Propofol rompharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROPOFOL ROMPHARM

Composition:

active substance: propofol;

1 ml of emulsion contains 10 mg of propofol;

excipients: refined soybean oil, egg phospholipids for injection, glycerol,

disodium edetate, 0.1 M solution of sodium hydroxide, water for injection.

Pharmaceutical form. Emulsion for injection and infusion.

Main physicochemical properties: milky-white oil-in-water emulsion.

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 rapid onset of effect, typically within approximately 30 seconds. Recovery from anesthesia is usually rapid. The mechanism of action, as with other general anesthetic agents, is not fully understood. However, it is believed that propofol exerts its sedative and anesthetic effects by positively influencing the inhibitory function of the neurotransmitter GABA (gamma-aminobutyric acid) through facilitation of the interaction of GABA with ligand-gated GABAA receptors.

Pharmacodynamic properties

When Propofol Rompharm 10 mg/mL 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 Propofol Rompharm 10 mg/mL, the reactions are qualitatively similar to those observed with other intravenous anesthetic agents and are easily managed in clinical practice.

Propofol Rompharm 10 mg/mL 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 rapid restoration of cognitive functions, with a low incidence of headache, postoperative nausea, and vomiting. Postoperative nausea and vomiting occur less frequently with Propofol Rompharm 10 mg/mL compared to inhaled anesthetic agents. Data suggest this may be related to the reduced emetogenic potential of propofol.

Propofol Rompharm 10 mg/mL does not suppress adrenal cortical hormone synthesis at clinically relevant concentrations.

Paediatric population

Limited study data on anesthesia using propofol in children indicate maintained safety and efficacy with anesthesia duration 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 Propofol Rompharm 10 mg/mL is administered for maintenance of anesthesia, blood concentrations asymptotically approach a steady state for a given infusion rate.

Clinical characteristics.

Distribution

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

Elimination

The decline in propofol 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 (half-life of distribution 2–4 minutes), a rapid elimination phase (elimination half-life 30–60 minutes), and a slower terminal phase reflecting redistribution of propofol from poorly perfused tissues.

Clearance is achieved through metabolic processes, predominantly 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 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). Furthermore, neonates showed considerable inter-patient variability in this parameter (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 Rompharm 10 mg/mL is administered within the recommended infusion rate range, the pharmacokinetics of the drug are linear.

Preclinical safety data

Published animal studies (including in primates), using doses that induce light to moderate anesthesia, indicate that administration of anesthetics during periods of rapid brain growth or synaptogenesis may lead to developing brain cell loss, potentially resulting in long-term cognitive impairment. The clinical significance of these preclinical findings is unknown.

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

In neonatal primates, anesthesia exposure up to 3 hours under conditions of light surgical anesthesia did not increase neuronal cell loss, whereas regimens of 5 hours or longer did result in increased neuronal loss. Data on effects in fetuses and neonates in rodents and primates indicate that neuronal and oligodendrocyte loss is associated with mild but persistent cognitive deficits in learning and memory. The clinical significance of these preclinical data is unknown; therefore, physicians should weigh the benefits of necessary anesthesia in children under 3 years of age and pregnant women requiring surgical procedures against the potential risks suggested by preclinical data.

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

Clinical characteristics.

Indications.

For short-term intravenous administration of the drug for general anesthesia:

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

Contraindications.

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

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

Propofol Rompharm 10 mg/mL contains soybean oil and is not intended for use in patients with hypersensitivity to peanuts or soy.

Propofol Rompharm 10 mg/mL should not be used for sedation in patients ≤ 16 years of age in the intensive care unit (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Propofol Rompharm 10 mg/mL has been used in combination with agents for spinal and epidural anesthesia, as well as with commonly used premedicants, muscle relaxants, inhalational anesthetics, and analgesics; no cases of pharmacological incompatibility have been observed. When used for general anesthesia or sedation in combination with local anesthetics, lower doses of Propofol Rompharm 10 mg/mL may be required. Cases of pronounced hypotension have been observed when propofol was used for anesthesia induction in patients receiving rifampicin.

The hypotensive effect of Propofol Rompharm 10 mg/mL 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 propofol dose.

Reduced propofol dosage requirements have also 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 propofol dose.

Special precautions for use.

Propofol Rompharm 10 mg/mL is indicated for use in healthcare facilities.

