4.1. Therapeutic indications

Propofol 10 mg/ml is a short-acting intravenous anaesthetic for the

- Induction and maintenance of anaesthesia in adults and children from 1 month of age,

- sedation of ventilated patients over 16 years of age during intensive care,

- Sedation of adults or children from 1 month of age for surgical and diagnostic procedures, alone or in combination with local or regional anaesthesia.

4.2. Posology and method of administration

Propofol 10 mg/ml may only be administered by doctors that have been trained in anaesthesiology intensive care. Sedation or anaesthesia with Propofol 10 mg/ml and the surgical or diagnostic procedure may not be performed by the same person.

The cardiac, circulatory and respiratory functions should be continuously monitored (e.g. ECG, pulse oxymetry). The customary equipment for possible accidents during anaesthesia or sedation must be ready for use at all times.

The dosage should be adjusted individually while taking the premedication and the patient's reaction into consideration.

Normally, the additional administration of analgesics is necessary.

Anaesthesia for adults:

Induction of anaesthesia:

For the induction of anaesthesia, Propofol 10 mg/ml is administered, titrated at a speed of 20 - 40 mg propofol every 10 seconds, until unconsciousness occurs.

Most adults less than 55 years of age would normallyrequire a total dose of 1.5 to 2.5 mg propofol/kg of body weight.

For patients in risk groups ASA III and IV, especially in the case of prior cardiac damage and elderly patients, it may be necessary to reduce the total dosage of Propofol 10 mg/ml down to 1 mg propofol/kg body of mass, Whereby Propofol 10 mg/ml is administered at slower infusion speed (approximately 20 mg propofol every 10 seconds).

Maintenance of anaesthesia:

The anaesthesia can be maintained with a long-term infusion or repeated bolus injections of Propofol 10 mg/ml.

Continuous infusion

For maintenance of anaesthesia by means of continuous infusion, the dosage and infusion speed must be adjusted for each individual. Normally, the dosage is 4-12 mg propofol/kg of body mass per hour in order to maintain a satisfactory level of anaesthesia.

In the case of elderly patients in a poor general state of health or with hypovolemia and patients in the risk groups ASA III and IV, the dosage of Propofol 10 mg/ml may be reduced down to 4 mg Propofol/kg of body mass per hour.

Repeated bolus injection

For maintenance of anaesthesia by means of repeated bolus injection, generally 25 - 50 mg propofol (2.5 - 5 ml Propofol 10 mg/ml) are subsequently injected.

Anaesthesia in children from 1 month of age

Induction of anaesthesia

For the induction of anaesthesia, Propofol 10 mg/ml is titrated slowly until clinical signs can be seen that indicate the start of anaesthesia. The dose should be adjusted based on the age and/or body weight. Most children over 8 years of age require approximately 2.5 mg Propofol/kg of body mass for induction of anaesthesia. In the case of younger children, especially those in the age range of 1 month to 3 years, the required dose may be higher (2.5 - 4 mg Propofol/kg of body mass). Lower doses are recommended for patients in the risk groups ASA III and IV (see section 4.4).

Maintenance of anaesthesia

Maintenance of the required depth of anaesthesia can be achieved with the administration of Propofol 10 mg/ml by means of an infusion or repeated bolus administration. The required dosage rates vary considerably among patients, however a satisfactory state of anaesthesia is normally achieved at doses in the range of 9 - 15 mg/kg of body mass per hour. In the case of younger children, especially those in the age range of 1 month to 3 years, the required dose may be higher.

Lower doses are recommended for patients in the risk groups ASA III and IV (see section 4.4).

Sedation of patients over 16 years of age during intensive care:

For the sedation of ventilated patients during intensive care, Propofol 10 mg/ml should be administered as a continuous infusion. The dosage is based on the required depth of sedation. Normally, the desired depths of sedation can be achieved with doses in the range of 0.3 to 4.0 mg propofol/kg of body mass per hour. (see section 4.4).

Propofol 10 mg/ml may not be used for the sedation of children aged 16 years or younger as part of intensive care.

The administration of Propofol 10 mg/ml by means of a TCI system is not recommended for sedation as part of intensive care.

Sedation of adults for surgical and diagnostic procedures:

During the administration of Propofol 10 mg/ml, the patient must be continually monitored for signs of a decrease in blood pressure, respiratory tract obstruction and oxygen deficiency and the customary emergency equipment for accidents must be kept ready.

For induction of anaesthesia, generally 0.5 – 1.0 mg propofol/kg of body mass are administered for 1 -5 minutes. . For the maintenance of anaesthesia, the dosage is determined based on the desired depth of sedation and is generally in the range between 1.5 - 4.5 mg propofol/kg of body mass per hour.

