Propofol
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROPOFOL (PROPOFOL)
Composition:
Active substance: propofol;
1 ml of emulsion contains 10 mg of propofol;
Excipients: soybean oil, glycerol, egg lecithin, sodium oleate, sodium hydroxide, water for injections.
Pharmaceutical form. Emulsion for infusion.
Main physicochemical properties: milky-white emulsion, practically free from foreign 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 anaesthetic agent with a rapid onset of effect, typically within approximately 30 seconds. Recovery from anaesthesia is usually rapid. The mechanism of action, as with other general anaesthetic agents, is not fully understood. However, propofol is believed to exert its sedative and anaesthetic effects by positively modulating the inhibitory function of the neurotransmitter GABA through facilitation of its interaction with ligand-gated GABAA receptors.
Pharmacodynamic properties
When propofol is used for induction and maintenance of anaesthesia, a reduction in mean arterial pressure and minor changes in heart rate are usually observed. However, haemodynamic parameters remain relatively stable during maintenance of anaesthesia, and the incidence of adverse haemodynamic reactions is low.
Although respiratory depression may occur after administration of propofol, any such reactions are qualitatively similar to those seen with other intravenous anaesthetic agents and are easily managed in clinical practice.
Propofol reduces cerebral blood flow, intracranial pressure, and cerebral metabolism. The reduction in intracranial pressure is more pronounced in patients with initially elevated intracranial pressure.
Clinical safety and efficacy
Recovery from anaesthesia is typically rapid and characterized by rapid restoration of cognitive functions, with a low incidence of headache and postoperative nausea and vomiting.
Postoperative nausea and vomiting are generally less frequent with propofol compared to inhaled anaesthetic agents. Evidence suggests this may be related to the reduced emetogenic potential of propofol.
Propofol does not suppress adrenal cortical hormone synthesis at clinically used concentrations.
Paediatric population
Limited data from studies on anaesthesia using propofol in children indicate maintained safety and efficacy with anaesthesia durations of up to 4 hours. Published data suggest that the medicinal product can be used in children undergoing prolonged procedures without changes in safety or efficacy.
Pharmacokinetics.
Absorption
When propofol is used for maintenance of anaesthesia, blood concentrations asymptotically approach a steady state for a given infusion rate.
Distribution
Propofol is widely distributed and rapidly cleared from the body (total clearance is 1.5–2.0 L/min).
Elimination
The decline in propofol concentrations after a bolus dose or at the end of an infusion can be described by an open three-compartment model, with a very rapid distribution phase (distribution half-life of 2–4 minutes), a rapid elimination phase (elimination half-life of 30–60 minutes), and a slower terminal phase reflecting redistribution of propofol from poorly perfused tissues.
Clearance is achieved primarily through metabolic processes, mainly in the liver, where it is blood flow-dependent, resulting in the formation of inactive conjugates of propofol and the corresponding quinol, which are excreted in urine.
After 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). In addition, 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 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 that produce light to moderate anaesthesia, indicate that administration of anaesthetics 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, 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, anaesthetic exposure of up to 3 hours under conditions producing light surgical anaesthesia did not increase neuronal cell loss, whereas anaesthetic regimens of 5 hours or longer were associated with increased neuronal cell loss. The clinical significance of these preclinical findings is unknown. Therefore, physicians should weigh the benefits of appropriate anaesthesia in children under 3 years of age and pregnant women requiring surgical procedures against the potential risks suggested by preclinical data.
Clinical characteristics.
Indications.
For short-term 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, alone or in combination with local or general anesthetic agents, in adults and children aged > 1 month;
- sedation of patients aged > 16 years who are undergoing mechanical ventilation in the intensive care unit (ICU).
Contraindications.
Hypersensitivity to the active substance or to any of the excipients.
Age under 1 month (for induction and maintenance of general anesthesia).
Propofol contains soybean oil and is not intended for use in patients with hypersensitivity to peanuts or soy.