Propofol Rompharm 10 mg/mL must be administered by a specialist experienced in anesthesia (or, if necessary, by a physician experienced in intensive care unit practice).

Continuous patient monitoring is required. Equipment for maintaining airway patency, artificial ventilation of the lungs, oxygen supply, and other resuscitation measures must be readily available and ready for immediate use. Propofol Rompharm 10 mg/mL must not be administered by the same individual performing the diagnostic or surgical procedure.

Cases of abuse and development of drug dependence on Propofol Rompharm 10 mg/mL have been reported, primarily among healthcare professionals. As with other general anesthetic agents, administration of Propofol Rompharm 10 mg/mL without respiratory support may lead to life-threatening respiratory complications.

When administering Propofol Rompharm 10 mg/mL 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 Propofol Rompharm 10 mg/mL for sedation during surgical procedures may result in involuntary movements. Such movements may pose a risk to the patient during procedures requiring immobilization.

Sufficient time should elapse before discharge to ensure full recovery of bodily functions following administration of Propofol Rompharm 10 mg/mL. Very rarely, use of Propofol Rompharm 10 mg/mL may be associated with postoperative loss of consciousness, which may be accompanied by increased muscular tone. This condition may be preceded by a period of insomnia. Although this condition resolves spontaneously, appropriate assistance should be provided to any patient who loses consciousness.

Typically, functional impairments caused by Propofol Rompharm 10 mg/mL are no longer detectable within 12 hours. The effects of Propofol Rompharm 10 mg/mL, the nature of the procedure performed, concomitant medication use, patient age, and patient condition should be considered when advising patients on:

• the advisability of leaving the healthcare facility accompanied by another person;
• the time interval before resuming activities involving complex or hazardous tasks, such as driving vehicles;
• the use of other CNS depressant medications (e.g., benzodiazepines, opioids, ethyl alcohol).

As with other intravenous anesthetic agents, Propofol Rompharm 10 mg/mL 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 Propofol Rompharm 10 mg/mL depends on blood circulation; therefore, concomitant administration of drugs that reduce cardiac output will lead to decreased clearance of Propofol Rompharm 10 mg/mL.

Propofol Rompharm 10 mg/mL has no pronounced vagolytic activity, but its use has been associated with cases of bradycardia (in some cases, profound) and asystole. Consideration should be given to the intravenous administration of an anticholinergic agent prior to induction or during maintenance of anesthesia, especially in cases of possible vagal dominance or when Propofol Rompharm 10 mg/mL 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 Propofol Rompharm 10 mg/mL.

Particular caution is required 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 opioid analgesics, may enhance CNS depression. Combined use of Propofol Rompharm 10 mg/mL with parenterally administered CNS depressants may result in severe depression of respiratory and cardiovascular functions.

It is recommended to administer Propofol Rompharm 10 mg/mL after administration of an analgesic, 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 medicinal products.

In some cases, intravenous fluids and/or reduction of the infusion rate of Propofol Rompharm 10 mg/mL may be required to manage hypotension during the maintenance phase of anesthesia.

There is a risk of seizures when administering Propofol Rompharm 10 mg/mL to patients with epilepsy.

Appropriate management should be provided for patients with lipid metabolism disorders and conditions requiring caution with lipid emulsions (see section "Method of administration and dosage").

Use during electroconvulsive therapy is not recommended.

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

The benefit-risk ratio of the proposed procedure should be carefully evaluated 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 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 children with respiratory infections who have received doses exceeding those recommended for adult sedation in ICU settings.

Major 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 Rompharm 10 mg/mL (usually at doses exceeding 4 mg/kg/hour for more than 48 hours).

Healthcare professionals should be prepared for the possible occurrence of these events in patients with the above-mentioned risk factors and must discontinue propofol immediately if these signs develop. Doses of all CNS depressants and other medications 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 these therapeutic changes.

It is advisable not to exceed a dose of 4 mg/kg/hour.

Appropriate management should be provided for patients with lipid metabolism disorders and other conditions requiring caution with lipid emulsions.

Monitoring of blood lipid concentrations is recommended when administering propofol to patients at particular risk of lipid overload. If monitoring results indicate impaired fat clearance, propofol administration should be adjusted accordingly. If other lipid-containing intravenous fluids are administered simultaneously, the dose of propofol should be reduced to account for the amount of fat delivered via the propofol formulation; 1.0 mL of Propofol Rompharm 10 mg/mL contains approximately 0.1 g of fat.

