DIPROFOL 2 %

Israel - English - Ministry of Health

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Active ingredient:
PROPOFOL
Available from:
TARO INTERNATIONAL LTD, ISRAEL
ATC code:
N01AX10
Pharmaceutical form:
EMULSION FOR INJECTION OR INFUSION
Composition:
PROPOFOL 20 MG/ML
Administration route:
I.V
Prescription type:
Required
Manufactured by:
SYNTHON HISPANIA S.L., SPAIN
Therapeutic group:
PROPOFOL
Therapeutic area:
PROPOFOL
Therapeutic indications:
Propofol 2% is a short- acting intravenous general anaesthetic for:โ€ข Induction and maintenance of general anaethesia in adults and children > 3 years.โ€ข Sedation of ventilated patients >16 years of age in the intensive care unit.โ€ข Sedation for diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia in adults and children > 3 years.
Authorization number:
125 15 30376 00
Authorization date:
2020-01-31

ื•ืจืช ืœื ื•ื™ืฉื ืจื˜ื ื™ื

ืž"ืขื‘

ืจื•ื˜ื™ืงื”

.ื“.ืช

10347

ื”ืคื™ื— ืฅืจืคืž ,

2624761

:ืœื˜

04-8475700

:ืกืงืค

04-8727165

ืจื‘ืžื‘ื•ื 

2018

ื”/ื“ื‘ื›ื  ื”/ืืคื•ืจ

ืช/ื“ื‘ื›ื  ืช/ื—ืงื•ืจ

ื™ื› ืื›ืขื™ื“ื•ื”ืœ ืชืฉืงื‘ืž ื•ืจืช ืชืจื‘ื— ืืคื•ืจืœ ืื™ื ื•ืœืขื”

ืœืฉ ืจื™ืฉื›ืชื” ืื™

Diprofol 1% amp and vials and

Diprofol 2% vials

ื›ื“ื•ืข ื•ื 

.

ืื”ื‘ ืื™ืคื™ืขืกื” ืงืจ ืื™ื ื™ื•ืฆืž ื•ื– ื”ืขื“ื•ื”ื‘ ืื™ื™ืชื•ื”ืž ืื™ื™ื•ื ื™ืฉ ื•ืฉืขื 

ืืคื•ืจืœ ืื™ื ื•ืœืขื‘ ืขื‘ืฆื‘ ื•ื ืžื•ืก ืชื•ืคืกื•ืช . ืื•ื“ื

ืœื•ื—ื› ืขื‘ืฆื‘ ื•ื ืžื•ืก ืชื•ืงื™ื—ืžื”

ื”ืงื™ื—ืž ื•ืง

ื•ืœืขื”

ื›ื“ื•ืขืžื”

ืžื•ืกืจืค ืšืจื•ืฆืœ ืชื•ืื™ืจื‘ื” ื“ืจืฉืžืœ ื—ืœืฉื 

:ืชื•ืื™ืจื‘ื” ื“ืจืฉืž ืจืชืื‘ืฉ ืชื•ืคื•ืจืชื” ืจื’ืืžื‘

www.health.gov.il

ืœื‘ืงืœ ืŸืชื™ื ื•

:ืื•ืฉื™ืจื” ืœืขื‘ืœ ื”ื™ื™ื ืค ื™ื“ื™ ืœืข ืกืคื“ื•ืž

ื•ืจืช ืœื ื•ื™ืฉื ืจื˜ื ื™ื

ืจื•ื˜ื™ืงื” ื‘ื•ื—ืจ ,ืž"ืขื‘

ื“.ืช ,

10347

ื”ืคื™ื— ืฅืจืคืž

2624761

,ื”ื›ืจื‘ื‘

ืŸืžื“ืœื•ื’ ื”ื ื™ืจืž

ื”ื ื•ืžืž ืชื—ืงื•ืจ

Diprofol 1%, ampoules and vials

ืœื™ืขืค ื‘ื™ื›ืจืž

:

Propofol 10mg/ml

ื”ื™ื•ื•ืชื”ื”

:ืจื™ืฉื›ืชืœ ืชืจืฉื•ืืžื”

Diprofol 1% is a short-acting intravenous general anaesthetic for:

induction and maintenance of general anaesthesia in adults and children > 1 month.

sedation of ventilated patients >16 years of age in the intensive care unit.

sedation for diagnostic and surgical procedures, alone or in combination with local or

regional anaesthesia in adults and children > 1 month.

ืื™ื ื•ื›ื“ืข

ืœ ืŸื•ืœืขื‘ ืืคื•ืจ

:

4.4 Special warnings and precautions for use

The benefits and risks of the proposed procedure should be considered prior to proceeding with

repeated or prolonged use (>3 hours) of propofol in young children (< 3 years) and in pregnant

women as there have been reports of neurotoxicity in preclinical studies, see Section 5.3.

5.3

Preclinical safety data

Published studies in animals demonstrate that the use of anaesthetic agents during the period of

rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss

in the developing brain and alterations in synaptic morphology and neurogenesis. Based on

comparisons across species, the window of vulnerability to these changes is believed to correlate

with exposures in the third trimester through the first several months of life, but may extend out to

approximately 3 years of age in humans.

