PROPOFOL-LIPURO 0.5% (5 MG / ML) EMULSION FOR INJECTION OR INFUSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Propofol-Lipuro 0.5 % (5 mg/ml) emulsion for injection or infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml emulsion for injection or infusion contains 5 mg propofol.

1 ampoule with 20 ml contains 100 mg propofol

Excipients with known effects:

1 ml of emulsion contains

Soya-bean oil refined          50 mg

Sodium                   ­0.03 mg

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Emulsion for injection or infusion.

White milky oil-in-water emulsion.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Propofol-Lipuro 0.5 % (5 mg/ml) is a short-acting intravenous general anaesthetic indicated for

induction of general anaesthesia in adults and children > 1 month

induction of sedation for diagnostic and surgical procedures, in adults and children > 1 month

short term sedation for diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia in adults only.

4.2 Posology and method of administration

General instructions

Propofol-Lipuro 0.5 % (5 mg/ml) 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, pulseoxymeter) and facilities for maintenance of patient airways, artificial ventilation, and other resuscitation facilities should be immediately available at all times. For sedation during surgical or diagnostic procedures Propofol-Lipuro 0.5 % (5 mg/ml) should not be given by the same person that carries out the surgical or diagnostic procedure.

Propofol-Lipuro 0.5 % (5 mg/ml) is intended for use in children, adolescents and adults, especially the pain-sensitive ones, because of the lower pain on injection compared to higher strengths.

Supplementary analgesic medicinal products are generally required in addition to Propofol-Lipuro 0.5 % (5 mg/ml)

Posology

Propofol-Lipuro 0.5 % (5 mg/ml) is given intravenously. The dosage is adjusted individually according to the patient’s response.

General anaesthesia in adults

Induction of anaesthesia:

For induction of anaesthesia Propofol-Lipuro 0.5 % (5 mg/ml) should be titrated (20 – 40 mg of propofol every 10 seconds) against the patient’s response until the clinical signs show the onset of anaesthesia. Most adult patients younger than 55 years are likely to require 1.5 to 2.5 mg of propofol per kg body weight. Repeat bolus injections may be given according to clinical requirements.

In patients over this age and in patients of ASA grades III and IV, especially those with impaired cardiac function, the dosage requirements will be less and the total propofol dose may be reduced to a minimum of 1 mg/kg body weight. In these patients lower rates of administration should be applied (approximately 4 ml of Propofol-Lipuro 0.5 % (5 mg/ml), corresponding to 20 mg of propofol every 10 seconds).

Induction of general anaesthesia in children over 1 month of age

For induction of anaesthesia Propofol-Lipuro 0.5 % (5 mg/ml) should be slowly titrated against the patient’s response until the clinical signs show the onset of anaesthesia. The dosage should be adjusted according to age and/or body weight. Most patients over 8 years of age require approximately 2.5 mg of propofol per kg body weight for induction of anaesthesia. In younger children, especially between the age of 1 month and 3 years, dose requirement may be higher (2.5 – 4 mg of propofol per kg body weight).

Propofol-Lipuro 0.5 % (5 mg/ml) is contraindicated to be used for maintenance of anaesthesia (see also section 4.3)

For ASA III and IV patients lower doses are recommended (see also section 4.4).

s 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 of propofol per kg body weight over 1 to 5 minutes for onset of sedation. Maintenance of sedation may be accomplished by titrating Propofol-Lipuro 0.5 % (5 mg/ml) to the desired level, using e.g. a syringe pump. Most patients will require 1.5 – 4.5 mg of propofol per kg body weight per hour. Additional boluses of 10 – 20 mg of propofol (2 – 4 ml of Propofol-Lipuro 0.5 % (5 mg/ml)) may be given if a rapid increase of the depth of sedation is required.

In patients older than 55 years and in patients of ASA grade III and IV lower doses of Propofol-Lipuro 0.5 % (5 mg/ml) may be required and the rate of administration may need to be reduced.

