Propofol kabi

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROPOFOL KABI

Composition:

Active substance: propofol;

1 ml of emulsion contains 10 mg or 20 mg of propofol;

Excipients: refined soybean oil, medium-chain triglycerides, egg yolk phospholipids, glycerol, oleic acid, sodium hydroxide, water for injections.

Pharmaceutical form. Emulsion for intravenous administration.

Main physicochemical properties: white homogeneous emulsion.

Pharmacotherapeutic group.

Anaesthetics. Agents for general anaesthesia. ATC code N01AX10.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Propofol (2,6-diisopropylphenol) is a short-acting general anesthetic agent with a rapid onset of effect, typically within approximately 30 seconds. Recovery from anesthesia is usually rapid. The mechanism of action, as with other general anesthetic agents, is not fully understood. However, it is believed that propofol exerts its sedative and anesthetic effects by positively modulating the inhibitory function of the neurotransmitter GABA (gamma-aminobutyric acid) through facilitation of the interaction between GABA and ligand-gated GABAA receptors.

Pharmacodynamic properties

When Propofol Kabi is used for induction and maintenance of anesthesia, a reduction in mean arterial pressure and minor changes in heart rate are typically observed. However, hemodynamic parameters generally remain relatively stable during maintenance of anesthesia, and the incidence of adverse hemodynamic reactions is low.

Although respiratory depression may occur following administration of Propofol Kabi, the reactions are generally qualitatively similar to those observed with other intravenous anesthetics and are easily managed in clinical practice.

Propofol Kabi reduces cerebral blood flow, intracranial pressure, and cerebral metabolism. The reduction in intracranial pressure is more pronounced in patients with initially elevated intracranial pressure.

Clinical safety and efficacy

Recovery from anesthesia is usually rapid and characterized by rapid restoration of cognitive functions, with a low incidence of headache, postoperative nausea, and vomiting. Overall, postoperative nausea and vomiting occur less frequently with Propofol Kabi than with inhaled anesthetic agents.

Propofol Kabi does not suppress adrenal cortical hormone synthesis at clinically relevant concentrations.

Paediatric population

Limited data from studies on anesthesia using propofol in children indicate maintenance of safety and efficacy for anesthesia durations up to 4 hours. According to published data, the medicinal product can be used in children undergoing prolonged procedures without changes in safety or efficacy.

Pharmacokinetics.

Absorption

After intravenous administration, approximately 98% of propofol is bound to plasma proteins.

When Propofol Kabi is used for maintenance of anesthesia, blood concentrations asymptotically approach a steady state for a given infusion rate.

Distribution

Propofol is widely distributed and rapidly cleared from the body (total clearance is 1.5–2.0 L/min).

Elimination

The decline in propofol concentrations after a bolus dose or at the end of an infusion can be described by an open three-compartment model, with a very rapid distribution phase (distribution half-life of 2–4 minutes), a rapid elimination phase (elimination half-life of 30–60 minutes), and a slower terminal phase reflecting redistribution of propofol from poorly perfused tissues.

Clearance is achieved via metabolic processes, primarily in the liver, where it is blood flow-dependent, resulting in inactive metabolites—propofol conjugates and the corresponding quinol—which are excreted in the urine.

After a single intravenous dose of 3 mg/kg, propofol clearance per kg body weight increases with patient age as follows: mean clearance is significantly lower in neonates under 1 month of age (n = 25) (20 mL/kg/min) compared to older children (n = 36, age range 4 months – 7 years). Additionally, there was considerable inter-patient variability in this parameter among neonates (range 3.7–78 mL/kg/min). Due to these limited clinical data indicating significant variability, dosing recommendations cannot be provided for this patient group.

Mean propofol clearance in older children after a single bolus dose of 3 mg/kg was 37.5 mL/kg/min (4–24 months) (n = 8), 38.7 mL/kg/min (11–43 months) (n = 6), 48 mL/kg/min (1–3 years) (n = 12), 28.2 mL/kg/min (4–7 years) (n = 10), compared to 23.6 mL/kg/min in adults (n = 6). Due to the limited available data, target-controlled infusion (TCI) for administration of Propofol Kabi 1% is not recommended in children under 2 years of age.

Linearity

When Propofol Kabi is administered within the recommended infusion rate range, the pharmacokinetics of the medicinal product are linear.

Non-clinical safety data

Published animal studies (including primates), using doses that induce light or moderate anesthesia, indicate that administration of anesthetics during periods of rapid brain growth or synaptogenesis may lead to neuronal cell loss in the developing brain, potentially resulting in long-term cognitive deficits. Based on comparisons across species, the risk of such changes is believed to correlate with exposure during the third trimester of pregnancy and the first few months of life, but may persist up to approximately 3 years of age in humans. In neonatal primates, anesthesia exposure of up to 3 hours under conditions maintaining light surgical anesthesia did not increase neuronal cell loss; however, regimens of 5 hours or longer did result in increased neuronal loss. Data from rodent and primate studies on fetal and neonatal effects indicate that neuronal and oligodendrocyte loss is associated with mild but persistent cognitive deficits in learning and memory. The clinical significance of these non-clinical findings is unknown; therefore, physicians should weigh the benefits of appropriate anesthesia in children under 3 years of age and pregnant women requiring surgery against the potential risks suggested by non-clinical data.