In neonatal primates, exposure to 3 hours of an anaesthetic regimen that produced a light surgical

plane of anaesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or

ื•ืจืช ืœื ื•ื™ืฉื ืจื˜ื ื™ื

ืž"ืขื‘

ืจื•ื˜ื™ืงื”

.ื“.ืช

10347

ื”ืคื™ื— ืฅืจืคืž ,

2624761

:ืœื˜

04-8475700

:ืกืงืค

04-8727165

longer increased neuronal cell loss. Data in foetal and neonatal rodents and primates suggest that

the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive

deficits in learning and memory. The clinical significance of these preclinical findings is not

known, and healthcare providers should balance the benefits of appropriate anaesthesia in young

children less than 3 years of age and pregnant women who require procedures against the potential

risks suggested by the preclinical data.

Diprofol 2%, vials

ืœื™ืขืค ื‘ื™ื›ืจืž

:

Propofol 20mg/ml

ื”ื™ื•ื•ืชื”ื”

:ืจื™ืฉื›ืชืœ ืชืจืฉื•ืืžื”

Diprofol 2% is a short-acting intravenous general anaesthetic for:

induction and maintenance of general anaesthesia in adults and children > 3

years.

sedation of ventilated patients >16 years of age in the intensive care unit.

sedation for diagnostic and surgical procedures, alone or in combination with local or

regional anaesthesia in adults and children > 3 years.

ืœ ืŸื•ืœืขื‘ ืื™ื ื•ื›ื“ืข ืืคื•ืจ

:

4.4 Special warnings and precautions for use

The benefits and risks of the proposed procedure should be considered prior to proceeding with

repeated or prolonged use (>3 hours) of propofol in young children (< 3 years) and in pregnant

women as there have been reports of neurotoxicity in preclinical studies, see Section 5.3.

5.3

Preclinical safety data

Published studies in animals demonstrate that the use of anaesthetic agents during the period of

rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss

in the developing brain and alterations in synaptic morphology and neurogenesis. Based on

comparisons across species, the window of vulnerability to these changes is believed to correlate

with exposures in the third trimester through the first several months of life, but may extend out to

approximately 3 years of age in humans.

In neonatal primates, exposure to 3 hours of an anaesthetic regimen that produced a light surgical

plane of anaesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or

longer increased neuronal cell loss. Data in foetal and neonatal rodents and primates suggest that

the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive

deficits in learning and memory. The clinical significance of these preclinical findings is not

known, and healthcare providers should balance the benefits of appropriate anaesthesia in young

children less than 3 years of age and pregnant women who require procedures against the potential

risks suggested by the preclinical data.

Diprofol

ยฎ

2%

Propofol 2%

For IV Administration

1. Name of the medicinal product

Diprofol 2% (propofol 20 mg/ml)

2. Qualitative and quantitative composition

Diprofol 20 mg/ml, emulsion for injection or infusion,

contains 20 mg/ml propofol.

The emulsion contains as excipients soybean oil

and egg lecithin, which are also used in intravenous

feeding. It contains no preservatives.

For the full list of excipients, see Section 6.1.

3. Pharmaceutical form

Emulsion for injection or infusion

Diprofol is a white, aqueous isotonic oil-in-water

emulsion

intravenous

administration.

4. Clinical particulars

4.1 Therapeutic indications

Diprofol 2% is a short-acting intravenous general

anaesthetic for

induction and maintenance of general anaesthesia

in adults and children > 3 years.

sedation of ventilated patients > 16 years of age

in the intensive care unit.

sedation for diagnostic and surgical procedures,

alone or in combination with local or regional

anaesthesia in adults and children > 3 years.

4.2 Posology and method of administration

Posology

4.2.1 Induction of General Anaesthesia

Propofol

must

used

only

well

equipped

hospitals

medical

centers

doctors

trained

in anaesthesia or the treatment of intensive care

patients.

Continual

monitoring

circulation

respiration

(for

example

pulse

oxymeter) is necessary. Provisions for prevention

airway

obstruction,

artificial

respiration

other resuscitation provisions must be immediately

available at all times. As regards sedation during

surgical or diagnostic operations propofol must not

be administered by the same person who performs

the surgical or diagnostic operation.

Additional analgesics are generally necessary in

combination with propofol.

Adults

Diprofol 2% may be used to induce anaesthesia

by infusion. Administration of Diprofol 2% by bolus

injection is not recommended.

Diprofol 2% may be used to induce anaesthesia by

infusion but only in those patients who will receive

Diprofol 2% for maintenance of anaesthesia.

In unpremedicated and premedicated patients, it is

recommended that Diprofol 2% should be titrated

(approximately 2ml [40mg] every 10 seconds in

an average healthy adult by 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 require1.5โ€“2.5mg/

kg of Diprofol 2%. The total dose required can be

reduced by lower rates of administration (1โ€“2.5ml/

min [20โ€“50mg/min]).

In patients over this age and in patients of ASA

grades III and IV, especially those with impaired

cardiac

function,

dosage

requirements

will

be less and the total dose of Diprofol 2% may be

reduced to a minimum of 1 mg/kg body weight. In

these patients lower rates of administration should

be applied (approximately 1 ml, corresponding to

20 mg every 10 seconds).

Elderly

In older people the dose requirement for induction

of anaesthesia with Diprofol 2% is reduced. The

reduction should take into 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.

Paediatric population

Diprofol

indicated

induction

anaesthesia in children less than 3 years of age.

