PROPOFOL 1 % FRESENIUS

לע העדוה לע העדוה לע העדוה ( הרמחה ( הרמחה ( הרמחה

עדימ עדימ עדימ ל ןולעב )תוחיטב ל ןולעב )תוחיטב ל ןולעב )תוחיטב אפור אפור אפור

ןכדועמ( ןכדועמ( ןכדועמ(

.102.50

.102.50

.102.50

:ךיראת

.3.3.3

םושיר רפסמו תילגנאב רישכת םש

:

1g100

ml emulsion for injection or infusion

Propofol 1% Fresenius

121-62-30136-00, 121-62-30136-01, 121-62-30136-02

םושירה לעב םש

Cure Medical & Technical Supply

ה טורפל דעוימ הז ספוט דבלב תורמחה

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

4. CLINICAL

PARTICULARS

4.4 Special warnings

and precautions for use

epileptic

Delayed epileptiform attacks may occur even in non

patients, the delay period ranging from a few hours to several

days.

Cardiac, circulatory or pulmonary insufficiency and

hypovolaemia should be compensated before administration

of propofol.

Propofol should not be administered in patients with advanced

cardiac failure or other severe myocardial disease except with

extreme caution and intensive monitoring.

4.5 Interaction with

other medicinal

products and other

forms of interaction

Due to a higher dosage in patients with severe overweight the

risk of haemodynamic effects on the cardiovascular system

should be taken into consideration.

Before anaesthesia of an epileptic patient, it should be

checked that the patient has received the antiepileptic

treatment.

Patients with a high intracranial pressure

Special care should be recognised in patients with a high

intracranial pressure and a low mean arterial pressure as

there is a risk of a significant decrease of the intracerebral

perfusion pressure.

Concomitant use of benzodiazepines, parasympatholytic

agents or inhalational anaesthetics has been reported to

prolong the anaesthesia and to reduce the respiratory rate.

After additional premedication with opioids, the sedative

effects of propofol may be intensified and prolonged, and

there may be a higher incidence and longer duration of

apnoea.

It should be taken into consideration that concomitant use of

propofol and medicinal products for premedication, inhalation

agents or analgesic agents may potentiate anaesthesia and

cardiovascular side effects. Concomitant use of central

nervous system depressants (e.g. alcohol, general

anaesthetics, narcotic analgesics) will result in intensification

of their sedative effects. When Propofol 1% Fresenius is

combined with centrally depressant drugs administered

4.6 Fertility, Pregnancy

and lactation

4.7 Effects on ability to

drive and use machines

4.8 Undesirable effects

See Table 2

parenterally, severe respiratory and cardiovascular depression

may occur.

After administration of fentanyl, the blood level of propofol may

temporarily

increased

with

increase

rate

apnoea.

Bradycardia and cardiac arrest may occur after treatment with

suxamethonium or neostigmine.

Leucoencephalopathy has been reported with administration

lipid

emulsions

as used for

Propofol

Fresenius

patients receiving cyclosporine.

High doses (more than 2.5 mg propofol/kg bodyweight for

induction or 6 mg propofol/kg bodyweight/h for maintenance of

anaesthesia) should be avoided.

After administration of Propofol 1%, the patient should be kept

under

observation for an

appropriate period of

time. The

patient should be instructed not to drive, operate machinery,

or work in potentially hazardous situations. The patient should

not be allowed to go home unaccompanied, and should be

instructed to avoid consumption of alcohol.

See Table 1

ב"צמ נמוסמ ובש ,ןולעה תו

תורמחהה שקובמה תו בוהצ עקר לע

.

ונמוס תורמחה רדגב םניאש םייוניש )ןולעב(

.טסקטה םוקימב םייוניש אלו יתוהמ ןכות קר ןמסל שי .הנוש עבצב

Table 1

Nervous system

disorders:

Common

(>1/100, <1/10)

Headache during recovery

phase

Rare

0 000, <1/1000)

(>1/1

Epileptiform movements,

including convulsions and

opisthotonus during induction,

maintenance and recovery.

Very rare

(<1/10 000)

Postoperative

unconsciousness

Frequency not known

Involuntary movements

Table 2

Nervous system

disorders:

Common

(>1/100, <1/10)

Headache during recovery

phase

Rare

(>1/10 000, <1/1000)

Epileptiform movements,

including convulsions and

opisthotonus during induction,

maintenance and recovery.

