DIPRIVAN 10 MG/ML (1%) EMULSION FOR INJECTION OR INFUSION

Active substance: PROPOFOL

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4. Possible side effects

Like all medicines, Diprivan may cause side effects although
not everybody gets them.
Side effects that can happen during anaesthesia
The following side effects can happen during anaesthesia
(while the injection is being given to you or when you are
sleepy or asleep). Your doctor will be looking out for these. If
they happen, your doctor will give you appropriate treatment.
Very common (affects more than 1 in 10 people)
• A feeling of pain at the site of the injection (while the
injection is being given, before you fall asleep).

Common (affects less than 1 in 10 people)
• Low blood pressure.
• Changes in your breathing pattern.
• Slow heart beat.

Rare (affects less than 1 in 1,000 people)
• Twitching and shaking of your body, or a fit (may also
happen when you wake up).
• Unusual colour of urine (may also happen when you
wake up).

Very rare (affects less than 1 in 10,000 people)
• Allergic reactions.
• Stopping of your heart beat.
• Build up of fluid in the lungs which can make you very
breathless (may also happen when you wake up).
Side effects that can happen after anaesthesia
The following side effects can happen after anaesthesia
(when you are waking up or after you have woken up).
Common (affects less than 1 in 10 people)
• Feeling sick (nausea).
• Being sick (vomiting).
• Headache.

Uncommon (affects less than 1 in 100 people)
• Swelling and redness along a vein or blood clots.

Very rare (affects less than 1 in 10,000 people)
• Feeling sexually aroused.
• High temperature (fever).
• Redness or soreness where the injection was given.
• Being unconscious after the operation. (When this has
happened, the patients have recovered without problems.)
Other possible side effects
The following side effects have been seen when Diprivan is
used in intensive care at higher doses than recommended.

Very rare (affects less than 1 in 10,000 people)
• Heart failure.
• Inflamed pancreas (pancreatitis) which causes severe
stomach pain.
• Too much acid in your blood. This may make you breathe
more quickly.
• Increased amount of potassium in your blood.
• High blood level of a type of fat called lipids.
• Abnormal heart beat.
• Enlargement of the liver.
• Kidney failure.
The following side effects have been seen in children in
intensive care when Diprivan has been stopped suddenly.

Common (affects less than 1 in 10 people)
• ‘Withdrawal symptoms’. These include unusual behaviour,
sweating, shaking and feeling anxious.
• Flushing of the skin.
Do not be concerned by this list of possible side effects. You
may not get any of them.

P032400-2 Leaflet.indd 1

Side effects of unknown frequency may include
• Euphoric mood.
• Involuntary movements.
• Drug abuse, mostly by healthcare professionals.
• Abnormal ECG.
• Breakdown of muscle cells (rhabdomyolysis).
If you think you have a side effect or if you notice any side
effects not listed in this leaflet, please tell your doctor or nurse.

Table of Adverse Drug Reactions
System Organ Class
Frequency
Immune system disorders:
Very rare
(<1/10 000)

Metabolism and Nutritional
disorder:

Frequency not known (9)

Psychiatric disorders:
Nervous system disorders:

5. How to store Diprivan

Frequency not known (9)
Common
(>1/100, <1/10)
Rare
(>1/10 000, <1/1000)

6. Further information

Very rare
(<1/10 000)
Frequency not known (9)
Common
(>1/100, <1/10)
Very rare
(<1/10 000)
Frequency not known (9)

• The doctor and hospital pharmacist are responsible for
storing, using and disposing of Diprivan correctly.
• Store Diprivan between 2°C and 25°C. Do not freeze.
• Do not use Diprivan after the expiry date which is stated on
the carton.

Cardiac disorders:

What Diprivan 1% contains
The active substance is propofol. There is 10 mg of propofol in
each millilitre.
The other ingredients are glycerol, purified egg phosphatide,
sodium hydroxide, soya bean oil, water for injections, nitrogen
and disodium edetate.

Vascular disorders:

Respiratory, thoracic and
mediastinal disorders:
Gastrointestinal disorders:

What Diprivan 1% looks like and contents of the pack
Diprivan 1% is a milky, white liquid. It comes in glass ampoules
of 20 ml, glass vials of 50 ml or 100 ml, or pre-filled syringes of
20 ml or 50 ml.
Marketing Authorisation Holder and Manufacturer
The Marketing Authorisation for Diprivan 1% is held by
AstraZeneca UK Ltd, 600 Capability Green, Luton, LU1 3LU, UK.
Diprivan 1% is manufactured by AstraZeneca UK Ltd,
Silk Road Business Park, Macclesfield, Cheshire,
SK10 2NA, UK.