For induction of anaesthesia in children over 3

years of age, Diprofol 2% should be titrated slowly

until clinical signs show the onset of anaesthesia.

The dose should be adjusted according to age

and/or bodyweight. Most patients over 8 years of

age require approximately 2.5mg/kg bodyweight of

Diprofol 2% for induction of anaesthesia. In younger

children, dose requirements may be higher (2.5โ€“

4mg/kg bodyweight).

patients

lower

doses

recommended (see also Section 4.4).

4.2.2 Maintenance of General Anaesthesia

Anaesthesia can be maintained by administering

Diprofol 2% by continuous infusion to prevent the

clinical signs of light anaesthesia. Administration of

Diprofol 2% by bolus injection is not recommended.

Recovery from anaesthesia is typically rapid and

it is therefore important to maintain Diprofol 2%

administration until the end of the procedure.

Adults

required

administration

varies

considerably between patients, but rates in the

region of 4โ€“12 mg/kg/h usually mai

ntain satisfactory

anaesthesia.

Elderly

When

Diprofol

used

maintenance

anaesthesia

rate

infusion

โ€˜target

concentrationโ€™ 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 older people

as this may lead to cardiorespiratory depression.

Paediatric population

Diprofol 2% is not indicated for maintenance of

anaesthesia in children less than 3 years of age.

Anaesthesia can be maintained in children over

3 years of age by administering Diprofol 2% by

infusion

maintain

depth

anaesthesia

required.

required

rate

administration

varies

considerably

between

patients

rates

in the region of 9โ€“15 mg/kg/h usually achieve

satisfactory anaesthesia. In younger children, dose

requirements

higher.

patients

lower

doses

recommended

(see

also

Section

4.4).

4.2.3 Sedation During Intensive Care

Adults

For sedation during intensive care it is advised that

Diprofol 2% 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 Diprofol 2% (See Section 4.4

Special warnings and precautions for use).

Diprofol 2% is not indicated for sedation in intensive

care of patients of 16 years of age or younger (see

Section 4.3 Contraindications).

It is recommended that blood lipid levels be monitored

should

Diprofol

administered

patients

thought to be at particular risk of fat overload.

Administration of Diprofol 2% should be adjusted

appropriately if the monitoring indicates that fat

is being inadequately cleared from the body. If

patient

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 Diprofol 2% formulation:

1.0 ml of Diprofol 2% contains approximately 0.1g

of fat.

If the duration of sedation is in excess of 3 days,

lipids should be monitored in all patients.

Elderly

When

Diprofol

used

sedation

anaesthesia 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 older people as this may lead

to cardiorespiratory depression.

Paediatric population

Diprofol 2% 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

administration

should

individualised

titrated

clinical

response.

Most patients will require 0.5โ€“1 mg/kg over 1โ€“5

minutes for onset of sedation.

Maintenance of sedation may be accomplished by

titrating Diprofol 2% infusion to the desired level of

sedation โ€“ most patients will require 1.5โ€“4.5 mg/

kg/h. In patients of ASA grades 3 and 4 the rate of

administration and dosage may need to be reduced.

According to required dose, alternatively Diprofol 1 %

may be used.

Elderly

When Diprofol 2% is used for sedation the rate of

infusion or โ€˜target concentrationโ€™ 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 older people as this may lead to

cardiorespiratory depression.

Paediatric population

Diprofol 2% is not indicated for surgical and diagnostic

procedures in children aged less than 3 years.

children

over

years

age,

doses

administration rates should be adjusted according

to the required depth of sedation and the clinical

response. Most paediatric patients require1โ€“2 mg/

kg body weight of Diprofol 2% for onset of sedation.

Maintenance of sedation may be accomplished by

titrating Diprofol 2% infusion to the desired level

of sedation. Most patients require1.5โ€“9 mg/kg/h

Diprofol 2%.

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

4.2.5 Method of Administration

Method of administration

Propofol

mg/ml

should

administered

undiluted intravenously. Propofol 20 mg/ml must

mixed

with

injection

infusion

fluids.

However, simultaneous administration of propofol

20 mg/ml together with an infusion of glucose 5%

or sodium chloride 0.9% via a Y - connector close

to the injection site is possible.

Ampoules and vials should be shaken before use.

Before use the neck of the ampoule and the rubber

stopper of the infusion vial must be disinfected with

medicinal alcohol (spray or tissues). After use, any

remaining medicine must be destroyed.

Propofol

does

contain

preservatives

promotes

growth

micro-organisms.

After opening of an ampoule or piercing of a vial,

the contents must therefore immediately be put

aseptically into a sterile syringe or infusion system

and then administered directly. During the infusion

period the sterility of both propofol and the infusion

system should be maintained.

Medicines or fluids that are added to a running

propofol

infusion

must

added

close

cannula. Propofol must not be administered via

infusion systems that are provided with microbial

filters. The contents of an ampoule or a vial of

propofol and any syringe of propofol are intended

single

administration

patient.

remaining medicine must be destroyed after use.

Infusion of undiluted propofol 20 mg/ml

When propofol is administered by means of a

continuous infusion, control of the infusion rate by

means of a burette, drop counter, syringe pump or

volumetric infusion pump is recommended. As is

the case for parenteral administration of all kinds

of fat emulsions, the duration of use of one infusion

system for a continuous infusion with propofol must

remain limited to 12 hours. The infusion system

and the container must be removed and replaced

after a maximum of 12 hours. Residues of propofol

left over at the end of the infusion period or after

changing of the system must be destroyed.

