Global Prescribing Information and International Prescribing
Notes
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4 . CLINICAL PARTICULARS
5. PHARMACOLOGICAL PROPERTIES
6. PHARMACEUTICAL PARTICULARS
Please consult full local prescribing information before using
Diprivan or Diprifusor.
1. NAME OF THE MEDICINAL PRODUCT
DIPRIVAN® Injection (1% & 2%)
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2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Propofol 10 mg/ml (DIPRIVAN 1%) or 20 mg/ml (DIPRIVAN 2%)
For excipients, see Section 6.1 List of excipients
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3. PHARMACEUTICAL FORM
White aqueous isotonic oil-in-water emulsion for iv injection
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4.CLINICAL PARTICULARS
4.1 Therapeutic indications
DIPRIVAN is a short-acting intravenous anaesthetic agent suitable
for induction and maintenance of general anaesthesia.
DIPRIVAN may be used for sedation of ventilated patients receiving
intensive care.
DIPRIVAN may be used for conscious sedation for surgical and
diagnostic procedures.
4.2 Posology and method of administration
Supplementary analgesic agents are generally required in addition
to DIPRIVAN.
DIPRIVAN has been used in association with spinal and epidural
anaesthesia and with commonly used premedicants, neuromuscular
blocking drugs, inhalation agents and analgesic agents; no pharmacological
incompatibility has been encountered. Lower doses of DIPRIVAN
may be required where general anaesthesia is used as an adjunct
to regional anaesthetic techniques.
For specific guidance relating to the administration of DIPRIVAN
using the DIPRIFUSOR target controlled infusion (TCI) system,
which incorporates DIPRIFUSOR TCI software, see section E. Such
use is restricted to induction and maintenance of anaesthesia,
conscious sedation for surgical and diagnostic procedures and
for the sedation of ventilated adult patients receiving intensive
care. The DIPRIFUSOR TCI system is not recommended for use in
children.
A ADULTS
Induction of General Anaesthesia
DIPRIVAN 1% may be used to induce anaesthesia by slow bolus
injection or infusion.
DIPRIVAN 2% should be used to induce anaesthesia by infusion
and only in those patients who will receive DIPRIVAN 2% for
maintenance of anaesthesia.
In unpremedicated and premedicated patients, it is recommended
that DIPRIVAN should be titrated (approximately 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 to 2.5 mg/kg of DIPRIVAN. The total dose required can be
reduced by lower rates of administration (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 20 mg every 10 seconds).
MAINTENANCE OF GENERAL ANAESTHESIA
Anaesthesia can be maintained by administering DIPRIVAN either
by continuous infusion or by repeat bolus injections to maintain
the depth of anaesthesia required.
Continuous Infusion: DIPRIVAN 1% or DIPRIVAN 2% may be used.
The required rate of administration varies considerably between
patients but rates in the region of 4 to 12 mg/kg/h usually
maintain satisfactory anaesthesia.
Repeat Bolus Injections: It is recommended that only DIPRIVAN
1% is used. If a technique involving repeat bolus injections
is used, increments of 25 mg to 50 mg may be given according
to clinical need.
SEDATION DURING INTENSIVE CARE
When used to provide sedation for ventilated adult patients
undergoing intensive care, it is recommended that DIPRIVAN be
given by continuous infusion. The infusion rate should be adjusted
according to the depth of sedation required but rates in the
region of 0.3 to 4.0 mg/kg/h should achieve satisfactory sedation.
CONSCIOUS SEDATION FOR SURGICAL AND DIAGNOSTIC PROCEDURES
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 to 1 mg/kg over 1 to 5 minutes
to initiate sedation.
Maintenance of sedation may be accomplished by titrating DIPRIVAN
infusion to the desired level of sedation - most patients will
require 1.5 to 4.5 mg/kg/h. In addition to the infusion, bolus
administration of 10 to 20 mg may be used if a rapid increase
in the depth of sedation is required. In patients in ASA grades
3 and 4 the rate of administration and dosage may need to be
reduced.
B ELDERLY PATIENTS
In elderly patients the dose requirement for induction of anaesthesia
with DIPRIVAN is reduced. The reduction should take account
of the physical status and age of the patient. The reduced dose
should be given at a slower rate and titrated against the response.
Where DIPRIVAN is used for maintenance of anaesthesia or 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.