To listen to or request a copy of this leaflet
in Braille, large print or audio please call,
free of charge:
0800 198 5000 (UK only)
Please be ready to give the following
information:
Product name
Diprivan 1%
Reference number
17901/0007
This is a service provided by the Royal
National Institute of the Blind.

Leaflet prepared: January 2012

Diprivan is a trade mark of the AstraZeneca group of companies.
© AstraZeneca 2012
UK PAI 11 0053a



Common
(>1/100, <1/10)
Uncommon
(>1/1000, <1/100)
Common
(>1/100, <1/10)
Common
(>1/100, <1/10)
Very rare
(<1/10 000)
Frequency not known (9)
Frequency not known (9)

Undesirable Effects
Anaphylaxis – may include
angioedema, bronchospasm,
erythema and hypotension
Metabolic acidosis (5),
hyperkalaemia (5),
hyperlipidaemia (5)
Euphoric mood, drug abuse(8)
Headache during recovery
phase
Epileptiform movements,
including convulsions and
opisthotonus during induction,
maintenance and recovery
Postoperative unconsciousness
Involuntary movements
Bradycardia (1)

Cardiac arrhythmia (5), cardiac
failure (5), (7)
Hypotension (2)
Thrombosis and phlebitis
Transient apnoea during
induction
Nausea and vomiting during
recovery phase
Pancreatitis

Hepatobiliary disorders
Hepatomegaly (5)
Musculoskeletal and
Rhabdomyolysis (3), (5)
connective tissue disorders:
Renal and urinary disorders Very rare
Discolouration of urine following
(<1/10 000)
prolonged administration
Frequency not known (9)
Renal failure(5)
Reproductive system and
Very rare
Sexual disinhibition
breast
(<1/10 000)
General disorders and
Very common
Local pain on induction (4)
administration site
(>1/10)
conditions:
Investigations
Frequency not known (9)
Brugada type ECG (5), (6)
Injury, poisoning and
Very rare
Postoperative fever
procedural complications:
(<1/10 000)
(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 Diprivan.
(3)
Very rare reports of rhabdomyolysis have been received where Diprivan 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
Diprivan 1% 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.
(9)
Not known as it cannot be estimated from the available clinical trial data.

Dystonia/dyskinesia have been reported.

4.9 Overdose

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










5.2


Pulmonary oedema

Local

The local pain which may occur during the induction phase of Diprivan 1%
anaesthesia can be minimised by the co-administration of lidocaine (see Dosage
and Administration) and by the use of the larger veins of the forearm and
antecubital fossa. Thrombosis and phlebitis are rare. Accidental clinical
extravasation and animal studies showed minimal tissue reaction. Intra-arterial
injection in animals did not induce local tissue effects.

5.
5.1




Pharmacological Properties
Pharmacodynamic properties
Propofol (2, 6-diisopropylphenol) is a short-acting general anaesthetic agent with
a rapid onset of action of approximately 30 seconds. Recovery from anaesthesia
is usually rapid. The mechanism of action, like all general anaesthetics, is poorly
understood. However, propofol is thought to produce its sedative/anaesthetic
effects by the positive modulation of the inhibitory function of the neurotransmitter
GABA through the ligand-gated GABAA receptors.
In general, falls in mean arterial blood pressure and slight changes in heart rate
are observed when Diprivan 1% is administered for induction and maintenance of
anaesthesia. However, the haemodynamic parameters normally remain relatively
stable during maintenance and the incidence of untoward haemodynamic changes
is low.
Although ventilatory depression can occur following administration of Diprivan 1%,
any effects are qualitatively similar to those of other intravenous anaesthetic
agents and are readily manageable in clinical practice.









5.3

6.
6.1








Diprivan 1% reduces cerebral blood flow, intracranial pressure and cerebral
metabolism. The reduction in intracranial pressure is greater in patients with an
elevated baseline intracranial pressure.
Recovery from anaesthesia is usually rapid and clear headed with a low incidence
of headache and postoperative nausea and vomiting.
In general, there is less postoperative nausea and vomiting following anaesthesia
with Diprivan 1% than following anaesthesia with inhalational agents. There is
evidence that this may be related to a reduced emetic potential of propofol.
Diprivan 1%, at the concentrations likely to occur clinically, does not inhibit the
synthesis of adrenocortical hormones.
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.

