Propofol-Lipuro 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 orregional anaesthesia in adults only.

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

Propofol-Lipuro 5 mg/ml is intended for use in children, adolescents and adults, especially the painsensitive ones, because of the lower pain on injection compared to higher strengths.
Supplementary analgesic medicinal products are generally required in addition to Propofol-Lipuro 5 mg/ml.

Posology
Propofol-Lipuro 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 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 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 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 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).

 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 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 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
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 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.

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

Administration of undiluted Propofol-Lipuro 5 mg/ml

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

Infusion of diluted Propofol-Lipuro 5 mg/ml

For infusion of diluted Propofol-Lipuro 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 5 mg/ml.

The maximum dilution must not exceed 1 part of Propofol-Lipuro 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 5 mg/ml: One
part of preservative-free lidocaine injection 10 mg/ml (1 %) may be added to 40 parts of Propofol-
Lipuro 5 mg/ml.

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

 Duration of administration
Propofol-Lipuro 5 mg/ml can be administered for a maximum period of 1 hour.

Propofol-Lipuro 5 mg/ml is contraindicated in patients with a known hypersensitivity to propofol or any of the excipients. Propofol-Lipuro 5 mg/ml contains soya-bean oil and should not be used in patients who are hypersensitive to peanut or soya. Propofol-Lipuro 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

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.

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 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 postoperative
unconsciousness, which may be accompanied by an increase in muscle tone. This may or
may not be preceded by a period of wakefulness. Although recovery is spontaneous, appropriate care
of an unconscious patient should be administered.

Propofol 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.
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.

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.

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 anaesthetic 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.

Additional precautions
Propofol-Lipuro 5 mg/ml contains no antimicrobial preservatives and supports growth of microorganisms.
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.

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

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.

Pregnancy
The safety of propofol during pregnancy has not been established. 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.

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).

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.

Reporting of side effects

National Pharmacovigilance & Drug Safety Center (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222,
Exts: 2317-2356-2353-2354-2334-2340
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

By reporting side effects you can help provide more information on
the safety of this medicine.

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.201216-15064

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

Mechanism of action, pharmacodynamic effect
After intravenous injection of Propofol-Lipuro 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 developement of Propofol-Lipuro 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.

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 B-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).

Preclinical data reveal no specific 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.

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

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

2 years. After first opening: to be used immediately. After dilution according to directions: administration of dilutions must commence immediately after preparation.

Do not store above 25 ^oC.
Do not freeze.
Keep the ampoules in the outer carton in order to protect from light.

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 x 20 mlction 6.2.m

Not all pack sizes may be marketed.

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

Containers should be shaken before use.

For single use 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 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 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.