Diprivan® edta

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIPROFOL® EDTA (Diprofol EDTA)

Composition:

Active substance: propofol;

1 ml of emulsion contains 20 mg of propofol;

Excipients: soybean oil, egg phospholipid, glycerin, sodium hydroxide, edetate disodium, water for injections.

Pharmaceutical form. Emulsion for infusion.

Main physicochemical properties: white or almost white homogeneous emulsion, practically free from solid particles and large oil droplets. Slight separation of the emulsion may occur after prolonged standing.

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 exerts its sedative and anesthetic effects by positively modulating the inhibitory function of the neurotransmitter GABA (gamma-aminobutyric acid) through facilitation of its interaction with ligand-activated GABAA receptors.

Pharmacodynamic properties

When propofol 2 % is used for induction and maintenance of anesthesia, a reduction in mean arterial pressure and slight 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 administration of propofol 2 % may result in respiratory depression, such reactions are qualitatively similar to those observed with other intravenous anesthetic agents and are easily managed in clinical practice.

Propofol 2 % 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.

Overall, postoperative nausea and vomiting occur less frequently with propofol 2 % compared to inhaled anesthetic agents. Evidence suggests this may be related to the reduced emetogenic potential of propofol.

Propofol 2 % does not suppress adrenal cortical hormone synthesis at clinically relevant 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. Published data suggest the medicinal product can be used in children undergoing prolonged procedures without changes in safety or efficacy.

Pharmacokinetics.

Absorption

When propofol 2 % is administered for maintenance of anesthesia, blood concentration asymptotically approaches a steady state for the 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 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 primarily via metabolic processes, mainly in the liver, where it is blood flow-dependent, resulting in the formation of inactive propofol conjugates and the corresponding quinol, which are excreted in urine.

After a single intravenous dose of 3 mg/kg, propofol clearance per kg body weight increases with age: 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 2 % is administered within the recommended infusion rate range, the pharmacokinetics of this medicinal product are linear.

Preclinical safety data

Published animal studies (including in primates), using doses producing light to moderate anesthesia, indicate that anesthetic exposure during periods of rapid brain growth or synaptogenesis may lead to developing brain cell loss, potentially resulting in long-term cognitive deficits. Based on comparisons across species, this risk is believed to be associated 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, whereas regimens of 5 hours or longer did result in such an increase. The clinical significance of these preclinical 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 indicated by preclinical data.

Clinical characteristics.

Indications.

As a short-acting general anesthetic agent, the drug is administered intravenously for:

• induction and maintenance of general anesthesia in adults and children aged > 3 years;
• sedation during diagnostic and surgical procedures, either alone or in combination with local or regional anesthetic agents, in adults and children aged > 3 years;
• 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 3 years of age (for induction and maintenance of general anesthesia).

Diprivan® EDTA 2 % contains soybean oil and is not intended for use in patients with hypersensitivity to peanuts or soy.

The medicinal product Diprivan® EDTA 2 % should 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 2 % has been used in combination with agents for spinal and epidural anesthesia, as well as commonly used premedications, 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 Diprivan® EDTA 2 % may be required. Cases of pronounced hypotension have been observed when propofol was administered to patients receiving rifampicin.

Concomitant use with other medicinal products that depress the central nervous system (CNS), such as premedication agents, inhalational anesthetics, and analgesics, may lead to enhanced sedative and analgesic effects, as well as increased depressant effects of Diprivan® EDTA 2 % on cardiovascular and respiratory function (see section "Special precautions").

In the presence of fentanyl, blood levels of propofol may increase.

Leukoencephalopathy has been reported in patients receiving cyclosporine and lipid emulsions (such as propofol).

It has been observed that patients receiving midazolam require a lower dose of propofol. Concomitant use of midazolam with propofol may result in enhanced sedation and respiratory depression. When used together, consideration should be given to reducing the dose of propofol.

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

Special precautions for use.

The medicinal product Diprivan® EDTA 2% must 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 supply, and other resuscitation measures must be readily available and ready for immediate use. Diprivan® EDTA 2% 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 2% propofol, primarily among healthcare professionals, have been reported. As with other general anaesthetic agents, administration of Diprivan® EDTA 2% without respiratory support may lead to life-threatening respiratory complications.