Pharmacokinetic properties
The decline in propofol concentrations following a bolus dose or following the
termination of an infusion can be described by a three compartment open model
with very rapid distribution (half-life 2–4 minutes), rapid elimination
(half-life 30–60 minutes), and a slower final phase, representative of redistribution
of propofol from poorly perfused tissue.
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.
When Diprivan 1% is used to maintain anaesthesia, blood concentrations
asymptotically approach the steady-state value for the given administration rate.
The pharmacokinetics are linear over the recommended range of infusion rates of
Diprivan 1%.
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 safety data
Propofol is a drug on which extensive clinical experience has been obtained. All
relevant information for the prescriber is provided elsewhere in the Summary of
Product Characteristics.
Pharmaceutical Particulars
List of excipients
Glycerol Ph. Eur
Purified egg phosphatide
Sodium Hydroxide Ph. Eur
Soya bean oil, Refined Ph. Eur
Water for injections Ph. Eur
Nitrogen Ph. Eur
Disodium Edetate Ph. Eur

6.2 Incompatibilities

The neuromuscular blocking agents, atracurium and mivacurium should not be
given through the same intravenous line as Diprivan 1% without prior flushing.
6.3 Shelf life
6.3.1 Shelf life of the product as packaged for sale

Ampoules

3 years

Vials

3 years

Pre-filled syringe

2 years

6.3.2 Shelf life after dilution

Use of diluted Diprivan must begin immediately following dilution.
6.4


6.5



6.6



7.








Special precautions for storage
Store between 2°C and 25°C.
Do not freeze.

Nature and contents of container
a) Clear neutral glass ampoules of 20 ml in boxes of 5
b) Clear neutral glass vials of 50 ml and 100 ml
c) Type 1 glass pre-filled syringe of 50 ml

Instructions for use and handling
In-use precautions: Containers should be shaken before use.
Any portion of the contents remaining after use should be discarded.
Diprivan 1% should not be mixed prior to administration with injections or
infusion fluids other than 5% Dextrose or Lidocaine Injection (see Section 4.2.5).
Marketing Authorisation Holder
AstraZeneca UK Limited,
600 Capability Green,
Luton, LU1 3LU, UK.
Leaflet updated: January 2012
© AstraZeneca 2012
Diprivan is a trade mark of the AstraZeneca group of companies.
PAI 11 0053a

P032400

Medical Information Leaflet

Diprivan 1%

(Issued to the Medical Professions Only)
1.


Trade Name of the Medicinal Product
Diprivan 10 mg/ml (1%) emulsion for injection or infusion

2.


Qualitative and Quantitative Composition
Propofol 10 mg/ml

3.



Pharmaceutical Form
Emulsion for injection or infusion.
White aqueous isotonic oil-in-water emulsion.

4.
4.1


Clinical Particulars
Therapeutic indications
Diprivan 1% 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
For specific guidance relating to the administration of Diprivan 1% with a target
controlled infusion (TCI) device, which incorporates Diprifusor TCI software,
(see Section 4.2.5). Such use is restricted to induction and maintenance of
anaesthesia in adults. The Diprifusor TCI system is not recommended for use in
ICU sedation or sedation for surgical and diagnostic procedures, or in children.

4.2.1 Induction of general anaesthesia
Adults
In unpremedicated and premedicated patients, it is recommended that Diprivan 1%

should be titrated (approximately 4 ml [40 mg] every 10 seconds in an average
healthy adult by bolus injection or infusion) against the response of the patient until
the clinical signs show the onset of anaesthesia. Most adult patients aged less than
55 years are likely to require 1.5–2.5 mg/kg of Diprivan 1%. The total dose required
can be reduced by lower rates of administration (2–5 ml/min [20–50 mg/min]). Over
this age, the requirement will generally be less. In patients of ASA Grades 3 and 4,
lower rates of administration should be used (approximately 2 ml [20 mg] every
10 seconds).



Elderly patients
In elderly patients the dose requirement for induction of anaesthesia with
Diprivan 1% is reduced. The reduction should take into account the physical
status and age of the patient. The reduced dose should be given at a slower rate
and titrated against the response.