In addition to the infusion, 10 – 20 mg may be injected as a bolus if a quick increase in the depth of sedation is necessary.

A lower dosage and slower administration may be necessary for patients in risk groups ASA III and IV. A lower dosage may also be necessary in patients over 55 years of age.

Note

In the case of elderly patients, smaller doses are required for the induction of anaesthesia with Propofol 10 mg/ml. The patient's general state of health and age should be taken into account. The lowered dose should be administered more slowly and titrated according to the reaction.

Even when using Propofol 10 mg/ml for maintenance of anaesthesia and for sedation, the infusion rate and the selected Propofol concentration in the blood should be decreased.

An additional lowering of the dosage and the infusion rate is necessary for patients in risk groups ASA III and IV. Elderly patients should not be given any bolus injections (individual or multiple), since circulatory and respiratory depression may result.

Sedation of children from 1 month of age for surgical and diagnostic procedures

The dosage and the periods between doses are selected based on the desired depth of sedation and the clinical response. For the induction of sedation, a dose of 1 - 2 mg Propofol/kg of body weight is necessary for most paediatric patients. Maintenance of the sedation is achieved with the titration of Propofol 10 mg/ml via an infusion until the desired depth of sedation is reached. For most patients, 1.5 - 9 mg Propofol /kg of body mass per hour is required. The infusion can be supplemented with bolus administration of up to 1 mg Propofol/kg of body mass, if a rapid increase in the depth of sedation is required.

Lower doses may be necessary for patients in the risk groups ASA III and IV.

Propofol 10 mg/ml may not be used for the sedation of children aged 16 years or younger as part of intensive care.

Method of use

Prior to use, the rubber stopper must be cleaned with alcohol spray or a swab dipped in alcohol. . Opened containers should be destroyed after use. Propofol 10 mg/ml is administered intravenously, either undiluted from plastic syringes or glass vials or as a mixture with 5% glucose solution in PVC bags or glass vials.

Propofol 10 mg/ml does not contain any antimicrobial preservation media and the growth of microorganisms is facilitated due to its composition.

The emulsion must be drawn into a sterile syringe or a sterile administration device under aseptic conditions immediately after breaking the seal on the vial. The administration must be started immediately.

Strict asepsis must be adhered to both for Propofol 10 mg/ml and for the infusion equipment used during the period of the infusion. The addition of drugs or fluids into the ongoing infusion of Propofol 10 mg/ml must occur in close proximity to the cannula.

When using Propofol 10 mg/ml, no bacteria filters may be used.

The content of a vial and the respective infusion system are only intended for a single use in one patient.

Infusion of undiluted Propofol 10 mg/ml:

For an infusion of undiluted Propofol 10 mg/ml, an infusion pump or volumetric pump should be employed.

The duration of an infusion of Propofol 10 mg/ml from one infusion system may not exceed 12 hours, as is customary for fat emulsions. At the end of the infusion, but after 12 hours at the latest, t residual quantities of Propofol 10 mg/ml and the infusion system may not be further used; if necessary, the infusion system must be changed out.

Infusion of diluted Propofol 10 mg/ml:

The infusion of diluted Propofol 10 mg/ml must occur by means of a controllable infusion system (burette or volumetric pump), in order to prevent the accidental administration of larger quantities of Propofol 10 mg/ml.

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

The maximum dilution must not exceed 1 part of Propofol with 4 parts of glucose 50 mg/ml (5%) solution for injection, sodium chloride 9 mg/ml (0.9%) solution for injection or sodium chloride 1.8 mg/ml (0.18%) and glucose 40 mg/ml (4%) solution for injection (minimum concentration 2 mg propofol/ml). The mixture should be prepared aseptically (controlled and validated conditions preserved) immediately prior to administration and must be administered within 12 hours after preparation.

To reduce pain at the injection site lidocaine may be injected immediately before the use of Propofol 10 mg/ml or Propofol 10 mg/ml may be mixed, immediately before use, with preservative free lidocaine injection (20 parts of Propofol 10 mg/ml with up to 1 part of lidocaine 10 mg/ml (1%) solution for injection) under controlled and validated aseptical conditions. The mixture has to be administered within 12 hours after preparation.

For storage conditions after dilution of the medicinal product, see section 6.3.

The muscle relaxants atracurium and mivacurium should not be administered through the same intravenous access as Propofol 10 mg/ml without first rinsing it out.

The vials should be shaken before use.

Duration of use

Propofol 10 mg/ml may only be used in a patient for a maximum of 7 days.