Propofol 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 has been used in combination with agents for spinal and epidural anesthesia, as well as commonly used premedicants, 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 hypertension have been observed when propofol was administered to patients receiving rifampicin.
Concomitant use with other central nervous system (CNS) depressants, such as premedicants, inhalational anesthetics, and analgesics, may enhance sedative and analgesic effects, as well as the depressant effects of propofol on cardiovascular and respiratory function (see section "Special precautions").
Reduced propofol dosage 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
Propofol should be administered only by a specialist experienced in anesthesia (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 be readily available and ready for immediate use. The same individual should not administer Propofol and perform the diagnostic or surgical procedure.
Cases of abuse and development of drug dependence on Propofol have been reported, primarily among healthcare professionals. As with other general anesthetics, administration of Propofol without respiratory support may lead to life-threatening respiratory complications.
When Propofol is used for sedation without loss of consciousness during surgical or diagnostic procedures, continuous monitoring of the patient is essential to detect early signs of hypotension, airway obstruction, and decreased oxygen saturation.
As with other central nervous system (CNS) depressants, involuntary movements may occur in patients receiving Propofol for sedation during surgical procedures. These movements may pose a risk to the patient during procedures requiring immobilization.
Sufficient time should elapse before discharge to ensure full recovery of physiological functions after Propofol administration. Very rarely, the use of Diprivan 1% may be associated with delayed 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 supportive care should be provided to patients who lose consciousness.
Typically, functional disturbances caused by Propofol administration are no longer evident within 12 hours. The effects of Propofol, the nature of the procedure performed, concomitant medication use, patient age, and patient condition should be considered when advising patients on:
- the need for discharge in the presence of another person;
- the time required before resuming activities involving complex or hazardous tasks, such as driving vehicles;
- the use of other CNS depressants (e.g., benzodiazepines, opioids, ethanol).
As with other intravenous anesthetics, Propofol should be used with caution in patients with impaired cardiac, respiratory, renal, or hepatic function, as well as in hypovolemic or debilitated patients. Propofol clearance depends on blood flow; therefore, concomitant administration of drugs that reduce cardiac output will lead to decreased Propofol clearance.
Propofol has no significant vagolytic activity; however, cases of bradycardia (in some cases profound) and asystole have been reported with the use of this medicinal product. Consideration should be given to intravenous administration of an anticholinergic agent prior to induction or during maintenance of anesthesia, especially when vagal tone is likely to predominate or when Propofol is used in combination 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 Propofol administration.
Particular caution is required when administering bolus doses of Propofol during surgical procedures in patients with acute respiratory insufficiency or respiratory depression.
Concomitant use of Propofol with other CNS depressants, such as ethanol, general anesthetics, or opioid analgesics, may potentiate CNS depression. Combined use of Propofol with parenterally administered CNS depressants may result in severe respiratory and cardiovascular depression. 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").
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 Propofol infusion rate during the maintenance phase may be required to manage hypotension.
There is a risk of seizures when Propofol is administered to patients with epilepsy.
Appropriate management should be provided for patients with lipid metabolism disorders or conditions requiring cautious use of lipid emulsions (see section "Method of administration and dosage").
Propofol is not recommended for use during electroconvulsive therapy.
As with other anesthetic agents, sexual disinhibition may occur during emergence from anesthesia.
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, which may lead to fatal outcomes. Cases have been reported of a combination of adverse events including metabolic acidosis, rhabdomyolysis, hyperkalemia, hepatomegaly, renal failure, hyperlipidemia, cardiac arrhythmia, Brugada-type ECG (ST-segment elevation and convex T-wave), and rapidly progressive heart failure, usually unresponsive to inotropic support. This combination 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 those recommended for adult sedation in ICU settings.
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 Propofol (usually at doses exceeding 4 mg/kg/hour for more than 48 hours).
