Diprivan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIPRIVAN® (DIPRIVAN®)

Composition:

Active substance: propofol;

1 ml of emulsion contains 10 mg of propofol;

Excipients: soybean oil, glycerin, purified egg phosphatides, disodium edetate, sodium hydroxide, 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 may occur after prolonged standing.

Pharmacotherapeutic group. Anesthetics. 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, 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, propofol is believed to produce sedative and hypnotic effects by positively modulating the inhibitory function of the neurotransmitter GABA (gamma-aminobutyric acid) through facilitation of its interaction with ligand-gated GABAA receptors.

Pharmacodynamic Properties

When Diprivan**®** 1% is used for induction and maintenance of anesthesia, a reduction in mean arterial pressure and minor changes in heart rate are typically observed. However, hemodynamic parameters generally remain relatively stable during maintenance of anesthesia, and the incidence of adverse hemodynamic reactions is low.

Although respiratory depression may occur following administration of Diprivan**®** 1%, the responses are generally qualitatively similar to those seen with other intravenous anesthetic agents and are easily managed in clinical practice.

Diprivan**®** 1% 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 typically 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 Diprivan**®** 1% compared to inhaled anesthetic agents.

Diprivan**®** 1% does not suppress adrenal cortical hormone synthesis at clinically relevant concentrations.

Paediatric Population

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

Pharmacokinetics.

Absorption

When Diprivan**®** 1% is used for maintenance of anesthesia, blood concentrations asymptotically approach a steady state for a given infusion rate.

Distribution

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

Elimination

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

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

Following intravenous administration of a single 3 mg/kg dose, propofol clearance per kg of 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 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 Diprivan**®** 1% is administered within the recommended infusion rate range, the pharmacokinetics of the medicinal product are linear.

Non-clinical Safety Data.

Published animal studies (including in primates), using doses that produce light or moderate anesthesia, indicate that administration of anesthetics during periods of rapid brain growth or synaptogenesis leads to neuronal cell loss in the developing brain, which may result in long-term cognitive deficits. The clinical significance of these non-clinical findings is unknown.

Published animal study results demonstrate that administration of anesthetic agents during periods of rapid brain growth or synaptogenesis causes widespread neuronal and oligodendrocyte cell loss in the developing brain, as well as morphological changes in synapses and neurogenesis. Based on data comparisons across species, the risk of such changes is believed to correlate with exposure during the third trimester of pregnancy and the first few months of life, but may persist up to approximately 3 years of age in humans.

In neonatal primates, anesthesia exposure of up to 3 hours under conditions of light surgical anesthesia did not increase neuronal cell loss; however, anesthesia regimens lasting 5 hours or longer were associated with increased neuronal loss. Data on effects in fetuses and neonates from rodent and primate studies suggest that neuronal and oligodendrocyte loss is associated with mild but persistent cognitive deficits in learning and memory. The clinical relevance of these non-clinical findings 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 indicated by non-clinical data.

Propofol is a medicinal product with extensive clinical experience. All necessary information for the prescribing physician is provided in the product's summary of characteristics.

Clinical characteristics.

Indications.

For short-acting general anesthesia, the drug 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 regional 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.

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

Diprivan**®** 1 % contains soybean oil and is not intended for use in patients with hypersensitivity to peanuts or soy.

Diprivan**®** 1 % 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.

Diprivan**®** 1 % has been used in combination with spinal and epidural anesthetics, as well as with commonly used premedicants, neuromuscular blocking agents, 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 Diprivan**®** 1 % may be required. Cases of marked hypotension have been observed when propofol was used for anesthesia induction in patients receiving rifampicin. The hypotensive effect of Diprivan**®** 1 % may be enhanced when administered concomitantly with opioid analgesics. This effect may be more pronounced in elderly patients and when agents such as alfentanil are used for infusion.

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 may lead to enhanced sedation and respiratory depression. When used together, consideration should be given to reducing the dose of propofol.

Special precautions for use.

Diprivan**®** 1 % is indicated for use in healthcare facilities.

Diprivan**®** 1 % must be administered by a specialist experienced in anesthesia (or, if necessary, by a physician experienced in intensive care).

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. Diprivan**®** 1 % must not be administered by the same individual performing the diagnostic or surgical procedure.

Cases of misuse and development of drug dependence on Diprivan**®** 1 % have been reported, primarily among healthcare professionals. As with other general anesthetic agents, administration of Diprivan**®** 1 % without respiratory support may lead to life-threatening respiratory complications.

When Diprivan**®** 1 % is administered 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) depressants, administration of Diprivan**®** 1 % for sedation during surgical procedures may result in involuntary movements. In procedures requiring immobilization, such movements may pose a risk to the patient.

