Propofol 10 Mg/Ml (1%) Emulsion For Injection/Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Propofol 10mg/ml (1%) emulsion for injection/infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml emulsion for injection/infusion contains 10 mg propofol.
Each 20 ml ampoule/vial contains 200 mg propofol.
Each 50 ml vial contains 500 mg propofol.
Each 100 ml vial contains 1000 mg propofol.
Excipients:
1 ml emulsion for injection/infusion contains 100 mg soya-bean oil, refined and 0.0018 mmol (0.04 mg) sodium.
Each 20 ml ampoule/vial contains 2 g soya-bean oil, refined and 0.036 mmol (0.8 mg) sodium.
Each 50 ml vial contains 5 g soya-bean oil, refined and 0.09 mmol (2 mg) sodium.
Each 100 ml vial contains 10 g soya-bean oil, refined and 0.18 mmol (4 mg) sodium.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Emulsion for injection/infusion.
White aqueous isotonic oil-in-water emulsion. Osmolality: 285 to 320 mOsm/Kg pH is in the range of 6.0 - 8.5
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
Propofol must only be administered 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 a patient airways, artificial ventilation, and other resuscitation facilities should be immediately available at all times.
For sedation during surgical and diagnostic procedures Propofol should not be administered by the same person conducting the surgical or diagnostic procedure.
Propofol has no analgesic properties and therefore supplementary analgesic agents are generally required in addition to Propofol.
Posology
The dose of Propofol should be individually adapted according to the patient’s response.
Rapid bolus administration (single or repeated) should not be used in older people as this may lead to cardiorespiratory depression.
General anaesthesia in adults
Induction of anaesthesia
For induction of anaesthesia Propofol must be titrated (20-40 mg propofol every 10 seconds) against the response of the patient until clinical signs show the onset of anaesthesia.
Usually an adult patient below 55 years will require 1.5 to 2.5 mg/kg body weight.
In patients over 55 years and in patients of ASA (American Society of Anaesthesiologists) classification III and IV, especially in those with impaired cardiac function the requirements will generally be less and the total dose of Propofol may be reduced to a minimum of 1 mg propofol/kg body weight. These patients also need lower rates of administration (approximately 2 ml corresponding to 20 mg propofol every 10 seconds).
Maintenance of anaesthesia
Anaesthesia can be maintained by administering Propofol either by continuous infusion or repeat bolus injections (Propofol 10 mg/ml (1%) Emulsion for Injection/Infusion only).
Continuous Infusion:
When using a continuous infusion for maintenance of anaesthesia generally doses of 4 to 12 mg/kg/h should be given. In older people, patients in unstable general conditions, patients with impaired cardiac function or hypovolaemic patients and patients of ASA grades III and IV, the dosage of Propofol may be further reduced depending on the patient’s condition and on the applied anaesthetic method.
Repeat Bolus Injection:
For maintenance of anaesthesia using repeat bolus injections dosages of 25 mg up to 50 mg (=2.5 up to 5 ml Propofol 10 mg/ml (1%) Emulsion for Injection/Infusion) should be administered depending on the clinical requirements.
Sedation of mechanically ventilated patients during intensive care
Adults and adolescents (> 16 years of age)
When used to provide sedation for mechanically ventilated patients under intensive care conditions, the administration of Propofol as continuous infusion it is recommended. The rate of administration has to be adapted to the level of sedation required.
A satisfactory level of sedation can generally be achieved with a dosage of 0.3-4.0 mg/kg body weight/h (see section 4.4).
Administering Propofol through a TCI-system for sedation in intensive care is not recommended.
It is recommended that blood lipid levels be monitored should Propofol be 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 (1%) Emulsion for Injection/Infusion contains approximately 0.1g of fat.
If the duration of sedation is in excess of 3 days, lipids should be monitored in all patients.
Sedation for diagnostic and surgical procedures in adult patients
To provide sedation during surgical and diagnostic procedures, doses and administration rates need to be adapted to the clinical response.
Most patients will require 0.5 to 1.0 mg/kg body weight over 1 to 5 minutes for induction of sedation.
For maintenance of sedation the Propofol infusion should be titrated until the desired level of sedation is achieved. Generally 1.5 to 4.5 mg/kg body weight/h will be required.
The infusion may be supplemented by bolus injections of 10 to 20 mg (1 to 2 ml Propofol 10 mg/ml (1%) Emulsion for Injection/Infusion) if a deeper level of sedation is rapidly required.
In patients older than 55 years and in patients of ASA classification III and IV the rate of administration and dosage may need to be reduced.