Healthcare professionals should be prepared for the possible occurrence of these events in patients with the aforementioned risk factors and should promptly decide whether to reduce or discontinue Propofol upon development of these signs. Doses of all CNS depressants and other drugs used in ICU should be titrated to ensure adequate oxygen delivery and maintenance of hemodynamic parameters. Patients with elevated intracranial pressure should receive appropriate treatment aimed at maintaining adequate cerebral perfusion pressure during changes in therapy.
It is advisable not to exceed a dose of 4 mg/kg/hour.
Patients with lipid metabolism disorders or other conditions requiring cautious use of lipid emulsions should receive appropriate management.
Monitoring of blood lipid concentrations is recommended when propofol is administered to patients at particular risk of lipid overload. If monitoring results indicate impaired lipid 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 lipids delivered as part of the propofol formulation; 1.0 mL of Propofol contains approximately 0.1 g of lipids.
Propofol contains 0.0018 mmol/mL of sodium. This should be taken into account when treating patients on a sodium-restricted diet.
Additional precautions
Patients with mitochondrial diseases should be treated with caution. Anesthesia, surgical procedures, and other ICU interventions may trigger exacerbation of the disease in these patients. Normothermia, carbohydrate supply, and adequate fluid intake are recommended in such patients. Early signs of mitochondrial disease exacerbation and propofol infusion syndrome may be similar.
Propofol 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 Propofol, consideration should be given to additional zinc supplementation, particularly in patients prone to zinc deficiency, such as those with burns, diarrhea, and/or severe sepsis.
Before administration, Propofol 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 handling of Propofol and infusion equipment during infusion must be performed under aseptic conditions. Any infusion solutions should be added to the infusion line containing Propofol immediately before the administration site. Propofol should not be used with infusion systems containing a microbial filter.
Propofol and syringes containing this medicinal product are intended for single-patient, single-use only. According to established 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 propofol container and 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.
Propofol should not be mixed with injectable or infusion solutions prior to administration, except for 5% glucose solution or lidocaine injection solution (see "Method of administration and dosage").
The benefit-risk balance should be carefully considered before repeated or prolonged (>3 hours) use of propofol in young children (<3 years of age) or pregnant women, due to reports of neurotoxicity in preclinical studies.
Use during pregnancy or breastfeeding
Animal studies have demonstrated reproductive toxicity.
Pregnancy
The safety of Propofol during pregnancy has not been established. Propofol should not be used in pregnant women except when absolutely necessary. However, Propofol may be used for termination of pregnancy.
Labour and delivery
Propofol crosses the placental barrier and may cause depression in newborns. This medicinal product should not be used for anesthesia during labor 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.
Effect on ability to drive or operate machinery
Propofol has a moderate effect on the ability to drive 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 anesthesia.
Typically, functional disturbances caused by Propofol administration are no longer evident within 12 hours (see section "Special precautions for use").
Method of Administration and Dosage
Detailed instructions for administering the medicinal product Propofol using a target-controlled infusion (TCI) device, including the "Diprifusor" TCI software, are provided below. This mode of administration is restricted to induction and maintenance of anesthesia in adults. The Diprifusor TCI system is not recommended for sedation in intensive care units (ICU), sedation during surgical or diagnostic procedures, or for use in pediatric patients.
Induction of General Anesthesia
Adults
For adult patients, with or without premedication, the dose of Propofol should be titrated (administered as a bolus injection or infusion of approximately 4 mL [40 mg] every 10 seconds) according to clinical response until signs of anesthesia appear. For most adults under 55 years of age, a dose of 1.5–2.5 mg/kg of Propofol is generally sufficient. The total required dose may be reduced by decreasing the infusion rate (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. For patients with an ASA (American Society of Anesthesiologists) physical status score of 3 or 4, Propofol should be administered at a slower rate (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 age and overall health status. The reduced dose should be administered more slowly and titrated according to clinical response.
Pediatric Population
Propofol is not recommended for induction of anesthesia in children under 1 month of age.