In order to diminish pain at the beginning of the

injection

propofol

mg/ml

induction

general

anaesthesia,

lidocaine

injected

directly before injection of propofol 20 mg/ml.

Before administering the muscle relaxant atracurium,

after administration of propofol, through the same

infusion system, it is recommended to flush out the

infusion system.

Duration of administration

Propofol can be administered for a maximum of 7

days.

4.3 Contraindications

Hypersensitivity to the active substance or to any of

the excipients listed in section 6.1.

Diprofol 2% contains soybean oil and should not be

used in patients who are hypersensitive to peanut

or soya.

Diprofol 2% must not be used in patients of 16

years of age or younger for sedation in intensive

care (see section 4.4).

4.4 Special warnings and precautions for use

Diprofol 2% should be given by those trained in

anaesthesia (or, where appropriate, doctors trained

in the care of patients in Intensive Care).

Patients

should

constantly

monitored

facilities for maintenance of a patient airway, artificial

ventilation

oxygen

enrichment

other

resuscitative facilities should be readily available at

all times. Diprofol 2% should not be administered

by the person conducting the diagnostic or surgical

procedure.

Abuse

dependence

Diprofol

predominantly by health care professionals, have

been reported. As with other general anaesthetics,

the administration of Diprofol 2% without airway

care may result in fatal respiratory complications.

When Diprofol 2% is administered for conscious

sedation, for surgical and diagnostic procedures,

patients should be continually monitored for early

signs of hypotension, airway obstruction and oxygen

desaturation.

During induction of anaesthesia, hypotension and

transient apnoea may occur depending on the dose

and use of premedicants and other agents.

Occasionally,

hypotension

require

intravenous fluids and reduction of the rate of

administration of Diprofol 2% during the period of

anaesthetic maintenance.

As with other sedative agents, when Diprofol 2%

is used for sedation during operative procedures,

involuntary patient movements may occur. During

procedures requiring immobility these movements

maybe hazardous to the operative site.

An adequate period is needed prior to discharge

of the patient to ensure full recovery after use of

Diprofol 2%. Very rarely the use of Diprofol 2% may

be associated with the development of a period

post-operative

unconsciousness,

which

be accompanied by an increase in muscle tone.

This may or may not be preceded by a period of

wakefulness. Although

recovery

spontaneous,

appropriate care of an unconscious patient should

administered.

Diprofol 2% induced impairment is not generally

detectable beyond 12 hours. The effects of Diprofol

2%, 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

driving

The use of other agents that may sedate (e.g.,

benzodiazepines,

opiates,

alcohol)

with

other

intravenous

anaesthetic

agents,

caution should be applied in patients, with cardiac,

respiratory,

renal

hepatic

impairment

hypovolaemic or debilitated patients. Diprofol 2%

clearance

blood

flow

dependent;

therefore,

concomitant medication that reduces cardiac output

will also reduce Diprofol 2% clearance.

Diprofol 2% lacks vagolytic activity and has been

associated with reports of bradycardia (occasionally

profound)

also

asystole.

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 Diprofol

2% is used in conjunction with other agents likely to

cause a bradycardia.

When Diprofol 2% 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).

Use is not recommended with electroconvulsive

treatment.

As with other anaesthetics sexual disinhibition may

occur during recovery.

The benefits and risks of the proposed procedure

should

considered

prior

proceeding

with

repeated or prolonged use (>3 hours) of propofol in

young children (< 3 years) and in pregnant women

as there have been reports of neurotoxicity in

preclinical studies, see Section 5.3.

Paediatric population

The use of Diprofol 2% is not indicated 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

administering doses recommended for older children

and result in severe cardio vascular depression.

Diprofol 2% is not recommended for use in children <3

years of age due to difficulty in titrating small volumes.

Propofol must not be used in patients of 16 years of

age or younger for sedation for intensive care as the

safety and efficacy of propofol for sedation in this age

group have not been demonstrated (see Section 4.3).

Advisory statements concerning Intensive Care

Unit management

Use of propofol emulsion infusions for ICU sedation

been

associated

with

constellation

metabolic derangements and organ system failures

that may result in death. Reports have been received

of combinations of the following: Metabolic acidosis,

Rhabdomyolysis,

Hyperkalaemia,

Hepatomegaly,

Renal failure, Hyperlipidaemia, Cardiac arrhythmia,

Brugada-type

(elevated

ST-segment

coved T-wave)

rapidly

progressive

Cardiac

failure usually unresponsive to inotropic supportive

treatment. Combinations of these events have been

referred

Propofol

Infusion

Syndrome.

These events were mostly seen in patients with

serious head injuries and children with respiratory

tract infections who received dosages in excess of

those advised in adults for sedation in the intensive

care unit.

The following appear to be the major risk factors for

the development of these events: decreased oxygen

delivery to tissues; serious neurological injury and/or

sepsis; high dosages of one or more of the following

pharmacological agents - vasoconstrictors, steroids,

inotropes and/or Diprofol 2% (usually at dose rates

greater than 4mg/kg/h for more than 48 hours).

Prescribers

should

alert

these

events

patients with the above risk factors and immediately

discontinue propofol when the above signs develop.

sedative

therapeutic

agents

used

intensive

care

unit

(ICU),

should

titrated

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 4mg/kg/h.