Very rare

(<1/10 000)

Postoperative

unconsciousness

Frequency not known

Involuntary movements

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Propofol 1% Fresenius

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Propofol 1% Fresenius, emulsion for injection or infusion, contains 10 mg/ml propofol

The solution contains as excipients:

Soybean oil and egg lecithin, which are also used in intravenous feeding.

Sodium

It contains no preservatives.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Emulsion for injection or infusion

Propofol 1% Fresenius is a white homogeneous emulsion.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Propofol 1% Fresenius is a short-acting intravenous general anaesthetic for

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

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

regional anaesthesia in adults and children >1 month

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

4.2

Posology and method of administration

Propofol 1% Fresenius must only be given in hospitals or adequately equipped day therapy

units by physicians trained in anaesthesia or in the care of patients in intensive care.

Circulatory

respiratory

functions

should

constantly

monitored

(e.g.

ECG,

pulse

oximetry) and facilities for maintenance of patient airways, artificial ventilation, and other

resuscitation facilities should be immediately available at all times.

For sedation during surgical and diagnostic procedures Propofol 1% Fresenius should not be

administered by the same person conducting the surgical or diagnostic procedure.

The dose of Propofol 1% Fresenius emulsion should be individualised based on the response

of the patient and premedications used.

Supplementary analgesic agents are generally required in addition to Propofol 1% Fresenius.

Posology

General anaesthesia in adults

Induction of anaesthesia:

For induction of anaesthesia Propofol 1% Fresenius should be titrated (approximately 20 -

40 mg propofol every 10 seconds) against the response of the patient until 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 propofol/kg

bodyweight.

In patients over this age and in patients of ASA grades III and IV, especially those with

impaired cardiac function, the requirements will generally be less and the total dose of

Propofol 1% Fresenius may be reduced to a minimum of 1 mg propofol/kg bodyweight.

Lower rates of administration of Propofol 1% Fresenius should be used (approximately 2 ml

(20 mg propofol) every 10 seconds).

Maintenance of anaesthesia:

Anaesthesia can be maintained by administering Propofol 1% Fresenius either by continuous

infusion or repeat bolus injections.

For maintenance of anaesthesia generally doses of 4 to 12 mg propofol/kg bodyweight/h

should

given.

reduced

maintenance

dose

approximately

propofol/kg

bodyweight/h may be sufficient during less stressful surgical procedures such as minimal

invasive surgery.

In elderly patients, patients in unstable general conditions, patients with impaired cardiac

function or hypovolaemic patients and patients of ASA grades III and IV the dosage of

Propofol Fresenius may be reduced further depending on the severity

of the patient’s

condition and on the performed anaesthetic technique.

For maintenance of anaesthesia using repeat bolus injections dose increments of 25 to 50 mg

propofol (= 2.5 – 5 ml Propofol 1% Fresenius) should be given according to clinical

requirements.

Rapid bolus administration (single or repeated) should not be used in the elderly as this may

lead to cardiopulmonary depression.

General anaesthesia in children over 1 month of age

Induction of anaesthesia:

For induction of anaesthesia Propofol Fresenius should be titrated slowly until clinical signs

show

onset

anaesthesia.

dose

should

adjusted

according

and/or

bodyweight. Most patients over 8 years of age require approximately 2.5 mg/kg bodyweight

Propofol Fresenius 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 bodyweight).

Maintenance of general anaesthesia:

Anaesthesia can be maintained by administering Propofol Fresenius by infusion or repeated

bolus

injection

maintain

depth

anaesthesia

required.

required

rate

administration varies considerably between patients but rates in the region of 9 - 15 mg/kg/h

usually achieve satisfactory anaesthesia. In younger children, especially between the age of 1

month and 3 years, dose requirements may be higher.

For ASA III and IV patients lower doses are recommended (see also section 4.4).

Sedation for diagnostic and surgical procedures in adult patients

To provide sedation during surgical and diagnostic procedures, doses and administration rates

should be adjusted according to the clinical response. Most patients will require 0.5 - 1 mg

propofol/kg bodyweight over 1 to 5 minutes for onset of sedation. Maintenance of sedation

may be accomplished by titrating Propofol Fresenius infusion to the desired level of sedation.