For induction of anesthesia in children aged 1 month and older, the dose of Propofol should be slowly titrated until clinical signs of anesthesia appear. The dose should be adjusted according to age and/or body weight. For most patients aged 8 years and older, a dose of approximately 2.5 mg/kg of Propofol is sufficient for induction. Younger children, especially those aged 1 month to 3 years, may require higher doses (2.5–4 mg/kg).
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 Propofol drug with the Diprifusor TCI system is not recommended for induction of general anesthesia in children.
Maintenance of General Anesthesia
Adults
Maintenance of anesthesia can be achieved by continuous infusion or repeated bolus injections of Propofol to maintain the desired depth of anesthesia. Recovery from anesthesia is typically rapid; therefore, it is important to continue administering Propofol until the end of the procedure.
Continuous Infusion
The required infusion rate may vary significantly between patients, but rates within the range of 4–12 mg/kg/hour are generally sufficient to maintain adequate anesthesia depth.
Repeated Bolus Injections
When using repeated bolus injections, incremental doses from 25 mg (2.5 mL) to 50 mg (5.0 mL) should be administered according to clinical need.
Elderly Patients
When using Propofol for maintenance of anesthesia, 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) should be avoided in elderly patients, as it may lead to cardiovascular and respiratory depression.
Pediatric Population
Propofol 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 Propofol to maintain the desired depth of anesthesia. The required infusion rate may vary significantly between patients, but rates within the range of 9–15 mg/kg/hour are generally sufficient to achieve adequate anesthesia depth. 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 Propofol drug with the Diprifusor TCI system is not recommended for maintenance of general anesthesia in children.
Sedation of Patients in Intensive Care Units
Adults
For sedation of patients in intensive care units, Propofol should be administered via continuous infusion. The infusion rate should be adjusted according to the desired depth of sedation. In most patients, adequate sedation depth can be achieved with a dose of Diprivan 1% of 0.3–4.0 mg/kg/hour (see section "Special Warnings and Precautions for Use").
Propofol should not be used for sedation of patients under 16 years of age in intensive care units (see section "Contraindications"). Administration of Propofol using the Diprifusor TCI system is not recommended for sedation of ICU patients.
Propofol can be diluted with 5% dextrose solution (see Table 1).
Lipid blood concentration monitoring is recommended when administering Propofol to patients at special risk of lipid overload. If monitoring results indicate impaired fat clearance, administration of Propofol should be adjusted accordingly. If other lipid-containing intravenous solutions are administered simultaneously, the dose of Propofol should be reduced to account for the amount of fat administered as part of the formulation; 1.0 mL of Propofol contains approximately 0.1 g of fat.
Lipid concentration monitoring should be performed in all patients if sedation duration exceeds 3 days.
Elderly Patients
When using Propofol 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) should be avoided in elderly patients, as it may lead to cardiovascular and respiratory depression.
Pediatric Population
Propofol should not be used for sedation in children under 16 years of age who are receiving mechanical ventilation in intensive care units.
Sedation Prior to Diagnostic and Surgical Procedures
Adults
To achieve adequate sedation during diagnostic and surgical procedures, the infusion rate should be individually adjusted and the dose titrated according to clinical response.
In most patients, sedation can be induced by administering 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 Propofol administered by 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 a rapid increase in sedation depth is required. Patients with an ASA score of 3 or 4 may require reduced infusion rates and doses.
Administration of Propofol using the Diprifusor TCI system is not recommended for sedation prior to diagnostic and surgical procedures.
Elderly Patients
When using Propofol 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) should be avoided in elderly patients, as it may lead to cardiovascular and respiratory depression.
Pediatric Population
Propofol is not recommended for use during diagnostic and surgical procedures in children under 1 month of age.
For children aged 1 month and older, doses and infusion rates 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 Propofol 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.
Method of Administration
Propofol has no analgesic activity; therefore, concomitant administration of additional analgesic medicinal products is usually necessary.
