SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Fresenius Propoven 2%, emulsion for injection or infusion

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

1 ml emulsion contains 20 mg propofol.

Each 50 ml vial contains 1000 mg propofol.

Excipients:

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

sodium    max. 0.06 mg

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Emulsion for injection or infusion White oil-in-water emulsion

4.    CLINICAL PARTICULARS

4.1 Therapeutic indications

Fresenius Propoven 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

Fresenius Propoven 2% 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 Fresenius Propoven 2% should not be administered by the same person conducting the surgical or diagnostic procedure.

The dose of Fresenius Propoven 2% emulsion should be individualised based on the response of the patient and premedications used.

Supplementary analgesic agents are generally required in addition to Fresenius Propoven 2%.

Posology

General anaesthesia in adults

Induction of anaesthesia:

For induction of anaesthesia Fresenius Propoven 2% 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 Fresenius Propoven 2% may be reduced to a minimum of 1 mg propofol/kg bodyweight. Lower rates of administration of Fresenius Propoven 2% should be used (approximately 1 ml (20 mg propofol) every 10 seconds).

Maintenance of anaesthesia:

Anaesthesia can be maintained by administering Fresenius Propoven 2% by continuous infusion.

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 Fresenius Propoven 2% may be reduced further depending on the severity of the patient’s condition and on the performed anaesthetic technique.

General anaesthesia in children over 3 years of age

Induction of anaesthesia:

For induction of anaesthesia Fresenius Propoven 2% 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 Fresenius Propoven 2% for induction of anaesthesia. In younger children, dose requirements may be higher (2.5 - 4 mg/kg bodyweight).

Maintenance of general anaesthesia:

Anaesthesia can be maintained by administering Fresenius Propoven 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 915 mg/kg/h usually achieve satisfactory anaesthesia. In younger children, 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 Fresenius Propoven 2% 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 (0.5 - 1 ml Fresenius Propoven 2%) 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 Fresenius Propoven 2% may be required and the rate of administration may need to be reduced.

Sedation for diagnostic and surgical procedures 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 bodyweight propofol for onset of sedation. Maintenance of sedation may be accomplished by titrating Fresenius Propoven 2% infusion to the desired level of sedation. Most patients require 1.5 - 9 mg/kg/h propofol.

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 Fresenius Propoven 2% 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 Special warnings and precautions for use).

Administration of Fresenius Propoven 2% by a target controlled infusion (TCI) system is not advised for sedation in the intensive care unit (ICU).

Method of administration

For intravenous use

Fresenius Propoven 2% is administered undiluted intravenously by continuous infusion. Fresenius Propoven 2% should not be given by repeat bolus injection for maintenance of anaesthesia.

Fresenius Propoven 2% is infused, it is recommended that equipment such as burettes, drop counter, syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

Containers should be shaken before use.

Use only homogeneous preparations and undamaged containers.

Prior to use, the rubber membrane should be cleaned using an alcohol spray or a swab dipped in alcohol. After use, tapped containers must be discarded.

Fresenius Propoven 2% is a lipid containing emulsion without antimicrobial preservatives and may support rapid growth of microorganisms.

The emulsion must be drawn aseptically into a sterile syringe or giving set immediately after breaking the vial seal. Administration must commence without delay.

Asepsis must be maintained for both Fresenius Propoven 2% and infusion equipment throughout the infusion period. Co-administration of other medicinal products or fluids added to the Fresenius Propoven 2% infusion line must occur close to the cannula site using a Y-piece connector or a three-way valve.

Fresenius Propoven 2% must not be mixed with other solutions for infusion or injection. But 5% w/v glucose solution, 0.9% w/v sodium chloride solution or 0.18% w/v sodium chloride and 4% w/v glucose solution may be administered via suitable appendages at the cannula site.

Fresenius Propoven 2% must not be administered via a microbiological filter.

Fresenius Propoven 2% and any infusion equipment containing Fresenius Propoven 2% are for single administration in an individual patient. After use remaining solution of Fresenius Propoven 2% has to be discarded.

As usual for fat emulsions, the infusion of Fresenius Propoven 2% via one infusion system must not exceed 12 hours. After 12 hours, the infusion system and reservoir of Fresenius Propoven 2% must be discarded or replaced if necessary.