Paediatric population
General anaesthesia in children over 1 month of age
Propofol is not recommended for induction and maintenance of anaesthesia in paediatric patients less than one month of age (see section 4.4).
Induction of anaesthesia
For induction of anaesthesia 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 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).
Maintenance of general anaesthesia
Anaesthesia can be maintained 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 III and IV patients lower doses are recommended (see also section 4.4).
Sedation of ventilated paediatric patients during intensive care
Propofol is contraindicated in paediatric patients of 16 years of age or younger
in the indication for sedation in intensive care (see section 4.3).
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 Propofol for onset of sedation. Maintenance of sedation may be accomplished by titrating Propofol 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.
In ASA III and IV patients lower doses may be required.
Method of administration
Containers should be shaken before use. If two layers can be seen after shaking, the emulsion should not be used.
Propofol is administered intravenously as an injection or as a continuous infusion, undiluted or diluted with glucose 50 mg/ml (5%) intravenous infusion solution or sodium chloride 9 mg/ml (0.9%) intravenous infusion solution or a combination solution of glucose 40 mg/ml (4%) and sodium chloride 1.8 mg/ml (0.18%) (see section 6.6).
Prior to use, the ampoule neck and rubber stopper should be disinfected using a medicinal alcohol (spray or dipped swab). After use, any remaining contents must be discarded (see section 6.6).
Propofol does not contain antimicrobial preservatives and is capable of supporting the growth of microorganisms. The emulsion must be drawn aseptically into a sterile syringe or infusion system immediately after opening the ampoule or spiking the vial.
Administration must commence without delay. During infusion sterility of Propofol as well as the infusion system must be maintained.
Medicinal products or liquids that are added to a running Propofol infusion should be added close to the cannula.
Propofol must not be administered via infusion systems that are provided with a microbiological filter.
The contents of one vial of Propofol and any infusion equipment are intended for single use in one patient.
Any remainder must be discarded immediately after use.
Infusion of undiluted Propofol
When Propofol is administered as a continuous infusion, it is recommended that equipment such as burettes, drop counter, syringe pumps or volumetric infusion pumps should always be used to control infusion rates.
As applies to parenteral administration of all kinds of fat emulsions, the duration of use for one infusion system for a continuous infusion of Propofol must not exceed 12 hours. The infusion system and the container must be discarded and replaced after a maximum of 12 hours.
The simultaneous administration of Propofol together with an infusion solution of glucose 50 mg/ml (5%), sodium chloride 9 mg/ml (0.9%) intravenous infusion solution or a combination solution of glucose 40 mg/ml (4%) and sodium chloride 1.8 mg/ml (0.18%) close to the Y-connector near the place of injection, is possible.
Any Propofol remaining at the end of the infusion period or after changing the system needs to be discarded and destroyed.
Infusion of diluted Propofol
When Propofol is administered diluted as a continuous infusion it is recommended that equipment such as burettes, drop counter, syringe pumps or volumetric infusion pumps should always be used to control infusion rates and to prevent the accidental administration of large volumes of diluted Propofol. Propofol must not be mixed with other solutions for injection or infusion except those mentioned in section 6.6.
To reduce pain on the injection site lidocaine may be injected immediately before the use of Propofol or Propofol may be mixed, immediately prior to administration, with preservative-free lidocaine injection (see section 6.6). For the specific risks of lidocaine see sections 4.4 and 4.8.
The infusion system should be rinsed before administration of muscle relaxants like atracurium and mivacurium when using the same infusion system for Propofol.
Duration of administration
Propofol can be administered for a maximum of 7 days.
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- Propofol contains soya oil and should not be used in patients who are hypersensitive to soya or peanut
- Propofol must not be used in patients of 16 years of age or younger for sedation in intensive care (see section 4.4)
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 patent 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 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.
During induction of anaesthesia, hypotension and transient apnoea may occur depending on the dose and use of premedications and other agents.
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 (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 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 or during maintenance 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 a 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.
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 contains approximately 0.1 g of fat.
Use of Propofol is not recommended with electroconvulsive therapy.
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 20 mg/ml (2%) Emulsion for Injection/Infusion is not recommended for use in children < 3 years of age due to difficulty in titrating small volumes.
Advisory statements concerning Intensive Care Unit management
The safety and efficacy of Propofol for (background) sedation in children younger than 16 years of age have not been demonstrated. Although no causal relationship has been established, serious undesirable effects with (background) sedation in patients younger than 16 years of age (including cases with fatal outcome) have been reported during unlicensed use. In particular these effects concerned occurrence of metabolic acidosis, hyperlipidemia, rhabdomyolysis and/or cardiac failure. These effects were most frequently seen in children with respiratory tract infections who received dosages in excess of those advised in adults for sedation in the intensive care unit.