Non-clinical data from standard repeated-dose toxicity and genotoxicity studies have not revealed any special hazard for humans. Carcinogenicity studies have not been conducted. No teratogenic effects were observed. Local tolerance studies showed tissue damage at the injection site after intramuscular administration. Paravenous and subcutaneous administration resulted in tissue reactions with inflammatory infiltration and focal fibrosis.

Clinical characteristics.

Indications.

Propofol Kabi 1 %

A short-acting agent for general anesthesia administered intravenously for:

• induction and maintenance of general anesthesia in adults and children older than 1 month of age;
• sedation of patients older than 16 years who are undergoing mechanical ventilation in intensive care units (ICU);
• sedation during diagnostic and surgical procedures, either alone or in combination with locally or regionally acting anesthetic agents, in adults and children older than 1 month of age.

Propofol Kabi 2 %

A short-acting agent for general anesthesia administered intravenously for:

• induction and maintenance of general anesthesia in adults and children older than 3 years of age;
• sedation of patients older than 16 years who are undergoing mechanical ventilation in intensive care units (ICU);
• sedation during diagnostic and surgical procedures, either alone or in combination with locally or regionally acting anesthetic agents, in adults and children older than 3 years of age.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Propofol Kabi 1 % is contraindicated in children under 1 month of age.

Propofol Kabi 2 % is contraindicated in children under 3 years of age.

Propofol Kabi 1 % and 2 % contain soybean oil and therefore should not be used in patients with hypersensitivity to peanuts or soy.

Propofol Kabi 1 % and 2 % are contraindicated for sedation in patients ≤ 16 years of age in intensive care units (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Propofol Kabi has been used in combination with spinal and epidural anesthetics, as well as with commonly used premedications, muscle relaxants, inhalational anesthetics, and analgesics; no cases of pharmacological incompatibility have been observed. When general anesthesia or sedation is used in combination with local anesthetics, lower doses of Propofol Kabi may be required. Cases of pronounced arterial hypotension have been observed when propofol was used for induction of anesthesia in patients taking rifampicin. The hypotensive effect of Propofol Kabi may be enhanced when administered concomitantly with opioid analgesics. This effect may be more pronounced in elderly patients and when agents such as alfentanil are used for infusion.

Concomitant use with other central nervous system (CNS) depressants, such as premedication agents, inhalational anesthetics, and analgesics, may lead to enhanced sedative and anesthetic effects, as well as increased depressive effects of Propofol Kabi on cardiovascular and respiratory function (see section "Special precautions").

Concomitant use of benzodiazepines, parasympatholytics, and inhalational anesthetics leads to prolonged anesthesia and reduced respiratory rate.

Concomitant use of substances that depress the central nervous system (e.g., alcohol, general anesthetics, and narcotic analgesics) leads to enhanced sedative effects.

Combining propofol with parenterally administered central depressants may result in severe respiratory and cardiovascular depression.

Reduced propofol requirements have been observed in patients receiving midazolam. Concomitant administration of propofol and midazolam may lead to enhanced sedation and respiratory depression. When used concomitantly, consideration should be given to reducing the dose of propofol.

After additional premedication with opioids, the sedative effect of propofol may be enhanced and prolonged, and apnea may occur more frequently and last longer.

Transient elevation of blood propofol levels and consequently increased frequency of apnea may be caused by fentanyl administration.

Bradycardia or cardiac arrest may occur after administration of suxamethonium or neostigmine when propofol is used.

Concomitant use of propofol emulsion and cyclosporine may lead to leukoencephalopathy.

Reduced propofol requirements have been observed in patients taking valproate. When used concomitantly, consideration should be given to reducing the dose of propofol.

Special precautions for use.

Propofol Kabi must be administered by a specialist experienced in anaesthesia (or, if necessary, by a physician experienced in intensive care).

Continuous monitoring of the patient’s condition is required. Equipment for maintaining airway patency, artificial ventilation of the lungs, oxygen supply, and other resuscitation measures must be readily available and ready for use at all times. Propofol Kabi must not be administered by the same individual who is performing the diagnostic or surgical procedure.

Cases of abuse and development of drug dependence on Propofol Kabi have been reported, primarily among healthcare professionals. As with other drugs used for general anaesthesia, administration of Propofol Kabi without respiratory support may lead to life-threatening respiratory complications.

When Propofol Kabi is administered for sedation without loss of consciousness during surgical or diagnostic procedures, continuous monitoring of the patient for early signs of arterial hypotension, airway obstruction, and decreased oxygen saturation is essential.

As with other central nervous system (CNS) depressants, involuntary movements may occur in patients receiving Propofol Kabi for sedation during surgical procedures. During procedures requiring immobilization, such movements may pose a risk to the patient.