Children

Diprivan 1% is not recommended for induction of anaesthesia in children aged
less than 1 month.

For induction of anaesthesia in children over 1 month of age, Diprivan 1% 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 of Diprivan 1% for induction
of anaesthesia. In younger children, especially between the age of 1 month and
3 years, dose requirements may be higher (2.5–4 mg/kg body weight).
For ASA 3 and 4 patients lower doses are recommended (see also Section 4.4).


Administration of Diprivan 1% by a Diprifusor TCI system is not recommended
for induction of general anaesthesia in children.
4.2.2 Maintenance of general anaesthesia
Adults
Anaesthesia can be maintained by administering Diprivan 1% either by continuous

infusion or by repeat bolus injections to prevent the clinical signs of light anaesthesia.
Recovery from anaesthesia is typically rapid and it is therefore important to
maintain Diprivan 1% administration until the end of the procedure.








Continuous infusion
The required rate of administration varies considerably between patients, but
rates in the region of 4–12 mg/kg/h usually maintain satisfactory anaesthesia.

Repeat bolus injections
If a technique involving repeat bolus injections is used, increments of 25 mg (2.5 ml)
to 50 mg (5 ml) may be given according to clinical need.
Elderly patients
When Diprivan 1% is used for maintenance of anaesthesia the rate of infusion
or ‘target concentration’ should also be reduced. Patients of ASA grades 3 and 4
will require further reductions in dose and dose rate. Rapid bolus administration
(single or repeated) should not be used in the elderly as this may lead to
cardiorespiratory depression.

Children

Diprivan 1% is not recommended for maintenance of anaesthesia in children
aged less than 1 month. Anaesthesia can be maintained in children over 1 month
of age by administering Diprivan 1% 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 3 and 4 patients lower doses are recommended (see also Section 4.4).
Administration of Diprivan 1% by a Diprifusor TCI system is not recommended for
maintenance of general anaesthesia in children.

4.2.3 Sedation during intensive care
Adults

For sedation during intensive care it is advised that Diprivan 1% should be
administered by continuous infusion. The infusion rate should be determined by
the desired depth of sedation. In most patients sufficient sedation can be obtained
with a dosage of 0.3–4 mg/kg/h of Diprivan 1% (see 4.4 Special warnings and
special precautions for use). Diprivan 1% is not indicated for sedation in intensive
care of patients of 16 years of age or younger (see 4.3 Contraindications).
Administration of Diprivan 1% by Diprifusor TCI system is not advised for sedation
in the intensive care unit.

Diprivan 1% may be diluted with 5% Dextrose (see Dilution and Co-administration
table below).

It is recommended that blood lipid levels be monitored should Diprivan 1%
be administered to patients thought to be at particular risk of fat overload.
Administration of Diprivan 1% 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
Diprivan 1% formulation; 1 ml of Diprivan 1% contains approximately 0.1 g of fat.

If the duration of sedation is in excess of 3 days, lipids should be monitored in all
patients.



Elderly patients
When Diprivan 1% is used for sedation the rate of infusion should also be
reduced. Patients of ASA grades 3 and 4 will require further reductions in dose
and dose rate. Rapid bolus administration (single or repeated) should not be used
in the elderly as this may lead to cardiorespiratory depression.

Children

Diprivan 1% is contraindicated for the sedation of ventilated children aged
16 years or younger receiving intensive care.

4.2.4 Sedation for surgical and diagnostic procedures
Adults

To provide sedation for surgical and diagnostic procedures, rates of
administration should be individualised and titrated to clinical response.

Most patients will require 0.5–1 mg/kg over 1–5 minutes for onset of sedation.

Maintenance of sedation may be accomplished by titrating Diprivan 1% infusion
to the desired level of sedation – most patients will require 1.5–4.5 mg/kg/h. In
addition to the infusion, bolus administration of 10–20 mg may be used if a rapid
increase in the depth of sedation is required. In patients of ASA Grades 3 and 4
the rate of administration and dosage may need to be reduced.

11/01/2012 12:33



Administration of Diprivan 1% by a Diprifusor TCI system is not recommended
for sedation for surgical and diagnostic procedures.