Sufficient time should elapse before discharge to ensure complete recovery of physiological functions after administration of Diprivan**®** 1 %. Very rarely, use of Diprivan**®** 1 % may be associated with postoperative loss of consciousness, which may be accompanied by increased muscle tone. This state may be preceded by a period of insomnia. Although this condition resolves spontaneously, appropriate care should be provided to patients who lose consciousness.

Functional disturbances caused by Diprivan**®** 1 % are typically no longer evident within 12 hours. The effects of Diprivan**®** 1 %, the nature of the procedure performed, concomitant medication use, patient age, and patient condition should be considered when advising on:

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

As with other intravenous anesthetic agents, Diprivan**®** 1 % 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**®** 1 % depends on blood circulation; therefore, concomitant administration of drugs that reduce cardiac output will lead to decreased clearance of Diprivan**®** 1 %.

Diprivan**®** 1 % has no pronounced vagolytic activity; however, cases of bradycardia (in some cases, profound) and asystole have been reported with its use. The intravenous administration of an anticholinergic agent should be considered prior to induction or during maintenance of anesthesia, especially in cases of possible vagal dominance or when Diprivan**®** 1 % is used concomitantly with other drugs 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 administration of Diprivan**®** 1 %.

Particular caution should be exercised during bolus administration of the drug during surgical procedures in patients with acute respiratory insufficiency or respiratory depression.

Concomitant use with CNS depressants, such as ethyl alcohol, general anesthetics, and narcotic analgesics, will enhance CNS depression. Combined use of Diprivan**®** 1 % with parenterally administered CNS depressants may result in severe depression of respiratory and cardiovascular function. Diprivan**®** 1 % is recommended to be administered 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").

Hypotension and transient apnea may occur during induction of anesthesia, depending on the dose, premedication, and concomitant use of other drugs.

In some cases, intravenous fluids and reduction of the infusion rate of Diprivan**®** 1 % may be required to manage hypotension during the maintenance phase of anesthesia.

There is a risk of seizures when administering Diprivan**®** 1 % 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, disinhibition with sexual connotations may occur during emergence from anesthesia.

The benefit-risk ratio of the proposed procedure should be carefully considered before repeated or prolonged (> 3 hours) use of propofol in young children (< 3 years) or pregnant women, 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 multiorgan failure that may lead to fatal outcomes. Cases of combined adverse events have been reported, including metabolic acidosis, rhabdomyolysis, hyperkalemia, hepatomegaly, renal failure, hyperlipidemia, cardiac arrhythmia, Brugada-type ECG (ST-segment elevation and convex T-wave), and rapidly progressive cardiac failure usually unresponsive to inotropic support. This combination of events is known as propofol infusion syndrome and is typically observed in patients with severe head injuries and children with respiratory infections who received doses exceeding the recommended adult doses 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 drugs: vasoconstrictors, steroids, inotropes, and/or Diprivan**®** 1 % (usually at doses exceeding 4 mg/kg/hour for more than 48 hours).

Healthcare professionals should be prepared for the potential occurrence of these events in patients with the aforementioned risk factors and must discontinue propofol immediately if such events develop. Doses of all CNS depressants and other ICU medications should be titrated to ensure adequate oxygen delivery and hemodynamic stability. Patients with elevated intracranial pressure should receive appropriate treatment to maintain 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 requiring cautious use of lipid emulsions.

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 simultaneously, 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**®** 1 % contains approximately 0.1 g of fat.

Diprivan**®** 1 % contains less than 1 mmol of sodium (23 mg) per dose and is therefore considered sodium-free. The medicinal product Diprivan**®** 1 % contains 100 mg of refined soybean oil per 1 mL. This medicinal product should not be administered to patients with peanut or soy allergy (see section "Contraindications").

Additional precautions

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

Diprivan**®** 1 % 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**®** 1 %, consideration should be given to the need for additional zinc supplementation, particularly in patients prone to zinc deficiency, such as those with burns, diarrhea, and/or severe sepsis.

Diprivan**®** 1 % should be drawn into a sterile syringe or infusion system under aseptic conditions immediately after opening the ampoule or vial and administered immediately. All procedures involving Diprivan**®** 1 % and infusion equipment should be performed under aseptic conditions during infusion. Any infusion solutions should be added to the infusion line containing Diprivan**®** 1 % immediately before the site of administration. Diprivan**®** 1 % should not be used with microbial filter systems.