Sufficient time should elapse before discharge to ensure full recovery of physiological functions after administration of Propofol Kabi. Very rarely, postoperative unconsciousness may occur following use of Propofol Kabi, which may be accompanied by increased muscular tone. This condition may be preceded by a period of insomnia. Although this state resolves spontaneously, appropriate supportive care should be provided to unconscious patients.

Adverse effects caused by Propofol Kabi administration usually resolve within 12 hours. The effects of Propofol Kabi, the nature of the procedure performed, concomitant medication use, patient age, and patient condition should be taken into account when advising patients on:

• the need for being accompanied when leaving the healthcare facility;
• the time required before resuming activities involving complex or hazardous tasks, such as driving vehicles;
• the use of other medicinal products that may depress the central nervous system (e.g., benzodiazepines, opioids, ethanol).

As with other intravenous anaesthetic agents, Propofol Kabi should be used with caution in patients with impaired cardiac, respiratory, renal, or hepatic function, as well as in hypovolemic or debilitated patients. The elimination rate of propofol from blood depends on blood flow intensity; therefore, concomitant administration of drugs that reduce cardiac output will lead to decreased drug clearance.

Propofol Kabi has no pronounced vagolytic activity, but its use has been associated with cases of bradycardia (in some cases profound) and asystole. Consideration should be given to intravenous administration of an anticholinergic agent prior to induction or during maintenance of anaesthesia, especially if there is a risk of vagal dominance or when Propofol Kabi is used concomitantly with other drugs that may cause bradycardia.

Appropriate care should be provided to patients with lipid metabolism disorders and other conditions requiring cautious use of lipid emulsions.

During induction of anaesthesia, arterial hypotension and transient apnoea may occur, depending on the dose, premedication, and concomitant use of other medicinal products.

In individual cases, intravenous fluids may be required to correct arterial hypotension, and the infusion rate of Propofol Kabi may need to be reduced during maintenance of anaesthesia.

There is a risk of seizures when Propofol Kabi is administered to patients with epilepsy.

Delayed epileptic seizures may occur even in non-epileptic patients, with a latency period ranging from several hours to several days.

Patients with epilepsy should receive antiepileptic therapy prior to anaesthesia. Although some studies confirm the efficacy of the drug in treating epilepsy, administration of propofol to such patients may increase the risk of seizures.

Propofol is not recommended for use during electroconvulsive therapy.

Particular attention should be paid to patients with elevated intracranial pressure and low arterial pressure during anaesthesia, as there is a risk of significant reduction in cerebral perfusion pressure.

Paediatric patients

Propofol Kabi is not recommended for use in neonates, as this patient group has not been sufficiently studied. Pharmacokinetic data indicate that clearance in neonates is significantly reduced and exhibits high inter-individual variability. Relative overdose may occur when doses recommended for older children are administered, potentially leading to severe cardiovascular depression.

Propofol Kabi 1% is not recommended for general anaesthesia in children under 1 month of age.

Administration of Propofol Kabi 1% using a target-controlled infusion system is not recommended in children under 2 years of age due to limited data.

Propofol Kabi 2% is not recommended for general anaesthesia in children under 3 years of age.

Propofol Kabi 1% and 2% are not recommended for sedation in intensive care units (ICU) in patients aged ≤16 years, as the safety and efficacy of the drug for sedation in this age group have not been established.

Before repeated or prolonged (>3 hours) use of propofol in young children (<3 years) or pregnant women, the benefits and risks of the proposed procedure should be carefully weighed, as neurotoxicity has been reported in preclinical studies (see section "Preclinical safety data").

Recommendations for use in intensive care unit (ICU) patients

The use of propofol emulsion for infusion for sedation in ICU has been associated with various metabolic disturbances and multi-organ failure that may lead to fatal outcomes. Cases of a combination of adverse events have been reported: metabolic acidosis, rhabdomyolysis, hyperkalaemia, hepatomegaly, renal failure, hyperlipidaemia, cardiac arrhythmia, Brugada-type ECG (ST-segment elevation and convex T-wave), and rapidly progressive cardiac failure usually unresponsive to inotropic support. This combination of events is known as propofol infusion syndrome and is typically observed in patients with severe head injuries and children with respiratory infections who have received doses exceeding the recommended adult dose for ICU sedation.

Key risk factors for developing these events include: tissue hypoxia; severe neurological injury and/or sepsis; administration of high doses of one or more of the following drugs: vasoconstrictors, steroids, inotropes, and/or Propofol Kabi (usually at doses exceeding 4 mg/kg/hour for more than 48 hours).

Healthcare professionals should be prepared for the possible occurrence of these events in patients with the above-mentioned risk factors and must discontinue Propofol Kabi immediately if such signs develop. Doses of all CNS depressants and other drugs used in ICU should be titrated to ensure adequate oxygen delivery and maintenance of haemodynamic parameters. Patients with elevated intracranial pressure should receive appropriate treatment aimed at maintaining adequate cerebral perfusion pressure during these therapeutic changes.

It is advisable not to exceed a dose of 4 mg/kg/hour.