4.3. Contraindications

Do not use Propofol 10 mg/ml

• in the case of hypersensitivity to active substance, soybeans, peanuts, or to any of the other ingredients of the emulsion listed in section 6.1

• for the sedation of patients aged 16 years or younger as part of intensive care (see section 4.4).

4.4. Special warnings and precautions for use

During the use of Propofol 10 mg/ml for sedation for surgical and diagnostic procedures, the patient must be continually monitored for the first signs of a decrease in blood pressure, respiratory tract obstruction and oxygen deficiency.

As is also the case with other sedatives, spontaneous movements of the patient during surgical procedures may occur with the use of Propofol 10 mg/ml for sedation. For procedures that require an immobile patient, these movements may jeopardise the success of the operation.

Misuse and dependency on Propofol has been reported, primarily among healthcare personnel. As with all medications for general anaesthesia, it may not be used without securing an airway; otherwise, there is the risk of deadly respiratory complications.

After the use of Propofol 10 mg/ml, it should be ensured that the patient has fully recovered from the anaesthesia prior to discharge.

In individual cases, a postoperative unconsciousness phase can occur with the use of Propofol 10 mg/ml, which may be accompanied by increased muscle tone. The occurrence of this is dependent on whether or not the patient was previously awake. Even though the patient will spontaneously regain consciousness, an unconscious patient should be kept under intensive observation.

The impairments caused by Propofol 10 mg/ml are usually not observed for longer than 12 hours. When explaining the effect of Propofol 10 mg/ml to the patient, and when making the following recommendations, the doctor should take into consideration the type of procedure, the concomitant medication, the age and the condition of the patient.

• The patient should only return home when accompanied by another person.

• The patient should be made aware of when manual activities or activities requiring dexterity / risky activities (e.g. operating a motor vehicle) can be carried out again.

• The patient should be made aware that taking other sedatives (e.g. benzodiazepine, opiates, alcohol) may prolong and increase the impairments.

As with other intravenous anaesthetics, Propofol 10 mg/ml should be administered in a slower manner than usual and used with particular caution in patients with cardiac, respiratory, renal and hepatic disorders, hypovolemia or who are in a reduced general state of health (see section 4.2).

Heart, circulatory and respiratory insufficiency as well as hypovolaemia should be compensated prior to administration of the drug, if possible.

In the case of patients with severe cardiac damage, Propofol 10 mg/ml must be administered with corresponding caution and in combination with intensive monitoring.

A pronounced drop in blood pressure may necessitate the administration of plasma substitutes, possibly of vasoconstrictors, and slower administration of Propofol 10 mg/ml. The possibility of a massive drop in blood pressure should be taken into consideration for patients with reduced coronary or cerebral perfusion or with hypovolemia. The Propofol clearance is dependent on the blood flow. Therefore, if drugs are used at the same time that reduce the cardiac output, the Propofol clearance will also be reduced.

Propofol does not have a vagolytic effect. The use has been associated with the occurrence of bradycardia with an occasionally severe outcome (cardiac arrest). Therefore, in situations where there is pre-existing high vagal tone or when Propofol 10 mg/ml is administered with other drugs, which may decrease the heart rate, intravenous administration of an anticholinergic agent should be considered before or during anaesthesia with Propofol 10mg/ml.

When using Propofol 10 mg/ml in people with epilepsy, it is possible for a seizure to be triggered.

Before repeated or longer (> 3 hours) use of Propofol in small children (< 3 years of age) and pregnant women, the benefits and risks of the planned procedure should be taken into account, since there are reports of neurotoxicity from preclinical studies; see section 5.3.

Paediatric Population

The use of Propofol 10 mg/ml in newborns is not recommended, since this patient group has not been sufficiently evaluated. Pharmacokinetic data (see section 5.2) indicate that the clearance of Propofol is considerably reduced in newborns and varies widely per individual.. When using doses that are recommended for older children, an overdose occur and lead to severe circulatory and respiratory depression (see section 4.8).

Propofol may not be used for sedation in patients 16 years of age or younger during intensive care, since the safety and efficacy of Propofol has not been validated for sedation in this age group (see section 4.3).

Notes regarding intensive medical care

The use of infusions with Propofol emulsion for sedation as part of intensive care is associated with a series of metabolic disorders and organ failure, which may lead to death.

In addition, combined occurrence of the following undesirable effects has also been reported: metabolic acidosis, rhabdomyolysis, hyperkalaemia, hepatomegaly, renal failure, hyperlipidaemia, heart arrhythmia, Brugada-type ECG (saddle or tent shaped ST segment elevations in the right precordial leads [V1-V3] and concave T waves) and/or quickly progressing heart failure, which was usually not able to be treated with supportive inotropic therapeutic measures.