C CHILDREN
ALL INDICATIONS
Administration of DIPRIVAN by a DIPRIFUSOR TCI system is not
recommended for any indication in children.
INDUCTION OF GENERAL ANAESTHESIA
DIPRIVAN is not recommended for use in infants less than 1
month old (see section 4.4 and 4.8).
When used to induce anaesthesia in children, it is recommended
that DIPRIVAN be given slowly until the clinical signs show
the onset of anaesthesia. The dose should be adjusted for age
and/or weight. Most patients over 8 years of age are likely
to require approximately 2.5 mg/kg of DIPRIVAN for induction
of anaesthesia. Between the ages of one month and eight years
of age the requirement may be more. Lower dosage is recommended
for children of ASA grades 3 and 4.
MAINTENANCE OF GENERAL ANAESTHESIA
DIPRIVAN is not recommended for use in infants less than 1
month old.
Anaesthesia can be maintained by administering DIPRIVAN by
infusion or repeat bolus injection to maintain the depth of
anaesthesia required. It is recommended that only DIPRIVAN 1%
is used if repeat bolus injections are used. The required rate
of administration varies considerably between patients but rates
in the region of 9 to 15 mg/kg/h usually achieve satisfactory
anaesthesia.
CONSCIOUS SEDATION FOR SURGICAL AND DIAGNOSTIC PROCEDURES
DIPRIVAN is not recommended for conscious sedation in children
as safety and efficacy have not been demonstrated.
SEDATION DURING INTENSIVE CARE
When used to provide sedation for ventilated paediatric patients
undergoing intensive care, it is recommended that DIPRIVAN be
given by continuous infusion. The depth of sedation should be
regularly monitored and the rate of infusion adjusted to the
minimum required to achieve and maintain a satisfactory level
of sedation. The rate of administration required varies considerably
between patients and with age. Infusion rates in the region
of 0.6 to 8 mg/kg/h achieve satisfactory sedation in the majority
of patients. Neonates (aged 0 to 1 month) and adolescents (aged
12 years and above) generally require infusion rates towards
the lower end of this range.
Children are at particular risk of fat overload. Therefore
serum lipids should be monitored in children receiving DIPRIVAN
(see Section 4.4 Warnings and precautions for use).
Supplementary analgesic agents are generally required in addition
to DIPRIVAN.
Following infusion of DIPRIVAN, discontinuation should be gradual
to minimise the risk of withdrawal symptoms.
D ADMINISTRATION
Administration of DIPRIVAN 2% by bolus injection is not recommended.
DIPRIVAN can be used for infusion undiluted from plastic syringes
or glass infusion bottles or DIPRIVAN pre-filled syringes. When
DIPRIVAN 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 also be used diluted with 5% dextrose intravenous
infusion only, in PVC infusion bags or glass infusion bottles.
Dilutions, which must not exceed 1 in 5 (2 mg propofol /ml)
should be prepared aseptically immediately before administration.
The mixture is stable for up to 6 hours.
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. 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 dilution in the burette.
DIPRIVAN may be administered via a Y-piece close to the injection
site, into infusions of dextrose 5% intravenous infusion, sodium
chloride 0.9% intravenous infusion or dextrose 4% with sodium
chloride 0.18% intravenous infusion.
The glass pre-filled syringe (PFS) has a lower frictional resistance
than plastic disposable syringes and operates more easily. Therefore,
if DIPRIVAN 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 pre- filled syringe.
DIPRIVAN 1% may be premixed with alfentanil injection containing
500 micrograms/ml alfentanil ('Rapifen'; Janssen Pharmaceuticals
Ltd.) 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.
To reduce pain on initial injection, DIPRIVAN 1% used for induction
may be mixed with lignocaine injection in a plastic syringe
in the ratio of 20 parts DIPRIVAN 1% with up to one part of
0.5 or 1% lignocaine injection immediately prior to administration.
Administration of DIPRIVAN by a DIPRIFUSOR TCI system is restricted
to induction and maintenance of general anaesthesia, conscious
sedation for surgical and diagnostic procedures and for the
sedation of ventilated adult patients receiving intensive care.
It is not recommended for use in children.
DIPRIVAN 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 by TCI and with the correct use of the syringe identification
system, all of which are set out in the DIPRIFUSOR training
manual available from AstraZeneca at the address below.
The system allows the anaesthetist or intensivist to achieve
and control a desired speed of induction and depth of anaesthesia
or sedation by setting and adjusting target (predicted) blood
concentrations of propofol.
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 or sedation 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 to 8 mcg/ml. An initial target of 4 mcg/ml is recommended
in premedicated patients and in unpremedicated patients an initial
target of 6 mcg/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 concentrations can then be increased in
steps of 0.5 to 1.0 mcg/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 to 6 mcg/ml usually maintain satisfactory anaesthesia.
The predicted propofol concentration on waking is generally
in the region of 1.0 to 2.0 mcg/ml and will be influenced by
the amount of analgesia given during maintenance.
CONSCIOUS SEDATION FOR SURGICAL AND DIAGNOSTIC PROCEDURES
Target blood propofol concentration settings in the range of
0.5 to 2.5 mcg/ml will generally be required. The target concentration
setting should be titrated against the response of the patient
to achieve the depth of conscious sedation required.
An initial target concentration towards the upper end of this
range will allow more rapid induction of conscious sedation.
An initial target concentration towards the lower end of this
range should be used in elderly patients and in patients of
ASA grades 3 and 4.
SEDATION DURING INTENSIVE CARE
Target blood propofol concentration settings in the range of
0.2 to 2.0 mcg/ml will generally be required. Administration
should begin at a low target setting which should be titrated
against the response of the patient to achieve the depth of
sedation desired.
If the DIPRIFUSOR TCI system has been used for anaesthesia,
it can be continued into the postoperative period to provide
sedation during intensive care, with appropriate selection of
a target concentration.
4.3 Contraindications
DIPRIVAN is contraindicated
in patients with a known allergy to DIPRIVAN
for the sedation of children under the age of 3 years with
serious viral
respiratory tract infections receiving intensive care
for the sedation of children of all ages with croup or epiglottitis
receiving
intensive care (see Section 4.4).
4.4 Special warnings and special precautions for use
DIPRIVAN 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. DIPRIVAN should not be administered
by the person conducting the diagnostic or surgical procedure.
When DIPRIVAN 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 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 general anaesthesia. Very rarely
the use of DIPRIVAN 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.
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 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 is used in conjunction with other agents likely
to cause a bradycardia.
When DIPRIVAN 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 DIPRIVAN is administered to patients thought to be at particular
risk of fat overload. Administration of DIPRIVAN 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 formulation; 1.0 ml of DIPRIVAN
contains approximately 0.1 g of fat.
Diprivan is not recommended for use in neonates for induction
and maintenance of anaesthesia. Data from off-label use have
indicated that if the paediatric (1 month to 16 years of age)
dose regimen is applied in neonates, a relative overdose could
occur which may result in cardio-respiratory depression (see
section 4.2 and 4.8).
There are no data to support the use of DIPRIVAN for the sedation
of premature neonates receiving intensive care.
There are no clinical trials data to support the use of DIPRIVAN
for the sedation of children with croup or epiglottitis receiving
intensive care.
EDTA-containing formulation only:
EDTA is a chelator of metal ions, including zinc. The need for
supplemental zinc should be considered during prolonged administration
of DIPRIVAN, particularly in patients who are predisposed to
zinc deficiency, such as those with burns, diarrhoea and/or
major sepsis.
ADDITIONAL PRECAUTIONS
DIPRIVAN contains no antimicrobial preservatives and supports
growth of micro-organisms.
When DIPRIVAN 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
and infusion equipment throughout the infusion period. Any infusion
fluids added to the DIPRIVAN line must be administered close
to the cannula site. DIPRIVAN must not be administered via a
microbiological filter.
DIPRIVAN and any syringe containing DIPRIVAN are for single
use in an individual patient. In accordance with established
guidelines for other lipid emulsions, a single infusion of DIPRIVAN
must not exceed 12 hours. At the end of the procedure or at
12 hours, whichever is the sooner, both the reservoir of DIPRIVAN
and the infusion line must be discarded and replaced as appropriate.
4.5 Interaction with other medicinal products and other forms
of interaction
DIPRIVAN 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 may be required where general anaesthesia
is used as an adjunct to regional anaesthetic techniques.
4.6 Pregnancy and lactation
Pregnancy
DIPRIVAN should not be used in pregnancy. DIPRIVAN has been
used, however, during termination of pregnancy in the first
trimester.