Appropriate care should be provided to patients with lipid metabolism disorders and other conditions requiring cautious use of lipid emulsions.

Monitoring of blood lipid concentrations is recommended when propofol is administered to patients at particular risk of lipid overload. If monitoring results indicate impaired fat clearance, propofol administration should be adjusted accordingly. When other lipid-containing intravenous fluids are administered simultaneously, the dose should be reduced to account for the amount of fat delivered during infusion as part of the propofol formulation; 1.0 mL of Propofol Kabi contains approximately 0.1 g of fat.

If sedation duration exceeds 3 days, lipid concentration monitoring should be performed in all patients.

To reduce injection site pain, lidocaine may be administered immediately before Propofol Kabi 1%, 2%. Alternatively, immediately before administration, Propofol Kabi 1% may be mixed under controlled and verified aseptic conditions with lidocaine injection solution that does not contain preservatives (see section "Instructions for use and dosage").

The mixture must be administered within 6 hours after preparation.

A skin test for lidocaine tolerance should be performed before administration.

Lidocaine for intravenous use is not recommended in patients with hereditary acute porphyria.

The medicinal product contains less than 1 mmol (23 mg) of sodium per 100 mL, i.e., it is essentially sodium-free.

As with other anaesthetic agents, sexual disinhibition may occur during emergence from anaesthesia.

Additional precautions

Patients with mitochondrial diseases should be treated with caution. Exacerbation of the disease may occur during anaesthesia, surgical procedures, and other interventions in ICU. In such patients, normothermia should be maintained, and adequate carbohydrate and fluid supply ensured. Early signs of mitochondrial disease exacerbation and propofol infusion syndrome may be similar.

Propofol Kabi does not contain antimicrobial preservatives and therefore does not prevent microbial growth.

Before administration, the ampoule neck or vial rubber stopper should be disinfected with an alcohol spray or wiped with an alcohol-soaked swab. After use, opened containers must be discarded. Propofol Kabi should be drawn into a sterile syringe or infusion system under aseptic conditions immediately after opening the ampoule or vial. Administration of the medicinal product should begin immediately thereafter. All procedures involving Propofol Kabi and infusion equipment during infusion must be performed under aseptic conditions. Any infusion solutions should be added to the infusion line containing Propofol Kabi immediately before the administration site. The product should not be used with microbial filters.

Propofol Kabi and syringes containing this medicinal product are intended for single use only and for use in a single patient. According to accepted guidelines for other lipid emulsions, a single propofol infusion should not last longer than 12 hours. At the end of the procedure or after 12 hours, whichever comes first, the container with propofol and the infusion line should be discarded and replaced with new ones.

The contents of the primary packaging should be shaken before use. If two layers are visible after shaking, the emulsion must not be used. Only homogeneous preparations and undamaged packaging should be used.

Any unused volume of the medicinal product after administration must be discarded.

Propofol Kabi should not be mixed with other medicinal products before administration, except as specified in the section "Instructions for use and dosage".

Use during pregnancy or breastfeeding.

Pregnancy

The safety of Propofol Kabi during pregnancy has not been established. Propofol Kabi crosses the placenta and may cause depression of vital functions in newborns. Propofol Kabi should not be used in pregnant women except when absolutely necessary. However, the drug may be used for termination of pregnancy. High doses of propofol (more than 2.5 mg/kg body weight for induction or 6 mg/kg body weight/hour for maintenance of anaesthesia) should be avoided.

Animal studies have shown reproductive toxicity (see section "Preclinical safety data").

Lactation

Studies in breastfeeding women have shown that small amounts of Propofol Kabi are excreted in breast milk. Therefore, women should not breastfeed for 24 hours after administration of Propofol Kabi. Milk expressed during this period should be discarded.

Effect on ability to drive or operate machinery.

Patients should be warned that performing complex tasks such as driving vehicles or operating machinery may be impaired for some time after general anaesthesia. Adequate monitoring of the patient should be ensured for a certain period after administration of Propofol Kabi. Patients should be instructed not to drive, operate machinery, or be in potentially hazardous situations. Patients may go home only accompanied and should be instructed not to consume alcohol.

Adverse effects caused by Propofol Kabi administration usually resolve within 12 hours (see section "Special precautions for use").

Method of Administration and Dosage

The dosage of Propofol Kabi should be individually adjusted according to the patient's response and premedication administered.

In general, when using Propofol Kabi, additional analgesic agents are required.

Induction of General Anesthesia

Adults

For induction of anesthesia, Propofol Kabi is titrated according to the patient's response (approximately 20–40 mg of Propofol Kabi every 10 seconds) until clinical signs indicate the onset of general anesthesia.

In most adults under 55 years of age, a total dose of 1.5–2.5 mg of Propofol Kabi/kg body weight is usually required. For patients over 55 years of age, the dose required to achieve general anesthesia is generally lower.