Diprivan**®** 1 % and syringes containing this medicinal product are intended for single use in one patient only. According to accepted guidelines for other lipid emulsions, a single propofol infusion should not last longer than 12 hours. At the end of the procedure or after 12 hours, whichever comes first, the container with propofol and the infusion line should be discarded and replaced with new ones.

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

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

Diprivan**®** 1 % should not be mixed with injectable or infusion solutions prior to administration, except with 5 % dextrose solution or lidocaine injection solution (see section "Method of administration and dosage").

Use during pregnancy or breastfeeding

Pregnancy

The safety of Diprivan**®** 1 % during pregnancy has not been established. Animal studies have demonstrated reproductive toxicity (see section "Preclinical safety data"). Diprivan**®** 1 % should not be used in pregnant women except when absolutely necessary. Diprivan**®** 1 % crosses the placental barrier and may cause depression in newborns. However, Diprivan**®** 1 % may be used for induced termination of pregnancy.

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 mothers have shown that small amounts of Diprivan**®** 1 % are excreted in breast milk. Therefore, women should not breastfeed for 24 hours after administration of Diprivan**®** 1 %. Milk expressed during this period should be discarded.

Ability to affect reaction speed when driving vehicles or operating machinery

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

Functional disturbances caused by Diprivan**®** 1 % are typically no longer evident within 12 hours (see section "Special precautions for use").

Administration and Dosage

Dosage

Induction of General Anesthesia

Adults

Diprivan® 1% may be used for induction of anesthesia either as a slow bolus injection or by infusion.

For patients with or without premedication, the dose of Diprivan® 1% should be titrated (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 Diprivan® 1% is generally sufficient. The total required dose may 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 (American Society of Anesthesiologists) risk 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 smaller doses of Diprivan® 1% for induction of anesthesia. Dose reduction should take into account the patient's age and physical condition. The reduced dose should be administered at a slower rate and titrated according to clinical response.

Pediatric Population

Diprivan® 1% 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 Diprivan® 1% 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® 1% 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 Precautions").

Maintenance of General Anesthesia

Adults

Maintenance of anesthesia can be achieved by continuous infusion or repeated bolus injections of Diprivan® 1% to maintain the appropriate depth of anesthesia.

• 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 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 Diprivan® 1% for maintenance of anesthesia, the infusion rate or target concentration should be reduced. Patients with an ASA score of 3 or 4 require even greater 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

Diprivan® 1% 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 Diprivan® 1% to maintain the 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 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 Precautions").

Sedation of Intensive Care Unit Patients

Adults

For sedation of patients in the intensive care unit, Diprivan® 1% should be administered by continuous infusion. The infusion rate should be adjusted according to the desired depth of sedation. In most patients, adequate sedation depth is achieved with a dose of Diprivan® 1% of 0.3–4.0 mg/kg/hour (see section "Special Precautions").

Diprivan® 1% should not be used for sedation of patients in the intensive care unit who are ≤16 years of age (see section "Contraindications").

Elderly Patients

When using Diprivan® 1% for sedation, the infusion rate should be reduced. Patients with an ASA score of 3 or 4 require even greater 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

Diprivan® 1% should not be used for sedation in children under 16 years of age who are receiving mechanical ventilation in the intensive care unit.

Sedation Prior to Diagnostic and Surgical Procedures

Adults

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

In most patients, sedation can be induced by administering the drug 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® 1% administered by infusion to the desired depth of sedation; for most patients, 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® 1% for sedation, the infusion rate or target concentration should be reduced. Patients with an ASA score of 3 or 4 will require even greater 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

Diprivan® 1% is not recommended for use in children under 1 month of age during diagnostic and surgical procedures.

For children aged 1 month and older, the dose and administration rate should be adjusted according to the required depth of sedation and clinical response. In most children, sedation can be induced by administering Diprivan® 1% at a dose of 1–2 mg/kg body weight. Maintenance of sedation can be achieved by titrating Diprivan® 1% doses during infusion to achieve the desired depth of sedation. For most patients, a dose of 1.5–9.0 mg/kg/hour of Diprivan® 1% is sufficient. The 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

Diprivan® 1% has no analgesic activity; therefore, concomitant administration of additional analgesic drugs is usually necessary.

Diprivan® 1% may be administered for infusions either undiluted from the glass containers of Diprivan® 1% or diluted with 5% dextrose solution for intravenous infusion (Ph. Eur.) from polyvinyl chloride (PVC) infusion bags or glass infusion bottles. Dilution should not exceed 1 to 5 (2 mg propofol per 1 mL) and should be performed under aseptic conditions immediately before use. The diluted emulsion should be used within 6 hours after preparation.