Induction of 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 body weight of propofol for onset of sedation.

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

Method and duration of administration

Method of administration

Intravenous use

Propofol-Lipuro 0.5 % (5 mg/ml) is administered intravenously undiluted by injection either or by continuous infusion after dilution with glucose 50 mg/ml (5 % w/v) solution, sodium chloride 9 mg/ml (0.9 % w/v) solution.

Containers should be shaken before use.

Before use, the neck of the ampoule should be cleaned with medicinal alcohol (spray or swabs). After use, tapped containers must be discarded.

Propofol-Lipuro 0.5 % (5 mg/ml) contains no antimicrobial preservatives and supports growth of microorganisms. Therefore, Propofol-Lipuro 0.5 % (5 mg/ml) is to be drawn up aseptically into a sterile syringe immediately after opening the ampoule. Administration must commence without delay. Asepsis must be maintained for both Propofol-Lipuro 0.5 % (5 mg/ml) and administration equipment throughout the entire period of administration.

The contents of one ampoule of Propofol-Lipuro 0.5 % (5 mg/ml) and any syringe containing Propofol-Lipuro 0.5 % (5 mg/ml) are for single use in one patient.

If infusion sets with filters are to be used, these must be lipid-permeable.

Administration of undiluted Propofol-Lipuro 0.5 % (5 mg/ml)

When administering Propofol-Lipuro 0.5 % (5 mg/ml) continuously, administration rates should always be controlled by appropriate apparatus, e.g a syringe pump. Any portion of Propofol-Lipuro 0.5 % (5 mg/ml) remaining after the end of administration must be discarded.

Infusion of diluted Propofol-Lipuro 0.5 % (5 mg/ml)

For infusion of diluted Propofol-Lipuro 0.5 % (5 mg/ml), burettes, drop counters, syringe pumps, or volumetric infusion pumps should always be used to control infusion rates and to avoid the risk of accidentally uncontrolled infusion of large volumes of diluted Propofol-Lipuro 0.5 % (5 mg/ml).

The maximum dilution must not exceed 1 part of Propofol-Lipuro 0.5 % (5 mg/ml) with 4 parts of glucose 50 mg/ml (5 % w/v) solution or sodium chloride 9 mg/ml (0.9 % w/v) solution (minimum concentration 1 mg propofol/ml).

For suitable diluents please refer to section 6.6.

The pain on initial injection may be reduced by adding lidocaine to Propofol-Lipuro 0.5 % (5 mg/ml): One part of preservative-free lidocaine injection 10 mg/ml (1 %) may be added to 40 parts of Propofol-Lipuro 0.5 % (5 mg/ml).

Before giving the muscle relaxants atracurium or mivacurium subsequent to Propofol-Lipuro 0.5 % (5 mg/ml) through the same intravenous line, it is recommended that the line be rinsed prior to administration.

Duration of administration

Propofol-Lipuro 0.5 % (5 mg/ml) can be administered for a maximum period of 1 hour.

4.3 Contraindications

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

Propofol-Lipuro 0.5 % (5 mg/ml) is contraindicated:

for maintenance of general anaesthesia

for maintenance of sedation for diagnostic and surgical procedures in children

for sedation for intensive care

Safety and efficacy for these age groups have not been demonstrated.

4.4 Special warnings and precautions for use

Propofol 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 should not be administered by the person conducting the diagnostic or surgical procedure.

The abuse of and dependence on propofol, predominantly by health care professionals, has been reported. As with other general anaesthetics, the administration of propofol without airway care may result in fatal respiratory complications.

When propofol 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.

In case of repeated boli for induction of anaesthesia the maximum fat administration should not exceed 150 mg fat/kg/h which corresponds to 1.5 ml/kg/h of Propofol-Lipuro 0.5 % (5 mg/ml).

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.