The combination of these events is also called "Propofol infusion syndrome".

These events were most frequently observed in patients with severe head injuries and in children with respiratory tract infections, which had received higher doses than is foreseen for adults for the purpose of sedation during intensive care.

The following factors are believed to be significant risk factors for the development of this complication:

Low oxygen saturation in tissue, severe neurological damage and/or sepsis; high doses of one or more of the following listed drugs: vasoconstrictors, steroids, inotropic agents and/or Propofol (usually at dosages of > 4 mg Propofol/kg of body mass per hour for more than 48 hours).

The prescribing doctor should be aware of these possible undesired effects in patients with the risk factors described above and immediately discontinue the use of propofol if signs of the symptoms described above occur. All sedatives and drugs, which are used during intensive care, should be titrated in such a way that optimal oxygen supply is ensured and the haemodynamic parameters remain optimised. In the case of these changes in therapy, patients with elevated intracranial pressure should receive an appropriate treatment that supports cerebral perfusion. The treating doctor should make sure that the recommended dosage of 4 mg Propofol/kg of body mass per hour is not exceeded, to the greatest extent possible.

Attention must be paid to lipid metabolism disorders or other disorders, as a result of which fat-containing emulsions should be used with caution.

A check of the lipid metabolism parameters is recommended if Propofol 10 mg/ml is used in patients, where there is the suspicion of elevated blood lipid values. The administration of Propofol 10 mg/ml should be adjusted accordingly if the analysis indicates a lipid metabolism disorder. In the case of patients that are simultaneously receiving parenteral nutrition, the quantity of lipids administered as a result of Propofol 10 mg/ml should be taken into account. 1.0 ml Propofol 10 mg/ml contains 0.1 g of fat.

Additional precautions

Patients with mitochondrial disorders should be treated with caution. These patients could experience an exacerbation of their disease if anaesthesia is used on them or a surgical procedure or intensive care treatment is administered. It is recommended that a normal body temperature be maintained for these patients, that carbohydrates by administered and that they be provided with sufficient fluids. The early signs of an exacerbation of a mitochondrial disorder and Propofol infusion syndrome may be similar.

Propofol 10 mg/ml does not contain any antimicrobial preservation media, and the growth of microorganisms is facilitated due to its composition.

If Propofol 10 mg/ml is administered in combination with lidocaine, it should be noted that lidocaine may not be administered to patients with hereditary acute porphyria.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium- free'

4.5. Interaction with other medicinal products and other forms of interaction

Propofol 10 mg/ml is compatible with other agents for anaesthesia (premedication, muscle relaxants, inhaled anaesthesia, analgesics, local anaesthetics). In the case of regional anaesthesia procedures, smaller doses of Propofol 10mg/ml may be necessary. No indications of severe interactions have been observed. Some of the agents mentioned may decrease the blood pressure or impair respiration , so that there can be cumulative effects with the use of Propofol 10 mg/ml. A pronounced decrease in blood pressure when inducing anaesthesia with Propofol has been reported in patients that were treated with rifampicin.

If opiates are additionally administered prior to the anaesthesia, apnoea can occur more frequently and for a longer period of time.

In patients that take valproate, the necessity of lower doses of Propofol has been observed. In the case of simultaneous use, a reduction of in the propofol dose may be considered.

4.6. Fertility, pregnancy and lactation

Pregnancy

The safety of propofol during pregnancy has not been proven. Therefore, Propofol 10 mg/ml should only be used during pregnancy if absolutely necessary. Propofol 10 mg/ml crosses the placenta and may be associated with the depression of vital functions in newborns (see also section 5.3). Propofol can be employed as anaesthesia in the case of termination of pregnancy.

High dosages (more than 2.5 mg Propofol/kg body mass for induction or 6 mg Propofol/kg of body mass per hour for maintenance of anaesthesia) should be avoided.

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

Breast-feeding

Studies with breast-feeding women have shown that propofol passes into breast milk in small quantities . Therefore, mothers should suspend breast-feeding for up to 24 hours after administration of propofol and discard the corresponding breast milk.

4.7. Effects on ability to drive and use machines

After the administration of Propofol 10 mg/ml, the patient should be observed for an appropriate period of time. Patients should be made aware of fact that the ability to participate in traffic and use machinery may be impaired for some time after the administration of Propofol 10 mg/ml. The impairments caused by Propofol 10 mg/ml are usually not observed for longer than 12 hours (see section 4.4).. The patient may only return home when accompanied by another person and may not drink any alcohol.

