Propofol-novo

INSTRUCTIONS for medical use of the medicinal product PROPOFOL-NOVO (PROPOFOL-NOVO)

Composition:

Active substance: propofol;

1 ml of emulsion contains propofol 10 mg;

Excipients: soybean oil, lecithin, glycerol, 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. Agents for general anesthesia. 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 occurring within approximately 0.5 minutes. 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 exerts its sedative and anesthetic effects by positively modulating the inhibitory function of the neurotransmitter gamma-aminobutyric acid (GABA) through facilitating 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 after propofol administration, such reactions are qualitatively similar to those observed with other intravenous anesthetics 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 relevant concentrations.

Children.

Limited data from studies on anesthesia using propofol in children indicate maintained safety and efficacy with anesthesia duration up to 4 hours. Published data suggest that the drug can be used in children undergoing prolonged procedures without altering its safety or efficacy profile.

Pharmacokinetics.

Absorption.

When propofol is administered for maintenance of anesthesia, blood concentration asymptotically approaches a steady state corresponding to the infusion rate.

Distribution.

Propofol is widely distributed and rapidly eliminated 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), rapid elimination (elimination half-life: 30–60 minutes), and a slower terminal phase reflecting redistribution of propofol from poorly perfused tissues.

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

After intravenous administration of a single 3 mg/kg dose, propofol clearance per kg of body weight increases with 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 substantial 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).

Linearity.

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

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 medicinal products for local or general anesthesia, 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.

Age under 1 month in children (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 must not be used for sedation in patients aged ≤ 16 years in the intensive care unit (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Propofol has been used in combination with medicinal products for spinal and epidural anesthesia, as well as commonly used premedication agents, muscle relaxants, inhalational anesthetics, and analgesics; no cases of pharmacological incompatibility have been observed. When general anesthesia is used in combination with local anesthetics, lower doses of propofol may be required. Cases of marked arterial hypertension have been observed when propofol was administered to patients receiving rifampicin.

Concomitant use with other medicinal products that depress the central nervous system, such as premedication agents, inhalational anesthetics, and analgesics, may lead to enhanced sedative and analgesic effects, as well as increased depressant effects of propofol on cardiovascular and respiratory function (see section "Special precautions").

In patients receiving valproate, a reduced dose requirement for propofol has been observed. When used concomitantly, the need to reduce the dose of propofol should be considered.

Special precautions for use.

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

Continuous monitoring of the patient's condition is required. Equipment for maintaining airway patency, artificial ventilation of the lungs, oxygen delivery, and other resuscitation measures must always be readily available and prepared for immediate use. The medicinal product must not be administered by the same individual who is performing the diagnostic or surgical procedure.

Cases of misuse and development of drug dependence on propofol have been reported, primarily among healthcare professionals. As with other medicinal products used for general anaesthesia, administration of propofol emulsion without respiratory support may lead to life-threatening respiratory complications.

When administering the medicinal product 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, administration of propofol for sedation during surgical procedures may result in involuntary movements in the patient. Such movements may pose a danger to the patient during procedures requiring immobilization.

Sufficient time should elapse before discharging the patient to ensure full recovery from the effects of propofol. Very rarely, postoperative loss of consciousness may occur after propofol administration, which may be accompanied by increased muscle tone. This condition may be preceded by a period of insomnia. Although this state 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 use of other medicinal products, patient age, and overall condition should be taken into account when advising patients regarding:

• the need for discharge from the healthcare facility in the presence of another person;
• the time required to recover before resuming activities involving complex or hazardous tasks, such as driving a vehicle;
• 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 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 is dependent on blood flow; therefore, concomitant use of medicinal products that reduce cardiac output will lead to decreased propofol clearance.

Propofol does not possess significant 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 in cases of potential vagal dominance or when propofol is used concomitantly with other medicinal products that may cause bradycardia.

As with other intravenous anaesthetic agents 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 ethanol, general anaesthetics, and opioid analgesics, will potentiate 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 forms of interaction").

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

In some cases, intravenous fluids and/or reduction of the propofol infusion rate during the maintenance phase may be required to manage arterial hypotension.

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

Appropriate management is required for patients with lipid metabolism disorders or conditions where lipid emulsions should be used with caution (see section "Method of administration and dosage").

The use of this medicinal product is not recommended during electroconvulsive therapy.