Propofol can be administered undiluted via infusion from glass containers, plastic syringes, pre-filled syringes of Propofol, or diluted with 5% dextrose solution (for intravenous infusion Ph. Eur.) from 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 administration. The diluted emulsion should be used within 6 hours of preparation.
When using diluted Propofol, it is recommended to completely replace the volume of 5% dextrose solution removed from the infusion bag during dilution with Propofol emulsion (see Table 1).
Dilution can be performed using various infusion control devices, but using only an infusion set does not eliminate the risk of accidental uncontrolled infusion of large volumes of diluted Propofol. The infusion line should include a burette, drip counter, or volumetric pump. The risk of uncontrolled infusion should be considered when determining the maximum volume of Propofol in the burette.
When using undiluted Propofol for maintenance of anesthesia, it is recommended to always use equipment such as a syringe or volumetric infusion pump to control the infusion rate.
Propofol can be administered through a Y-connector located 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.
The glass pre-filled syringe has lower friction resistance than plastic disposable syringes and is more convenient to use. Therefore, if Propofol is administered using a pre-filled syringe, the infusion line between the syringe and the patient must not be left open unattended.
When using a pre-filled syringe with a syringe infusion pump, compatibility must be ensured. Particular attention should be paid to ensuring that the pump design prevents siphoning and that the occlusion alarm is set to a value greater than 1000 mmHg. When using a programmable pump or equivalent capable of using various syringes, only the 'B-D' 50/60 mL 'PLASTIPAK' option should be selected when using a pre-filled syringe with Propofol.
Propofol can 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 of preparation.
To reduce pain on initial injection, Propofol can be mixed with lidocaine injection solution (0.5% or 1%, without preservatives) (see Table 1).
Target-Controlled Infusion: Administration of Propofol to Adults Using the Diprifusor TCI System
Administration of Propofol using the Diprifusor TCI system is limited to induction and maintenance of general anesthesia in adults. It is not recommended for sedation in ICU, sedation during diagnostic or surgical procedures, or for use in children.
Propofol can be administered as a TCI only using the Diprifusor TCI system with Diprifusor TCI software. Such systems will only operate with electronically labeled pre-filled syringes of 1% or 2% propofol for injection. The Diprifusor TCI system automatically sets the infusion rate based on the recognized propofol concentration. Users must be familiar with the infusion pump operating instructions, guidelines for administering Propofol using the TCI system, and proper handling of the syringe recognition system.
The Diprifusor TCI 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. Some Diprifusor TCI systems offer an alternative effect-site targeting mode, but its safety and efficacy have not yet been established.
The Diprifusor TCI system assumes the initial propofol concentration in the patient's blood is zero. Therefore, if the patient has previously received propofol, a lower initial target concentration may be required when using the Diprifusor TCI system. It is also not recommended to immediately restart the Diprifusor TCI system after stopping the pump.
Below are recommendations for target propofol concentrations. Due to variability in propofol pharmacokinetics and pharmacodynamics among patients, the target concentration of propofol should be titrated according to clinical response, regardless of whether premedication was administered, to achieve the required depth of anesthesia.
Induction and Maintenance of General Anesthesia
In adult patients under 55 years of age, anesthesia is typically achieved at target propofol concentrations in the range 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. The time to induction at these target concentrations is typically 60–120 seconds. Higher rates may lead to earlier induction of anesthesia but may also be associated with more pronounced cardiovascular and respiratory depression.
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 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 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 maintenance of anesthesia.