Appropriate care should be applied in patients with

disorders of fat metabolism and in other conditions

where lipid emulsions must be used cautiously.

It is recommended that blood lipid levels should

be monitored if propofol is administered to patients

thought to be at particular risk of fat overload.

Administration

propofol

should

adjusted

appropriately if the monitoring indicates that fat

is being inadequately cleared from the body. If

patient

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; 1.0mL

of Diprofol 2% contains approximately 0.1g of fat.

Diprofol 2% contains 0.06 mg sodium per ml. To be

taken into consideration by patients on a controlled

sodium diet.

Additional Precautions

Caution should be taken when treating patients

with

mitochondrial

disease.

These

patients

be susceptible to exacerbations of their disorder

when undergoing anaesthesia, surgery and ICU

care. Maintenance of normothermia, provision of

carbohydrates and good hydration are recommended

such

patients.

early

presentations

mitochondrial

disease

exacerbation

โ€˜Propofol

Infusion

Syndromeโ€™

maybe

similar.

Diprofol 2% 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

considered

during

prolonged

administration of Diprofol 2%, particularly in patients

who are predisposed to zinc deficiency, such as those

with burns, diarrhoea and/or major sepsis.

When Diprofol 2% is to be aspirated, it must be

drawn aseptically into a sterile syringe or giving set

immediately after opening the ampoule or breaking

vial

seal.

Administration

must

commence

without delay. Asepsis must be maintained for both

Diprofol 2% and infusion equipment throughout the

infusion period. Any infusion fluids added to the

Diprofol 2% line must be administered close to the

cannula site. Diprofol 2% must not be administered

via a microbiological filter.

Diprofol 2% and any syringe containing Diprofol

2% are for single use in an individual patient. In

accordance with established guidelines for other

lipid emulsions, a single infusion of Diprofol 2% must

not exceed 12 hours. At the end of the procedure

or at 12 hours, whichever is the sooner, both the

reservoir of Diprofol 2% and the infusion line must

be discarded and replaced as appropriate.

4.5 Interaction with other medicinal products

and other forms of interaction

Diprofol

been

used

association

with

spinal and epidural anaesthesia and with commonly

used

premedicants,

neuromuscular

blocking

drugs, inhalational agents and analgesic agents;

pharmacological

incompatibility

been

encountered. Lower doses of Diprofol 2% may be

required where general anaesthesia is used as an

adjunct to regional anaesthetic techniques. Profound

hypotension has been reported following anaesthetic

with propofol in patients treated with rifampicin.

concurrent

administration

other

depressants

such

pre-medication

drugs,

inhalation agents, analgesic agents may add to

sedative,

anaesthetic

cardiorespiratory

depressant effects of Diprofol 2% (see Section 4.4).

need

lower

propofol

doses

been

observed in patients taking valproate. When used

concomitantly, a dose reduction of propofol may be

considered.

4.6 Fertility, pregnancy and lactation

Pregnancy

Teratology studies in rats and rabbits showed no

teratogenic

effects.

The safety of Diprofol 2% during pregnancy has not

been established. Studies in animals have shown

reproductive toxicity (see section 5.3). Diprofol 2%

should

given

pregnant

women

except

when absolutely necessary. Diprofol 2% crosses the

placenta and can cause neonatal depression. Diprofol

2% can, however, be used during an induced abortion.

Obstetrics

Diprofol 2% crosses the placenta and can cause

neonatal depression. It should not be used for

obstetric anaesthesia.

Breast-feeding

Studies of breast-feeding mothers showed that small

quantities of Diprofol 2% are excreted in human

milk. Women should therefore not breast-feed for

24 hours after administration of Diprofol 2%. Milk

produced during this period should be discarded.

4.7 Effects on ability to drive and use machines

Diprofol 2% has moderate influence on the 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.

Diprofol 2% induced impairment is not generally

detectable beyond 12 hours (see Section 4.4).

4.8 Undesirable effects

General

Induction

maintenance

anaesthesia

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.

nature,

severity

incidence

adverse

events observed in patients receiving Diprofol 2%

may be related to the condition of the recipients

and the operative or therapeutic procedures being

undertaken.

The following definitions of frequencies are used:

Very common (โ‰ฅ1/10), common (โ‰ฅ1/100 to <1/10),

uncommon (โ‰ฅ1/1,000 to <1/100), rare (โ‰ฅ1/10,000

to <1/1,000), very rare (<1/10,000) and not known

(cannot be estimated from the available data).

Table of Adverse Drug Reactions

System Organ

Class

Frequency

Undesirable Effects

Immune system

disorders

Very rare

Anaphylaxis โ€“ may

include angioedema,

bronchospasm, erythema

and hypotension

Metabolism

and nutrition

disorders

Frequency not

known

Metabolic acidosis

Hyperkalaemia

Hyperlipidaemia

Psychiatric

disorders

Not known

Euphoric mood.