Elderly patients
When Diprivan 1% is used for sedation the rate of infusion or ‘target concentration’
should also be reduced. Patients of ASA grades 3 and 4 will require further
reductions in dose and dose rate. Rapid bolus administration (single or repeated)
should not be used in the elderly as this may lead to cardiorespiratory depression.

Children

Diprivan 1% is not recommended for surgical and diagnostic procedures in
children aged less than 1 month.






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 Diprivan 1% for onset of
sedation.
Maintenance of sedation may be accomplished by titrating Diprivan 1% infusion
to the desired level of sedation. Most patients require 1.5–9 mg/kg/h Diprivan 1%.
The infusion may be supplemented by bolus administration of up to 1 mg/kg body
weight if a rapid increase of depth of sedation is required.
























The Diprifusor TCI system assumes that the initial blood propofol concentration in
the patient is zero. Therefore, in patients who have received prior propofol, there
may be a need to select a lower initial target concentration when commencing
Diprifusor TCI. Similarly, the immediate recommencement of Diprifusor TCI is not
recommended if the pump has been switched off.
Guidance on propofol target concentrations is given below. In view of interpatient
variability in propofol pharmacokinetics and pharmacodynamics, in both
premedicated and unpremedicated patients the target propofol concentration
should be titrated against the response of the patient in order to achieve the depth
of anaesthesia required.






Induction and maintenance of general anaesthesia
In adult patients under 55 years of age anaesthesia can usually be induced
with target propofol concentrations in the region of 4–8 microgram/ml. An initial
target of 4 microgram/ml is recommended in premedicated patients and in
unpremedicated patients an initial target of 6 microgram/ml is advised. Induction
time with these targets is generally within the range of 60–120 seconds. Higher
targets will allow more rapid induction of anaesthesia but may be associated with
more pronounced haemodynamic and respiratory depression.
A lower initial target concentration should be used in patients over the age of
about 55 years and in patients of ASA grades 3 and 4. The target concentration
can then be increased in steps of 0.5–1 microgram/ml at intervals of 1 minute to
achieve a gradual induction of anaesthesia.
Supplementary analgesia will generally be required and the extent to which
target concentrations for maintenance of anaesthesia can be reduced will be
influenced by the amount of concomitant analgesia administered. Target propofol
concentrations in the region of 3–6 microgram/ml usually maintain satisfactory
anaesthesia.
The predicted propofol concentration on waking is generally in the region of
1–2 microgram/ml and will be influenced by the amount of analgesia given during
maintenance.



In ASA 3 and 4 patients lower doses may be required.

4.2.5 Administration

Diprivan 1% has no analgesic properties and therefore supplementary analgesic
agents are generally required in addition to Diprivan 1%.




Diprivan 1% can be used for infusion undiluted from glass containers, plastic
syringes or Diprivan 1% pre-filled syringes or diluted with 5% Dextrose
(Intravenous Infusion BP) only, in PVC infusion bags or glass infusion bottles.
Dilutions, which must not exceed 1 in 5 (2 mg propofol per ml) should be prepared
aseptically immediately before administration and must be used within 6 hours of
preparation.
It is recommended that, when using diluted Diprivan 1%, the volume of
5% Dextrose removed from the infusion bag during the dilution process is totally
replaced in volume by Diprivan 1% emulsion (see Dilution and co-administration
table below).







Dilution and co-administration of Diprivan 1% with other drugs or infusion fluids (see also
Additional precautions section)
Co-administration
Additive or Diluent Preparation
Precautions
Technique
Pre-mixing
Dextrose 5%
Mix 1 part of Diprivan 1%
Prepare aseptically
intravenous
with up to 4 parts of
immediately before
infusion
dextrose 5% intravenous
administration. The
infusion in either PVC
mixture is stable for up
infusion bags or glass
to 6 hours
infusion bottles. When
diluted in PVC bags it is
recommended that the bag
should be full and that the
dilution be prepared by
withdrawing a volume of
infusion fluid and replacing
it with an equal volume of
Diprivan 1%
Lidocaine
Mix 20 parts of Diprivan 1% Prepare mixture
aseptically immediately
hydrochloride
with up to 1 part of either
prior to administration.
injection (0.5%
0.5% or 1% lidocaine
Use for induction only
or 1% without
hydrochloride injection
preservatives)
Alfentanil injection
Mix Diprivan 1% with
Prepare mixture
(500 microgram/ml) alfentanil injection in a ratio aseptically; use within
of 20:1 to 50:1 v/v
6 hours of preparation
Co-administration via Dextrose 5%
Co-administer via a
Place the Y-piece
a Y-piece connector
intravenous infusion Y-piece connector
connector close to the
injection site
Sodium chloride
As above
As above
0.9% intravenous
infusion
Dextrose 4% with
As above
As above
sodium chloride
0.18% intravenous
infusion