When administering Diprivan® EDTA 2% for sedation without loss of consciousness during surgical or diagnostic procedures, continuous monitoring of the patient for early signs of hypotension, airway obstruction, and decreased oxygen saturation is essential.

As with other central nervous system (CNS)-depressant medicinal products, administration of Diprivan® EDTA 2% for sedation during surgical procedures may result in involuntary movements in the patient. During procedures requiring immobilization, such movements may pose a risk to the patient.

Sufficient time must elapse before discharge to ensure full recovery of bodily functions following administration of Diprivan® EDTA 2%. Very rarely, use of Diprivan® EDTA 2% may be associated with postoperative unconsciousness, 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 unconscious patients.

Functional disturbances caused by Diprivan® EDTA 2% are generally no longer detectable within 12 hours. The effects of Diprivan® EDTA 2%, the nature of the procedure performed, concomitant use of other medicinal products, and the patient’s age and condition should be considered when advising on:

• the need for the patient to leave the healthcare facility accompanied by another person;
• the time interval before resuming activities involving complex or hazardous tasks, such as driving a vehicle;
• the use of other CNS-depressant medicinal products (e.g., benzodiazepines, opioids, ethyl alcohol).

As with other intravenous anaesthetic agents, Diprivan® EDTA 2% should be used with caution in patients with impaired cardiac, respiratory, renal, or hepatic function, as well as in hypovolemic or debilitated patients. The clearance of Diprivan® EDTA 2% depends on blood circulation; therefore, concomitant use of medicinal products that reduce cardiac output will lead to decreased clearance of Diprivan® EDTA 2%.

Diprivan® EDTA 2% does not have pronounced vagolytic activity; however, administration of this medicinal product has been associated with cases of bradycardia (in some cases profound) and asystole. Consideration should be given to intravenous administration of an anticholinergic medicinal product prior to induction or during maintenance of anaesthesia, especially in cases of potential vagal dominance or when Diprivan® EDTA 2% is used concomitantly with other medicinal products that may cause bradycardia.

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

In individual cases, intravenous fluids may be required to manage hypotension, and the infusion rate of Diprivan® EDTA 2% may need to be reduced during the maintenance phase of anaesthesia.

There is a risk of seizure occurrence when administering Diprivan® EDTA 2% to patients with epilepsy.

Appropriate care should be provided to patients with lipid metabolism disorders and conditions where lipid emulsions should be used with caution (see section "Dosage and administration").

Use during electroconvulsive therapy is not recommended.

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

Before repeated or prolonged (>3 hours) use of propofol in young children (<3 years of age) or in pregnant women, the benefit-risk ratio of the proposed procedure should be carefully considered, as neurotoxicity has been reported in preclinical studies.

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 multiorgan failure that may lead to fatal outcomes. Cases of a combination of adverse effects have been reported: metabolic acidosis, rhabdomyolysis, hyperkalaemia, hepatomegaly, renal failure, hyperlipidaemia, cardiac arrhythmia, Brugada-type electrocardiogram (ECG) (elevated ST segment and convex T wave), and rapidly progressive cardiac failure usually unresponsive to inotropic support. This combination of effects 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 those recommended for adult sedation in ICU settings.

Major risk factors for the development of these effects 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 Diprivan® EDTA 2% (usually at doses exceeding 4 mg/kg/hour for more than 48 hours).

Healthcare professionals should be prepared for the potential occurrence of these effects in patients with the above-mentioned risk factors and must discontinue propofol immediately upon development of the described signs. Doses of all CNS-depressant medicinal products, as well as other drugs used in intensive care, 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.

Doses exceeding 4 mg/kg/hour are not recommended.

Appropriate care should be provided to 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 fat 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 during infusion as a component of the propofol formulation; 1.0 mL of Diprivan® EDTA 2% contains approximately 0.1 g of fat.

Diprivan® EDTA 2% contains soybean oil. This medicinal product should not be used in patients with known allergy to peanuts or soy.

Diprivan® EDTA 2% contains 0.0018 mmol/mL of sodium. This should be taken into account when treating patients on a sodium-controlled diet.