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

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 adverse events including: metabolic acidosis, rhabdomyolysis, hyperkalaemia, hepatomegaly, renal failure, hyperlipidaemia, cardiac arrhythmia, Brugada-type ECG (ST-segment elevation and convex T-wave), and rapidly progressive heart failure usually unresponsive to inotropic support. This constellation of events is known as propofol infusion syndrome and is typically observed in patients with severe head injuries and in children with respiratory infections who have received doses exceeding the recommended adult dosage for ICU sedation.

Key risk factors for developing these events include: reduced tissue oxygen delivery; severe neurological injury and/or sepsis; and administration 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 longer than 48 hours).

Healthcare professionals should be prepared for the possible occurrence of these events in patients with the aforementioned risk factors and should promptly decide to reduce the dose of propofol or discontinue the medicinal product if such signs develop. Doses of all CNS depressants and other medicinal products used in the 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 management is required for patients with lipid metabolism disorders and other conditions where lipid emulsions should be used with caution.

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

Additional precautions.

The medicinal product should be used with caution in patients with mitochondrial disorders. Exacerbation of the disease may occur in such patients during anaesthesia, surgical procedures, or other interventions in the ICU. These patients should be maintained in normothermia and provided with carbohydrates and adequate fluid intake. 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 container. Administration should begin immediately thereafter. All procedures 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 with propofol emulsion immediately before the site of administration. The medicinal product should not be used with infusion systems containing microbial filters.

The medicinal product and syringes containing it are intended for single-dose use in a single 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 should be discarded and replaced with new ones.

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

Do not use any remaining medicinal product.

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

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

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

Use during pregnancy or breastfeeding.

Pregnancy.

The safety of propofol use during pregnancy has not been established. Propofol should not be administered to pregnant women except in cases of absolute necessity. However, propofol may be used for induced termination of pregnancy.

Labour.

Propofol crosses the placental barrier and may cause depression in newborns. This medicinal product should not be used for anaesthesia during labour except in cases of absolute necessity.

Breastfeeding.

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

Ability to affect reaction speed when driving or operating machinery.

Propofol has a moderate effect on the ability to drive vehicles or operate machinery. Patients should be warned that performing complex tasks such as driving vehicles or working with automated systems may be impaired for some time after general anaesthesia.

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

Administration and Dosage.

Induction of General Anesthesia.

Adults.

For patients with or without premedication, it is recommended to titrate the dose of propofol (administered to adult patients as a bolus injection or infusion of 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 aged 55 years and older, the dose required to achieve general anesthesia is generally lower. Patients with an ASA (American Society of Anesthesiologists) physical status score of 3 or 4 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. The reduced dose should be administered at a slower rate and titrated according to clinical response.

Children.

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 selected based on 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).

Lower doses are recommended for patients with an ASA score of 3 or 4 (see section "Special Warnings and Precautions for Use").

Use of the TCI "Diprifusor" system is not recommended for induction of general anesthesia in children.

Maintenance of General Anesthesia.

Adults.

Anesthesia can be maintained by continuous infusion or repeated bolus injections of the drug to maintain adequate depth of anesthesia. Emergence from anesthesia is usually rapid; therefore, it is important to continue drug administration until the end of the procedure.

Continuous Infusion.

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

Repeated Bolus Injections.

When using 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.

Children.

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 of the drug to maintain adequate depth of anesthesia. The required rate of administration may vary significantly between patients; however, rates within 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.

Lower doses are recommended for patients with an ASA score of 3 or 4 (see also section "Special Warnings and Precautions for Use").

Use of the TCI "Diprifusor" system is not recommended for maintenance of general anesthesia in children.

Sedation of Intensive Care Unit Patients.

Adults.

For sedation of patients in the intensive care unit, 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 dose of 0.3–4.0 mg/kg/hour (see section "Special Warnings and Precautions for Use").

The drug should not be used for sedation of patients under 16 years of age in the intensive care unit (see section "Contraindications"). Use of the TCI "Diprifusor" system is not recommended for sedation of intensive care unit patients.

The drug may be diluted with 5% dextrose solution (see Table 1).

Monitoring of blood lipid concentrations is recommended when administering the drug to patients at particular risk of lipid overload. If monitoring results indicate impaired fat clearance, administration of the drug should be adjusted accordingly. If other lipid-containing solutions are being administered intravenously to the patient, the dose should be reduced to account for the amount of fat administered during infusion as a component of the propofol formulation; 1.0 mL of the drug contains approximately 0.1 g of fat.