Table 1
Dilution and co-administration of Propofol with other medicinal products or infusion solutions (see section "Special Warnings and Precautions for Use").
| Method of co-administration |
Excipient or solvent |
Preparation |
Precautions |
| Pre-mixing |
5 % glucose solution for intravenous infusion |
Mix 1 part of Propofol with 1–4 parts of 5 % glucose solution for intravenous infusion in a PVC infusion bag or a glass infusion bottle. When diluting in a PVC infusion bag, it is recommended that the bag be full and the dilution be performed by replacing a certain volume of infusion solution with an equivalent volume of Propofol. |
Prepare under aseptic conditions immediately before administration. The mixture is stable for up to 6 hours. |
| Lidocaine hydrochloride injection solution (0.5 % or 1 %, without preservatives) |
Mix 20 parts of Propofol with 1 part of 0.5 % or 1 % lidocaine hydrochloride injection solution. |
Prepare the mixture under aseptic conditions immediately before administration. Use only for induction. |
|
| Alfentanil injection solution (500 mcg/ml) |
Mix Propofol with alfentanil injection solution in a volume ratio ranging from 20:1 to 50:1. |
Prepare the mixture under aseptic conditions; use within 6 hours after preparation. |
|
| Co-administration via Y-site connector |
5 % glucose solution for intravenous infusion |
Co-administration via Y-site connector |
Position the Y-site connector immediately before the administration site |
| 0.9 % sodium chloride solution for intravenous infusion |
As stated above |
As stated above |
|
| 4 % glucose with 0.18 % sodium chloride solution for intravenous infusion |
As stated above |
As stated above |
Children.
The use of propofol is not recommended in neonates, as administration of the medicinal product to this patient group has not been fully investigated. Pharmacokinetic data (see section "Posology and method of administration") indicate that in neonates the clearance of the drug is significantly reduced and shows a very high inter-patient variability. Administration of doses recommended for older children may lead to relative overdose and development of severe cardiovascular depression.
The use of propofol 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 or younger for intensive care unit sedation, as the safety and efficacy of propofol for sedation in this age group are unknown (see section "Contraindications").
Overdose.
Accidental overdose is likely to manifest as depression of the cardiovascular and respiratory systems. Respiratory depression should be treated with artificial ventilation of the lungs and oxygen administration. In case of cardiovascular depression, the patient’s head should be lowered 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. 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 Propofol may be related to the patient's condition and the surgical or therapeutic procedures being performed.
In Table 2, the following criteria are used to define the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data).
Table 2
Table of adverse reactions
| System organ class |
Frequency |
Adverse reactions |
| Immune system disorders |
Very rare |
Anaphylaxis – may include angioedema, bronchospasm, erythema, and hypotension |
| Metabolism and nutrition disorders |
Not known (9) |
Metabolic acidosis (5), hyperkalemia (5), hyperlipidemia (5) |
| Psychiatric disorders |
Not known (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 |
|
| Not known (9) |
Involuntary movements |
|
| Cardiac disorders |
Common |
Bradycardia (1) |
| Very rare |
Lung edema |
|
| Not known (9) |
Cardiac arrhythmia (5), cardiac failure (5), (7) |
|
| Vascular disorders |
Common |
Arterial hypotension (2), flush in children (11) |
| Sometimes |
Thrombosis and phlebitis |
|
| Respiratory, thoracic and mediastinal disorders |
Common |
Transient apnea during induction |
| Not known (9) |
Respiratory depression (dose-dependent) |
|
| Gastrointestinal disorders |
Common |
Nausea and vomiting during emergence |
| Very rare |
Pancreatitis |
|
| Hepatobiliary disorders |
Not known (9) |
Hepatomegaly (5), hepatitis (12), acute liver failure (12) |
| Musculoskeletal and connective tissue disorders |
Not known (9) |
Rhabdomyolysis (3), (5) |
| Renal and urinary disorders |
Very rare |
Discoloration of urine after prolonged administration |
| Not known (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 |
|
| Not known (9) |
Local pain, swelling after accidental extravasation |
|
| Common |
Withdrawal symptoms in children (11) |
|
| Investigations |
Not known (9) |
Brugada-type ECG (5), (6) |
| Injury, poisoning and procedural complications |
Very rare |
Postoperative fever |
- Serious bradycardia is rare. There have been isolated reports of progression to asystole.
