction

Propoven 1% can be used in combination with other medicinal products for anaesthesia (premedications, volatile anaesthetics, analgesics, muscle relaxants, local anaesthetics). Severe interactions with these medicinal products have been reported. Some of these centrally acting medicinal products may exhibit a circulatory and respiratory depressive effect, thus leading to increased effects when used together with Propoven 1%.

Lower doses may be required when general anaesthesia is carried out in conjunction with regional anaesthesia.

Concomitant use of benzodiazepines, parasympatholytic agents or inhalational anaesthetics has been reported to prolong the anaesthesia and to reduce the respiratory rate.

After additional premedication with opioids, the sedative effects of propofol may be intensified and prolonged, and there may be a higher incidence and longer duration of apnoea.

It should be taken into consideration that concomitant use of propofol and medicinal products for premedication, inhalation agents or analgesic agents may potentiate anaesthesia and cardiovascular side effects.

Concomitant use of central nervous system depressants (e.g. alcohol, general anaesthetics, narcotic analgesics) will result in intensification of their sedative effects. When Propoven 1% is combined with centrally depressant drugs administered parenterally, severe respiratory and cardiovascular depression may occur.

After administration of fentanyl, the blood level of propofol may be temporarily increased with an increase in the rate of apnoea.

Bradycardia and cardiac arrest may occur after treatment with suxamethonium or neostigmine.

Leucoencephalopathy has been reported with administration of lipid emulsions such as propofol in patients receiving cyclosporine.

4.6 Fertility, Pregnancy and lactation

Pregnancy

The safety of propofol during pregnancy has not been established. Therefore, propofol should not be used in pregnant women unless clearly necessary. Propofol crosses the placenta and may be associated with neonatal depression (see section 5.3). High doses (more than 2.5 mg propofol/kg bodyweight for induction or 6 mg propofol/kg bodyweight/h for maintenance of anaesthesia) should be avoided.

Breast-feeding

Studies in breast-feeding women showed that propofol is excreted in small amounts into the milk. Therefore, mothers should stop breast-feeding and discard breast milk for 24 hours after administration of propofol.

4.7 Effects on ability to drive and use machines

Propoven 1% has major influence on the ability to drive and use machines. After administration of Propoven 1%, the patient should be kept under observation for an appropriate period of time. The patient should be instructed not to drive, operate machinery, or work in potentially hazardous situations. The patient should not be allowed to go home unaccompanied, and should be instructed to avoid consumption of alcohol.

4    CLINICAL PARTICULARS

4.8    Undesirable effects

Commonly observed undesirable effects of propofol are hypotension and respiratory depression. These effects depend on the propofol dose administered but also on the type of premedication and other concomitant medication.

In this section undesirable effects are defined as follows:

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)

Not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders:

Rare:

Clinical features of anaphylaxis, which may include angiooedema, bronchospasm, erythema and hypotension.

Very rare:

Allergic reactions caused by soya-bean oil.

Metabolism and nutrition disorders: Common:

Hypertriglyceridemia.

Psychiatric disorders:

Rare:

Euphoria, sexual phantasies, and sexual disinhibition during the recovery period.

Nervous system disorders:

Common:

During induction of anaesthesia spontaneous movements and myocloni, minimal excitation.

Rare:

Headache, vertigo, shivering and sensations of cold during the recovery period. Epileptiform movements including convulsions and opisthotonus.

Very rare:

Delayed epileptiform attacks, the delay period ranging from a few hours to several days.

Risk of convulsions in epileptic patients after administration of propofol.

Cases of postoperative unconsciousness (see section 4.4).

Cardiac disorders:

Common:

During induction of anaesthesia, hypotension, bradycardia, tachycardia, hot flushes can occur.

Uncommon:

Marked hypotension. This may require a lowering of the administration rate of Propoven 1% and/or fluid replacement therapy, if necessary vasoconstrictive medicinal products. Account should be taken of the possibility of a severe drop in blood pressure in patients with impaired coronary or cerebral perfusion or those with hypovolaemia.

Bradycardia during general anaesthesia with progressive severity (asystole). The intravenous administration of an anticholinergic medicinal product prior to induction or during maintenance of anaesthesia should be considered (see also section 4.4.).

Rare:

Arrhythmia during the recovery period.

Vascular disorders:

Rare:

Thrombosis and phlebitis.

Respiratory, thoracic and mediastinal disorders:

Common:

During induction of anaesthesia hyperventilation, transient apnoea, coughing, singultus.

Uncommon:

Coughing during maintenance of anaesthesia.

Rare:

Coughing during the recovery period.

Very rare: Pulmonary oedema.

Gastrointestinal disorders:

Rare:

Nausea or vomiting during the recovery period.

Very rare:

Pancreatitis has been reported after administration of propofol. A causal relationship, however, could not be established.

Skin and subcutaneous tissue disorders:

Very rare:

Severe tissue responses after accidental paravenous application.

Renal and urinary disorders:

Rare:

Cases of discoloration of urine following prolonged administration of propofol.

General disorders and administration site conditions:

Very common:

Local pain occurring during the initial injection. Prophylaxis or treatment see below. The local pain which may occur during the initial injection of Propoven 1% can be minimised by the co-administration of lidocaine (see section 4.2.) and by injection or infusion into the larger veins of the forearm and antecubital fossa. Upon coadministration of lidocaine the following undesirable effects may occur rarely (>1/10,000 to <1/1,000): giddiness, vomiting, drowsiness, convulsions, bradycardia, cardiac arrhythmia and shock.