The dilution may be used with a variety of infusion control techniques, but a giving
set used alone will not avoid the risk of accidental uncontrolled infusion of large
volumes of diluted Diprivan 1%. A burette, drop counter or volumetric pump must
be included in the infusion line. The risk of uncontrolled infusion must be taken
into account when deciding the maximum amount of Diprivan 1% in the burette.
When Diprivan 1% is used undiluted to maintain anaesthesia, it is recommended
that equipment such as syringe pumps or volumetric infusion pumps should
always be used to control infusion rates.
Diprivan 1% may be administered via a Y-piece close to the injection site into
infusions of the following:
• Dextrose 5% Intravenous Infusion B.P.
• Sodium Chloride 0.9% Intravenous Infusion B.P.
• Dextrose 4% with Sodium Chloride 0.18% Intravenous Infusion B.P.

The glass pre-filled syringe (PFS) has a lower frictional resistance than plastic
disposable syringes and operates more easily. Therefore, if Diprivan 1% is
administered using a hand held pre-filled syringe, the line between the syringe
and the patient must not be left open if unattended.

When the pre-filled syringe presentation is used in a syringe pump appropriate
compatibility should be ensured. In particular, the pump should be designed to
prevent siphoning and should have an occlusion alarm set no greater than
1000 mm Hg. If using a programmable or equivalent pump that offers options for
use of different syringes then choose only the B-D 50/60 ml PLASTIPAK setting
when using the Diprivan 1% pre-filled syringe.

Diprivan 1% may be premixed with alfentanil injection containing 500 microgram/ml
alfentanil in the ratio of 20:1 to 50:1 v/v. Mixtures should be prepared using sterile
technique and used within 6 hours of preparation.
In order to reduce pain on initial injection, Diprivan 1% may be mixed with
preservative-free Lidocaine Injection 0.5% or 1% (see Dilution and
Co-administration table below).

Target Controlled Infusion – Administration of Diprivan 1% by a Diprifusor
TCI System in adults
Administration of Diprivan 1% by a Diprifusor TCI system is restricted to induction
and maintenance of general anaesthesia in adults. It is not recommended for use
in ICU sedation or sedation for surgical and diagnostic procedures, or in children.
Diprivan 1% may be administered by TCI only with a Diprifusor TCI system
incorporating Diprifusor TCI software. Such systems will operate only on
recognition of electronically tagged pre-filled syringes containing Diprivan 1% or
2% Injection. The Diprifusor TCI system will automatically adjust the infusion rate
for the concentration of Diprivan recognised. Users must be familiar with the
infusion pump users’ manual, and with the administration of Diprivan 1% by TCI
and with the correct use of the syringe identification system.

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

P032400-2 Leaflet.indd 2

Sedation during intensive care
Target blood propofol concentration settings in the range of 0.2–2 microgram/ml
will generally be required. Administration should begin at low target setting which
should be titrated against the response of the patient to achieve the depth of
sedation desired.

4.3 Contraindications

Diprivan is contraindicated in patients with a known hypersensitivity to propofol or
any of the excipients.

Diprivan 1% must not be used in patients of 16 years of age or younger for
sedation in intensive care (see 4.4 Special warnings and precautions for use).

Diprivan 1% contains soya oil and should not be used in patients who are
hypersensitive to peanut or soya.
4.4





Special warnings and precautions for use
Diprivan 1% 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. Diprivan 1% should not be administered
by the person conducting the diagnostic or surgical procedure.
The abuse of Diprivan 1%, predominantly by health care professionals, has been
reported. As with other general anaesthetics, the administration of Diprivan 1%
without airway care may result in fatal respiratory complications.






