Propofol Rompharm 10 mg/mL contains 0.003 (0.06 mg) mmol/mL of sodium. This should be taken into account when treating patients on a sodium-restricted diet.

Additional precautions

Patients with mitochondrial disorders should be treated with caution. Exacerbation of the disease may occur during anesthesia, surgical procedures, or other ICU interventions. In such cases, normothermia, carbohydrate supply, and adequate fluid administration are recommended. Early signs of mitochondrial disorder exacerbation and propofol infusion syndrome may be similar.

Propofol Rompharm 10 mg/mL 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. During prolonged use of Propofol Rompharm 10 mg/mL, consideration should be given to the need for additional zinc supplementation, especially in patients prone to zinc deficiency, such as those with burns, diarrhea, and/or severe sepsis.

Prior to administration, Propofol Rompharm 10 mg/mL 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 operations involving Propofol Rompharm 10 mg/mL and infusion equipment should be performed under aseptic conditions during infusion. Any infusion solutions should be added to the infusion system containing Propofol Rompharm 10 mg/mL immediately before the site of administration. Propofol Rompharm 10 mg/mL should not be used with systems containing microbial filters.

Propofol Rompharm 10 mg/mL and syringes containing this medicinal product are intended for single use in one patient only. According to accepted guidelines for the use of other lipid emulsions, a single propofol infusion should not last longer than 12 hours. At the end of the procedure or after 12 hours, whichever comes first, the container with propofol and the infusion line should be discarded and replaced with new ones.

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

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

Propofol Rompharm 10 mg/mL should not be mixed with injectable or infusion solutions prior to administration, except for 5% dextrose solution or lidocaine injection solution (see section "Method of administration and dosage").

Use during pregnancy or breastfeeding.

Pregnancy

The safety of Propofol Rompharm 10 mg/mL during pregnancy has not been established.

Animal studies have demonstrated reproductive toxicity. Propofol Rompharm 10 mg/mL should not be used during pregnancy except when absolutely necessary. Propofol Rompharm 10 mg/mL crosses the placental barrier and may cause depression in newborns. However, Propofol Rompharm 10 mg/mL 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 propofol are excreted in breast milk. Therefore, women should not breastfeed for 24 hours after administration of Propofol Rompharm 10 mg/mL. Milk expressed during this period should be discarded.

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

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

Typically, functional impairments caused by Propofol Rompharm 10 mg/mL are no longer detectable within 12 hours (see section "Special precautions for use").

Method of Administration and Dosage

Dosage

Induction of General Anesthesia

Adults

Propofol Rompharm 10 mg/mL may be used for induction of anesthesia either by slow bolus injection or by infusion.

For patients with or without premedication, it is recommended to titrate the dose of Propofol Rompharm 10 mg/mL (administered to adult patients as a bolus injection or infusion at approximately 4 mL [40 mg] every 10 seconds) according to clinical response until signs of anesthesia appear. For most adult patients over 55 years of age, a dose of 1.5–2.5 mg/kg of Propofol Rompharm 10 mg/mL is generally sufficient. The total required dose can be reduced by decreasing the rate of administration (2–5 mL/min [20–50 mg/min]). In patients aged 55 years and older, 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, the drug should be administered at a slower rate (approximately 2 mL [20 mg] every 10 seconds).

Elderly Patients

Elderly patients require lower doses of Propofol Rompharm 10 mg/mL for induction of anesthesia. Dose reduction should take into account the patient's health status and age. The reduced dose should be administered more slowly and titrated according to clinical response.

Pediatric Population

Use of Propofol Rompharm 10 mg/mL for induction of anesthesia is not recommended in children under 1 month of age.

For induction of anesthesia in children aged 1 month and older, the dose of Propofol Rompharm 10 mg/mL should be slowly titrated until clinical signs of anesthesia appear. The dose should be adjusted according to age and/or body weight. In most patients aged 8 years and older, a dose of approximately 2.5 mg/kg body weight of Propofol Rompharm 10 mg/mL 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 Propofol Rompharm 10 mg/mL to maintain adequate depth of anesthesia.

• Continuous Infusion

The required infusion rate may vary significantly between patients, but rates in the range of 4–12 mg/kg/h are generally sufficient to maintain adequate depth of anesthesia.

• Repeated Bolus Injections

With repeated bolus injections, gradually increasing doses from 25 mg (2.5 mL) to 50 mg (5.0 mL) should be administered as clinically necessary.