Most patients will require 1.5 - 4.5 mg propofol/kg bodyweight/h. The infusion may be

supplemented by bolus administration of 10 – 20 mg propofol (1 – 2 ml Propofol 1%

Fresenius) if a rapid increase of the depth of sedation is required.

In patients older than 55 years and in patients of ASA grades III and IV lower doses of

Propofol Fresenius may be required and the rate of administration may need to be reduced.

Sedation for diagnostic and surgical procedures in children over 1 month of age

Doses and administration rates should be adjusted according to the required depth of sedation

and the clinical response. Most paediatric patients require 1 – 2 mg/kg bodyweight propofol

for onset of sedation. Maintenance of sedation may be accomplished by titrating Propofol

Fresenius infusion to the desired level of sedation. Most patients require 1.5 – 9 mg/kg/h

propofol. The infusion may be supplemented by bolus administration of up to 1 mg/kg

bodyweight if a rapid increase of depth of sedation is required.

In ASA III and IV patients lower doses may be required.

Sedation in adults during intensive care

When used to provide sedation for ventilated patients under intensive care conditions, it is

recommended that Propofol Fresenius should be given by continuous infusion. The dose

should be adjusted according to the depth of sedation required. Usually satisfactory sedation

is achieved with administration rates in the range of 0.3 to 4.0 mg propofol/kg bodyweight/h.

Rates of infusion greater than 4.0 mg propofol/kg bodyweight/h are not recommended (see

section 4.4).

Administration of propofol by a target controlled infusion (TCI) system is not advised for

sedation in the intensive care unit (ICU).

Method of administration

For intravenous use.

Propofol 1% Fresenius can be used for infusion undiluted or diluted with 5% w/v glucose

intravenous infusion solution or 0.9% w/v sodium chloride intravenous infusion solution only,

in glass infusion bottles.

When Propofol 1% Fresenius is infused undiluted, it is recommended that equipment such as

burettes, drop counter, syringe pumps or volumetric infusion pumps should always be used to

control infusion rates.

Containers should be shaken before use.

Use only homogeneous preparations and undamaged containers.

Prior to use, the ampoule neck or rubber membrane should be cleaned using an alcohol spray

or a swab dipped in alcohol. After use, tapped containers must be discarded.

Propofol Fresenius is a lipid containing emulsion without antimicrobial preservatives and may

support rapid growth of micro-organisms.

The emulsion must be drawn aseptically into a sterile syringe or giving set immediately after

opening the ampoule or breaking the vial seal. Administration must commence without delay.

Asepsis must be maintained for both Propofol Fresenius and infusion equipment throughout

the infusion period. Co-administration of other medicinal products or fluids added to the

Propofol Fresenius infusion line must occur close to the cannula site using a Y-piece

connector or a three-way valve.

Propofol Fresenius must not be mixed with other solutions for infusion or injection. But 5%

w/v glucose solution, 0.9% w/v sodium chloride solution or 0.18% w/v sodium chloride and

4% w/v glucose solution may be administered via suitable appendages at the cannula site.

Propofol Fresenius must not be administered via a microbiological filter.

Propofol Fresenius and any infusion equipment containing Propofol 1% Fresenius are for

single

administration in an

individual

patient. After use remaining solution of Propofol 1%

Fresenius has to be discarded.

Infusion of undiluted Propofol 1% Fresenius:

As usual for fat emulsions, the infusion of Propofol Fresenius via one infusion system must

not exceed 12 hours. After 12 hours, the infusion system and reservoir of Propofol Fresenius

must be discarded or replaced if necessary.

Infusion of diluted Propofol 1% Fresenius:

For administering infusion of diluted Propofol 1% Fresenius, burettes, drop counters or

volumetric infusion pumps should always be used to control infusion rates and to avoid the

risk of accidentally uncontrolled infusion of large volumes of diluted Propofol 1% Fresenius.

This risk has to be taken into account when the decision for the maximum dilution in the

burette is made.

The maximum dilution must not exceed 1 part of Propofol 1% Fresenius with 4 parts of 5%

w/v glucose solution or 0.9% w/v sodium chloride solution (minimum concentration 2 mg

propofol per ml). The mixture should be prepared aseptically (controlled and validated

conditions preserved) immediately prior to administration and must be administered within 6

hours after preparation.

Propofol 1% Fresenius must not be mixed with other solutions for infusion or injection.