When Diprivan 1% 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.
As with other sedative agents, when Diprivan 1% 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 Diprivan 1%. Very rarely the use of Diprivan 1% 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.
Diprivan 1% induced impairment is not generally detectable beyond 12 hours.
The effects of Diprivan 1%, 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. Diprivan 1% clearance is blood flow dependent, therefore,
concomitant medication that reduces cardiac output will also reduce Diprivan 1%
clearance.
Diprivan 1% 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 Diprivan 1% is used in conjunction with other
agents likely to cause a bradycardia.
As with other intravenous anaesthetic and sedative agents, patients should be
instructed to avoid alcohol before and for at least 8 hours after administration of
Diprivan 1%.
During bolus administration for operative procedures, extreme caution should be
exercised in patients with acute pulmonary insufficiency or respiratory depression.
Concomitant use of central nervous system depressants eg., alcohol, general
anaesthetics, narcotic analgesics, will result in accentuation of their sedative effects.
When Diprivan 1% is combined with centrally depressant drugs administered
parenterally, severe respiratory and cardiovascular depression may occur. It is
recommended that Diprivan 1% is administered following the analgesic and the
dose should be carefully titrated to the patient’s response (see Section 4.5).
During induction of anaesthesia, hypotension and transient apnoea may occur
depending on the dose and use of premedicants and other agents.
Occasionally, hypotension may require use of intravenous fluids and reduction
of the rate of administration of Diprivan 1% during the period of anaesthetic
maintenance.
When Diprivan 1% 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 (see section 4.2).
It is recommended that blood lipid levels should be monitored if Diprivan 1% 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
Diprivan 1% formulation; 1.0 mL of Diprivan contains approximately 0.1 g of fat.
Use is not recommended with electroconvulsive treatment.
As with other anaesthetics, sexual disinhibition may occur during recovery.
The use of Diprivan 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.
Diprivan 2% 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 Diprivan 1% 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.
















4.5




4.6





4.7



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 Diprivan 1% (usually following
extended dosing at dose rates greater than 4mg/kg/h).

Prescribers should be alert to these events and consider decreasing the
Diprivan 1% 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 Diprivan 1%, 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.
Diprivan 1% contains 0.0018 mmol sodium per ml.

Additional precautions
Diprivan 1% contains no antimicrobial preservatives and supports growth of
micro-organisms.

EDTA chelates metal ions, including zinc, and reduces microbial growth rates.
The need for supplemental zinc should be considered during prolonged
administration of Diprivan 1%, particularly in patients who are predisposed to zinc
deficiency, such as those with burns, diarrhoea and/or major sepsis.
When Diprivan 1% 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 Diprivan 1% and infusion equipment throughout the infusion period. Any
infusion fluids added to the Diprivan 1% line must be administered close to the
cannula site. Diprivan 1% must not be administered via a microbiological filter.

Diprivan 1% and any syringe containing Diprivan 1% are for single use in an
individual patient. In accordance with established guidelines for other lipid
emulsions, a single infusion of Diprivan 1% must not exceed 12 hours. At the
end of the procedure or at 12 hours, whichever is the sooner, both the reservoir of
Diprivan 1% and the infusion line must be discarded and replaced as appropriate.
Interaction with other medicinal products and other forms of interaction
Diprivan 1% 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 Diprivan 1% may be required where general
anaesthesia is used as an adjunct to regional anaesthetic techniques.
The concurrent administration of other CNS depressants such as pre-medication
drugs, inhalation agents, analgesic agents may add to the sedative, anaesthetic
and cardiorespiratory depressant effects of Diprivan 1% (see Section 4.4).

Pregnancy and lactation
Pregnancy The safety of Diprivan 1% during pregnancy has not been established.
Diprivan 1% should not be given to pregnant women except when absolutely
necessary. Diprivan 1% can, however, be used during an induced abortion.
Obstetrics Diprivan 1% crosses the placenta and can cause neonatal depression.
It should not be used for obstetric anaesthesia unless clearly necessary.
Lactation
Studies of breastfeeding mothers showed that small quantities of Diprivan 1%
are excreted in human milk. Women should therefore not breastfeed for 24 hours
after administration of Diprivan 1%. Milk produced during this period should be
discarded.
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.
Diprivan 1% induced impairment is not generally detectable beyond 12 hours
(Section 4.4).

4.8 Undesirable effects
General


Induction and maintenance of anaesthesia or sedation 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 Diprivan 1% may be related to the condition of the recipients
and the operative or therapeutic procedures being undertaken.