An adequate period is needed prior to discharge of the patient to ensure full recovery after use of propofol. Very rarely the use of propofol may be associated with the development of a period of post-operative unconsciousness, which may be accompanied by an increase in muscle tone. This may or may not be preceded by a period of wakefulness. Although recovery is spontaneous, appropriate care of an unconscious patient should be administered.

Propofol induced impairment is not generally detectable beyond 12 hours. The effects of propofol, 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 (e.g. benzodiazepines, opiates, alcohol.)

As with other intravenous 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 that reduces cardiac output will also reduce propofol clearance.

Propofol 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 of anaesthesia should be considered, especially in situations where vagal tone is likely to predominate or when propofol is used in conjunction with other agents likely to cause bradycardia.

When propofol 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.

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

Advisory statements concerning Intensive Care Unit management

Use of propofol for ICU sedation has been associated with a constellation of metabolic disturbances 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 (usually at dose rates greater than 4mg/kg/h for more than 48 hours).

Prescribers should be alert to these events in patients with the above risk factors and immediately discontinue propofol when the above signs develop. All sedative and therapeutic agents used in the intensive care unit (ICU), should be titrated to maintain optimal oxygen delivery and haemodynamic parameters. Patients with raised intra-cranial pressure (ICP) should be given appropriate treatment to support the cerebral perfusion pressure during these treatment modifications. Treating physicians are reminded if possible not to exceed the dosage of 4 mg/kg/h.

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

It is recommended that blood lipid levels should be monitored if propofol is administered to patients thought to be at particular risk of fat overload. Administration of propofol should be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from the body. If the patient is receiving other intravenous lipid concurrently, a reduction in quantity should be made in order to take account of the amount of lipid infused as part of the propofol formulation; 1.0 ml of Propofol-Lipuro 5 mg/ml contains 0.1 g of fat.

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-Lipuro 0.5 % (5 mg/ml) contains no antimicrobial preservatives and supports growth of micro-organisms.

When propofol 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 and infusion equipment throughout the infusion period. Any infusion fluids added to the propofol line must be administered close to the cannula site. If infusion sets with filters are to be used, these must be lipid-permeable.

Propofol and any syringe containing propofol 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.

This medicinal product contains less than 1 mmol (23 mg) sodium in 20 ml, i.e. essentially ‘sodium free’.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

4.6 Fertility, pregnancy and lactation

Pregnancy

The safety of propofol during pregnancy has not been established.

Studies in animals have shown reproductive toxicity (see section 5.3).

Propofol should not be given to pregnant woman except when absolutely necessary. Propofol crosses the placenta and can cause neonatal depression. Propofol can however be used during induced abortion.

Breast-feeding

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

4.7 Effects on ability to drive and use machines

Patients should be advised that performance at skilled tasks, such as driving and operating machinery, may be impaired for some time after use of propofol.

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

4.8 Undesirable effects

Induction and maintenance of anaesthesia or sedation with propofol is generally smooth with minimal evidence of excitation. The most commonly reported ADR 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.

Table of Adverse Drug Reactions

(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.

(3) Very rare reports of rhabdomyolysis have been received where propofol 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-Lipuro 0.5 % (5 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

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

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: other general anaesthetics, ATC-code N01AX10.

Mechanism of action, pharmacodynamic effect

After intravenous injection of Propofol-Lipuro 0.5 % (5 mg/ml), onset of the hypnotic effect occurs rapidly. 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 due to the rapid metabolism and excretion (4 – 6 minutes).

With the recommended dosage schedule, a clinically relevant accumulation of propofol after repeated bolus injection has not been observed.

Patients recover consciousness rapidly.

Bradycardia and hypotension occasionally occur during induction of anaesthesia probably due to a lack of vagolytic activity. The cardio-circulatory situation usually normalises during maintenance of anaesthesia.

The rationale for development of Propofol-Lipuro 0.5 % (5 mg/ml) was the reduction of pain at injection site; this was clearly demonstrated in two clinical studies, one in children and one in adults.

