Provive (Emulsion) Instructions for Use

Marketing Authorization Holder

Baxter Pharmaceuticals India, Pvt. Ltd. (India)

ATC Code

N01AX10 (Propofol)

Active Substance

Propofol (Rec.INN registered by WHO)

Dosage Form

Provive

Emulsion for intravenous administration 10 mg/ml: fl. 10 ml 5 pcs., 20 ml 5 or 10 pcs., 50 ml 1 pcs.; bot. 100 ml 1 pcs.

Dosage Form, Packaging, and Composition

Emulsion for infusion white or almost white, with no signs of phase separation.

Excipients: soybean oil 100 mg, egg lecithin 12 mg, glycerol 22.5 mg, sodium oleate 0.3 mg, sodium hydroxide q.s. to adjust pH to 7.0-8.5, water for injections q.s..

10 ml – glass vials (1) – cardboard packs.
20 ml – glass vials (1) – cardboard packs.
50 ml – glass vials (1) – cardboard packs.
100 ml – glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Intravenous anesthesia preparation

Pharmacotherapeutic Group

Agent for non-inhalation general anesthesia

Pharmacological Action

Propofol is a short-acting general anesthetic with a rapid onset of action within approximately 30-40 seconds. Recovery from general anesthesia is usually rapid.

The mechanism of action of propofol, like all general anesthetics, is not fully understood. Typically, when propofol is used for induction and maintenance of anesthesia, a decrease in mean arterial pressure and minor changes in heart rate are observed. However, hemodynamic parameters usually remain relatively stable during maintenance of anesthesia and the incidence of adverse hemodynamic changes is low.

Although respiratory depression may occur after drug administration, any of these effects are qualitatively similar to those occurring with other intravenous anesthetics and are easily controlled in clinical settings.

Propofol reduces cerebral blood flow, intracranial pressure and decreases cerebral metabolism. The reduction in intracranial pressure is more pronounced in patients with initially elevated intracranial pressure. Propofol reduces intraocular pressure.

Recovery from anesthesia is usually rapid, with clear consciousness and is accompanied by a low incidence of headache, postoperative nausea and vomiting.

Typically, after anesthesia with the drug, cases of postoperative nausea and vomiting occur less frequently than after inhalational anesthesia. This may be associated with the antiemetic effect of propofol. Propofol at concentrations usually achieved in clinical practice does not suppress adrenal hormone synthesis.

Pharmacokinetics

Propofol is 98% bound to plasma proteins. The decrease in propofol concentration after a bolus dose or after cessation of infusion can be described using an open three-compartment model. The first phase is characterized by very rapid distribution (distribution half-life is 2-4 min), the second by rapid elimination (T_1/2 is 30-60 min). This is followed by a slower terminal phase (T_1/2 is 200-300 min), characterized by redistribution of propofol from poorly perfused tissues into the blood.

The central V_d is 0.2-0.79 L/kg, the steady-state V_d is 1.8-5.3 L/kg. Propofol is metabolized primarily by conjugation in the liver, and also extrahepatically, with a clearance of about 2 L/min. Clearance in children is higher than in adults.

T_1/2 after IV infusion ranged from 277 to 403 min. Inactive metabolites are excreted mostly by the kidneys (about 88%). Only 0.3% of the administered drug is excreted unchanged in the urine.

In cases where Propofol is used for maintenance of anesthesia, its blood concentration asymptotically reaches a steady-state value corresponding to the infusion rate. Within the recommended infusion rate ranges, the pharmacokinetics of propofol are linear. With increasing patient age, the pharmacokinetic changes are such that higher drug concentrations are noted in plasma after IV bolus administration. High plasma concentrations in elderly patients may cause cardiovascular and respiratory effects such as decreased blood pressure, apnea, airway obstruction, and decreased blood oxygenation. Consequently, lower doses of propofol are recommended for induction and maintenance of anesthesia and for sedation in elderly patients.

No differences in the pharmacokinetics of propofol were identified in patients with chronic liver cirrhosis or chronic renal failure compared to adult patients with normal liver and kidney function.

The pharmacokinetics of propofol in patients with acute liver failure have not been studied.

Indications

• Induction and maintenance of general anesthesia;
• Sedation of patients receiving intensive care and on mechanical ventilation;
• Sedation of conscious patients during surgical or diagnostic procedures.

ICD codes

Dosage Regimen

Propofol is administered only intravenously.