Patients in ASA (American Society of Anesthesiologists) risk groups III and IV, especially those with impaired cardiac function, require a lower dose, and the total dose of Propofol Kabi may be reduced to 1 mg of propofol/kg body weight. Propofol Kabi should be administered more slowly (approximately 2 mL of Propofol Kabi 1% (20 mg propofol) every 10 seconds or approximately 1 mL of Propofol Kabi 2% (20 mg propofol) every 10 seconds).

Elderly Patients

Elderly patients require lower doses of Propofol Kabi for induction of anesthesia. Dose reduction should take into account the patient’s health status and age. The reduced dose should be administered at a slower rate and titrated according to clinical response.

Children

Use of Propofol Kabi 1% for induction of anesthesia is not recommended in children under 1 month of age.

Use of Propofol Kabi 2% for induction of anesthesia is not recommended in children under 3 years of age.

For induction of anesthesia, Propofol Kabi is slowly titrated until clinical signs of anesthesia appear.

Dosage should be adjusted according to the patient’s age and/or body weight. Most patients aged 8 years and older require approximately 2.5 mg of propofol/kg body weight for induction of anesthesia. For younger children, especially those aged 1 month to 3 years, the required dose may be higher (2.5–4 mg of propofol/kg body weight).

Maintenance of General Anesthesia

Adults

Maintenance of general anesthesia can be achieved by continuous infusion or repeated bolus injections of Propofol Kabi 1%, or by continuous infusion of Propofol Kabi 2%.

The required dose for maintenance of general anesthesia is usually in the range of 4–12 mg of propofol/kg body weight/hour. For minor surgical procedures, such as minimally invasive surgery, a reduced maintenance dose of approximately 4 mg of propofol/kg body weight/hour may be sufficient.

Patients with poor general condition, cardiac impairment, hypovolemia, or those in ASA risk groups III and IV may require further dose reduction depending on the patient's condition and anesthetic technique.

When maintaining anesthesia via repeated bolus injections, 25–50 mg of Propofol Kabi 1% (equivalent to 2.5–5 mL of Propofol Kabi 1%) are typically administered sequentially as clinically needed.

Elderly Patients

When using Propofol Kabi for maintenance of anesthesia, the infusion rate or target concentration should be reduced. Patients in ASA risk groups III and IV require even greater dose and infusion rate reductions. Rapid bolus administration (single or repeated) of the drug should be avoided, as it may lead to depression of cardiovascular and respiratory functions.

Children

Use of Propofol Kabi 1% for maintenance of anesthesia is not recommended in children under 1 month of age.

Use of Propofol Kabi 2% for maintenance of anesthesia is not recommended in children under 3 years of age.

For maintenance of anesthesia in children, Propofol Kabi 1% is administered as an infusion or repeated bolus injections, and Propofol Kabi 2% is administered as an infusion.

The required infusion rate may vary significantly between patients, but rates in the range of 9–15 mg of propofol/kg body weight/hour are generally sufficient to achieve adequate depth of anesthesia. For younger children, especially those aged 1 month to 3 years, the required dose may be higher.

Lower doses are recommended for patients in ASA risk groups III and IV (see section "Special Warnings and Precautions for Use").

Use of Propofol Kabi via target-controlled infusion (TCI) systems is not recommended for maintenance of general anesthesia in children.

Sedation of Patients in Intensive Care Units

Adults

For sedation of mechanically ventilated patients in intensive care units, Propofol Kabi should be administered by continuous infusion. The dosage should be determined based on the desired depth of sedation. In most patients, adequate sedation depth is achieved with a dose of 0.3–4.0 mg of propofol/kg body weight/hour (see section "Special Warnings and Precautions for Use"). Infusion rates exceeding 4.0 mg of propofol/kg body weight/hour are not recommended.

Use of Propofol Kabi via target-controlled infusion (TCI) systems is not recommended for sedation of patients in intensive care units.

Elderly Patients

When using Propofol Kabi for sedation, the infusion rate should be reduced. Patients in ASA risk groups III and IV require even greater dose and infusion rate reductions. Rapid bolus administration (single or repeated) of the drug should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory functions.

Children

Propofol Kabi should not be used for sedation of children aged ≤ 16 years who are receiving mechanical ventilation in intensive care units.

Sedation for Diagnostic and Surgical Procedures

Adults

To achieve appropriate sedation during diagnostic and surgical procedures, the infusion rate should be individually adjusted and the dose titrated according to clinical response.

In most patients, sedation can be induced by administering Propofol Kabi at a dose of 0.5–1.0 mg/kg over 1–5 minutes.

Maintenance of sedation is achieved by titrating the dose of Propofol Kabi administered as an infusion to the desired depth of sedation. For most patients, an infusion rate of 1.5–4.5 mg of propofol/kg body weight/hour is sufficient. In addition to the infusion, bolus doses of 10–20 mg of Propofol Kabi (1–2 mL of Propofol Kabi 1%; 0.5–1 mL of Propofol Kabi 2%) may be administered if a rapid increase in sedation depth is required.

Patients over 55 years of age and those in ASA risk groups III and IV may require reduced infusion rates and lower doses.

