Diprivan (propofol in lipid emulsions)

Because individual response to propofol is variable, dosage (including the infusion rate or amount and frequency of incremental doses) of the drug should always be adjusted to clinical effect and account for individual requirements, response, age, weight, clinical status (e.g., ASA physical status, degree of debilitation), blood lipid profile, underlying pathologic conditions (e.g., shock, intestinal obstruction, malnutrition, anemia, burns, advanced malignancy, ulcerative colitis, uremia, alcoholism), and the type and amount of premedication or concomitant medication(s) used. To provide adequate anesthesia in patients undergoing minor surgical procedures (e.g., on the body surface), propofol may be administered concomitantly with 60-70% nitrous oxide, while for major (e.g., intra-abdominal) surgical procedures or if nitrous oxide is not available or appropriate, administration rates of propofol and/or opiates may be increased. Similar to other sedatives, there appears to be wide interpatient variation in propofol dosage requirements that may increase or decrease with time. In general, the smallest effective dosage should be used.

Propofol injectable emulsion is administered by IV infusion or IV injection. When the drug is administered by IV infusion, use of a controlled infusion device (e.g., syringe or volumetric pump) is recommended. In patients undergoing magnetic resonance imaging (MRI) who are receiving IV infusion of propofol, metered controlled devices may be used when mechanical pumps are not suitable. Rarely, the drug also has been administered by continuous IV infusion using a patient-controlled infusion device+ in individuals receiving monitored anesthesia care (MAC) sedation while undergoing diagnostic or surgical procedures.

Propofol injectable emulsion should be shaken well prior to administration. The drug should not be used if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised. Slight creaming, which may be visible upon prolonged standing, should disappear after shaking.

Clinical experience with use of inline filters for propofol administration during general anesthesia, MAC, or critical care sedation is limited. An inline membrane filter may be used during administration of the drug; however, the mean pore diameter of the filter should not be less than 5 mcm, unless it has been demonstrated that the filter does not restrict the flow and/or cause the breakdown of the emulsion. Filters should be used with caution and only when clinically appropriate. Continuous monitoring for restricted flow and breakdown of the emulsion is required.

Commercially available propofol injectable emulsions should be stored at 4-25degreesC depending on the preparation and should be protected from freezing. Since propofol undergoes oxidative degradation in the presence of oxygen, the commercially available injectable emulsions are packaged under nitrogen to prevent such degradation.

The commercially available 1% (10 mg/mL) propofol injectable emulsion is a ready-to-use formulation that does not require dilution but may be diluted (see Dilution under Dosage and Administration). When the emulsion is administered directly from the original container, administration should be completed within 12 hours and unused portions should be discarded. If propofol injectable emulsion is transferred to another container, administration should begin promptly and be completed within 12 hours; unused portions also should be discarded. If dilution of propofol injectable emulsion is necessary, the drug may be diluted with 5% dextrose injection to a concentration of not less than 0.2% (2 mg/mL). It appears that stability of the diluted solutions is greater in glass than in plastic containers; potency of the diluted emulsions may decrease by about 5-8% after continuous IV infusion of propofol through a plastic (PVC) tubing for 2 hours. Potency may decrease even further (up to 35%) when the diluted solution is left stationary in a PVC tubing. It has been suggested that propofol injectable emulsion may adsorb to plastic IV tubing and such adsorption may be decreased by maintaining a constant flow of the solution.

The manufacturers state that propofol is compatible with several IV fluids (e.g., 5% dextrose, 5% dextrose and lactated Ringer's, lactated Ringer's, 5% dextrose and 0.2% or 0.45% sodium chloride) when a Y-type administration set is used. Propofol should not be administered through the same catheter as blood, serum, or plasma because compatibility has not been established. In vitro tests have shown that aggregates of the globular component of the vehicle containing propofol may form when the drug is in contact with blood, serum, or plasma. The clinical importance of these effects is not known.

Addition of lidocaine to propofol in quantities greater than 20 mg of lidocaine per 200 mg of propofol may cause instability of the propofol emulsion, resulting in increases in globule sizes over time; reduction of anesthetic potency has been reported in rats. The manufacturers recommend that lidocaine be given prior to administration of propofol or, alternatively, that lidocaine be added to propofol immediately before administration, in quantities not exceeding 20 mg lidocaine/200 mg propofol.

Propofol should not be mixed with other therapeutic agents prior to administration. Propofol has been reported to be physically and/or chemically incompatible with several drugs, but the compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for more specific information.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*Known hypersensitivity to propofol or any ingredient in the formulation.