Drug abuse and drug

dependence

Nervous system

disorders

Common

Headache during recovery

phase

Rare

Epileptiform movements,

including convulsions

and opisthotonus during

induction, maintenance and

recovery

Very rare

Postoperative

unconsciousness

Not known

Involuntary movements

Cardiac

disorders

Common

Bradycardia

Very rare

Pulmonary oedema

Not known

Cardiac arrhythmia

cardiac failure

(5),(7)

Vascular

disorders

Common

Hypotension

Uncommon

Thrombosis and phlebitis

Respiratory,

thoracic and

mediastinal

disorders

Common

Transient apnoea during

induction

Not known

Respiratory depression

(dose dependent)

Gastrointestinal

disorders

Common

Nausea and vomiting

during recovery phase

Very rare

Pancreatitis

Hepatobiliary

disorders

Not known

Hepatomegaly

Musculoskeletal

and connective

tissue disorders

Not known

Rhabdomyolysis

(3),(5)

Renal and

urinary disorders

Very rare

Discolouration of urine

following prolonged

administration

Not known

Renal failure

Reproductive

system and

breast disorders

Very rare

Sexual disinhibition

Not known

Priapism

General

disorders and

administration

site conditions

Very common

Local pain on induction

Very rare

Tissue necrosis

(10)

following accidental

extravascular

administration

Not known

Local pain, swelling,

following accidental

extravascular

administration

Investigations

Not known

Brugada type ECG

(5),(6)

Injury, poisoning

and procedural

complications

Very rare

Postoperative fever

Serious

bradycardias

rare. There

have

been

isolated

reports

progression

asystole.

Occasionally, hypotension may require use of intravenous

fluids and reduction of the administration rate of Diprofol.

Very rare reports of rhabdomyolysis have been received where

Diprofol has been given at doses greater than 4 mg/kg/hr for

ICU sedation.

May be minimized by using the larger veins of the forearm

and antecubital fossa. With Diprofol 1% local pain can also be

minimized by the co-administration of lidocaine.

Combinations of these events, reported as โ€œPropofol Infusion

Syndromeโ€, may be seen in seriously ill patients who often

have multiple risk factors for the development of the events,

see section 4.4.

Brugada-type ECG- elevated ST- segment and coved T-wave

in ECG.

Rapidly progressive cardiac failure (in some cases with fatal

outcome) in adults. The cardiac failure in such cases was

usually

unresponsive

inotropic

supportive

treatment.

Abuse

drug

dependence

propofol,

predominantly by healthcare professionals.

Not known as it cannot be estimated from the available clinical

trial data.

10. Necrosis

been

reported

where

tissue

viability

been impaired.

Dystonia/dyskinesia have been reported.

Local

local

pain

which

occur

during

induction phase can be minimized by the use of the

larger veins of the forearm and antecubital fossa.

Thrombosis

phlebitis

rare.

Accidental

clinical extravasation and animal studies showed

minimal tissue reaction. Intra-arterial injection in

animals did not induce local tissue effects.

Reporting of suspected adverse reactions

Reporting

suspected

adverse

reactions

after

authorization of the medicinal product is important.

It allows continued monitoring of the benefit/risk

balance of the medicinal product.

Any suspected adverse events should be reported

to the Ministry of Health according to the National

Regulation by using an online form:

https://sideeffects.health.gov.il

4.9 Overdose

Accidental

overdosage

likely

cause

cardiorespiratory depression. Respiratory depression

should be treated by artificial ventilation with oxygen.

Cardiovascular depression would require lowering

of the patientโ€™s head and, if severe, use of plasma

expanders and pressor agents.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic

group:

Other

general

anaesthetics

ATC code: N01AX10

Mechanism of action

Propofol (2,6-diisopropylphenol) is a short-acting

general anaesthetic agent with a rapid onset of

action

approximately

seconds.

Recovery

from anaesthesia is usually rapid. The mechanism

of action, like all general anaesthetics, is poorly

understood.

However,

propofol

thought

produce

sedative/anaesthetic

effects

positive modulation of the inhibitory function of the

neurotransmitter GABA through the ligand-gated

GABA

receptors.

Pharmacodynamic effects

In general, falls in mean arterial blood pressure

and slight changes in heart rate are observed

when Diprofol 2% is administered for induction

and maintenance of anaesthesia. However, the

haemodynamic

parameters

normally

remain

relatively

stable

during

maintenance

incidence of untoward haemodynamic changes is

low.

Although ventilatory depression can occur following

administration

Diprofol

effects

qualitatively similar to those of other intravenous

anaesthetic agents and are readily manageable in

clinical practice.

Diprofol 2% reduces cerebral blood flow, intracranial

pressure and cerebral metabolism. The reduction

in intracranial pressure is greater in patients with an

elevated baseline intracranial pressure.

Clinical efficacy and safety

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 Diprofol

2% than following anaesthesia with inhalational

agents. There is evidence that this may be related

to a reduced emetic potential of propofol.

Diprofol

concentrations

likely

occur clinically, does not inhibit the synthesis of

adrenocortical hormones.

Paediatric population

Limited studies on the duration of propofol based

anaesthesia in children indicate safety and efficacy

is unchanged up to duration of 4 hours. Literature

evidence of use in children documents use for

prolonged procedures without changes in safety or

efficacy.

5.2 Pharmacokinetic properties

Absorption

When Diprofol 2% is used to maintain anaesthesia,

blood concentrations asymptotically approach the

steady-state value for the given administration rate.

Distribution

Propofol is extensively distributed and rapidly

cleared from the body (total body clearance 1.5โ€“

2 litres/minute).

Elimination

decline

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

2โ€“4

minutes),

rapid

elimination

(half-life

30โ€“60

minutes), and a slower final phase, representative of

redistribution of propofol from poorly perfused tissue.