Elderly Patients

When using Propofol Kabi for sedation, the infusion rate or target concentration should be reduced. Patients in ASA risk groups III and IV require even greater dose and infusion rate reductions. Rapid bolus administration (single or repeated) of the drug should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory functions.

Children

Use of Propofol Kabi 1% for sedation during diagnostic and surgical procedures is not recommended in children under 1 month of age.

Use of Propofol Kabi 2% for sedation during diagnostic and surgical procedures is not recommended in children under 3 years of age.

The sedation dose and infusion rate should be adjusted according to the required depth of sedation and clinical response. In most children, sedation can be induced by administering Propofol Kabi at a dose of 1–2 mg/kg body weight. Maintenance of sedation can be achieved by titrating Propofol Kabi doses during infusion to achieve the desired depth of sedation. Most patients require an infusion rate of up to 1.5–9.0 mg of Propofol Kabi/kg body weight/hour. The infusion may be supplemented with a bolus dose of Propofol Kabi 1% at 1 mg/kg body weight if a rapid increase in sedation depth is required.

Patients in ASA risk groups III and IV may require reduced infusion rates and lower doses.

Method of Administration

Propofol Kabi has no analgesic activity; therefore, concomitant administration of additional analgesic medications is usually necessary.

Propofol Kabi may be used for infusion without dilution.

Propofol Kabi 2% must not be mixed with other injectable or infusion solutions prior to administration.

Propofol Kabi 1% must not be mixed with other injectable or infusion solutions prior to administration, except with 50 mg/mL (5%) glucose infusion solution, 9 mg/mL (0.9%) sodium chloride infusion solution, or 10 mg/mL (1%) preservative-free lidocaine hydrochloride injection solution. The maximum dilution should not exceed 1 part of Propofol Kabi 1% to 4 parts of 50 mg/mL (5%) glucose infusion solution or 9 mg/mL (0.9%) sodium chloride infusion solution (minimum concentration 2 mg of propofol/mL). The mixture must be prepared under aseptic conditions (controlled and validated conditions) immediately before administration. The mixture must be used within 6 hours after preparation.

The final concentration of propofol must not be less than 2 mg/mL.

Dilution may be performed using various infusion control devices, but using only an infusion set does not eliminate the risk of accidental uncontrolled infusion of large volumes of diluted Propofol Kabi 1%. The infusion line should include a burette, drip counter, or volumetric pump. The risk of uncontrolled infusion should be considered when determining the maximum volume of Propofol Kabi 1% in the burette.

When using undiluted Propofol Kabi for maintenance of anesthesia, it is recommended to always use equipment such as a syringe or volumetric infusion pump to control the infusion rate.

Propofol Kabi 1% and 2% may be administered through a Y-connector placed immediately before the infusion site of the following solutions:

• 5% glucose solution for intravenous infusion;
• 0.9% sodium chloride solution for intravenous infusion;
• 4% glucose with 0.18% sodium chloride solution for intravenous infusion.

Propofol Kabi 1% may be pre-mixed with alfentanil injection solution containing 500 mcg/mL alfentanil, at volume ratios from 20:1 to 50:1.

To reduce injection site pain, lidocaine may be administered to the patient immediately before Propofol Kabi 1% or 2%. Alternatively, immediately before administration, Propofol Kabi 1% may be mixed under controlled and validated aseptic conditions with preservative-free lidocaine injection solution (20 parts of Propofol Kabi 1% and one part of 1% lidocaine injection solution). The mixture must be administered within 6 hours after preparation.

A skin test for lidocaine tolerance should be performed before administration. Lidocaine for intravenous use is not recommended in patients with hereditary acute porphyria.

Prior to administration of muscle relaxants based on atracurium or mivacurium, the infusion line should be flushed after Propofol Kabi administration.

Infusion of Undiluted Propofol Kabi

The duration of continuous infusion of Propofol Kabi from a single infusion system must not exceed 12 hours. No later than 12 hours after starting the infusion, the infusion line and container for Propofol Kabi must be removed or replaced with a new system.

Duration of Use

The duration of use must not exceed 7 days.

Table 1

Dilution of Propofol Kabi 1% and co-administration of Propofol Kabi 1% or 2% with other medicinal products or infusion solutions

Method of simultaneous administration	Additive or solvent	Preparation	Precautions
Premixing of Propofol Kabi 1%	5% glucose solution or 0.9% sodium chloride solution for intravenous infusion	Mix 1 part of Propofol Kabi 1% with 1–4 parts of 5% glucose solution or 0.9% sodium chloride solution for intravenous infusion in a PVC infusion bag or a glass infusion bottle. When diluting in a PVC infusion bag, it is recommended that the bag be full and the dilution be performed by replacing a certain volume of infusion solution with an equivalent volume of Propofol Kabi 1%.	Prepare under aseptic conditions immediately before administration. The mixture is stable for up to 6 hours.
	Lidocaine hydrochloride injection solution (1%, preservative-free)	Mix 20 parts of Propofol Kabi 1% with 1 part of 1% lidocaine hydrochloride injection solution.	Prepare the mixture under aseptic conditions immediately before administration. Use only for induction.
	Alfentanil injection solution (500 mcg/mL)	Mix Propofol Kabi 1% with alfentanil injection solution in volume ratios ranging from 20:1 to 50:1.	Prepare the mixture under aseptic conditions; administer within 6 hours after preparation.
Concomitant administration via Y-type connector of Propofol Kabi 1%, 2%	5% glucose solution for intravenous infusion	Concomitant administration via Y-type connector.	Position the Y-type connector immediately before the administration site.
	0.9% sodium chloride solution for intravenous infusion	As specified above.	As specified above.
	4% glucose solution with 0.18% sodium chloride solution for intravenous infusion	As specified above.	As specified above.