Rare:

Cases of post-operative fever.

Very rare:

There have been reports of isolated cases of severe undesirable effects presenting as a complex of symptoms including: rhabdomyolysis, metabolic acidosis, hyperkalaemia, and cardiac failure, sometimes with fatal outcome. Most of these effects have been observed in patients in intensive care with doses exceeding 4 mg/kg bodyweight/h. For more detail, see section 4.4.

4.9 Overdose

Overdose is likely to cause cardiovascular and respiratory depression. Respiratory depression is treated with artificial ventilation. Cardiovascular depression may require lowering the patient’s head and administering plasma volume substitutes and vasopressive agents.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Anaesthetics; Other general anaesthetics ATC-Code: N01AX10

Mechanism of action/Pharmacodynamic effects

Propofol (2,6-diisopropylphenol) is a short-acting general anaesthetic agent with a rapid onset of action. Depending on the rate of injection, the time to induction of anaesthesia is between 30 and 40 seconds. The duration of action after a single bolus administration is short and lasts, depending on the metabolism and elimination, 4 to 6 minutes.

Clinical efficacy and safety

Under the usual maintenance regimen significant accumulation with either repeated injections or infusions of propofol has not been seen. Patients recover consciousness rapidly.

Bradycardia and hypotension reported during induction of anaesthesia may be caused by a cerebral vagotonic effect or inhibition of sympathetic activity. However, haemodynamics generally reverts to normal during maintenance of anaesthesia.

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.

5.2 Pharmacokinetic properties

Absorption

Propofol is bound to plasma proteins for 98%. Following intravenous administration the pharmacokinetics of propofol can be described by a 3-compartment model.

Distribution/ Biotransformation/Elimination

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.

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).

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies on repeated dose toxicity or genotoxicity. Carcinogenicity studies have not been conducted. Reproductive toxicity studies have shown effects related to pharmacodynamic properties of propofol only at high doses. Teratogenic effects have not been observed. In local tolerance studies, intramuscular injection resulted in tissue damage around the injection site, paravenous and subcutaneous injection induced histological reactions marked by inflammatory infiltration and focal fibrosis.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Soya-bean oil, refined Medium-chain triglycerides Purified egg phosphatides Glycerol Oleic acid Sodium hydroxide Water for injections

6 PHARMACEUTICAL PARTICULARS

6.2    Incompatibilities

Propoven 1% must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3    Shelf life 50 ml Plastic Syringe and 10 ml and 20 ml Glass Syringe:

Shelf life of the product in its original package before opening: 2 years. 10 ml Plastic Syringe:

Shelf life of the product in its original package before opening: 2 years.

Shelf life after first opening: Product must be used immediately after first opening. Administration systems with undiluted <invented name> should be replaced after 12 hours. Shelf life after dilution: Product must be used immediately after dilution. The administration should be completed within 6 hours after dilution.

6.4 Special precautions for storage

Do not store above 25 °C. Do not freeze.

6.5 Nature and contents of container

10 or 20 mL pre-filled syringe (glass, hydrolytic class 1) with brombutyl tip cap, brombutyl plunger and PP piston rod

10 or 20 ml pre-filled syringe (cyclo-olefine-copolymer) with bromobutyl tip cap, bromobutyl plunger and PP piston rod

50 ml pre-filled syringe (cyclo-olefine-copolymer) with bromobutyl tip cap, bromobutyl plunger and PP piston rod

Packs containing 5 glass syringes with 10 ml emulsion.

Packs containing 6 plastic syringes with 10 ml emulsion.

Packs containing 5 glass syringes with 20 ml emulsion.

Packs containing 6 plastic syringes with 20 ml emulsion.

Packs containing 1 plastic syringe with 50 ml emulsion.

6    PHARMACEUTICAL PARTICULARS

6.6    Special precautions for disposal

Propoven 1% should not be mixed prior to administration with injection or infusion solutions other than glucose 50 mg/ml (5%) solution for injection or sodium chloride 9 mg/ml (0.9%) solution for injection or preservative free lidocaine 10 mg/ml (1%) solution for injection. The maximum dilution must not exceed 1 part of Propoven 1% with 4 parts of glucose 50 mg/ml (5%) solution for injection or sodium chloride 9 mg/ml (0.9%) solution for injection (minimum concentration 2 mg propofol/ml). The mixture should be prepared aseptically (controlled and validated conditions preserved) immediately prior to administration and must be administered within 6 hours after preparation (see also section 4.2.).

Final propofol concentration must not be below 2 mg/ml.

Co-administration of a glucose 50 mg/ml (5%) solution for injection or sodium chloride 9 mg/ml solution for injection or sodium chloride 1.8 mg/ml (0.18%) solution for injection and glucose 40 mg/ml (4%) solution for injection with Propoven 1% is permitted via a Y-piece connector close to the injection site.

7 MARKETING AUTHORISATION HOLDER

Fresenius Kabi

Cestrian Court, Eastgate Way, Manor Park,

Runcorn Cheshire WA7 1NT UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 08828/0239

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/04/2013

10 DATE OF REVISION OF THE TEXT

24/08/2015