Additional precautions

Patients with mitochondrial disorders should be treated with caution. In such patients, anaesthesia, surgical procedures, and other interventions in ICU settings may trigger disease exacerbation. Normothermia, carbohydrate supply, and adequate fluid intake are recommended in these patients. Early signs of mitochondrial disorder exacerbation and propofol infusion syndrome may be similar.

Diprivan® EDTA 2% does not contain antimicrobial preservatives and therefore does not prevent microbial growth.

Disodium edetate is a chelator of metal ions, including zinc, and inhibits microbial growth. With prolonged use of Diprivan® EDTA 2%, consideration should be given to the need for additional zinc supplementation, particularly in patients predisposed to zinc deficiency, such as those with burns, diarrhoea, and/or severe sepsis.

Before administration, Diprivan® EDTA 2% should be drawn into a sterile syringe or infusion system under aseptic conditions immediately after opening the ampoule or vial. Administration should begin immediately thereafter. All procedures involving Diprivan® EDTA 2% and infusion equipment must be performed under aseptic conditions during infusion. Any infusion solutions should be added to the infusion line containing Diprivan® EDTA 2% immediately before the site of administration. Diprivan® EDTA 2% must not be used with infusion systems containing a microbial filter.

Diprivan® EDTA 2% and syringes containing this medicinal product are intended for single-use only 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 must be discarded and replaced with a new one.

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

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

Children

Propofol is not recommended for use in neonates, as this patient group has not been fully studied. Pharmacokinetic data (see section "Pharmacokinetics") indicate that clearance in neonates is significantly reduced and exhibits high inter-individual variability. Relative overdose may occur when using doses recommended for older children, potentially leading to severe cardiovascular depression.

Diprivan® EDTA 2% is not recommended for use in children under 3 years of age due to difficulties in titrating small volumes.

Propofol must not be used for sedation in ICU patients aged up to and including 16 years, as the safety and efficacy of propofol for sedation in this age group have not been demonstrated (see section "Contraindications").

Use during pregnancy or breastfeeding

Pregnancy

Studies in rats and rabbits demonstrated absence of teratogenic effects.

The safety of Diprivan® EDTA 2% during pregnancy has not been established. Animal studies have shown reproductive toxicity. Diprivan® EDTA 2% should not be administered to pregnant women except in cases of absolute necessity. 2% propofol crosses the placenta and may cause neonatal depression. However, Diprivan® EDTA 2% may be used for surgical termination of pregnancy.

Labour and delivery

Diprivan® EDTA 2% crosses the placental barrier and may cause neonatal depression (medication-induced neonatal depression syndrome). This medicinal product should not be used for obstetric anaesthesia.

Breastfeeding

Studies in breastfeeding women have shown that small amounts of 2% propofol are excreted in breast milk. Therefore, women should not breastfeed for 24 hours after administration of Diprivan® EDTA 2%. Breast milk expressed during this period should be discarded.

Effects on ability to drive and use machines

Diprivan® EDTA 2% has a moderate effect on the ability to drive vehicles or operate machinery. Patients should be advised that performance of complex tasks, such as driving vehicles or operating automated systems, may be impaired for some time after general anaesthesia.

Functional disturbances caused by Diprivan® EDTA 2% are generally no longer detectable within 12 hours (see section "Special precautions for use").

Method of Administration and Dosage

Induction of General Anesthesia

Adults

The medicinal product Diprivan® EDTA 2% may be used for anesthesia induction via infusion.

The use of Diprivan® EDTA 2% as a bolus injection is not recommended.

Diprivan® EDTA 2% may be used for anesthesia induction by infusion, but only in patients who will also receive Diprivan® EDTA 2% for anesthesia maintenance.

For patients with or without premedication, it is recommended to titrate the dose of Diprivan® EDTA 2% (administered to adult patients as an infusion of approximately 2 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 is generally sufficient. The total required dose can be reduced by decreasing the infusion rate (1–2.5 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 (approximately 1 mL [20 mg] every 10 seconds).

Elderly Patients

Elderly patients require lower doses of Diprivan® EDTA 2% for anesthesia induction. 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.

Paediatric Population

The use of Diprivan® EDTA 2% for anesthesia induction is not recommended in children under 3 years of age.