Reports have been received of combinations of the following: Metabolic acidosis, Rhabdomyolysis, Hyperkalaemia, Hepatomegaly, Renal failure, Hyperlipidaemia, Cardiac arrhythmia, Brugada-type ECG (elevated ST-segment and coved T-wave) and rapidly progressive Cardiac failure usually unresponsive to inotropic supportive treatment (in some cases with fatal outcome) in adults. Combinations of these events have been referred to as the Propofol infusion syndrome.
The following appear to be the major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents - vasoconstrictors, steroids, inotropes and/or Propofol (usually following extended dosing at dose rates greater than 4mg/kg/h).
Prescribers should be alert to these events and consider decreasing the Propofol dosage or switching to an alternative sedative at the first sign of occurrence of symptoms. All sedative and therapeutic agents used in the intensive care unit (ICU), including Propofol, 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.
This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml, i.e. essentially ‘sodium- free’.
Additional precautions
Propofol 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. Propofol must not be administered via a microbiological filter.
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.
Dilutions of Propofol 10 mg/ml (1%) emulsion for injection/infusion with lidocaine solution must not be used in patients with hereditary predisposition to acute porphyria.
4.5 Interaction with other medicinal products and other forms of interaction
Propofol can be used in combination with other active substances for anaesthesia (premedications, volatile anaesthetics, analgesics, muscle relaxants, local anaesthetics). Until now no severe interactions with these active substances have been reported. Some of these centrally acting active substances may exhibit a circulatory and respiratory depressive effect, thus leading to increased effects when used together with Propofol.
Concomitant use of benzodiazepines, parasympatholytic agents or volatile anaesthetics has been reported to prolong the anaesthesia and to reduce the respiratory rate.
When used in addition to local anaesthesia the dosage of Propofol may need to be reduced.
After additional premedication with opioids there may be a higher incidence and longer duration of apnoea.
Bradycardia and cardiac arrest may occur after treatment with suxamethonium or neostigmine.
It should be taken into consideration that concomitant use of propofol and active substances for premedication, volatile agents or analgesic agents may potentiate anaesthesia and cardiovascular side effects. Concomitant use of central nervous depressants e. g. alcohol, general anaesthetics, narcotic analgesics will result in intensification of their sedative effects.
After administration of fentanyl, the blood level of propofol may be temporarily increased with an increase in the rate of apnoea. Leucoencephalopathy has been reported with administration of lipid emulsions such as propofol in patients receiving ciclosporin.
4.6 Fertility, pregnancy and lactation
Pregnancy
The safety of as Propofol during pregnancy has not been established. Propofol should not be given to pregnant women except when absolutely necessary. Propofol crosses the placenta and can cause neonatal depression. Propofol can, however, be used during an induced abortion.
Breastfeeding
Studies of breastfeeding 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 general anaesthesia. Propofol induced impairment is not generally detectable beyond 12 hours (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 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.
Specifically, the following side effects have been observed. The frequency categories are defined as follows:
Very common Common Uncommon Rare
Very rare Not known
(>1/10)
(>1/100 to <1/10)
(>1/1,000 to <1/100)
(>1/10,000 to <1/1,000)
(<1/10,000)
(cannot be estimated from the available data)
|
Frequencies |
Very common |
Common |
Uncommon |
Rare |
Very rare |
Not known |
|
System Organ Class | ||||||
|
Immune system disorders |
anaphylaxis -may include angiooedema, bronchospasm, erythema and hypotension | |||||
|
Metabolism and nutritional disorders |
metabolic acidosis (5), hyperkalaemia (5), hyperlipidaemi a (5) | |||||
|
Psychiatric disorders |
Euphoric mood, drug abuse (8) | |||||
|
Nervous system disorders |
Excitation, headache during recovery period |
Epileptiform movements including convulsions and opisthotonus during induction, maintenance and recovery, vertigo, shivering and sensations of cold during recovery period |
Postoperative unconsciousnes s |
Involuntary movements | ||
|
Cardiac disorders |
Bradycardia (1) |
Pulmonary oedema |
Cardiac arrhythmia (5), cardiac failure (5), (7) | |||
|
Vascular disorders |
Hypotension (2) |
Thrombosis and phlebitis | ||||
|
Respiratory, thoracic and mediastinal disorders |
Hyperventilatio n transient apnoea, coughing during induction |
Coughing during maintenance |
Coughing during recoveryperiod |
|
Frequencies |
Very common |
Common |
Uncommon |
Rare |
Very rare |
Not known |
|
System Organ Class | ||||||
|
Gastrointestinal disorders |
Singultus during induction of anaesthesia, nausea and vomiting during recovery period |
Pancreatitis | ||||
|
Hepatobiliary disorders |
Hepatomegaly (5) | |||||
|
Musculoskeletal and connective tissue disorders |
Rhabdomyolys is (3), (5) | |||||
|
Renal and urinary disorders |
Discolouration of urine following prolonged administration |
Renal failure (5) | ||||
|
Reproductive system and breast |
Sexual disinhibition | |||||
|
General disorders and administration site conditions |
Local pain on induction (4) |
Hot flushes during induction |
severe tissue responses after accidental paravenous application | |||
|
Investigations |
Brugada type ECG (5), (6) | |||||
|
Injury, poisoning and procedural complications |
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.
