Propofol-novofarm

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROPOFOL-NOVOFARM (PROPOFOL-NOVOFARM)

Composition:

Active substance: propofol;

1 ml of emulsion contains 10 mg of propofol;

Excipients: soybean oil, refined; egg phospholipids (lecithin); glycerol; sodium oleate; sodium hydroxide; water for injections.

Pharmaceutical form. Emulsion for infusion.

Main physicochemical properties: white or almost white homogeneous emulsion, free from solid particles and large oil droplets.

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 anesthetics, is not fully understood. However, it is believed that propofol produces its sedative and anesthetic effects by positively influencing the inhibitory function of the neurotransmitter GABA (gamma-aminobutyric acid) through facilitation of the interaction of GABA with ligand-activated GABAA receptors.

Pharmacodynamic Properties

When propofol 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 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, such reactions are qualitatively similar to those observed with other intravenous anesthetic agents and are easily managed in clinical practice.

Propofol 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 quick restoration of cognitive functions, with a low incidence of headache, postoperative nausea, and vomiting.

Postoperative nausea and vomiting occur less frequently with propofol compared to inhaled anesthetic agents. Evidence suggests this may be related to the reduced emetogenic potential of propofol.

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

Paediatric Population

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

Pharmacokinetics.

Absorption

When propofol is administered for maintenance of anesthesia, blood concentration asymptotically approaches 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 concentration after a bolus dose or termination of infusion can be described by an open three-compartment model, with a very rapid distribution phase (distribution half-life: 2–4 minutes), a rapid elimination phase (elimination half-life: 30–60 minutes), and a slower terminal phase reflecting redistribution of propofol from poorly perfused tissues.

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

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

Mean propofol clearance in older children after a single 3 mg/kg bolus dose 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).

Linearity

When propofol 1% is administered within the recommended infusion rate range, the pharmacokinetics of the drug are linear.

Preclinical Safety Data

Published animal studies (including in primates), using doses producing light or moderate anesthesia, indicate that administration of anesthetics during periods of rapid brain growth or synaptogenesis leads to degeneration of developing brain cells, which may result in long-term cognitive impairment. The clinical significance of these preclinical findings is unknown.

Published results from animal studies demonstrate that administration of anesthetic agents during periods of rapid brain growth or synaptogenesis leads to widespread neuronal and oligodendrocyte loss in the developing brain, as well as morphological changes in synapses and neurogenesis. 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 several months of life, but may persist up to approximately three years of age in humans. In neonatal primates, anesthesia exposure for up to 3 hours under conditions of light surgical anesthesia did not lead to increased neuronal cell loss, whereas regimens of 5 hours or longer did result in such increases. Data on effects in fetuses and neonates in rodents and primates indicate that neuronal and oligodendrocyte loss is associated with mild but persistent cognitive deficits in learning and memory. The clinical significance of these preclinical data is unknown; therefore, physicians should weigh the benefits of appropriate anesthesia in children under 3 years of age and in pregnant women requiring surgery against the potential risks suggested by preclinical data.

Propofol is a medicinal product with extensive clinical experience. All necessary information for the prescribing physician is provided in the medicinal product’s instructions for medical use.

Clinical characteristics.

Indications.

For short-acting general anesthesia, the medicinal product is administered intravenously for:

• induction and maintenance of general anesthesia in adults and children aged > 1 month;
• sedation during diagnostic and surgical procedures, either alone or in combination with local or general anesthetic agents, in adults and children aged > 1 month;
• sedation of patients aged > 16 years who are undergoing mechanical ventilation in the intensive care unit (ICU).

Contraindications.

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

Children under 1 month of age (for induction and maintenance of general anesthesia).

The medicinal product contains soybean oil and is not intended for use in patients with hypersensitivity to peanuts or soy.

The medicinal product should not be used for sedation in patients aged ≤ 16 years in the intensive care unit (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Propofol has been used in combination with agents for spinal and epidural anesthesia, as well as with commonly used premedications, muscle relaxants, inhalational anesthetics, and analgesics; no cases of pharmacological incompatibility have been observed. When used for general anesthesia or sedation in combination with local anesthetics, lower doses of propofol may be required.

Cases of pronounced hypotension have been observed when propofol was used for anesthesia induction in patients receiving rifampicin.