Elderly Patients

When using Propofol Rompharm 10 mg/mL 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) of the drug should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory function.

Pediatric Population

Use of Propofol Rompharm 10 mg/mL for maintenance of anesthesia is not recommended 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 Rompharm 10 mg/mL to maintain adequate depth of anesthesia. The required infusion rate may vary significantly between patients, but rates in the range of 9–15 mg/kg/h are generally sufficient to achieve adequate depth of anesthesia. Younger children, especially those aged 1 month to 3 years, may require higher doses.

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

Sedation of Patients in Intensive Care Units

Adults

For sedation of patients in intensive care units, Propofol Rompharm 10 mg/mL 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 Propofol Rompharm 10 mg/mL of 0.3–4.0 mg/kg/h (see section "Special Precautions").

Propofol Rompharm 10 mg/mL should not be used for sedation of patients in intensive care units aged ≤ 16 years (see section "Contraindications").

Elderly Patients

When using Propofol Rompharm 10 mg/mL 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 drug should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory function.

Pediatric Population

Propofol Rompharm 10 mg/mL 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 Rompharm 10 mg/mL administered by infusion to the desired depth of sedation. For most patients, an infusion rate of 1.5–4.5 mg/kg/h 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 Propofol Rompharm 10 mg/mL 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 drug should be avoided in elderly patients, as it may lead to depression of cardiovascular and respiratory function.

Pediatric Population

Use of Propofol Rompharm 10 mg/mL for diagnostic and surgical procedures is not recommended 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 Rompharm 10 mg/mL at a dose of 1–2 mg/kg body weight. Maintenance of sedation can be achieved by titrating the dose of Propofol Rompharm 10 mg/mL during infusion to achieve the desired depth of sedation. Most patients require a dose of Propofol Rompharm 10 mg/mL of 1.5–9.0 mg/kg/h. Infusion may be supplemented with bolus doses up to 1 mg/kg body weight if a rapid increase in sedation depth is needed.

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

Method of Administration

Propofol Rompharm 10 mg/mL has no analgesic activity; therefore, concomitant administration of additional analgesic medications is usually required.

Propofol Rompharm 10 mg/mL may be administered for infusion either undiluted from glass vials of Propofol Rompharm 10 mg/mL or diluted with 5% dextrose solution from PVC infusion bags or glass infusion bottles. Dilutions should not exceed 1 to 5 (2 mg propofol per 1 mL) and should be prepared under aseptic conditions immediately before administration. The diluted emulsion should be used within 6 hours after preparation.

It is recommended that when using diluted Propofol Rompharm 10 mg/mL, the volume of 5% dextrose solution removed from the infusion bag during dilution be completely replaced with Propofol Rompharm 10 mg/mL emulsion (see Table 1).

Dilution can be performed using various infusion control devices, but using an infusion set alone does not eliminate the risk of accidental uncontrolled infusion of large volumes of diluted Propofol Rompharm 10 mg/mL. 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 Rompharm 10 mg/mL in the burette.

When using undiluted Propofol Rompharm 10 mg/mL 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 Rompharm 10 mg/mL 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.

Propofol Rompharm 10 mg/mL may be pre-mixed with alfenatnil injection solution containing 500 mcg/mL alfenatnil, at 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, Propofol Rompharm 10 mg/mL may be mixed with lidocaine injection solution (0.5% or 1%, without preservatives) (see Table 1).

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

Below are recommendations for target concentrations of propofol. Considering the variability in propofol pharmacokinetics and pharmacodynamics among patients, and whether or not premedication has been administered, the target propofol concentration should be titrated according to clinical response to achieve the required depth of anesthesia.

Induction and Maintenance of General Anesthesia

In adult patients under 55 years of age, anesthesia is usually achieved at 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 within 60–120 seconds. Higher rates may lead to 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 extent of reduction in target concentration for maintenance of 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 awakening is usually 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 Preservation of Consciousness During Surgical and Diagnostic Procedures

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

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

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

Oxygen delivery equipment must be available in the medical facility.