4.8. Undesirable effects

The induction and maintenance of anaesthesia and sedation with Propofol is normally gentle with only a few signs of excitation.The most frequently reported undesirable effects are pharmacologically foreseeable effects of anaesthetics / sedatives, such as, for example, hypotension and respiratory depression. The type, severity and frequency of these effects, which were observed in patients during the use of Propofol, are dependent on the patient's state of health, type of procedure and the therapeutic measures taken. The frequency of the occurrence of undesirable effects is based on the following categories:

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); not known (cannot be estimated from the available data).

The following undesirable effects were particularly observed:

System Organ Classes

Indications of Frequency

Undesirable effects

Immune system disorders

Very rare

severe allergic reactions (anaphylaxis), which can include angiooedema, bronchospasm, erythemas and hypotension

Metabolism and nutrition disorders

Not known

Metabolic acidosis5, hyperkalaemia5, hyperlipidaemia5

Psychiatric disorders

Not known

euphoric mood during the waking phase, abuse of the drug and dependency on the drug8

Nervous system disorders

Common

Spontaneous movements and muscle spasms during induction of anaesthesia, headache during the waking phase

Rare

Feeling of dizziness, chills and perception of cold during the waking phase, episodes similar to epilepsy with seizures and opisthotonus during induction, maintenance and the waking phase (very rarely delayed by hours to a few days)

Very rare

postoperative unconsciousness (also see section 4.4)

Not known

Involuntary movements

Cardiac disorders

Common

Bradycardia1

Very rare

Pulmonary oedema

Not known

Arrhythmia5, heart failure 5,7

Vascular disorders

Common

Hypotension2

Uncommon

Thrombosis and phlebitis

Respiratory, thoracic and mediastinal disorders

Common

Hyperventilation and coughing during induction of anaesthesia, temporary apnoea during induction of anaesthesia

Uncommon

Coughing during maintenance therapy

Rare

Coughing during the waking phase

Not known

Respiratory depression (depending on the dosage)

Gastrointestinal tract disorders

Common

Singultation during the induction, nausea and vomiting during the waking phase

Very rare

Pancreatitis

Hepatobiliary disorders

Not known

Hepatomegaly5

Hepatitis, acute hepatic failure10

Musculoskeletal and connective tissue disorders

Not known

Rhabdomyolysis 3,5

Renal and urinary disorders

Very rare

Discolouration of urine after longer periods of administration of Propofol 10 mg/ml

Not known

Renal failure5

Reproductive tract and breast disorders

Very rare

Sexual disinhibition

Not known

Priapism

General disorders and administration site conditions

Very common

Local pain during the first injection4

Common

Hot flushes during the induction of anaesthesia

Very rare

Severe tissue reactions and tissue necrosis9 after erroneous extravascular application

Not known

Local pain, swelling after erroneous extravascular application

Investigations

Not known

Brugada-type ECG5,6

Injury, poisoning and complications as a result of a procedure

Very rare

Postoperative fever

After simultaneous administration of lidocaine, the following side effects can occur: dizziness, vomiting, drowsiness, convulsions, bradycardia, arrhythmia and shock.

Soybean oil may trigger allergic reactions very rarely.

1 Severe bradycardia is rare; in some individual cases, progression up to and including asystole has been reported.

2 Occasionally, a decrease in blood pressure can make volume replacement therapy and a decrease in the speed of administering Propofol 10 mg/ml necessary.

3 Rhabdomyolysis was reported very rarely if Propofol 10 mg/ml was administered in high doses as 4 mg Propofol/kg of body mass per hour for sedation as part of intensive care.

4 This can be avoided for the most part by administering lidocaine simultaneously and by administering the drug in larger veins in the forearm or the cubital fossa.

5 A combination of these events, which is also called "Propofol infusion syndrome", occurs in severely ill patients who often have multiple risk factors for the development of these events (also see section 4.4).

6 Brugada syndrome - elevated ST segment and concave T waves in the ECG.

7 Quickly progressing heart failure (in some cases with a deadly outcome) in adults, which was usually not able to be treated with supportive inotropic therapeutic measures.

8 Misuse and dependency on Propofol, primarily by healthcare personnel.

9 In cases where viability of the tissue was impaired, necrosis has been reported.

10 After both long-and short-term treatment and in patients without underlying risk factors.

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. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

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4.9. Overdose

An overdose can lead to circulatory and respiratory depression. Apnoea requires artificial ventilation. In the case of circulatory depression, the usual measures should be taken of lowering the head position or/and plasma substitution and vasoconstrictors.