The hypotensive effect of propofol may be enhanced when administered concomitantly with opioid analgesics. This effect may be more pronounced in elderly patients. After additional premedication with opioids, the sedative effect of propofol may be intensified and prolonged, and the frequency and duration of apnea may be increased.

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

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

Special precautions for use.

Propofol-Novopharm is indicated for use in healthcare facilities.

The medicinal product must be administered by a specialist experienced in anesthesia (or, if necessary, a physician experienced in intensive care unit practice).

Continuous patient monitoring is required. Equipment for maintaining airway patency, artificial ventilation of the lungs, oxygen supply, and other resuscitation measures must always be available and ready for immediate use. Propofol-Novopharm 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 have been reported, primarily among healthcare professionals. As with other medicinal products used for general anesthesia, administration of propofol emulsion without respiratory support may lead to life-threatening respiratory complications.

When propofol 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 should be performed.

As with other central nervous system (CNS) depressants, involuntary movements may occur in patients receiving propofol 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 bodily functions after propofol administration. Very rarely, postoperative unconsciousness may occur following propofol use, which may be accompanied by increased muscular tone. This condition may be preceded by a period of insomnia. Although this condition resolves spontaneously, appropriate supportive care should be provided to patients who lose consciousness.

Typically, functional impairments caused by propofol administration are no longer detectable within 12 hours. The effects of propofol, the nature of the procedure performed, concomitant medication use, patient age, and patient condition should be taken into account when providing advice regarding:

• the advisability of leaving the healthcare facility accompanied by another person;
• 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, ethyl alcohol).

As with other intravenous anesthetic agents, propofol should be used with caution in patients with impaired cardiac, respiratory, renal, or hepatic function, as well as in hypovolemic or debilitated patients. Propofol clearance depends on blood circulation; therefore, concomitant use of medicinal products that reduce cardiac output will lead to decreased propofol clearance.

Propofol does not have pronounced vagolytic activity; however, administration of the drug has been associated with cases of bradycardia (in some cases, profound) and asystole. Consideration should be given to the intravenous administration of an anticholinergic medicinal product prior to induction or during maintenance of anesthesia, particularly in cases of potential vagal dominance or when propofol is used concomitantly with other medicinal products that may cause bradycardia.

As with other intravenous anesthetics and CNS depressants, patients should be advised to avoid alcohol consumption before and for at least 8 hours after propofol administration.

Particular caution should be exercised during bolus administration of the medicinal product in patients with acute respiratory insufficiency or respiratory depression.

Concomitant use with medicinal products that depress the central nervous system, such as ethyl alcohol, general anesthetics, and narcotic analgesics, will enhance CNS depression. Combined use of propofol with parenterally administered CNS depressants may result in severe depression of respiratory and cardiovascular function. It is recommended to administer propofol after analgesic administration, and the dose should be carefully titrated according to clinical response (see section "Interaction with other medicinal products and other types of interactions").

During induction of anesthesia, dose-dependent hypotension and transient apnea may occur, depending on the dose, premedication, and concomitant use of other medicinal products.

In some cases, intravenous fluids may be required to treat hypotension, and the rate of propofol infusion should be reduced during the maintenance phase of anesthesia.

There is a risk of seizure occurrence when administering propofol to patients with epilepsy.

Appropriate management is required for patients with lipid metabolism disorders and conditions requiring cautious use of lipid emulsions (see section "Method of administration and dosage").

Use during electroconvulsive therapy is not recommended.

As with other anesthetic agents, sexual disinhibition may occur during emergence from anesthesia.

Before repeated or prolonged (>3 hours) use of propofol in young children (<3 years of age) 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 patients has been associated with various metabolic disturbances and multi-organ failure that may lead to fatal outcomes. Cases have been reported of a combination of the following adverse events: metabolic acidosis, rhabdomyolysis, hyperkalemia, hepatomegaly, renal failure, hyperlipidemia, cardiac arrhythmia, Brugada-type ECG (ST-segment elevation and convex T-wave), and rapidly progressive heart failure, usually unresponsive to inotropic support therapy. 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 dosage for ICU sedation.

Main risk factors for developing these events include: reduced tissue oxygen delivery; severe neurological injury and/or sepsis; and use of high doses of one or more of the following medicinal products: vasoconstrictors, steroids, inotropes, and/or propofol (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 immediately upon their development. Doses of all CNS depressants and other medicinal products used in the ICU should be titrated to ensure adequate oxygen delivery and maintenance of hemodynamic 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 management is required for patients with impaired lipid metabolism and other conditions requiring cautious use of lipid emulsions.

Monitoring of blood lipid concentrations is recommended when administering propofol to patients at special risk of lipid overload. If monitoring results indicate impaired fat elimination from the body, propofol administration should be adjusted accordingly. If other lipid-containing intravenous fluids are required simultaneously, the dose should be reduced to account for the amount of fat administered as part of the propofol formulation; 1.0 mL of the medicinal product contains approximately 0.1 g of fat.

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

Additional precautions.

The medicinal product should be used with caution in patients with mitochondrial disorders. In such patients, anesthesia, surgical procedures, and other ICU interventions may trigger disease exacerbation. Normothermia, carbohydrate supply, and adequate fluid intake should be maintained in these patients. Early signs of mitochondrial disease exacerbation and propofol infusion syndrome may be similar.

The medicinal product does not contain antimicrobial preservatives and therefore does not prevent microbial growth.

Propofol emulsion should be drawn into a sterile syringe or infusion system under aseptic conditions immediately after opening the vial. Administration of the medicinal product should begin immediately thereafter. All operations involving propofol emulsion and infusion equipment should be performed under aseptic conditions during infusion. Any infusion solutions should be added directly to the infusion line containing propofol emulsion immediately before the site of administration. The medicinal product should not be used in systems with microbial filters.

The contents of the vial, prepared syringe, or corresponding infusion system are intended for single use in one patient only. According to accepted guidelines for the use of 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 must be discarded and replaced with new ones.

The contents of the primary packaging should be shaken before use.

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

Before administration, the medicinal product should not be mixed with injectable or infusion solutions except 5% glucose solution or lidocaine injection solution (see section "Method of administration and dosage").

Use during pregnancy or breastfeeding.

Pregnancy

The safety of the medicinal product during pregnancy has not been established. Animal studies have demonstrated reproductive toxicity (see section "Preclinical safety data"). The medicinal product should not be administered to pregnant women except in cases of absolute necessity. Propofol crosses the placental barrier and may cause depression in newborns. However, the medicinal product may be used for induced abortion.

High doses (more than 2.5 mg/kg for induction or 6 mg/kg/hour for maintenance of anesthesia) should be avoided.

Breastfeeding

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

Ability to affect reaction speed when driving vehicles or operating machinery.

Patients should be warned that performing complex tasks, such as driving vehicles or operating automated machinery, may be impaired for some time after general anesthesia.

Typically, functional impairments caused by propofol administration are no longer detectable within 12 hours (see section "Special precautions for use").

Method of Administration and Dosage.

Dosing.

Induction of General Anesthesia.

Adults

For patients with or without premedication, the dose of propofol should be titrated (administered to adult patients as a bolus injection or infusion at approximately 4 mL [40 mg] every 10 seconds) according to clinical response until clinical signs of anesthesia appear. For most adult patients under 55 years of age, a dose of 1.5–2.5 mg/kg of propofol is generally sufficient. The total required dose can be reduced by decreasing the rate of administration (2–5 mL/min [20–50 mg/min]). For patients over 55 years of age, the dose required to achieve general anesthesia is generally lower. Patients with an ASA score of 3 or 4 (American Society of Anesthesiologists classification) should receive the drug at a slower rate of administration (approximately 2 mL [20 mg] every 10 seconds).

Elderly Patients

Elderly patients require lower doses of propofol for induction of anesthesia. Dose reduction should take into account the patient's health status and age. Reduced doses should be administered at a slower rate and titrated according to clinical response.

Pediatric Population

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

For induction of anesthesia in children aged 1 month and older, the dose of propofol should be slowly titrated until clinical signs of anesthesia appear. The dose should be adjusted according to age and/or body weight. For most patients aged 8 years and older, a dose of approximately 2.5 mg/kg body weight of propofol is sufficient for induction of anesthesia. Younger children, especially those aged 1 month to 3 years, may require higher doses (2.5–4 mg/kg body weight).