However, co-administration of a 5% w/v glucose solution or 0.9% w/v sodium chloride

solution or 0.18% w/v sodium chloride and 4% w/v glucose solution with Propofol 1%

Fresenius is permitted via a Y-piece connector close to the injection site.

To reduce pain on the injection site, lidocaine may be injected immediately before the use of

Propofol 1% Fresenius (see section 4.4). Alternatively, Propofol 1% Fresenius may be mixed,

immediately for use, with preservative free lidocaine injection (20 parts of Propofol 1%

Fresenius with up to 1 part of 1% lidocaine injection solution) under controlled and validated

aseptical conditions. The mixture has to be administered within 6 hours after preparation.

Muscle relaxants like atracurium and mivacurium should only be administered after flush of

the same infusion site used for Propofol Fresenius.

Propofol may also be used by Target Controlled Infusion. Due to the different algorithms

available on the market for dosage recommendations please refer to the instructions for use

leaflet of the device manufacturer.

Duration of administration

The duration of administration must not exceed 7 days.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Propofol 1% Fresenius contains soybean oil and should not be used in patients who are

hypersensitive to peanut or soya.

Propofol 1% Fresenius must not be used in patients of 16 years of age or younger for sedation

for intensive care (see section 4.4).

4.4

Special warnings and precautions for use

Propofol 1% Fresenius should be given by those trained in anaesthesia (or, where appropriate,

doctors trained in the care of patients in Intensive Care).

Patients should be constantly monitored and facilities for maintenance of a patent airway,

artificial ventilation, oxygen enrichment and other resuscitative facilities should be readily

available at all times. Propofol 1% Fresenius should not be administered by the person

conducting the diagnostic or surgical procedure.

Abuse

dependence

Propofol

Fresenius,

predominantly

health

care

professionals, have been reported. As with other general anaesthetics, the administration of

Propofol 1% Fresenius without airway care may result in fatal respiratory complications.

When

Propofol

Fresenius

administered

conscious

sedation,

surgical

diagnostic

procedures,

patients

should

continually

monitored

early

signs

hypotension, airway obstruction and oxygen desaturation.

As with other sedative agents, when Propofol 1% Fresenius is used for sedation during

operative procedures, involuntary patient movements may occur. During procedures requiring

immobility these movements may be hazardous to the operative site.

An adequate period is needed prior to discharge of the patient to ensure full recovery after use

of Propofol 1% Fresenius. Very rarely the use of Propofol 1% Fresenius may be associated

with

development

period

post-operative

unconsciousness,

which

accompanied by an increase in muscle tone. This may or may not be preceded by a period of

wakefulness. Although recovery is spontaneous, appropriate care of an unconscious patient

should be administered.

Propofol 1% Fresenius induced impairment is not generally detectable beyond 12 hours. The

effects of Propofol 1% Fresenius, the procedure, concomitant medications, the age and the

condition of the patient should be considered when advising patients on:

The advisability of being accompanied on leaving the place of administration

The timing of recommencement of skilled or hazardous tasks such as driving

The use of other agents that may sedate (e.g., benzodiazepines, opiates, alcohol.)

As with other intravenous anaesthetic agents, caution should be applied in patients with

cardiac, respiratory, renal or hepatic impairment or in hypovolaemic or debilitated patients.

Propofol 1% Fresenius clearance is blood flow dependent, therefore, concomitant medication

that reduces cardiac output will also reduce Propofol 1% Fresenius clearance.

Propofol 1% Fresenius lacks vagolytic activity and has been associated with reports of

bradycardia (occasionally profound) and also asystole. The intravenous administration of an

anticholinergic agent before induction, or during maintenance of anaesthesia should be

considered, especially in situations where vagal tone is likely to predominate, or when

Propofol 1% Fresenius 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 Propofol 1% Fresenius.

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 e.g., alcohol, general anaesthetics,

narcotic analgesics will result in accentuation of their sedative effects. When Propofol 1%

Fresenius is combined with centrally depressant drugs administered parenterally, severe

respiratory and cardiovascular depression may occur. It is recommended that Propofol 1%

Fresenius 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 Propofol 1% Fresenius during the period of anaesthetic maintenance.

When Propofol 1% Fresenius 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 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.

Paediatric population

The use of Propofol 1% Fresenius is not recommended in newborn infants as this patient

population has not been fully investigated. Pharmacokinetic data (see section 5.2) indicate

that clearance is considerably reduced in neonates and has a very high inter-individual

variability. Relative overdose could occur on administering doses recommended for older

children and result in severe cardiovascular depression.