It is recommended that when using diluted Diprivan® 1%, the volume of 5% dextrose solution removed from the infusion bag during dilution be completely replaced with Diprivan® 1% emulsion (see Table 1).

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

When using undiluted Diprivan® 1% for maintenance of anesthesia, it is recommended to always use equipment such as a syringe or volumetric infusion pump to control the infusion rate.

Diprivan® 1% may be administered through a Y-connector placed immediately before the infusion site of the following solutions:

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

Diprivan® 1% may be pre-mixed 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, Diprivan® 1% may be mixed with lidocaine injection solution (0.5% or 1%, preservative-free) in a 20:1 ratio immediately before administration (see Table 1).

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

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

Induction and Maintenance of General Anesthesia

In adult patients under 55 years of age, anesthesia is usually achieved with blood propofol target concentrations in the range of 4–8 mcg/mL. An initial target concentration of 4 mcg/mL is recommended for patients who have received premedication and 6 mcg/mL for those without premedication. The induction time at these target concentrations is typically 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 mcg/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 needed to maintain anesthesia will depend on the dose of concomitantly administered analgesics. Propofol target concentrations in the range of 3–6 mcg/mL generally provide adequate anesthesia.

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

Sedation with Consciousness Preservation 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 between 0.5 and 2.5 mcg/mL is required. An initial blood target concentration at the upper end of the recommended range allows for faster onset of sedation with consciousness preservation.

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 at the medical facility.

Table 1

Dilution and Co-administration of Diprivan® 1% with Other Medicinal Products or Infusion Solutions

Children.

Diprivan**®** is not recommended for use in neonates, as administration of the medicinal product to this patient group has not been fully studied. Pharmacokinetic data (see section "Pharmacokinetics") indicate that drug clearance in neonates 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 system depression.

The use of Diprivan**®** 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 aged ≤ 16 years for sedation in intensive care units, 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 treated with artificial ventilation and oxygen administration. In case of cardiovascular depression, the patient should be placed in a horizontal position with low head elevation, and in severe cases, plasma expanders and pressor medicinal products should be administered.

Adverse reactions.

Systemic

Induction and maintenance of anesthesia or sedation usually proceed smoothly, with minimal excitation phase, although involuntary movements may occur in some patients. The most commonly reported adverse reactions are pharmacologically predictable side effects of an anesthetic agent / centrally acting depressant drug, such as hypotension. The nature, severity, and frequency of adverse events in patients receiving Diprivan® 1% may also be related to the patient's clinical condition and to 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 not known (cannot be estimated based on available data).

Table 2

Table of adverse reactions

(1) Serious bradycardia is rare. There have been isolated reports of progression to asystole.

(2) In isolated cases, intravenous fluids and reduction of the Diprivan**®** infusion rate may be required to manage hypotension.

(3) Rhabdomyolysis has been very rarely reported when Diprivan**®** was administered at doses exceeding 4 mg/kg/hour for sedation in intensive care.

(4) Pain on injection can be minimized by administration into larger diameter veins such as forearm or antecubital veins. When using Diprivan**®** 1%, local pain can also be reduced by co-administration of lidocaine.

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

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

(7) Rapidly progressive heart failure (sometimes 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 Diprivan**®** during intensive care therapy.

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

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

Reports on off-label use of Diprivan**®** 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 induction of anesthesia with Diprivan**®** 1%, 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. Instances of accidental extravascular administration in clinical practice and animal studies indicate minimal tissue reaction. Intra-arterial administration in animals did not show local tissue effects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows 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. The diluted preparation must be used immediately after preparation.

Storage conditions.

Store at a temperature between 2 and 25 °C. Do not freeze.

Keep out of reach of children.

Incompatibilities.

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

Packaging.

For manufacturer AstraZeneca UK Limited, United Kingdom (AstraZeneca UK Limited, United Kingdom):

20 ml in an ampoule; 5 ampoules in a blister pack; 1 blister pack in a cardboard box;

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

For manufacturer Corden Pharma Societa' Per Azioni, Italy (Corden Pharma Societa' Per Azioni, Italy):

20 ml in an ampoule; 5 ampoules in a cardboard holder (retainer) in a cardboard box;

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

Prescription status.

Prescription only.

Manufacturer.

1. AstraZeneca UK Limited / AstraZeneca UK Limited.
2. Corden Pharma Societa' Per Azioni / Corden Pharma Societa' Per Azioni.

Manufacturer's address and location of operations.

1. Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom /
   Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom.

2. Viale Dell'Industria, 3, Caponago (MB), 20867, Italy /
   Viale Dell'Industria, 3, Caponago (MB), 20867, Italy.