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

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.

Children.

The drug should not be used for sedation of children ≤ 16 years of age receiving mechanical ventilation in the intensive care unit.

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, sedation can be induced 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, a rate of 1.5–4.5 mg/kg/hour is sufficient. In addition to infusion, bolus doses of 10–20 mg may be administered if rapid increase in sedation depth is required. Patients with an ASA score of 3 or 4 may require reduced infusion rate and dose.

Use of the TCI "Diprifusor" system is not recommended for sedation prior to diagnostic and surgical procedures.

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.

Children.

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, sedation can be induced 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. Most patients require a dose of 1.5–9.0 mg/kg/hour. Infusion may be supplemented with bolus doses 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.

Administration Method.

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

The drug may be used for infusion either undiluted from glass containers, plastic syringes, pre-filled syringes, or diluted with 5% dextrose solution (for intravenous infusion) from PVC infusion bags or glass infusion bottles/flasks. Dilutions, which should not exceed a ratio of 1:5 (2 mg propofol per 1 mL), should be prepared under aseptic conditions immediately before administration, and the diluted emulsion should be used within 6 hours after preparation.

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

Dilution may be performed using various infusion control devices, but using only an infusion set will not eliminate the risk of accidental uncontrolled infusion of large volumes of diluted drug. An 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 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 located immediately before the infusion site of the following solutions:

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

A glass pre-filled syringe has lower friction resistance than plastic disposable syringes and is more convenient to use. Therefore, if the drug is administered using a pre-filled syringe, the infusion line between the syringe and the patient should not be left unattended.

When using a pre-filled syringe with a syringe infusion pump, compatibility between the two must be ensured. Particular attention should be paid to ensuring that the pump design prevents siphoning effects, and the occlusion alarm should be set to values greater than 1000 mmHg. When using a programmable pump or equivalent capable of using various syringes, only the "B-D" 50/60 mL "PLASTIKPAK" option should be selected when using a pre-filled syringe with the drug.

The drug may be premixed with alfentanil injection solution containing 500 mcg/mL alfentanil in volume ratios from 20:1 to 50:1. Mixtures should be prepared under sterile conditions and used within 6 hours after preparation.

To reduce pain upon initial injection, the drug may be mixed with lidocaine injection solution (0.5% or 1%, preservative-free) (see Table 1).

Target-controlled infusion: Administration of the drug to adults using the TCI "Diprifusor" system.

Administration of the drug using the TCI "Diprifusor" system is limited to induction and maintenance of general anesthesia in adults. It is not recommended for use in ICU sedation, sedation prior to diagnostic and surgical procedures, or in children.

The drug may be administered as TCI only using the TCI "Diprifusor" system with TCI "Diprifusor" software. Such systems will only operate with electronically labeled pre-filled syringes containing the drug. The TCI "Diprifusor" system will automatically set the infusion rate for the recognized propofol concentration. Users must be familiar with the infusion pump instruction manual, rules for drug administration using the TCI system, and proper handling of the syringe recognition system.

The TCI "Diprifusor" system allows the anesthesiologist to achieve and control the desired speed of induction and depth of anesthesia by setting and adjusting target (predicted) propofol concentrations in blood. An alternative effect-site targeting mode is available for some TCI "Diprifusor" systems, but its safety and efficacy have not yet been established.

The TCI "Diprifusor" system assumes the initial blood propofol concentration in the patient is zero. Therefore, if the patient has previously received propofol, a lower initial target concentration may be required when using the TCI "Diprifusor" system. It is also not recommended to immediately resume operation of the TCI "Diprifusor" system after stopping the pump.

Below are recommendations for target propofol concentrations. Due to variability in propofol pharmacokinetics and pharmacodynamics among patients, and depending on whether premedication was administered, the target propofol concentration should be titrated according to clinical response 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 target propofol concentrations of 4–8 mcg/mL. An initial target concentration of 4 mcg/mL is recommended for patients with premedication and 6 mcg/mL for those without premedication. Induction time at these target concentrations is usually 60–120 seconds. Higher rates will 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 mcg/mL per minute to achieve gradual induction of anesthesia.