Adults

Induction of general anesthesia

Provive can be used for induction of anesthesia by slow bolus injections or infusion. Regardless of whether premedication was administered or not, the drug administration is recommended to be titrated (bolus injections or infusion of approximately 4 ml (40 mg) every 10 seconds – for an average adult patient in satisfactory condition) depending on the patient’s response until clinical signs of anesthesia appear. For most adult patients under 55 years of age, the average dose of Provive is 1.5-2.5 mg/kg. The required total dose can be reduced by using lower administration rates (20-50 mg/min). For patients older than this age, a lower dose is generally required. For ASA (American Society of Anesthesiologists) class III and IV patients, administration should be performed at a lower rate (approximately 2 ml (20 mg) every 10 seconds).

Maintenance of general anesthesia

Anesthesia can be maintained by continuous infusion of Provive or by repeated bolus injections required to maintain the desired depth of anesthesia.

Continuous infusion. The required infusion rate varies significantly depending on individual patient characteristics. Typically, a rate within 4-12 mg/kg/h provides adequate maintenance of anesthesia.

Repeated bolus injections. If a technique involving repeated bolus injections is used, incremental doses from 25 mg to 50 mg are administered depending on clinical need.

Sedation during intensive care

When using Provive for sedation in adult patients on mechanical ventilation and receiving intensive care, it is recommended to administer it by continuous infusion. The infusion rate should be adjusted according to the required depth of sedation, but a rate within 0.3 to 4 mg/kg/h should provide satisfactory sedation.

Conscious sedation in patients during surgical and diagnostic procedures

For sedation during surgical and diagnostic procedures, the administration rate and dose should be individually tailored, depending on the patient’s clinical response. Most patients require 0.5-1 mg/kg over 1-5 minutes for sedation onset.

To maintain sedation, the infusion rate should be adjusted according to the required depth of sedation; most patients require a rate within 1.5-4.5 mg/kg/h. If a rapid increase in sedation depth is required, a bolus of 10-20 mg of propofol may be used in addition to the infusion. For ASA class III and IV patients, a reduction in dose and administration rate may be required.

Elderly patients

Elderly patients require lower doses of Provive for induction anesthesia. The dose reduction should be guided by the patient’s physical status and age. The reduced dose should be administered at a slower rate than usual and titrated according to the patient’s response. When using Provive for maintenance of anesthesia or for sedation, the infusion rate or “target concentration” of the drug should be reduced. For ASA class III and IV patients, further reduction in dose and administration rate may be required. To avoid depression of the cardiac and respiratory systems, rapid bolus administration (single or repeated) is not recommended in elderly patients.

Children

Induction of general anesthesia

Provive is not recommended for use in children under 1 month of age. When using Provive for induction of anesthesia in children, it is recommended to administer it slowly until clinical signs of anesthesia onset appear. The dose should be adjusted according to the child’s age and/or weight. For most children over 8 years of age, approximately 2.5 mg/kg of Provive will probably be required for induction of anesthesia. For children aged from 1 month to 8 years, the required dose may be higher. A lower dose is recommended for ASA class III and IV children.

Maintenance of general anesthesia

Provive is not recommended for use in children under 1 month of age. Maintenance of anesthesia is achieved by administering Provive via continuous infusion, or by repeated bolus injections required to maintain the necessary depth of anesthesia. The required infusion rate varies significantly among different patients; satisfactory anesthesia is usually provided at an infusion rate within 9-15 mg/kg/h.

Conscious sedation during surgical and diagnostic procedures

Propofol should not be used for conscious sedation in children aged 16 years and younger.

Sedation during intensive care

Provive should not be used for sedation during intensive care in children aged 16 years and younger.

Administration

Propofol can be administered undiluted using syringes or glass vials. In cases where Propofol is used undiluted for maintenance of general anesthesia, it is always recommended to use calibrated infusion or syringe pumps to control the administration rate.

Propofol can also be used diluted only with 5% dextrose solution for IV administration. The solution, whose dilution should not exceed a ratio of 1:5 (2 mg propofol/ml), should be prepared aseptically immediately before use. The mixture remains stable for 6 hours. The diluted drug solution can be administered using various regulated infusion systems; however, the use of such devices alone does not completely avoid the risk of accidental uncontrolled administration of large volumes of diluted propofol. Syringe pumps or calibrated infusion pumps should always be part of the infusion line. When choosing the maximum volume of diluted propofol in the burette, the risk of uncontrolled administration should be considered.

Propofol can be administered through a Y-site connector near the injection site simultaneously with the administration of 5% dextrose for IV infusion, 0.9% sodium chloride for IV infusion, or 4% dextrose with 0.18% sodium chloride for IV infusion.

To reduce pain at the injection site, the induction dose of propofol can be mixed in a syringe immediately before administration with lidocaine hydrochloride injection solution (20 parts propofol and 1 part 1% lidocaine hydrochloride injection solution), or 2 ml of 1% lidocaine hydrochloride injection solution or 1 ml of 2% lidocaine hydrochloride injection solution can be administered immediately before propofol administration.

Adverse Reactions

Common side effects of propofol are decreased blood pressure and respiratory depression. These effects are dose-dependent on propofol, as well as on the type of premedication and concomitant therapy.

Very common (>10%); common (>1% and <10%); uncommon (>0.1% and <1%); rare (>0.01% and <0.1%); very rare (<0.01%).

Digestive system common – vomiting and nausea during recovery; very rare – pancreatitis.

Cardiovascular system: common – decreased blood pressure, bradycardia, tachycardia, flushing; uncommon – marked decrease in blood pressure. It may be necessary to reduce the propofol infusion rate and/or administer fluid replacement, and if necessary, vasoconstrictors. The possibility of a sharp decrease in blood pressure should be considered in patients with impaired coronary or cerebral blood flow or in patients with hypovolemia. Increasing bradycardia up to asystole during general anesthesia. IV administration of m-cholinolytics may be possible during induction of general anesthesia or during maintenance anesthesia. Rare – arrhythmia during the recovery period, thrombosis, phlebitis.

Nervous system: common – spontaneous movements and myoclonus during induction of anesthesia, minimal excitation, agitation; uncommon – delirium; rare – headache, dizziness, chills and feeling of cold during induction of anesthesia; minimal excitation; epileptiform seizures, including convulsions and opisthotonus during induction, maintenance of anesthesia and awakening; very rare – late epileptiform seizures developing several hours or days later; risk of seizure development in patients with epilepsy after propofol administration; cases of unconsciousness after surgery.

Respiratory system common – during induction of anesthesia, hyperventilation, transient apnea, cough, hiccups; uncommon – cough during maintenance anesthesia; rare – cough during the recovery period; very rare – pulmonary edema.

Urinary system rare – discoloration of urine after prolonged use of propofol.

Immune system rare – anaphylactic reactions, including angioedema, bronchospasm; erythema and decreased blood pressure.

Metabolism common – hypertriglyceridemia.

Mental disorders rare – euphoria and increased sexual function during the recovery period.

Other: common – withdrawal syndrome in children; rare – postoperative fever; very rare – rhabdomyolysis. In very rare cases, when propofol was used in doses exceeding 4 mg/kg/h for sedation in intensive care, cases of rhabdomyolysis, metabolic acidosis, hyperkalemia and heart failure, sometimes fatal, have been reported.

Local reactions very common – pain at the injection site. Pain at the propofol injection site can be minimized by simultaneous administration of lidocaine or by infusing the drug into a larger vein of the forearm or antecubital fossa. The following adverse effects were rarely observed with concomitant lidocaine administration: dizziness, vomiting, drowsiness, convulsions, bradycardia, cardiac arrhythmias and shock.

Contraindications

• Induction and maintenance of general anesthesia in children under 1 month of age;
• Sedation of patients under 16 years of age on mechanical ventilation during intensive care;
• Sedation of conscious patients under 16 years of age during surgical and diagnostic procedures;
• Pregnancy, as well as use in obstetric practice, except for termination of pregnancy in the first trimester;
• Breastfeeding period;
• Soy intolerance;
• Hypersensitivity to any of the components of the drug.

With caution epilepsy, hypovolemia, lipid metabolism disorders, severe decompensated diseases of the cardiovascular system, respiratory system, kidneys and liver, anemia, severely debilitated patients, children under 3 years of age.

Use in Pregnancy and Lactation

Propofol crosses the placental barrier and may have a depressant effect on the fetus. Contraindicated during pregnancy, as well as in high doses exceeding 2.5 mg/kg for general anesthesia or 6 mg/kg/h for maintenance of anesthesia during delivery. Propofol is used during termination of pregnancy in the first trimester.

The safety of propofol use during lactation has not been established, therefore breastfeeding is not recommended during propofol use.

Pediatric Use

Contraindicated

• Induction and maintenance of general anesthesia in children under 1 month of age;
• Sedation of patients under 16 years of age on mechanical ventilation during intensive care;
• Sedation of conscious patients under 16 years of age during surgical and diagnostic procedures.

With caution children under 3 years of age.

Special Precautions

Provive should be used by personnel trained in anesthesia (or in appropriate situations, by physicians trained in intensive care patient management). Patients must be under constant monitoring, equipment for maintaining airway patency, for artificial ventilation, oxygen enrichment, and other resuscitation means must be constantly ready for use. Provive should not be administered by the person performing the diagnostic or surgical procedure.

When using the drug during surgical or diagnostic procedures for conscious sedation, constant monitoring of the patient is necessary to detect early signs of decreased blood pressure, airway obstruction and insufficient blood oxygenation.

As with the use of other sedative drugs, involuntary movements of patients are possible when Provive is administered for procedural sedation. During procedures requiring immobility, these movements may be dangerous for the operative site.

An adequate period of time for patient observation is necessary to ensure complete recovery from general anesthesia. In very rare cases, unconsciousness in the postoperative period is possible after Provive use, which may be accompanied by increased muscle tone. Sometimes loss of consciousness occurs after a period of wakefulness. Despite spontaneous awakening, appropriate monitoring should be established for a patient in an unconscious state.

The drug has weak m-cholinolytic activity and its use has been associated with cases of bradycardia (which can sometimes be serious), as well as asystole. It is advisable to administer m-cholinolytics intravenously before the induction of anesthesia or during its maintenance, especially in cases where there is a likelihood of vagal tone predominance, or when Provive is used in combination with other agents that may cause bradycardia. If the drug is administered to a patient suffering from epilepsy, there is a risk of seizures.

Cases of pancreatitis have been described following the administration of propofol, although a causal relationship has not been established.

Anaphylaxis to Propofol is rare.

Due attention should be paid to patients with disorders of lipid metabolism, as well as in other conditions requiring cautious use of lipid emulsions.

Monitoring of blood lipid concentration is recommended in cases where Provive is prescribed to patients who are at particular risk of lipid accumulation. If monitoring indicates insufficient elimination of fats from the body, the administration of the drug should be adjusted appropriately. When another lipid agent is administered intravenously to a patient simultaneously, its dose should be reduced, taking into account the amount of lipid administered as part of Provive; 1 ml of Provive contains approximately 0.1 g of fat.

Provive does not contain preservatives with antimicrobial activity and can serve as a favorable medium for the growth of microorganisms. When filling a sterile syringe or infusion line with Provive, aseptic techniques must be observed; the drug must be drawn up immediately after opening the vial. Administration should begin immediately.

Aseptic conditions must be ensured throughout the entire infusion period for both Provive and the administration equipment. Any infusion solutions added to the infusion line in combination with Provive should be administered as close as possible to the cannula site. The drug should not be administered through a microbiological filter.

A syringe with Provive is single-use and intended for use in one patient. In accordance with the rules established for other lipid emulsions, the duration of continuous infusion of propofol should not exceed 12 hours. Upon completion of the drug infusion or after the 12-hour period, both the container with Provive and the infusion line must be replaced.

Containers with the drug should be shaken before use. Any remaining contents in the container after its use must be destroyed. Aseptic conditions must be ensured for both Provive and the administration equipment.

Effect on the ability to drive vehicles and operate machinery

After the use of propofol, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms depression of the cardiovascular and respiratory systems.

Treatment in case of respiratory depression, artificial ventilation of the lungs with oxygen should be performed. In case of impaired cardiovascular function, the patient’s head should be lowered; in severe cases, the administration of plasma substitutes and vasopressor agents may be required.

Drug Interactions

Propofol can be used in combination with other drugs commonly used for premedication, inhalation anesthesia, analgesics, muscle relaxants, or local anesthetics. The use of benzodiazepines, m-cholinolytics, or inhalation anesthetics in combination with the drug prolongs the anesthetic effect and reduces the respiratory rate.

Concomitant use with drugs that depress the CNS, such as alcohol, general anesthetics, or narcotic analgesics, leads to a pronounced manifestation of their sedative effect.

After concomitant premedication with opioids, the frequency and duration of apnea may increase.

In patients who have received premedication with narcotic analgesics (morphine, pethidine, fentanyl, and others) or a combination of narcotic analgesics with sedatives (benzodiazepines, barbiturates, chloral hydrate, droperidol, and others), a reduction in the dose of propofol is possible.

Against the background of suxamethonium or neostigmine methylsulfate administration, bradycardia and cardiac arrest may occur.

After fentanyl administration, a transient increase in the blood concentration of propofol is possible, accompanied by an increased likelihood of apnea.

Pharmacological incompatibility

Pharmaceutically incompatible with injectable and infusion solutions of other medicinal products, except for 5% dextrose solution, 0.9% sodium chloride solution, or 4% dextrose solution with 0.18% sodium chloride solution, lidocaine hydrochloride solution. When administering the muscle relaxants atracurium and mivacurium, the same infusion line should not be used for Provive without prior flushing.

Storage Conditions

In a place protected from light at a temperature from 4°C (39.2°F) to 25°C (77°F). Do not freeze. Keep out of reach of children.

Shelf Life

The shelf life is 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.