To reduce pain on the injection site, Fresenius Propoven 2% should be administered in a larger vein or lidocaine injection solution may be administered before induction of anaesthesia with Fresenius Propoven 2% (see section 4.4 Special warnings and precautions for use).

Muscle relaxants like atracurium and mivacurium should only be administered after flush of the same infusion site used for Fresenius Propoven 2%.

Duration of administration

The duration of administration must not exceed 7 days.

4.3 Contraindications

Fresenius Propoven 2% must not be used

•    in patients with a known hypersensitivity to propofol, soya, peanut or to any of the excipients of the emulsion

•    in patients who are allergic to soya or peanut

•    in patients of 16 years of age or younger for sedation in intensive care

4.4 Special warnings and precautions for use

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 Fresenius Propoven 2%.

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.

Fresenius Propoven 2% 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 Fresenius Propoven 2% should be considered, especially in situations where vagal tone is likely to predominate or when Fresenius Propoven 2% is used in conjunction with other agents likely to cause a bradycardia.

Use of Fresenius Propoven 2% is not recommended with electroconvulsive therapy.

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.

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 Fresenius Propoven 2% formulation: 1.0 ml Fresenius Propoven 2% 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.

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.

To reduce pain on the injection site during induction of anaesthesia with Fresenius Propoven 2%, lidocaine can be injected prior to the propofol emulsion. Lidocaine must not be used in patients with hereditary acute porphyria.

Fresenius Propoven 2% is not recommended in children < 3 years of age since the 2% strength is difficult to be adequately titrated in small children due to the extremely small volumes needed. The use of Fresenius Propoven 1% should be considered in children between 1 month and 3 years of age if a dose less than e.g. 100 mg/h is expected.

Administration of Fresenius Propoven 2% by a target controlled infusion (TCI) system is not advised for the use in children.

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.

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.

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.

The use of Fresenius Propoven 2% 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 inter-individual variability. Relative overdose could occur administering doses recommended for older children resulting in severe cardiovascular depression.

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.

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

Fresenius Propoven 2% 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 Fresenius Propoven 2%.

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 Fresenius Propoven 2% is combined with centrally depressant agents 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 cyclosporin.

4.6 Pregnancy and lactation

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 also section 5.3 Preclinical safety data). High doses (more than 2.5 mg propofol/kg body weight for induction or 6 mg propofol/kg body weight/h for maintenance of anaesthesia) should be avoided.

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

After administration of Fresenius Propoven 2%, 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.

4.8    Undesirable effects

Commonly observed side 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 Special warnings and precautions for use).

Cardiac disorders / Vascular disorders:

Common:

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

Uncommon:

Marked hypotension. This may require a lowering of the administration rate of Fresenius Propoven 2% 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. Special warnings and precautions for use).

Rare:

Arrhythmia during the recovery period.

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 Fresenius Propoven 2% can be minimised by the administration of lidocaine prior to the propofol emulsion and by the use of larger veins of the forearm and antecubital fossa (see section 4.2 Method of administration). Upon administration 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 Special warnings and precautions for use.

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: Other general anaesthetics ATC-Code: NO1AX10

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.

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.

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

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

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 Triglycerides medium-chain Purified egg phosphatides Glycerol Oleic acid Sodium hydroxide Water for injections

6.2    Incompatibilities

This medicinal product must not    be mixed with other medicinal products.

6.3    Shelf life

The shelf life of the product in its original package is 3 years.

Administration systems with undiluted Fresenius Propoven 2% should be replaced after 12 hours.

After opening the product must be used immediately.

6.4    Special precautions for storage

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

6.5    Nature and contents of container

Colourless glass vial(s) (type II) of 50 ml with a bromobutyl rubber closure.

Packs containing 1 glass vial with 50 ml emulsion Packs containing 10 glass vials with 50 ml emulsion Packs containing 15 glass vials with 50 ml emulsion

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

For single use. Any unused emulsion must be discarded.

Containers 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 containers.

Prior to use, the rubber membrane should be cleaned using an alcohol spray or a swab dipped in alcohol. After use, tapped containers must be discarded.

7    MARKETING AUTHORISATION HOLDER

Fresenius Kabi Limited

Melbury Park

Birchwood

Warrington

Cheshire

WA3 6FF

United Kingdom

8    MARKETING AUTHORISATION NUMBER

PL 08828/0168

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 25/10/2010

10 DATE OF REVISION OF THE TEXT

25/10/2010