Patients with an ASA score of 3 or 4 are recommended to receive lower doses (see section "Special Instructions").

Maintenance of General Anesthesia.

Adults

Anesthesia can be maintained by continuous infusion or repeated bolus injections of the drug to sustain the appropriate depth of anesthesia. Recovery from anesthesia is usually rapid; therefore, it is important to continue administering the drug until the end of the procedure.

Continuous Infusion

The required rate of administration may vary significantly among different patients; however, rates in the range of 4–12 mg/kg/hour are generally sufficient to maintain adequate depth of anesthesia.

Repeated Bolus Injections

For repeated bolus injections, gradually increasing doses from 25 mg (2.5 mL) to 50 mg (5.0 mL) should be administered according to clinical need.

Elderly Patients

When using the drug for maintenance of anesthesia, the rate of administration or target concentration should be reduced. Patients with an ASA score of 3 or 4 require further dose and rate reduction. Rapid bolus administration (single or repeated) should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory function.

Pediatric Population

The drug is not recommended for maintenance of anesthesia in children under 1 month of age.

Maintenance of anesthesia in children aged 1 month and older can be achieved by infusion or repeated bolus injections to maintain the appropriate depth of anesthesia. The required rate of administration may vary significantly among patients; however, rates in the range of 9–15 mg/kg/hour are generally sufficient to achieve adequate depth of anesthesia. Younger children, especially those aged 1 month to 3 years, may require higher doses.

Patients with an ASA score of 3 or 4 are recommended to receive lower doses (see also section "Special Instructions").

Sedation of Patients in Intensive Care Units.

Adults

For sedation of patients in intensive care units, the drug should be administered via continuous infusion. The infusion rate should be determined based on the desired depth of sedation. In most patients, adequate sedation depth can be achieved with a propofol dose of 0.3–4.0 mg/kg/hour (see section "Special Instructions").

The drug should not be used for sedation in patients under 16 years of age in intensive care units (see section "Contraindications").

Elderly Patients

When using the drug for sedation, the infusion rate should be reduced. Patients with an ASA score of 3 or 4 require further dose and rate reduction. Rapid bolus administration (single or repeated) should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory function.

Pediatric Population

The drug should not be used for sedation in children aged ≤16 years who are undergoing mechanical ventilation in intensive care units.

Sedation Prior to Diagnostic and Surgical Procedures.

Adults

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

In most patients, induction of sedation can be achieved by administering propofol 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 administered as an infusion to the desired depth of sedation. For most patients, administration of 1.5–4.5 mg/kg/hour is sufficient. In addition to infusion, bolus doses of 10–20 mg may be administered if a rapid increase in sedation depth is required. Patients with an ASA score of 3 or 4 may require reduced infusion rates and doses.

Elderly Patients

When using the drug for sedation, the rate of administration or target concentration should be reduced. Patients with an ASA score of 3 or 4 will require further dose and rate reduction. Rapid bolus administration (single or repeated) should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory function.

Pediatric Population

The drug is not recommended for use during diagnostic and surgical procedures in children under 1 month of age.

For children aged 1 month and older, the dose and rate of administration should be adjusted according to the required depth of sedation and clinical response. In most children, induction of sedation can be achieved by administering propofol at a dose of 1–2 mg/kg body weight. Maintenance of sedation can be achieved by titrating propofol doses during infusion to achieve the desired depth of sedation. For most patients, a dose of 1.5–9.0 mg/kg/hour is sufficient. Infusion may be supplemented with bolus doses of up to 1 mg/kg body weight if a rapid increase in sedation depth is required.

Patients with an ASA score of 3 or 4 may require dose reduction.

Method of Administration.

Propofol does not exhibit analgesic activity; therefore, concomitant administration of additional analgesic drugs is usually necessary.

The drug may be used for infusion either undiluted from glass containers or diluted with 5% glucose solution (for intravenous infusion) in PVC infusion bags or glass infusion bottles. Dilution, which should not exceed a 1:5 ratio (2 mg propofol per 1 mL), should be performed under aseptic conditions immediately before administration, and the diluted emulsion should be used within 6 hours after preparation.

When using the diluted drug, it is recommended to completely replace the volume of 5% glucose solution removed from the infusion container during dilution with propofol emulsion (see Table 1).

Dilution may be performed using various infusion control devices; however, using an infusion set alone will not eliminate the risk of accidental uncontrolled infusion of large volumes of diluted drug. A burette, drop counter, or volumetric pump should be included in the infusion line. The risk of uncontrolled infusion should be considered when determining the maximum volume of propofol emulsion in the burette.

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

The drug 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 solution with 0.18% sodium chloride solution for intravenous infusion.

A pre-filled glass syringe has lower plunger resistance compared to a plastic disposable syringe and is easier to operate. Therefore, when manually administering the drug using a pre-filled syringe, the infusion system between the syringe and the patient must not be left unattended without medical supervision.

When using a pre-filled syringe with a syringe pump, compatibility between the two must be ensured. In particular, the pump design should prevent siphoning and have an occlusion alarm at a pressure of no more than 1000 mm Hg. If a programmable or equivalent pump allowing the use of different syringes is used, only the "B-D" 50/60 mL "PLASTIPAK" mode should be selected when using a pre-filled syringe.

To reduce pain at the beginning of administration, the drug may be mixed with lidocaine injection solution (0.5% or 1%, without preservatives) (see Table 1). In such cases, skin sensitivity tests to lidocaine should be performed beforehand.

Muscle relaxants, atracurium, and mivacurium should not be administered through the same intravenous line used for propofol without prior flushing.

Below are recommendations for target concentrations of propofol. Considering the variability of propofol pharmacokinetics and pharmacodynamics among patients, the target concentration of propofol should be titrated according to clinical response, regardless of whether premedication was administered, to achieve the required depth of anesthesia.

Induction and Maintenance of General Anesthesia

In adult patients under 55 years of age, anesthesia is usually achieved at blood 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. A higher rate may allow earlier induction of anesthesia but may be associated with more pronounced depression of cardiovascular and respiratory function.

Patients aged 55 years and older and/or with an ASA score of 3 or 4 should receive a lower initial target concentration. The target concentration may then be gradually increased by 0.5–1.0 µg/mL per minute to achieve gradual induction of anesthesia.

Additional analgesia will usually be required. In such cases, the degree of reduction in the target concentration for maintenance of anesthesia will depend on the dose of concomitantly administered analgesics. Target concentrations of propofol in the range of 3–6 µg/mL generally provide adequate anesthesia.

The expected propofol concentration at awakening is usually in the range of 1.0–2.0 µg/mL; this value will be influenced by the dose of analgesics administered during anesthesia maintenance.

Sedation with Preservation of Consciousness During Surgical and Diagnostic Procedures

To achieve the required depth of sedation, the target concentration should be titrated according to the patient's response.

Typically, an initial blood target concentration of propofol in the range of 0.5–2.5 µg/mL is required. An initial blood target concentration at the upper end of the recommended range allows for faster onset of sedation with preserved consciousness.

Elderly patients and patients with an ASA score of 3 or 4 should receive initial blood target concentrations at the lower end of the range.

Oxygen delivery equipment must be available in the medical facility.

Dilution and Concurrent Administration of Propofol-NovoFarm

with Other Medicinal Products or Infusion Solutions

Table 1

Method of co-administration	Excipient or solvent	Preparation	Precautions
Pre-mixing	5 % glucose solution for intravenous infusion	Mix 1 part of Propofol-Novofarm with 1–4 parts of 5 % glucose solution for intravenous infusion in a PVC infusion bag or 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 the infusion solution with an equivalent volume of Propofol-Novofarm	Prepare under aseptic conditions immediately before administration. The mixture is stable for up to 6 hours.
	Lidocaine hydrochloride injection solution (0.5 % or 1 %, preservative-free)	Mix 20 parts of Propofol-Novofarm with 1 part of 0.5 % or 1 % lidocaine hydrochloride injection solution	Prepare the mixture under aseptic conditions immediately before administration. Use only for induction
Co-administration via Y-site connector	5 % glucose solution for intravenous infusion	Co-administration via Y-site connector	Position the Y-site connector immediately before the administration site
	0.9 % sodium chloride solution for intravenous infusion	As stated above	As stated above
	4 % glucose solution with 0.18 % sodium chloride solution for intravenous infusion	As stated above	As stated above

Children.