Target-controlled infusion (TCI) – administration of Propofol Kabi using infusion pumps

Administration of Propof combustible Kabi using target-controlled infusion systems (TCI systems) is limited to induction and maintenance of anesthesia in adults. It is not recommended for sedation during intensive care or for sedation during surgical and diagnostic procedures.

Propofol Kabi should be administered using a TCI system controlled by appropriate software. The user must be familiar with the instructions and with the administration of Propofol Kabi using TCI systems.

The system enables the anesthesiologist to achieve the desired speed of induction and depth of anesthesia by programming and adjusting the target (predefined) concentration of propofol in plasma and/or at the effect site.

Different operational modes of various infusion systems must be taken into account. For example, a TCI system may require that the initial concentration of propofol in the patient's blood be zero.

For this reason, patients who have previously received propofol may require a lower initial target concentration during TCI. Similarly, it is not recommended to resume TCI system operation in the previous mode after it has been switched off.

Recommended target concentrations of propofol are provided below.

Due to variability in the pharmacokinetics and pharmacodynamics of propofol among patients, the target concentration should be titrated according to the patient's response to achieve the required depth of anesthesia, regardless of whether premedication was administered.

Induction and maintenance of anesthesia using TCI

In adult patients under 55 years of age, anesthesia is usually achieved at propofol target concentrations in the range of 4–8 µg/mL. An initial target concentration of 4 µg/mL is recommended for patients who have received premedication and 6 µg/mL for those without premedication. The induction time at these target concentrations is typically within 60–120 seconds. Higher target concentrations will allow earlier induction of anesthesia but may be associated with more pronounced cardiovascular and respiratory depression.

For patients aged 55 years and older and for those in ASA risk groups III and IV, a lower initial target concentration should be used. The target concentration can then be gradually increased by 0.5–1.0 µg/mL per minute to achieve gradual induction of anesthesia.

Additional analgesia is usually required. In such cases, the extent of reduction in the target concentration needed to maintain anesthesia will depend on the dose of concomitantly administered analgesics. Target concentrations of propofol in the range of 3–6 µg/mL usually provide adequate anesthesia.

The expected propofol concentration at awakening is typically in the range of 1.0–2.0 µg/mL. This value is influenced by the dose of analgesics administered during anesthesia maintenance.

Sedation during intensive care (TCI not recommended)

Target blood concentrations of propofol usually required are within the range of 0.2–2.0 µg/mL. Administration should begin at a lower baseline level, which is then titrated to the desired depth according to the patient's response.

Children

Propofol Kabi 1% is contraindicated in children under 1 month of age.

Pharmacokinetic data (see section "Posology and method of administration") indicate that in neonates, drug clearance is significantly reduced and shows high inter-patient variability. Administration of doses recommended for older children may lead to relative overdose and development of severe cardiovascular depression.

Propofol Kabi 2% (20 mg/1 mL) is contraindicated in children under 3 years of age because the drug is difficult to titrate adequately in children due to the small volumes required.

The safety of Propofol Kabi 1% and 2% for sedation (background) in the pediatric intensive care unit in children under 16 years of age has not been demonstrated.

Overdose

Accidental overdose is highly likely to manifest as cardiovascular and respiratory depression. Respiratory depression should be treated with artificial ventilation and oxygen supplementation. In case of cardiovascular depression, the patient should be placed in a horizontal position with low head elevation, and in severe cases, plasma expanders and pressor agents should be administered.

Adverse reactions.

Systemic

Induction and maintenance of anesthesia or sedation usually proceed smoothly, with minimal excitation phase. The most frequently reported adverse reactions are pharmacologically predictable side effects of an anesthetic agent / CNS depressant drug, such as arterial hypotension. The nature, severity, and frequency of adverse events in patients receiving Propofol Kabi may be related to the patient's condition and the surgical or therapeutic procedures being performed.

The following frequency categories are used in Table 2 to classify the incidence of adverse reactions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).