The formulation of propofol in a mixed medium- and long-chain triglyceride emulsion leads to lower concentrations of free propofol in the aqueous phase compared to pure long-chain triglyceride emulsions. This difference may explain the reduced pain frequency and intensity observed with Propofol-Lipuro formulations in comparative clinical studies, especially with Propofol-Lipuro 5 mg/ml due to the very low concentration of free propofol.

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

Distribution

After intravenous administration about 98 % of propofol is bound to plasma protein. After intravenous bolus administration the initial blood level of propofol declines rapidly due to rapid distribution into different compartments (a-phase). The distribution half-life has been calculated as 2 – 4 minutes.

During elimination the decline of blood levels is slower. The elimination half-life during the ß-phase is in the range of 30 to 60 minutes. Subsequently a third deep compartment becomes apparent, representing the re-distribution of propofol from weakly perfused tissue.

The central volume of distribution is in the range of 0.2 – 0.79 l/kg body weight, the steady-state volume of distribution in the range of 1.8 – 5.3 l/kg body weight.

Biotransformation

Propofol is mainly metabolized in the liver to form glucuronides of propofol and glucuronides and sulphate conjugates of its corresponding quinol. All metabolites are inactive.

Elimination

Propofol is rapidly cleared from the body (total clearance approx. 2 l/min). Clearance occurs by metabolism, mainly in the liver, where it is blood flow dependent.

Clearance is higher in children compared with adults. About 88 % of an administered dose is excreted in the form of metabolites in urine. Only 0.3 % is excreted unchanged in urine.

Paediatric population

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 specific hazard for humans based on conventional studies on repeated dose toxicity or genotoxicity. Carcinogenicity studies have not been conducted.

Published studies in animals (including primates) at doses resulting in light to moderate anaesthesia demonstrate that the use of anaesthetic agents during the period of rapid brain growth or synaptogenesis results in cell loss in the developing brain that can be associated with prolonged cognitive deficiencies. The clinical significance of these nonclinical findings is not known.

Teratogenic effects have not been observed.

In local tolerance studies, intramuscular injection resulted in tissue damage around the injection site.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Soya-bean oil, refined, medium-chain triglycerides, glycerol, egg lecithin, sodium oleate, water for injections.

6.2 Incompatibilities

This medicinal product must not be mixed with other products except those mentioned in section section 6.6.

6.3 Shelf life

2 years.

After first opening: to be used immediately.

After dilution according to directions: administration of dilutions must commence immediately after preparation.

6.4 Special precautions for storage

Do not store above 25 °C.

Do not freeze.

6.5 Nature and contents of container

This medicinal product is supplied in glass ampoules of 20 ml

Glass ampoules are made of colourless glass (type I) according to Pharm. Eur..

Pack sizes:

Glass ampoules: 5 × 20 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

Containers should be shaken before use.

For single use in one patient only. Any portion of contents remaining after use must be discarded.

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

Propofol-Lipuro 0.5% (5 mg/ml) should only be mixed with the following products: glucose 50 mg/ml (5 % w/v)solution, sodium chloride 9 mg/ml (0.9 % w/v) solution and preservative-free lidocaine injection 10 mg/ml (1 %) (refer to section 4.2, subsection “Infusion of diluted Propofol-Lipuro 5 mg/ml”)

Co-administration of Propofol-Lipuro 0.5% (5 mg/ml) together with glucose 50 mg/ml (5% w/v) solution or sodium chloride 9 mg/ml (0.9 % w/v) solution via a Y-connector close to the injection site is possible.

7 MARKETING AUTHORISATION HOLDER

B. Braun Melsungen AG

Carl-Braun-Straße 1

34212 Melsungen, Germany

Postal address:

34209 Melsungen, Germany

Phone: +49/5661/71–0

Fax: +49/5661/71–4567

8 MARKETING AUTHORISATION NUMBER(S)

PL 03551/0113

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/06/2013