Propofol is not recommended for use in neonates, as administration of the medicinal product to this patient group has not been fully investigated. Pharmacokinetic data (see section "Pharmacokinetics") indicate that in neonates, propofol clearance is significantly reduced and exhibits very high inter-patient variability. Administration of doses recommended for older children may lead to relative overdose and development of severe cardiovascular depression.

Propofol should not be used in patients aged ≤ 16 years for sedation in intensive care units, as the safety and efficacy of propofol for sedation in this age group are unknown (see section "Contraindications").

Overdose.

Accidental overdose will most likely manifest as depression of cardiovascular and respiratory function. Respiratory depression should be treated with artificial ventilation of the lungs and oxygen administration. In case of cardiovascular depression, the patient should be placed in a supine position with the head down, and in severe cases, plasma expanders and pressor agents should be administered.

Adverse reactions.

Systemic.

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

In Table 2, the following criteria are used to define the frequency 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), and frequency not known (cannot be estimated based on available data).

Table 2

Adverse reactions

System organ 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. 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
	very rare	Postoperative unconsciousness
	frequency unknown (9)	Involuntary movements
Cardiac disorders	common	Bradycardia (1)
	very rare	Pulmonary edema
	frequency unknown (9)	Cardiac arrhythmia (5), cardiac failure (5), (7)
Vascular disorders	common	Arterial hypotension (2), flushing in children (11)
	uncommon	Thrombosis and phlebitis
Respiratory, thoracic and mediastinal disorders	common	Transient apnea 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	Change in urine color after prolonged use
	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)
	common	Withdrawal symptoms in children (11)
	very rare	Tissue necrosis (10) following accidental extravasation
	frequency unknown (9)	Local pain, swelling after accidental extravasation
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 fluid administration and reduction of the drug infusion rate may be required to manage hypotension.

(3) Very rare cases of rhabdomyolysis have been reported when propofol was administered at doses exceeding 4 mg/kg/hour for sedation in intensive care units (ICU).

(4) Pain on injection can be minimized by administration into larger-diameter veins, such as forearm or antecubital veins; local pain can also be reduced by co-administration of lidocaine.

(5) This combination of events is known as propofol infusion syndrome, which may occur in critically ill patients with multiple risk factors for these events (see section "Special precautions for use").

(6) Brugada-type ECG: ST-segment elevation and convex T-wave on ECG.

(7) Rapidly progressive heart failure (in some cases with fatal outcome) in adults. Heart failure in these cases was typically unresponsive to inotropic supportive 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) Following abrupt discontinuation of propofol infusion during intensive care treatment.

(12) After both prolonged and short-term treatment, and also in patients without major risk factors.

Cases of pulmonary edema, arterial hypotension, asystole, bradycardia, seizures, and development of dystonia/dyskinesia have been reported. Rarely, rhabdomyolysis, metabolic acidosis, hyperkalemia, or heart failure—sometimes fatal—have been observed with propofol administration at doses exceeding 4 mg/kg/hour for sedation in intensive care settings.

Reports on off-label use of propofol 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 with propofol, can be minimized by concomitant administration of lidocaine (see section "Dosage and administration") and by injection into larger-diameter veins such as forearm or antecubital veins. Cases of thrombosis and phlebitis are rare. Cases of accidental extravascular administration and animal studies indicate minimal tissue reaction. No local tissue effects were observed in animals following intra-arterial administration.

Reporting of suspected adverse reactions.

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

Shelf life.

2 years.

After first opening, use immediately.

The diluted medicinal product must be used immediately after preparation.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach and sight of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except as specified in the section "Special precautions for use".

Muscle relaxants, atracurium and mivacurium, must not be administered through the same intravenous line used for propofol emulsion without prior flushing of the line.

Packaging.

20 ml in a vial; 5 vials in a blister pack; 1 blister pack in a carton; 50 ml in a vial; 1 vial in a carton.

Prescription status.

Prescription only.

Manufacturer.

Limited liability company "Novopharm-Biosyntez".

Manufacturer's address and location of its business activity.

Ukraine, 11700, Zhytomyr Oblast, Zvyagel Raion, city of Zvyagel, Zhytomyrska Street, building 38.