Propofol 1% Fresenius 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 has been associated with a constellation

of metabolic derangements and organ system failures that may result in death. Reports have

been

received

combinations

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. Combinations of these events

have been referred to as the 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 Propofol 1% Fresenius (usually at dose rates greater than 4 mg/kg/h for more than 48

hours).

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

immediately discontinue propofol when the above signs develop. All sedative and therapeutic

agents used in the intensive care unit (ICU), 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.

Appropriate care should be applied in patients with disorders of fat metabolism and in other

conditions where lipid emulsions must be used cautiously.

It is recommended that blood lipid levels should be monitored if propofol is administered to

patients thought to be at particular risk of fat overload. Administration of propofol should be

adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from

the body. If the patient is receiving other intravenous lipid concurrently, a reduction in

quantity should be made in order to take account of the amount of lipid infused as part of the

propofol formulation; 1.0 mL of Propofol 1% Fresenius contains approximately 0.1 g of fat.

This medicinal product contains less than 1 mmol (23 mg) sodium per 100 ml, i.e. essentially

"sodium - free".

Additional precautions

Caution should be taken when treating patients with mitochondrial disease. These patients

may be susceptible to exacerbations of their disorder when undergoing anaesthesia, surgery

and ICU care. Maintenance of normothermia, provision of carbohydrates and good hydration

recommended

such

patients.

early

presentations

mitochondrial

disease

exacerbation and of the ‘propofol infusion syndrome’ may be similar.

Propofol 1% Fresenius 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 Propofol 1%

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

burns, diarrhoea and/or major sepsis.

When Propofol 1% Fresenius is to be aspirated, it must be drawn aseptically into a sterile

syringe or giving set immediately after opening the ampoule or breaking the vial seal.

Administration must commence without delay. Asepsis must be maintained for both Propofol

1% Fresenius and infusion equipment throughout the infusion period. Any infusion fluids

added to the Propofol 1% Fresenius line must be administered close to the cannula site.

Propofol 1% Fresenius must not be administered via a microbiological filter.

Propofol 1% Fresenius and any syringe containing Propofol 1% Fresenius are for single use in

an individual patient. In accordance with established guidelines for other lipid emulsions, a

single infusion of propofol must not exceed 12 hours. At the end of the procedure or at 12

hours, whichever is the sooner, both the reservoir of propofol and the infusion line must be

discarded and replaced as appropriate.

4.5

Interaction with other medicinal products and other forms of interaction

Propofol 1% Fresenius has been used in association with spinal and epidural anaesthesia and

with commonly used premedicants, neuromuscular blocking drugs, inhalational agents and

analgesic agents; no pharmacological incompatibility has been encountered. Lower doses of

Propofol 1% Fresenius may be required where general anaesthesia is used as an adjunct to

regional

anaesthetic

techniques.

Profound

hypotension

been

reported

following

anaesthetic induction 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 Propofol 1% Fresenius (see section 4.4).

A need for lower propofol doses has been observed in patients taking valproate. When used

concomitantly, a dose reduction of propofol may be considered.

4.6

Fertility, pregnancy and lactation

Pregnancy

The safety of Propofol 1% Fresenius during pregnancy has not been established. Studies in

animals have shown reproductive toxicity (see section 5.3). Propofol 1% Fresenius should not

be given to pregnant women except when absolutely necessary. Propofol 1% Fresenius can,

however, be used during an induced abortion.

Obstetrics

Propofol 1% Fresenius crosses the placenta and can cause neonatal depression. It should not

be used for obstetric anaesthesia unless clearly necessary.

Breast-feeding

Studies of breast-feeding mothers showed that small quantities of Propofol 1% Fresenius are

excreted

human

milk.

Women

should

therefore

breast-feed

hours

after

administration

Propofol

Fresenius.

Milk

produced

during

this

period

should

discarded.

4.7

Effects on ability to drive and use machines

Propofol 1% Fresenius 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

Propofol 1% Fresenius induced impairment is not generally detectable beyond 12 hours (see

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 Propofol 1% Fresenius 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 (≥1/10), common (≥1/100 to <1/10), uncommon ((≥1/1,000 to <1/100),

rare (≥1/10,000 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 – may include

angioedema, bronchospasm,

erythema and hypotension

Metabolism and Nutritional

disorder:

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

dependant)

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 are rare. There have been isolated reports of progression to asystole.

Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of

Propofol.

Very rare reports of rhabdomyolysis have been received where Propofol has been given at doses greater

than 4 mg/kg/hr for ICU sedation.

May be minimised by using the larger veins of the forearm and antecubital fossa. With Propofol 1 %

Fresenius local pain can also be minimised by the co-administration of lidocaine.

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.

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 to inotropic supportive treatment.

Abuse of and drug dependence on propofol, predominantly by health care professionals.

Not known as it cannot be estimated from the available clinical trial data.

(10)

Necrosis has been reported where tissue viability has been impaired.

Dystonia/dyskinesia have been reported.

Local

The local pain which may occur during the induction phase of Propofol 1% Fresenius

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

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/

and emailed to the Registration Holder’s Patient Safety Unit at:

drugsafety@neopharmgroup.com

4.9

Overdose

Accidental overdosage is likely to cause cardiorespiratory depression. Respiratory depression

should be treated with artificial ventilation

with oxygen

. Cardiovascular depression would

require lowering the patient’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 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 GABA

receptors.

Pharmacodynamic properties

In general, falls in mean arterial blood pressure and slight changes in heart rate are observed

when Propofol 1% Fresenius 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 Propofol 1%

Fresenius, any effects are qualitatively similar to those of other intravenous anaesthetic agents

and are readily manageable in clinical practice.

Propofol 1% Fresenius 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

Propofol 1% Fresenius than following anaesthesia with inhalational agents. There is evidence

that this may be related to a reduced emetic potential of propofol.

Propofol 1% Fresenius, at the concentrations likely to 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 Propofol 1% Fresenius 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 1.5

– 2 litres/minute).

Elimination

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.

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 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).

Linearity

The pharmacokinetics are linear over the recommended range of infusion rates of Propofol

1% Fresenius.

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 the period of rapid brain

growth or synaptogenesis results in cell loss in the developing brain that can be associated

with prolonged cognitive deficiencies. 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. The clinical significance of these

nonclinical 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.

Propofol is a drug on which extensive clinical experience has been obtained. All relevant

information

prescriber

provided

elsewhere

Summary

Product

Characteristics

.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Water For Injections

Soya-bean oil

Glycerol

Egg lecithin

Oleic acid

Sodium Hydroxide

6.2

Incompatibilities

The neuromuscular blocking agent, atracurium should not be given through the same

intravenous line as Propofol 1% Fresenius without prior flushing.

This medicinal product must not be mixed with other medicinal products except those

mentioned in section 6.6.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

Administration systems with undiluted Propofol Fresenius should be replaced after 12 hours.

Dilutions

with

glucose

solution

0.9%

sodium

chloride

solution

admixture with 1% preservative free lidocaine injection solution (at least 2 mg propofol per

should

prepared

aseptically

(controlled

validated

conditions

preserved)

immediately before administration and administration should be completed within 6 hours

after dilution.

After opening the product must be used immediately.

6.4

Special precautions for storage

Do not store above 25 °C. Do not freeze.

6.5

Nature and contents of container

Colourless glass ampoule(s) (type I) of 20 ml

Colourless glass vial(s) (type II) of 50 ml with a bromobutyl rubber closure

Colourless glass vial(s) (type II) of 100 ml with a bromobutyl rubber closure

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

Propofol 1% (10 mg/1 ml) Fresenius should not be mixed prior to administration with

injection or infusion solutions other than 5% w/v glucose solution or 0.9% w/v sodium

chloride solution or 1% preservative free lidocaine injection solution (see also section 4.2

Posology and method of administration). Final propofol concentration must not be below 2

mg/ml.

For single use. Any unused emulsion must be discarded.

Containers should be shaken before use.

If two layers can be seen after shaking the emulsion should not be used.

Use only homogeneous preparations and undamaged containers.

Prior to use, the ampoule neck or rubber membrane should be cleaned using an alcohol spray

or a swab dipped in alcohol. After use, tapped containers must be discarded.

7.

MANUFACTURER

Fresenius Kabi Deutschland GmbH, Germany.

8.

REGISTRATION NUMBERS

121-62-30136

9. REGISTRATION HOLDER:

Cure Medical & Technical Supply,

6 Hashiloach St., P.O.B 3340, Petah Tikva.

Revised in January 2021