*Known hypersensitivity to eggs, egg products, soybeans, or soy products.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

The most common adverse reactions (>1%) reported with propofol were bradycardia, arrhythmia, tachycardia, hypotension, hypertension, decreased cardiac output, movement, apnea, respiratory acidosis during weaning, rash, pruritus, burning/stinging or pain at injection site, and hyperlipemia.

In adults, the adverse effect profile in patients undergoing monitored anesthesia care (MAC) sedation was similar to that of patients undergoing anesthesia, although more severe adverse respiratory effects (e.g., cough, upper airway obstruction, apnea, hypoventilation, dyspnea) were reported in those undergoing MAC sedation. In addition, the adverse effect profile in pediatric patients 6 days to 16 years of age undergoing anesthesia was similar to that of adults receiving propofol for anesthesia, although apnea may occur more frequently in children than in adults.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

The manufacturers state that the safety and efficacy of propofol for the induction of general anesthesia have not been established in pediatric patients younger than 3 years of age. For maintenance of general anesthesia, the manufacturers state that safety and efficacy of the drug have not been established in pediatric patients younger than 2 months of age. In addition, the manufacturers state that propofol is not recommended for ICU sedation, for use in combination with regional anesthesia, or for MAC sedation in pediatric patients younger than 16 years of age, because safety for these procedures in this patient population has not been established.

Propofol has been used in pediatric patients undergoing ICU sedation. Although a causal relationship to propofol has not been definitely established, case reports describe a severe, progressive metabolic (e.g., lactic) acidosis syndrome (that may progress to death) in several ventilated pediatric patients (mainly with respiratory infections) receiving propofol for ICU sedation. In some of these children, increasing metabolic acidosis was accompanied or followed by hypocalcemia, hypoglycemia, high serum lipid concentrations (hypertriglyceridemia), elevated serum liver enzyme concentrations, enlarged liver, oliguria, myoglobinuria, fever, multisystem organ failure, cardiac failure, bradycardia, hypotension, AV block of varying degrees, bundle branch block, asystole, and death. The mechanism of this syndrome is not known and the possibility that causes other than administration of propofol may be involved has been suggested.

Results of a multicenter, comparative, clinical trial in pediatric patients undergoing ICU sedation (excluding those with upper respiratory infection) indicate that the incidence of mortality was increased in those receiving propofol (9%) compared with those receiving standard sedative agents (4%). Although a causal relationship of such incidence of mortality to propofol has not been established, the manufacturer and FDA state that there may be important safety concerns associated with the use of propofol injectable emulsion in pediatric patients undergoing sedation in critical care settings. Therefore, propofol is not labeled and should not be employed for such use in children 16 years of age or younger.

Propofol also has been used in pediatric patients undergoing MAC sedation for surgical, diagnostic, and other procedures (e.g., lumbar puncture with intrathecal chemotherapy, bone marrow aspiration and biopsy, central venous catheter placement, transesophageal echocardiogram, cardiac catheterization, radiologic examinations, orthopedic manipulations). However, the manufacturers state that propofol should not be used for MAC sedation in pediatric patients, because safety and efficacy for such use have not been established.

In pediatric patients receiving prolonged IV infusions of propofol, abrupt discontinuance of the drug may result in flushing of the hands and feet, agitation, tremulousness, hyperirritability, increased incidence of bradycardia, agitation, or jitteriness.

FDA warns that repeated or prolonged use of general anesthetics and sedation drugs, including propofol, in children younger than 3 years of age or during the third trimester of pregnancy may affect brain development. Animal studies in multiple species, including nonhuman primates, have demonstrated that use for longer than 3 hours of anesthetic and sedation drugs that block N-methyl-d-aspartic acid (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity leads to widespread neuronal and oligodendrocyte cell loss and alterations in synaptic morphology and neurogenesis in the brain, resulting in long-term deficits in cognition and behavior. Across animal species, vulnerability to these neurodevelopmental changes occurs during the period of rapid brain growth or synaptogenesis; this period is thought to correlate with the third trimester of pregnancy through the first year of life in humans, but may extend to approximately 3 years of age. The clinical relevance of these animal findings to humans is not known.

While some published evidence suggests that similar deficits in cognition and behavior may occur in children following repeated or prolonged exposure to anesthesia early in life, other studies have found no association between pediatric anesthesia exposure and long-term adverse neurodevelopmental outcomes. Most studies to date have had substantial limitations, and it is not clear whether the adverse neurodevelopmental outcomes observed in children were related to the drug or to other factors (e.g., surgery, underlying illness). There is some clinical evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders; however, further research is needed to fully characterize the effects of exposure to general anesthetics in early life, particularly for prolonged or repeated exposures and in more vulnerable populations (e.g., less healthy children).

Results from an observational study (the Pediatric Anesthesia Neurodevelopment Assessment (PANDA) study) and preliminary results from an ongoing multicenter, randomized trial (the General Anesthesia Compared to Spinal Anesthesia (GAS) trial) provide some evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders. The PANDA study compared global cognitive function (as measured by intelligence quotient (IQ) score) of children 8-15 years of age who had a single anesthesia exposure for elective inguinal hernia surgery before the age of 3 years with that of a biologically related sibling who had no anesthesia exposure before the age of 3 years. All of the children had a gestational age at birth of at least 36 weeks, and sibling pairs were within 3 years of being the same age. Children who underwent the elective procedure were mostly males (90%) and generally healthy. The mean duration of anesthesia was 84 minutes; 16% of those receiving anesthesia had exposures exceeding 2 hours. The study found no substantial difference in IQ score between children who had a single anesthesia exposure before the age of 3 years and their siblings who had not. The GAS trial was designed to compare neurodevelopmental outcomes in children who received general anesthesia with those in children who received awake regional (caudal and/or spinal) anesthesia for inguinal herniorrhaphy before they reached a postmenstrual age of 60 weeks (with a gestational age at birth of more than 26 weeks); the primary outcome was the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale IQ at 5 years of age. In an interim analysis at the age of 2 years, no difference in composite cognitive score (as measured by the Bayley Scales of Infant and Toddler Development III) was detected between children who had received sevoflurane anesthesia of less than 1 hour's duration (median duration: 54 minutes) compared with those who had received awake regional anesthesia.

Anesthetic and sedation drugs are an essential component of care for children and pregnant women who require surgery or other procedures that cannot be delayed; no specific general anesthetic or sedation drug has been shown to be less likely to cause neurocognitive deficits than any other such drug. Pending further accumulation of data in humans from well-designed studies, decisions regarding the timing of elective procedures requiring anesthesia should take into consideration both the benefits of the procedure and the potential risks. When procedures requiring the use of general anesthetics or sedation drugs are considered for young children or pregnant women, clinicians should discuss with the patient, parent, or caregiver the benefits, risks (including potential risk of adverse neurodevelopmental effects), and appropriate timing and duration of the procedure. FDA states that procedures that are considered medically necessary should not be delayed or avoided.

There are no adequate and controlled studies to date using propofol in pregnant women. Reproduction studies in rats and rabbits using IV propofol dosages of 15 mg/kg daily (approximately equivalent to the human propofol induction dose on a mg/m2 basis) did not reveal any evidence of harm to the fetus, but decreased pup survival and increased postimplantation loss were observed.

Propofol readily crosses the placenta and similar to other general anesthetics, administration of propofol may be associated with neonatal depression. Limited data indicate that the ratio of umbilical vein to maternal vein concentration at parturition is about 0.7 after rapid IV (''bolus'') administration of 2.5 mg/kg of propofol to women undergoing cesarean section. In one study, mean propofol concentrations of 0.078 mcg/mL were detected 2 hours after delivery in neonates whose mothers had received an IV propofol infusion of 5 mg/kg per hour for about 26 minutes while undergoing cesarean section. The manufacturers state that propofol is not recommended for obstetric surgery (e.g., cesarean section).

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including propofol, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus. The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs.

Propofol reportedly is distributed into human milk. The manufacturers state that the drug should not be used in nursing women because the effects of oral absorption of small amounts of propofol are not known. Some clinicians state that nursing women undergoing surgery may receive usual anesthetic induction doses of propofol; however, since trace amounts of the drug may be present in milk, drowsiness of the infants may occur on the day of the procedure. It should be considered that in reproduction studies in rats and rabbits, IV propofol dosages (15 mg/kg daily) administered to dams during lactating periods have been shown to cause maternal deaths and decreased pup survival. It has been suggested that the pharmacologic effect (anesthesia) of propofol on the dams probably is responsible for the adverse effects observed in the offspring.

Lower doses are recommended for initiation and maintenance of sedation and anesthesia in geriatric patients.

Studies in geriatric patients have shown that these patients may require lower dosages of propofol for anesthesia and other indications. The manufacturers state that lower induction doses and a slower rate of maintenance IV infusion should be used in patients 55 years of age and older. In addition, to minimize the risk of adverse effects, including cardiorespiratory depression (e.g., hypotension), apnea, airway obstruction, and/or arterial oxygen desaturation, rapid (single or repeated) IV (''bolus'') administration of propofol should not be used in geriatric patients during general anesthesia or MAC sedation.