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.

After a single dose of 3 mg/kg intravenously,

propofol

clearance/kg

body

weight

increased

with

follows:

Median

clearance

considerably

lower

neonates

<1

month

(n=25) (20 ml/kg/min) compared to older children

(n=36, age range 4 monthsโ€“7 years). Additionally,

inter-individual

variability

considerable

neonates (range 3.7โ€“78 ml/kg/min). Due to these

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

(4โ€“24 months) (n=8), 38.7 ml/min/kg (11โ€“43 months)

(n=6), 48 ml/min/kg (1โ€“3 years) (n=12), 28.2 ml/min/

kg (4โ€“7 years) (n=10) as compared with 23.6 ml/min/

kg in adults (n=6).

Linearity

pharmacokinetics

linear

over

recommended range of infusion rates of Diprofol 2%.

5.3 Preclinical safety data

Published studies in animals (including primates)

at doses resulting in light to moderate anaesthesia

demonstrate that the use of anaesthetic agents

during

period

rapid

brain

growth

synaptogenesis results in cell loss in the developing

brain

that

associated

with

prolonged

cognitive

deficiencies.

Based

comparisons

across species, the window of vulnerability to these

changes is believed to correlate with exposures in

the third trimester through the first several months

of life, but may extend out to approximately 3 years

of age in humans.

In neonatal primates, exposure to 3 hours of an

anaesthetic regimen that produced a light surgical

plane

anaesthesia

increase

neuronal

cell loss, however, treatment regimens of 5 hours

or longer increased neuronal cell loss. The clinical

significance

these

nonclinical

findings

known, and healthcare providers should balance the

benefits of appropriate anaesthesia in young children

less than 3 years of age and pregnant women who

require

procedures

against

potential

risks

suggested by the preclinical data.

Propofol

drug

which

extensive

clinical

experience has been obtained. All relevant information

prescriber

provided

elsewhere

this

document.

6. Pharmaceutical particulars

6.1 List of excipients

Soybean oil, glycerol, egg lecithin, oleic acid, sodium

hydroxide and water for injection.

6.2 Incompatibilities

Diprofol

should

mixed

prior

administration

with

injections

infusion

fluids.

However, Diprofol 2% may be administered via a

Y-piece connector close to the injection site with the

products

mentioned

section

4.2.

neuromuscular

blocking

agent,

atracurium,

should not be given through the same intravenous

line as Diprofol 2% without prior flushing.

6.3 Shelf life

Shelf life of the product as packaged for sale

The expiry date of the product is indicated on the

packaging materials.

Shelf life after dilution

Diprofol 2% should not be diluted.

6.4 Special precautions for storage

Protect from light.

Store below 25ยฐC. Do not freeze.

Vials that their contents have been frozen can no

longer be used.

6.5 Nature and contents of container

Diprofol 20 mg/ml: Glass vials of 50 ml

6.6 Special precautions for disposal and other

handling

In use precautions:

Vials must be shaken before use.

Any portion of the contents remaining after use

should

discarded.

layers

remain

visible

after

shaking,

product

should

used.

Additional precautions:

Diprofol 2% contains no antimicrobial preservatives

and supports growth of micro-organisms. Asepsis

must be maintained for both Diprofol 2% and infusion

equipment throughout the infusion period. Any drugs

or fluids added to the Diprofol 2% infusion line must

be administered close to the cannula site. Diprofol 2%

must not be administered via a microbiological filter.

Diprofol 2% and any syringe containing Diprofol 2%

are for single use in an individual patient. For use in

long-term maintenance of anaesthesia or sedation

in intensive care it is recommended that the infusion

line and reservoir of Diprofol 2% be discarded and

replaced at regular intervals.

7. Manufacturer

Synthon Hispania S.L., Barcelona, Spain

8. License Holder

Taro International Ltd.,

14 Hakitor St., Haifa Bay 2624761

9. Registration Number

125.15.30376.00

Revised in June 2020.

DOR-Dip-2%-SPC-0620-06

ื•ืจืช ืœ๏ฃฟื•ื™ืฉ๏ฃฟืจื˜๏ฃฟื™ื

ืž"ืขื‘

ืจื•ื˜ื™ืงื”

.ื“.ืช

10347

ื”ืคื™ื— ืฅืจืคืž ,

2624761

:ืœื˜

04-8475700

:ืกืงืค

04-8727165

ื™ื ื•ื™

2020

ื”/ื“ื‘ื›ื  ื”/ืืคื•ืจ

ืช/ื“ื‘ื›ื  ืช/ื—ืงื•ืจ

ื™ื› ืื›ืขื™ื“ื•ื”ืœ ืชืฉืงื‘ืž ื•ืจืช ืชืจื‘ื— ืืคื•ืจืœ ืื™ื ื•ืœืขื”

ืœืฉ ืจื™ืฉื›ืชื” ืื™

Diprofol 1% amp and vials and

Diprofol 2% vials

ื›ื“ื•ืข ื•ื 

.