Dilution and Co-administration of Propofol Rompharm 10 mg/mL with Other Medicinal Products or Infusion Solutions

Table 1

Method of co-administration	Excipient or solvent	Preparation	Precautions
Pre-mixing	5% glucose solution for intravenous infusion	Mix 1 part of Propofol Rompharm 10 mg/mL 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 dilution be performed by replacing a certain volume of infusion solution with an equivalent volume of Propofol Rompharm 10 mg/mL	Prepare under aseptic conditions immediately before administration. The mixture is stable for up to 6 hours.
	Lidocaine hydrochloride injection solution (0.5% or 1%, preservative-free)	Mix 20 parts of Propofol Rompharm 10 mg/mL 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 Rompharm 10 mg/mL 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-type connector	5% glucose solution for intravenous infusion	Co-administration via Y-type connector	Position the Y-type connector immediately before the administration site.
	0.9% sodium chloride solution for intravenous infusion	As stated above	As stated above.
	4% glucose and 0.18% sodium chloride solution for intravenous infusion	As stated above	As stated above.

Children.

Propofol Rompharm 10 mg/ml is not recommended for use in neonates, as the use of this medicinal product in this patient group has not been fully investigated. Pharmacokinetic data (see section "Pharmacokinetics") indicate that drug clearance in neonates is significantly reduced and shows very high inter-patient variability.

Administration of doses recommended for older children may lead to relative overdosage and development of severe cardiovascular depression.

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

Overdose.

Accidental overdose is highly likely to manifest as depression of cardiovascular and respiratory function. Respiratory depression should be treated with artificial ventilation and oxygen supplementation. In case of cardiovascular depression, the patient should be placed in a supine position with low head elevation, 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 frequently reported adverse reactions are pharmacologically predictable side effects of an anesthetic/CNS depressant agent, such as hypotension. The nature, severity, and frequency of adverse events in patients receiving Propofol Rompharm 10 mg/mL may be related to the patients' clinical 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 (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data).

Table of adverse reactions

Table 2

System organ class	Frequency	Adverse reactions
Immune system disorders	Very rare	Anaphylaxis, which may include angioneurotic edema, 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	Pulmonary edema
	Not known(9)	Cardiac arrhythmia(5), cardiac failure(5), (7)
Vascular disorders	Common	Arterial hypotension(2), flushes in children(11)
	Occasionally	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
	Not known	Priapism
General disorders and administration site conditions	Very common	Local pain during induction(4)
	Very rare	Tissue necrosis(10) following accidental extravascular injection
	Not known(9)	Local pain, swelling following accidental extravascular injection
	Common	Withdrawal symptoms in children(11)
Investigations	Not known(9)	Brugada-type ECG(5), (6)
Injury, poisoning and procedural complications	Very rare	Postoperative fever

(1) Cases of severe bradycardia are rare. There have been isolated reports of progression to asystole.

(2) In individual cases, intravenous fluids may be required to correct hypotension, along with a reduction in the infusion rate of Propofol Rompharm.

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

(4) This can be minimized by administration into larger-diameter veins: forearm veins and antecubital fossa veins. When using Propofol Rompharm, local pain can also be reduced by co-administration of lidocaine.

(5) The combination of these phenomena is 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 for use".

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

(7) Rapidly progressive heart failure (sometimes fatal) in adults. Heart failure in these cases was usually 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 impaired tissue viability.

(11) Following abrupt discontinuation of Propofol Rompharm infusion during intensive care therapy.

(12) After both long-term and short-term treatment, as well as in patients without underlying 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 when propofol was used at doses exceeding 4 mg/kg/hour to achieve sedative effect in intensive care settings.

Reports on off-label use of Propofol Rompharm for induction of anesthesia 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 Rompharm 10 mg/mL anesthesia, can be minimized by concomitant administration of lidocaine (see section "Method of administration and dosage") and by injection into larger-diameter veins: forearm and antecubital fossa veins.

Cases of thrombosis and phlebitis are rare. Accidental extravascular administration and animal studies indicate minimal tissue reaction. Intra-arterial administration in animals did not show local tissue effects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

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

Packaging

20 mL in a glass vial with a rubber stopper and aluminum cap with flip-off plastic cap; 5 vials per cardboard box.

Prescription status

Prescription only.

Manufacturer

K.T. Rompharm Company S.R.L. / S.C. ROMPHARM COMPANY S.R.L.

Manufacturer's address and location of operations

Eroilor str. No 1 A, Otopeni city, 075100, county Ilfov, Romania.

Marketing Authorization Holder

LLC Rompharm Company Georgia.

Address of the Marketing Authorization Holder

Georgia, Tbilisi, Saakadze Downhill, 8, office 7a.