- In individual cases, intravenous fluids and reduction of the infusion rate of Propofol may be required to manage hypotension.
- Rhabdomyolysis has been very rarely reported when Propofol was administered at doses exceeding 4 mg/kg/hour for sedation in intensive care units (ICU).
- The risk can be minimized by administration into larger diameter veins: forearm and antecubital veins. Local pain associated with Propofol administration can also be reduced by co-administration of lidocaine.
- The combination of these events is known as propofol infusion syndrome, which may occur in critically ill patients with multiple risk factors for these events; see section "Special precautions".
- Brugada-type ECG: ST-segment elevation and convex T-waves on ECG.
- Rapidly progressive heart failure (in some cases fatal) in adults. Heart failure in these cases was usually unresponsive to supportive therapy with inotropes.
- Abuse and drug dependence related to propofol, primarily reported among healthcare professionals.
- Frequency is unknown, as it cannot be estimated from available clinical trial data.
- Necrosis has been reported in cases of tissue viability impairment.
- Following abrupt discontinuation of Propofol infusion during intensive care treatment.
- After both long-term and short-term treatment, and also in patients without major risk factors.
- Following abrupt discontinuation of Propofol infusion during intensive care treatment.
- Necrosis has been reported in cases of tissue viability impairment.
- Frequency is unknown, as it cannot be estimated from available clinical trial data.
- Abuse and drug dependence related to propofol, primarily reported among healthcare professionals.
- Rapidly progressive heart failure (in some cases fatal) in adults. Heart failure in these cases was usually unresponsive to supportive therapy with inotropes.
- Brugada-type ECG: ST-segment elevation and convex T-waves on ECG.
- The combination of these events is known as propofol infusion syndrome, which may occur in critically ill patients with multiple risk factors for these events; see section "Special precautions".
- The risk can be minimized by administration into larger diameter veins: forearm and antecubital veins. Local pain associated with Propofol administration can also be reduced by co-administration of lidocaine.
- Rhabdomyolysis has been very rarely reported when Propofol was administered at doses exceeding 4 mg/kg/hour for sedation in intensive care units (ICU).
- In individual cases, intravenous fluids and reduction of the infusion rate of Propofol may be required to manage hypotension.
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 the induction phase with Propofol anesthesia, can be minimized by concomitant administration of lidocaine (see section "Dosage and method of administration") and by administration into larger diameter veins: forearm and antecubital veins. Cases of thrombosis and phlebitis are rare. Cases of accidental extravascular administration and animal studies indicate minimal tissue reaction. Intra-arterial administration in animals did not show local tissue effects.
Shelf life. 3 years.
The diluted preparation should be used immediately after preparation.
After opening the container, administer immediately.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze.
Keep out of reach of children.
Incompatibilities.
Propofol must not be mixed with other injectable or infusion solutions prior to administration, except those specified in the section "Method of administration and dosage".
Propofol must not be administered through the same catheter as blood or plasma. In vitro studies have demonstrated that the lipid component of the emulsion forms aggregates upon contact with human plasma.
The muscle relaxants atracurium and mivacurium should not be administered through the same intravenous line used for Propofol without prior flushing of the line.
Packaging.
10 ml, 20 ml, 50 ml, or 100 ml in vials sealed with a rubber stopper and aluminum crimp cap.
One vial per cardboard pack.
Prescription status.
Prescription only.
Manufacturer.
BAXTER PHARMACEUTICALS INDIA PRIVATE LIMITED
BAXTER PHARMACEUTICALS INDIA PRIVATE LIMITED
Manufacturer's address and location.
Chacharwadi-Vasana, Ahmedabad, 382213, India
Chacharwadi-Vasana, Ahmedabad, in 382213, India
Marketing Authorization Holder.
M.Biotech Ltd
M.Biotech Ltd
Address of Marketing Authorization Holder.
Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom
Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom