Fresofol200 mg/20 ml

Fresofol is a short-acting intravenous sedative-hypnotic agent used in anesthesia and critical care. Its evidence-based uses include:

• Induction of general anesthesia (FDA-approved) in patients 3 years of age and older.
• Maintenance of general anesthesia (FDA-approved) in patients 2 months of age and older, typically as part of a balanced anesthetic technique with analgesics and/or inhalational agents.
• Monitored anesthesia care (MAC) sedation in adults undergoing diagnostic or surgical procedures (FDA-approved).
• Sedation of intubated, mechanically ventilated patients in the intensive care unit (ICU) (FDA-approved in adults; not approved for ICU sedation in pediatric patients).
• Combination use: commonly combined with opioids, benzodiazepines, or local/regional anesthesia to reduce required doses and improve hemodynamic stability; requires careful dose titration when combined with other CNS depressants.
• Off-label use: Fresofol is used off-label in some settings for refractory status epilepticus and for procedural sedation outside the operating room, under the direct supervision of clinicians trained in general anesthesia.

Fresofol is not indicated for use outside settings equipped for airway management and cardiorespiratory monitoring.

Propofol is formulated as a sterile, single-use, oil-in-water lipid emulsion for intravenous injection/infusion, typically supplied as 10 mg/mL (1%) Propofol.

Each mL typically contains Propofol 10 mg in a vehicle of soybean oil, purified egg lecithin (egg yolk phospholipid), glycerol, and, in most formulations, disodium edetate (EDTA) or sodium metabisulfite as an antimicrobial-growth-retardant additive. Exact excipients vary by brand; check the pack insert for the specific product dispensed.

Fresofol is a phenol derivative (2,6-diisopropylphenol) that acts as a rapid-onset, short-acting general anesthetic and sedative-hypnotic agent, administered only by the intravenous route as a white, oil-in-water lipid emulsion.

After a single intravenous dose, onset of anesthesia occurs within about 15-45 seconds, and recovery is typically rapid due to fast redistribution and hepatic metabolism, making Fresofol suitable for both single-use induction and continuous-infusion maintenance of anesthesia or sedation.

General (intravenous) anesthetic; sedative-hypnotic agent. Fresofol belongs to the class of intravenous induction agents used for general anesthesia and procedural/ICU sedation.

Propofol is believed to produce its sedative-hypnotic and anesthetic effects primarily through potentiation of gamma-aminobutyric acid type A (GABA-A) receptor activity, which slows the channel-closing time and increases chloride ion influx into neurons, producing central nervous system depression.

Pharmacokinetics: Propofol is highly lipophilic and highly protein-bound (~97-99%). It has a large volume of distribution and undergoes rapid redistribution from the central compartment to peripheral tissues, accounting for its quick offset of action. It is extensively metabolized in the liver (and to some extent extrahepatically) via glucuronidation and hydroxylation to inactive metabolites, which are renally excreted. Because clearance exceeds hepatic blood flow, extrahepatic metabolism (e.g., in the lungs) is thought to contribute.

Fresofol is for intravenous use only, given as a slow bolus injection or continuous infusion using a calibrated infusion pump. It should not be administered by intramuscular, subcutaneous, intra-arterial, or epidural routes.

The emulsion may be used undiluted or diluted with 5% dextrose injection (not below a concentration of 2 mg/mL) when infused. Once a vial or ampoule is opened, contents should be drawn up using strict aseptic technique and administration should begin promptly; unused drug from an opened container must be discarded within the time specified by the manufacturer (typically within 6-12 hours), as the lipid emulsion supports rapid microbial growth.

Injection-site pain during induction can be reduced by prior injection of lidocaine or by administration through a larger vein.

• CNS depressants (opioids, benzodiazepines, inhalational anesthetics): co-administration with Fresofol produces additive sedative, respiratory-depressant, and hypotensive effects; reduce doses of both agents and monitor closely.
• Fentanyl and other opioids: concurrent use with Fresofol has been associated with bradycardia, and rarely asystole, particularly in pediatric patients; monitor heart rate closely.
• Valproate/valproic acid: may increase Fresofol plasma concentrations, potentially requiring a lower Fresofol dose.
• Vasoconstrictors, corticosteroids, or other agents that increase metabolic demand: may increase the risk of Fresofol Infusion Syndrome during prolonged high-dose Fresofol infusion (see Precautions and Warnings).
• Alcohol and other sedative-hypnotics: additive CNS and respiratory depression; avoid concurrent recreational or therapeutic use around the time of Fresofol administration.

Very common/common: pain, burning, or stinging at the injection site; hypotension; transient apnea during induction; bradycardia; involuntary movements; headache; nausea and vomiting on emergence.

Less common but clinically important: hypertension, arrhythmias, hyperlipidemia/hypertriglyceridemia with prolonged infusion, urine discoloration (green, pink, or cloudy - benign metabolite effect), thrombophlebitis, and rare anaphylactoid/anaphylactic reactions.

Rare but serious: severe bradycardia and asystole, pulmonary edema, seizure-like activity/opisthotonos on emergence, and Fresofol Infusion Syndrome with prolonged high-dose ICU infusion (see Precautions and Warnings for details).

Fresofol readily crosses the placenta. It has not been shown to cause birth defects in available human data, but animal studies at doses producing maternal toxicity showed decreased offspring survival. Fresofol should be used in pregnancy only if clearly needed and the potential benefit justifies the potential risk to the fetus; use only under the direct supervision of a physician experienced in obstetric anesthesia when used during labor and delivery, since neonatal depression (hypotonia, sedation) can occur.

Fresofol passes into breast milk in small amounts. Available data suggest the amount transferred is low and generally considered compatible with breastfeeding after recovery from anesthesia/sedation, but a breastfeeding mother receiving Fresofol should consult her physician; monitoring of the breastfed infant for unusual sedation is prudent, particularly after prolonged or repeated exposure.

Fresofol Infusion Syndrome (PRIS)

A rare but potentially fatal complication associated with prolonged (>48 hours), high-dose (>4 mg/kg/hour) Fresofol infusion, especially in critically ill patients. Features include severe metabolic acidosis, rhabdomyolysis, hyperkalemia, cardiac arrhythmias/failure, and renal failure. Risk is increased by concurrent vasopressor or corticosteroid use, serious neurological or systemic illness, and high fat/low carbohydrate intake. Use the lowest effective dose for the shortest necessary duration during ICU sedation, and monitor for early signs (unexplained metabolic acidosis, rising triglycerides, rhabdomyolysis, arrhythmia) with prompt dose reduction or discontinuation if suspected.

Cardiorespiratory Depression

Fresofol causes dose-dependent hypotension, bradycardia, and respiratory depression, including apnea. It must be administered only by persons trained in general anesthesia and airway management (not involved in the surgical/diagnostic procedure itself), with continuous monitoring of oxygenation, ventilation, and circulation, and immediate access to resuscitation equipment.

Aseptic Technique / Bacterial Contamination

The lipid emulsion supports rapid growth of microorganisms if contaminated. Strict aseptic technique must be used when drawing up and administering Fresofol; the drug must be used promptly after opening a vial/ampoule, and any unused portion discarded within the manufacturer-specified time (do not use as a multi-dose vial beyond that window).

Allergy Considerations

Because the emulsion contains egg lecithin and soybean oil, use caution in patients with known egg or soy allergy (see Contraindications).

Other Precautions

Use with caution in patients with epilepsy (rare reports of seizure activity/opisthotonos on emergence), in patients with disorders of fat metabolism (monitor serum lipids with prolonged infusion), and in patients with hepatic or renal impairment. Abrupt discontinuation after prolonged ICU sedation may be associated with withdrawal-like effects. Avoid concurrent alcohol or other CNS depressants around the time of administration.

Overdose of Fresofol may cause profound respiratory depression/apnea, severe hypotension, bradycardia progressing to cardiac arrest, and loss of consciousness. There is no specific antidote for Fresofol.

Suspected overdose is a medical emergency: seek immediate medical attention or contact emergency services. Management is supportive and includes discontinuing the infusion, securing and maintaining the airway, providing ventilatory support with oxygen as needed, and maintaining blood pressure and circulation with intravenous fluids and vasopressors under close monitoring in a facility equipped for advanced cardiac life support.

Store at room temperature (below 25°C), protected from light. Do not freeze. Shake well before use if separation of the emulsion is visible. Once a vial/ampoule is opened, use promptly under aseptic conditions and discard any unused portion within the time specified by the manufacturer. Keep out of reach of children.

Pediatric use: Fresofol is approved for induction of anesthesia in patients 3 years of age and older, and for maintenance of anesthesia in patients 2 months of age and older; it is not recommended for anesthesia induction below 3 years of age and is not approved for ICU sedation in pediatric patients of any age. See Pediatric Uses for details.

Elderly patients: Require lower induction and maintenance doses, given more slowly, due to increased sensitivity to hypotension and respiratory depression.

Hepatic/renal impairment: No routine dose adjustment is established, but such patients may show altered pharmacodynamic sensitivity; titrate cautiously and monitor closely.

Critically ill/ICU patients: Increased risk of Fresofol Infusion Syndrome with prolonged, high-dose infusion; use the lowest effective dose and monitor closely (see Precautions and Warnings).

Pregnant and lactating women: See Pregnancy and Lactation section.

Duration of Fresofol administration depends entirely on the clinical indication: induction doses are single, brief boluses; maintenance during surgical anesthesia typically lasts for the duration of the procedure; and ICU sedation may continue for hours to several days, with the shortest effective duration and lowest effective dose used to minimize the risk of Fresofol Infusion Syndrome during prolonged infusions.

General (intravenous) anesthetics; sedative-hypnotic agents. Propofol is the prototypical short-acting IV anesthetic/sedative in this class.

Propofol is thought to produce sedative-hypnotic and anesthetic effects mainly by potentiating GABA-A receptor-mediated inhibitory neurotransmission in the central nervous system, increasing chloride channel opening duration and causing neuronal hyperpolarization, which results in dose-dependent sedation, hypnosis, amnesia, and general anesthesia.

B

Fresofol is FDA-approved for induction of general anesthesia in patients 3 years of age and older, and for maintenance of general anesthesia in patients 2 months of age and older, typically requiring higher weight-based maintenance infusion rates than adults (approximately 125-300 mcg/kg/min).

Fresofol is not recommended for induction of anesthesia in children under 3 years of age, and safety and efficacy for ICU sedation have not been established in pediatric patients of any age - Fresofol must not be used for this purpose in children. Bradycardia and rare cardiac arrest have been reported in children, particularly with concurrent fentanyl use. Repeated or prolonged anesthetic exposure in children under 3 years may be associated with effects on brain development based on animal data; anesthesia and sedation duration in young children should be limited to what is clinically necessary.