ืื”ื‘ ืื™ืคื™ืขืกื” ืงืจ ืื™ื ื™ื•ืฆืž ื•ื– ื”ืขื“ื•ื”ื‘ ืื™ื™ืชื•ื”ืž ืื™ื™ื•ื ื™ืฉ ื•ืฉืขื 

ืืคื•ืจืœ ืื™ื ื•ืœืขื‘ ืขื‘ืฆื‘ ื•ื ืžื•ืก ืชื•ืคืกื•ืช . ืื•ื“ื

ื•ืœืขื” ืื™ื 

ื›ื“ื•ืขืžื” ืื™ื 

ื—ืœืฉื 

ืžื•ืกืจืค ืšืจื•ืฆืœ ืชื•ืื™ืจื‘ื” ื“ืจืฉืžืœ

:ืชื•ืื™ืจื‘ื” ื“ืจืฉืž ืจืชืื‘ืฉ ืชื•ืคื•ืจืชื” ืจื’ืืžื‘

www.health.gov.il

ืœื‘ืงืœ ืŸืชื™ื ื•

ืกืคื“ื•ืž ืื™

:ืื•ืฉื™ืจื” ืœืขื‘ืœ ื”ื™ื™ื ืค ื™ื“ื™ ืœืข

ื•ืจืช ืœื ื•ื™ืฉื ืจื˜ื ื™ื

ืจื•ื˜ื™ืงื” ื‘ื•ื—ืจ ,ืž"ืขื‘

ื“.ืช ,

10347

ื”ืคื™ื— ืฅืจืคืž

2624761

,ื”ื›ืจื‘ื‘

ืŸืžื“ืœื•ื’ ื”ื ื™ืจืž

ื”ื ื•ืžืž ืชื—ืงื•ืจ

Diprofol 1%, ampoules and vials

ืœื™ืขืค ื‘ื™ื›ืจืž

:

Propofol 10mg/ml

ื”ื™ื•ื•ืชื”ื”

:ืจื™ืฉื›ืชืœ ืชืจืฉื•ืืžื”

Diprofol 1% is a short-acting intravenous general anaesthetic for:

induction and maintenance of general anaesthesia in adults and children > 1 month.

sedation of ventilated patients >16 years of age in the intensive care unit.

sedation for diagnostic and surgical procedures, alone or in combination with local or

regional anaesthesia in adults and children > 1 month.

ืื™ื ื•ื›ื“ืข

ืœ ืŸื•ืœืขื‘ ืืคื•ืจ

:

4.4 Special warnings and precautions for use

Paediatric population

Diprofol 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

Prescribers should be alert to these events in patients with the above risk factors and

immediately discontinue propofol when the above signs develop.

Additional Precautions

EDTA chelates metal ions, including zinc, and reduces microbial growth rates. The need for

supplemental zinc should be considered during prolonged administration of Diprofol 1%,

particularly in patients who are predisposed to zinc deficiency, such as those with burns,

diarrhoea and/or major sepsis.

ื•ืจืช ืœ๏ฃฟื•ื™ืฉ๏ฃฟืจื˜๏ฃฟื™ื

ืž"ืขื‘

ืจื•ื˜ื™ืงื”

.ื“.ืช

10347

ื”ืคื™ื— ืฅืจืคืž ,

2624761

:ืœื˜

04-8475700

:ืกืงืค

04-8727165

4.5 Interaction with other medicinal products and other forms of interaction

Lower doses of Diprofol 1% may be required where general anaesthesia is used as an

adjunct to regional anaesthetic techniques. Profound hypotension has been reported

following anaesthetic with propofol in patients treated with rifampicin.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

4.8 Undesirable effects

Reproductive system and

breast

disorders

Not known

Priapism

Diprofol 2%, vials

ืœื™ืขืค ื‘ื™ื›ืจืž

:

Propofol 20mg/ml

ื”ื™ื•ื•ืชื”ื”

:ืจื™ืฉื›ืชืœ ืชืจืฉื•ืืžื”

Diprofol 2% is a short-acting intravenous general anaesthetic for:

induction and maintenance of general anaesthesia in adults and children > 3

years.

sedation of ventilated patients >16 years of age in the intensive care unit.

sedation for diagnostic and surgical procedures, alone or in combination with local or

regional anaesthesia in adults and children > 3 years.

ืœ ืŸื•ืœืขื‘ ืื™ื ื•ื›ื“ืข ืืคื•ืจ

:

Advisory statements concerning Intensive Care Unit management

Prescribers should be alert to these events in patients with the above risk factors and

immediately discontinue propofol when the above signs develop.

Additional Precautions

EDTA chelates metal ions, including zinc, and reduces microbial growth rates. The need for

supplemental zinc should be considered during prolonged administration of Diprofol 1%,

particularly in patients who are predisposed to zinc deficiency, such as those with burns,

diarrhoea and/or major sepsis.

ื•ืจืช ืœ๏ฃฟื•ื™ืฉ๏ฃฟืจื˜๏ฃฟื™ื

ืž"ืขื‘

ืจื•ื˜ื™ืงื”

.ื“.ืช

10347

ื”ืคื™ื— ืฅืจืคืž ,

2624761

:ืœื˜

04-8475700

:ืกืงืค

04-8727165

4.5 Interaction with other medicinal products and other forms of interaction

Diprofol 2% 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 Diprofol 2% may be required where general anaesthesia is used as an adjunct

to regional anaesthetic techniques. Profound hypotension has been reported following

anaesthetic with propofol in patients treated with rifampicin.

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 Diprofol 2% (see Section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

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

4.8 Undesirable effects

Reproductive system and

breast

disorders

Not known

Priapism

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