For anesthesia induction in children aged 3 years and older, the dose of Diprivan® EDTA 2% 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 Diprivan® EDTA 2% is sufficient for anesthesia induction. Younger children 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 Warnings and Precautions for Use").

Maintenance of General Anesthesia

Adults

Anesthesia maintenance can be achieved by continuous infusion of Diprivan® EDTA 2% to maintain an appropriate depth of anesthesia. Bolus injection of Diprivan® EDTA 2% is not recommended. Emergence from anesthesia is typically rapid; therefore, it is important to continue administration of Diprivan® EDTA 2% until the end of the procedure.

Continuous Infusion

The required infusion rate may vary significantly among patients, but a range of 4–12 mg/kg/hour is generally sufficient to maintain an appropriate depth of anesthesia.

Elderly Patients

When using Diprivan® EDTA 2% for anesthesia maintenance, the infusion rate or target concentration should be reduced. Patients with an ASA score of 3 or 4 require further dose and infusion rate reduction. Rapid bolus administration (single or repeated) of the medicinal product should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory function.

Paediatric Population

The use of Diprivan® EDTA 2% for anesthesia maintenance is not recommended in children under 3 years of age.

Anesthesia maintenance in children aged 3 years and older can be achieved by infusion of Diprivan® EDTA 2% to maintain an appropriate depth of anesthesia. The required infusion rate may vary significantly among patients, but a range of 9–15 mg/kg/hour is generally sufficient to achieve an appropriate depth of anesthesia. Younger children may require higher doses.

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

Sedation of Patients in Intensive Care Units

Adults

For sedation of patients in intensive care units, the medicinal product Diprivan® EDTA 2% should be administered by continuous infusion. The infusion rate should be adjusted according to the desired depth of sedation. In most patients, adequate sedation can be achieved with a dose of 0.3–4.0 mg/kg/hour (see section "Special Warnings and Precautions for Use").

Diprivan® EDTA 2% should not be used for sedation of patients under 16 years of age in intensive care units (see section "Contraindications").

Lipid concentration monitoring in blood is recommended when using Diprivan® EDTA 2% in patients at special risk of lipid overload. If monitoring results indicate impaired fat clearance, administration of Diprivan® EDTA 2% should be adjusted accordingly. If other lipid-containing intravenous solutions are administered simultaneously, the dose should be reduced to account for the amount of fat administered as part of the Diprivan® EDTA 2% formulation: 1.0 mL of Diprivan® EDTA 2% 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 Diprivan® EDTA 2% for sedation, the infusion rate should be reduced. Patients with an ASA score of 3 or 4 require further dose and infusion rate reduction. Rapid bolus administration (single or repeated) of the medicinal product should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory function.

Paediatric Population

Diprivan® EDTA 2% is contraindicated for sedation in children < 16 years of age who are receiving mechanical ventilation in intensive care units.

Sedation Prior to 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 induction can be achieved by administering the medicinal product at a dose of 0.5–1.0 mg/kg over 1–5 minutes.

Maintenance of sedation is achieved by titrating the dose of Diprivan® EDTA 2% administered by infusion to the desired depth of sedation. For most patients, a dose 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 Diprivan® EDTA 2% for sedation, the infusion rate or target concentration should be reduced. Patients with an ASA score of 3 or 4 will require further dose and infusion rate reduction. Rapid bolus administration (single or repeated) of the medicinal product should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory function.

Paediatric Population

The use of Diprivan® EDTA 2% is not recommended for diagnostic and surgical procedures in children under 3 years of age.

For children aged 3 years and older, doses and infusion rates should be adjusted according to the required depth of sedation and clinical response. In most children, sedation induction can be achieved with a dose of 1–2 mg/kg body weight of Diprivan® EDTA 2%. Maintenance of sedation can be achieved by titrating the dose of Diprivan® EDTA 2% during infusion to achieve the desired depth of sedation. Most patients require a dose of 1.5–9.0 mg/kg/hour. Patients with an ASA score of 3 or 4 may require dose reduction.

Method of Administration

Diprivan® EDTA 2% has no analgesic activity; therefore, concomitant administration of analgesic medicinal products is usually necessary.