Table 2

Side effects

Organ system class	Frequency	Adverse reactions
Immune system disorders	Very rare	Anaphylaxis, which may include angioedema, bronchospasm, erythema, and hypotension
Metabolism and nutrition disorders	Frequency unknown (9)	Metabolic acidosis (5), hyperkalemia (5), hyperlipidemia (5)
Psychiatric disorders	Frequency unknown (9)	Euphoria, sexual dysfunction. Abuse and drug dependence (8)
Nervous system disorders	Common	Headache during emergence
	Uncommon	Epileptiform movements, including seizures and opisthotonus during induction, maintenance of anesthesia, and emergence, dizziness, tremor, and shivering during emergence from anesthesia
	Very rare	Postoperative unconsciousness
	Frequency unknown (9)	Involuntary movements
Cardiac disorders	Common	Bradycardia (1) and tachycardia during induction
	Very rare	Pulmonary edema
	Frequency unknown (9)	Cardiac arrhythmia (5), cardiac failure (5), (7)
Vascular disorders	Common	Hypotension (2), flushing in children (11)
	Uncommon	Thrombosis and phlebitis
Respiratory, thoracic and mediastinal disorders	Common	Transient apnea, cough, and hiccup during induction
	Frequency unknown (9)	Respiratory depression (dose-dependent)
Gastrointestinal disorders	Common	Nausea and vomiting during emergence
	Very rare	Pancreatitis
Hepatobiliary disorders	Frequency unknown (9)	Hepatomegaly (5) Hepatitis (12), acute liver failure (12)
Musculoskeletal and connective tissue disorders	Frequency unknown (9)	Rhabdomyolysis (3), (5)
Renal and urinary disorders	Very rare	Discoloration of urine after prolonged administration
	Frequency unknown (9)	Renal failure (5)
Reproductive system and breast disorders	Very rare	Sexual disinhibition
	Frequency unknown	Priapism
General disorders and administration site conditions	Very common	Local pain during induction (4)
	Very rare	Tissue necrosis (10) following accidental extravascular injection
	Frequency unknown (9)	Local pain, swelling after accidental extravascular injection
	Common	Withdrawal symptoms in children (11)
Investigations	Frequency unknown (9)	Brugada-type ECG (5), (6)
Injury, poisoning and procedural complications	Very rare	Postoperative fever

1. Cases of severe bradycardia are rare. There have been isolated reports of progression to asystole.
2. In individual cases, intravenous fluids and reduction of the infusion rate of Propofol Kabi may be required to manage hypotension.
3. Rhabdomyolysis has very rarely been reported when Propofol Kabi was administered at doses exceeding 4 mg/kg/hour for sedation in intensive care.
4. This can be minimized by administration into larger diameter veins: forearm veins and antecubital fossa veins. When using Propofol Kabi, local pain can also be reduced by co-administration of lidocaine.
5. The combination of these phenomena is known as propofol infusion syndrome, which may occur in critically ill patients with multiple risk factors for developing these events (see section "Special warnings and precautions for use").
6. Brugada-type ECG: ST-segment elevation and coved T-wave on ECG.
7. Rapidly progressive heart failure (in some cases with fatal outcome) in adults. Heart failure in these cases was usually unresponsive to inotropic support therapy.
8. Abuse and drug dependence on propofol, primarily among healthcare professionals.
9. Frequency unknown, as it cannot be estimated from the available clinical trial data.
10. Necrosis has been reported in cases of compromised tissue viability.
11. After abrupt discontinuation of the drug during intensive therapy.
12. After both long-term and short-term treatment, as well as in patients without underlying risk factors.

Pulmonary edema, arterial hypotension, asystole, bradycardia, seizures, and cases of dystonia/dyskinesia have been reported. Rhabdomyolysis, metabolic acidosis, hyperkalemia, or heart failure, sometimes fatal, have been rarely observed with propofol administered at doses exceeding 4 mg/kg/hour for sedation in intensive care settings. Reports regarding off-label use of Propofol Kabi for anesthesia induction in neonates indicate that cardiovascular and respiratory depression may occur when pediatric dosing regimens are applied.

Local

Local pain, which may occur during the induction phase of anesthesia, can be minimized by concomitant administration of lidocaine (see section "Dosage and administration") and by injection into larger diameter veins: forearm and antecubital fossa veins. Cases of thrombosis and phlebitis are rare. Cases of accidental extravascular administration and animal studies indicate minimal tissue reaction. Intra-arterial administration in animals did not show local tissue effects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

Keep out of reach and sight of children. Store at temperatures not exceeding 25 °C.

Do not freeze.

Incompatibilities.

Propofol Kabi must not be mixed with other medicinal products, except as specified in the section "Dosage and administration".

Packaging.

20 ml in ampoules, pack of 5 in a cardboard box.

50 ml in a vial, stoppered with a rubber plug and sealed with an aluminum cap with a plastic flip-off cap.

50 ml in a vial, stoppered with a rubber plug and sealed with an aluminum cap with a plastic flip-off cap,

1 vial in a cardboard box or 10 vials in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Fresenius Kabi Austria GmbH.

Manufacturer's address.

Haasnerstrasse 36, 8055 Graz, Austria.

Marketing Authorization Holder.

Fresenius Kabi Deutschland GmbH, Germany.

Address of the Marketing Authorization Holder and/or its representative.

Else-Kröner-Strasse 1, 61352 Bad Homburg, Germany.