(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 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) Drug abuse, predominantly by health care professionals.
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 (www.mhra.gov.uk/yellowcard).
4.9 Overdose
Accidental overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require 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: Anaesthetics, general; other general anaesthetics, ATC code: N01AX10
After intravenous injection of propofol, 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 or after infusion 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.
Paediatric population
Limited studies on the duration of propofol based anaesthesia in children indicate safety and efficacy is unchanged up to a 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
After intravenous administration about 98 % of propofol is bound to plasma protein.
Propofol is extensively distributed and rapidly cleared from the body (total body clearance: 1.5-2 l/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 metabolite quinol, which are excreted in urine.
During elimination the decline of blood levels is slower. The elimination halflife during the -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.
Clearance is higher in children compared with adults.
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
Non-clinical 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Soya-bean oil, refined Egg phospholipids Glycerol
Sodium hydroxide (for pH-adjustment)
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
The neuromuscular blocking agents, atracurium and mivacurium should not be given through the same infusion system as Propofol without prior flushing.
6.3 Shelf life
Shelf life before opening Ampoules/vials: 2 years
Shelf life after first opening/dilution
The mixture should be prepared aseptically immediately prior to administration and must be administered within 6 hours after preparation.
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.
Chemical and physical in-use stability of the medicinal product has been demonstrated for 24 hours at 25°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
6.4 Special precautions for storage
Store below 30°C Do not freeze
Keep the vial/ampoule in the outer carton in order to protect from light For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
20ml emulsion for injection/infusion in colourless Type I glass ampoules/vials with bromobutyl rubber stopper in pack sizes of 5 ampoules/vials.
50ml emulsion for injection/infusion in colourless Type I glass vials with bromobutyl rubber stopper in the pack size of 1 vial and 5 times 1 vial.
100ml emulsion for injection/infusion in colourless Type I glass vials with bromobutyl rubber stopper in the pack size of 1 vial.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Propofol should not be mixed prior to administration with injection or infusion fluids other than glucose 50 mg/ml (5%) intravenous infusion solution or sodium chloride 9 mg/ml (0.9%) intravenous infusion solution or a combination solution of glucose 40 mg/ml (4%) and sodium chloride 1.8 mg/ml (0.18%).
The maximum dilution must not exceed 1 part of Propofol and 4 parts of the above mentioned intravenous infusion solution (at least 2 mg/ml ). The mixture should be prepared aseptically immediately prior to administration and must be administered within 6 hours after preparation.
Further Propofol may be mixed, immediately prior to administration, with preservative-free lidocaine injection (20 parts Propofol with up to one part of 1% lidocaine injection solution).
The simultaneous administration of Propofol together with an intravenous infusion solution of glucose 50 mg/ml (5%) or sodium chloride 9 mg/ml (0.9%) intravenous infusion solution or a combination solution of glucose 40 mg/ml (4%) and sodium chloride 1.8 mg/ml (0.18%) close to the Y-connector near the place of injection, is possible.
For single use only.
Parenteral products should be inspected visually for particulate matter prior to administration. If particulate matter is evident emulsion should not be used.
Containers should be shaken before use. If two layers can be seen after shaking, the emulsion should not be used.
Prior to use, the ampoule neck and rubber stopper should be disinfected using a medicinal alcohol (spray or dipped swab).
Any remaining contents after use should be discarded.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Sandoz Limited
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 04416/1316
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/06/2012
10 DATE OF REVISION OF THE TEXT
03/11/2014