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

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

Table 1

Dilution and Compatible Administration of Propofol-Neon with Other Medicinal Products or Infusion Solutions (see section "Special Warnings and Precautions for Use")

Method of combined administration	Excipient or solvent	Preparation	Precautions
Pre-mixing	5% glucose solution for intravenous infusion	Mix 1 part of Propofol-Novo with 1–4 parts of 5% glucose solution for intravenous infusion in a PVC infusion bag or glass infusion bottle/flask. 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-Novo	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-Novo with 1 part of 0.5% or 1% lidocaine hydrochloride injection solution	Prepare the mixture under aseptic conditions immediately before administration. Use for induction only
	Alfentanil injection solution (500 mcg/mL)	Mix Propofol-Novo with alfentanil injection solution in volume ratios from 20:1 to 50:1	Prepare the mixture under aseptic conditions; use within 6 hours after preparation
Concomitant administration via Y-connector	5% glucose solution for intravenous infusion	Concomitant administration via Y-connector	Position the Y-connector immediately before the administration site
	0.9% sodium chloride solution for intravenous infusion	As stated above	As stated above
	4% glucose with 0.18% sodium chloride solution for intravenous infusion	As stated above	As stated above

Children.

The medicinal product can be used in children aged 1 month and older according to the specified indications.

The use of the medicinal product is not recommended in neonates, as its use in this patient group has not been fully investigated. Pharmacokinetic data (see section "Dosage and administration") indicate that propofol clearance is significantly reduced in neonates and shows 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 intensive care unit sedation, as the safety and efficacy of propofol for sedation in this age group have not been established (see section "Contraindications").

Overdose.

Accidental overdose is highly likely to manifest as depression of cardiovascular and respiratory function. Respiratory depression should be managed by artificial ventilation and oxygen supplementation. In case of cardiovascular depression, the patient's head should be lowered, and in severe cases, plasma substitutes and pressor medicinal products should be administered.

Adverse reactions.

Systemic.

Induction and maintenance of anesthesia or sedation usually proceed smoothly, with minimal excitation phase. Most frequently reported adverse reactions are pharmacologically predictable side effects of anesthetic drugs / central nervous system depressants, such as arterial hypotension. The nature, severity, and occurrence of adverse events in patients receiving the drug may be related to the patient's condition and to the surgical or therapeutic procedures being performed.

The following criteria are used in Table 2 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

Organ system class	Frequency	Adverse reactions
Immune system disorders	very rare	Anaphylaxis, which may include angioedema, bronchospasm, erythema, and arterial 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), heart failure (5), (7)
Vascular disorders	common	Arterial hypotension (2), flushing in children (11)
	uncommon	Thrombosis and phlebitis
Respiratory system 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)
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
General disorders and administration site conditions	very common	Local pain during induction (4)
	very rare	Tissue necrosis (10) following accidental extravasation
	frequency unknown (9)	Local pain, swelling after accidental extravasation
Investigations	common	Withdrawal symptoms in children (11)
	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 isolated cases, intravenous fluids and reduction of the drug infusion rate may be required to manage arterial 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 may 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 "Dosage and Administration").

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

(7) Rapidly progressive heart failure (in some cases fatal) in adults. Heart failure in these cases was typically unresponsive to supportive therapy with inotropes.

(8) Abuse and drug dependence on propofol, primarily among healthcare professionals.

(9) Frequency unknown, as it cannot be estimated from 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.

Pulmonary edema, arterial hypotension, asystole, bradycardia, seizures, and dystonia/dyskinesia have been reported. Rhabdomyolysis, metabolic acidosis, hyperkalemia, or heart failure—sometimes fatal—have rarely been observed with propofol administration at doses exceeding 4 mg/kg/hour for sedative effect in intensive care settings.

Reports on off-label use of propofol for induction of anesthesia in neonates suggest that cardiac 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 injecting into larger-diameter veins, such as forearm or antecubital veins. Cases of thrombosis and phlebitis are rare. Accidental extravascular administration and animal studies indicate minimal tissue reaction. Intra-arterial administration in animals did not show local tissue effects.

Incompatibilities.

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

Shelf life. 3 years.

After opening the container (primary packaging), the medicinal product should be used immediately.

Shelf life of diluted emulsion.

The diluted emulsion must be used immediately after preparation.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children. Do not freeze.

Packaging.

20 ml in a vial; 5 vials in a blister pack in a cardboard box.

50 ml in a vial; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC Company "Novopharm-Biosyntez".

Manufacturer's address and place of business.

38 Zhytomyrska St., Novohrad-Volynskyi, Zhytomyr region, 11700, Ukraine.