Obstetrics
DIPRIVAN crosses the placenta and may be associated with neonatal
depression. It should not be used for obstetric anaesthesia.
Lactation
Safety to the neonate following the use of DIPRIVAN in mothers
who are breast-feeding has not been established.
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.
4.8 Undesirable effects
Induction of anaesthesia with DIPRIVAN is generally smooth
with minimal evidence of excitation. The most commonly reported
ADRs are pharmacologically predictable side effects of an anaesthetic
agent, such as hypotension. Given the nature of anaesthesia
and those patients receiving intensive care, events reported
in association with anaesthesia and intensive care may also
be related to the procedures being undertaken or the recipient's
condition.
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.
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5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anaesthetics, general
ATC code: N01A X10
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.
In general, falls in mean arterial blood pressure and slight
changes in heart rate are observed when DIPRIVAN 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, any effects are qualitatively similar to those
of other intravenous anaesthetic agents and are readily manageable
in clinical practice.
DIPRIVAN 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 post-operative nausea and
vomiting.
In general, there is less post-operative nausea and vomiting
following anaesthesia with DIPRIVAN than following anaesthesia
with inhalational agents. There is evidence that this may be
related to an antiemetic effect of propofol.
DIPRIVAN, at the concentrations likely to occur clinically,
does not inhibit the synthesis of adrenocortical hormones.
5.2 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. The first phase is characterised
by a very rapid distribution (half-life: 2-4 minutes) followed
by 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, to form
inactive conjugates of propofol and its corresponding quinol,
which are excreted in urine.
When DIPRIVAN is used to maintain anaesthesia, blood concentrations
of propofol asymptotically approach the steady-state value for
the given administration rate. The pharmacokinetics are linear
over the recommended range of infusion rates of DIPRIVAN.
5.3 Preclinical safety data
Propofol is a drug on which extensive clinical experience has
been obtained. Relevant information for the prescriber is provided
elsewhere in the Core Prescribing Information.
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6. PHARMACEUTICAL PARTICULARS
(Check locally)
6.1 List of excipients
DIPRIVAN 1% (F5114) and 2% (F6520)
Glycerol Ph. Eur.
Purified Egg Phosphatide
Sodium Hydroxide Ph. Eur.
Soya-bean Oil Ph. Eur.
Water for Injections Ph. Eur.
DIPRIVAN 1% (F11309) and 2%
(F11356) (EDTA-containing formulations)
Glycerol Ph. Eur.
Purified Egg Phosphatide
Sodium Hydroxide Ph. Eur.
Soya-bean Oil Ph. Eur.
Water for Injections Ph. Eur.
Disodium Edetate Ph. Eur.
6.2 Incompatibilities
DIPRIVAN should not be mixed prior to administration with injections
or infusion fluids with the exception of DIPRIVAN 1% which can
be mixed with 5% dextrose in PVC bags or glass infusion bottles
or lignocaine injection or alfentanil injection in plastic syringes
(see section 4.2 Dosage and method of administration D).
The neuromuscular blocking agents, atracurium and mivacurium
should not be given through the same iv line as DIPRIVAN without
prior flushing.
6.3 Shelf-life
As packaged for sale:
3 years for DIPRIVAN and DIPRIVAN (EDTA-containing formulation)
1% ampoules and vials.
2 years for DIPRIVAN and DIPRIVAN (EDTA-containing formulation)
2% vials.
2 years for DIPRIVAN and DIPRIVAN (EDTA-containing formulation)1%
and 2% pre-filled syringes.
After dilution use within 6 hours of dilution.
6.4 Special precautions for storage
Store between 2°C and 25°C. Do not freeze.
6.5 Nature and contents of container
DIPRIVAN 1%: (and EDTA-containing formulation)
glass ampoules (20ml) (boxes of 5)
glass vials (20ml, only EDTA containing formulation) (50ml)
(100ml)
glass pre-filled syringe (20ml) (50ml)
DIPRIVAN 2%: (and EDTA-containing formulation)
glass pre-filled syringe (10ml) (50ml)
glass vial (50 ml)
6.6 Instructions for use, handling and disposal
Containers should be shaken before use. Any portion of the
contents remaining after use should be discarded.
Asepsis for DIPRIVAN and infusion equipment must be maintained
(see Section 4.4 Warnings and Precautions for Use).
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