Propofol 2% has been used in combination with spinal and epidural anesthetics, as well as with medicinal products commonly used for premedication, 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 Diprivan® EDTA 2% may be possible. Cases of marked hypotension have been observed when propofol was used in patients taking rifampicin.

Diprivan® EDTA 2% should not be diluted. It can be administered undiluted from glass containers for infusion.

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

Diprivan® EDTA 2% should not be mixed prior to administration with other injectable or infusion solutions. Diprivan® EDTA 2% may be administered through a Y-connector placed 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 with 0.18% sodium chloride solution for intravenous infusion.

The following are recommendations for target concentrations of propofol. Due to the variability in propofol pharmacokinetics and pharmacodynamics among patients, the target concentration of propofol should be titrated according to clinical response, with or without premedication, to achieve the required depth of anesthesia.

In adult patients under 55 years of age, anesthesia is usually achieved at propofol target concentrations of 4–8 µg/mL. A starting target concentration of 4 µg/mL is recommended for patients with premedication and 6 µg/mL for those without premedication. Induction time at these target concentrations is typically 60–120 seconds. Higher rates may lead to earlier anesthesia induction 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 can then be gradually increased by 0.5–1.0 µg/mL per minute to achieve gradual anesthesia induction.

Additional analgesia will usually be required. In such cases, the degree of reduction in the target concentration for anesthesia maintenance will depend on the dose of concomitantly administered analgesics. Propofol target concentrations 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.

Children

Diprivan® EDTA 2% is used in children aged 3 years and older according to the specified indications.

The use of Diprivan® EDTA 2% is not recommended in children under 3 years of age due to the difficulty in titrating small volumes.

Propofol should not be used in patients under 16 years of age 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 is highly likely to result in depression of cardiovascular and respiratory function. Respiratory depression should be treated with artificial ventilation and oxygen administration. In case of cardiovascular depression, the patient should be placed in a supine position with the head low, 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/CNS depressant agent, such as hypotension. The nature, severity, and frequency of adverse reactions in patients receiving Diprivan® EDTA 2% may be related to the patient's condition and the surgical or therapeutic procedures being performed.

The following criteria are used in the table to define the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from available data).

• Serious bradycardia is rare. There have been isolated reports of progression to asystole.
  • In some cases, intravenous fluids and reduction of the infusion rate may be required to manage hypotension.
    • Rhabdomyolysis has been very rarely reported when propofol was administered at doses exceeding 4 mg/kg/hour for ICU sedation.
      • Can be minimized by administration into larger diameter veins: forearm and antecubital veins. When using the medicinal product Diprivan EDTA 1%, local pain can also be reduced by co-administration of lidocaine.
        • These combined events are referred to as propofol infusion syndrome, which may occur in critically ill patients with multiple risk factors for developing these events (see section "Special precautions").
          • Brugada-type ECG: ST-segment elevation and convex T-wave.
            • Rapidly progressive heart failure (in some cases fatal) in adults. Heart failure in these cases was typically unresponsive to inotropic support therapy.
              • Abuse and dependence on propofol, primarily among healthcare professionals.
                • Frequency unknown, as it cannot be estimated from available clinical trial data.
                  • Necrosis has been reported in cases of compromised tissue viability.
                    • After abrupt discontinuation of propofol during intensive care treatment.
                      • After both long-term and short-term treatment, and also in patients without underlying risk factors.

Cases of dystonia/dyskinesia have been reported.

Local

Local pain, which may occur during the induction phase with Diprivan® EDTA 2%, can be minimized by administration into larger diameter veins: forearm and antecubital veins. 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.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

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.

Diprivan® EDTA is incompatible with injectable and infusion solutions (including sodium chloride solution, Ringer's lactate solution), and therefore should not be mixed with them prior to administration. If the same intravenous access is used for other medications, they should be administered at the end of the infusion line.

Atracurium and mivacurium are incompatible with the medicinal product Diprivan® EDTA. The muscle relaxants atracurium and mivacurium should not be administered through the same intravenous line used for Diprivan® EDTA 2% without prior flushing of the line.

Packaging. 20 ml in an ampoule. 5 ampoules per pack.

20 ml in a vial. 1, 5, or 10 vials per pack.

50 ml in a vial. 1 vial per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.