For further copies of this leaflet, visit emc.medicines.org.uk or call AstraZeneca on 01582 836836.
PACKAGE LEAFLET: INFORMATION FOR THE USER

Diprivan 10 mg/ml (1%)
Emulsion for Injection or Infusion
propofol

Read all of this leaflet carefully before you start having this
medicine.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• If you think you have a side effect, or if you notice any side
effects not listed in this leaflet, please tell your doctor or nurse.

• Your body has lost lots of water (you are dehydrated).
• You have any other health problems, such as problems with
your heart, breathing, kidneys or liver.
• You have been generally unwell for some time.
If you are not sure if any of the above apply to you, talk to your
doctor or nurse before having Diprivan.

In this leaflet:
1. What Diprivan is and what it is used for
2. Before you have Diprivan
3. How to have Diprivan
4. Possible side effects
5. How to store Diprivan
6. Further information

Taking other medicines
Tell your doctor if you are taking or have recently taken any
other medicines. This includes medicines that you buy without
a prescription and herbal medicines.

1. What Diprivan is and what it is used for
Diprivan contains a medicine called propofol. This belongs to
a group of medicines called ‘general anaesthetics’. General
anaesthetics are used to cause unconsciousness (sleep) so
that surgical operations or other procedures can be performed.
They can also be used to sedate you (so that you are sleepy
but not completely asleep).
Diprivan will be given to you as an injection by a doctor.

In adults and children over 1 month of age it is used to:
• Help put you to sleep before an operation or other procedure.
• Keep you asleep during an operation or other procedure.
• Sedate you during diagnostic and surgical procedures,
alone or in combination with local or regional anaesthesia.
In people over 16 years of age it is also used to:
• Sedate you when receiving artificial respiration in an
Intensive Care Unit (ICU).
2. Before you have Diprivan
Do not have Diprivan if:
• You are allergic (hypersensitive) to propofol or any of the
other ingredients of Diprivan (listed in Section 6: Further
information).
• You are allergic to peanut or soya. This is because Diprivan
contains soya oil.
• You are pregnant (see the section called ‘Pregnancy and
breast-feeding’).
• You are 16 years of age or younger for sedation in
intensive care.
If any of the above apply to you, do not have Diprivan and tell
your doctor, anaesthetist or nurse. If you are not sure, talk to
one of these people before having Diprivan.

Take special care with Diprivan
The use of Diprivan is not recommended in newborn infants.
Before you have this medicine, tell your doctor, anaesthetist or
nurse if:
• You have ever had a fit or convulsion.
• You have ever been told that you have very high levels of
fat in your blood.
• You have ever been told that your body has problems
using fat.

Pregnancy and breast-feeding
• Do not have Diprivan if you are pregnant.
• If you are trying to get pregnant or if you are breast-feeding,
talk to your doctor or nurse before having this medicine.
Driving and using machines
After having Diprivan, you may still feel sleepy for some time.
Do not drive or use any tools or machines until you are sure the
effects have worn off.
• If you are able to go home shortly after having Diprivan, do
not drive a car or use any tools or machines.
• Ask your doctor when you can start doing these activities
again and when you can go back to work.
Important information about some of the ingredients of
Diprivan
Diprivan contains sodium. If you are on a sodium controlled
diet, you will need to take this into account.
Diprivan contains soya oil. If you are allergic to peanut or soya,
do not use this medicine.
Diprivan contains disodium edetate. During prolonged use of
Diprivan for intensive care, you may need to be given a zinc
(a mineral) supplement.
3. How to have Diprivan
You will be given Diprivan by a doctor. It will be given to you as
an injection into a vein. This is usually in the back of your hand
or in your forearm.
• The doctor will give you the injection using a needle or
through a fine plastic tube called a ‘cannula’.
• The doctor can also use an electric pump to control how fast
the injection is given. This may be done if you are having a
long operation or if you are in an Intensive Care Unit.
The dose of Diprivan varies from one patient to another. The
amount of Diprivan that you need depends on your age, size,
physical fitness and the level of sleepiness or sleep that you
need. The doctor will give you the correct dose to start and
to sustain anaesthesia or to achieve the required level of
sedation, by carefully watching your responses and vital signs
(pulse, blood pressure, breathing etc.).
You may need several different medicines to keep you asleep
or sleepy, free from pain, breathing in a healthy way and to
keep your blood pressure steady. The doctor will decide which
medicines you need and when you need them.
P032400

11/01/2012 12:33

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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