Propofol injectable emulsion USP, 10 mg per mL is an anesthetic available as a sterile, nonpyrogenic, white, homogeneous emulsion for intravenous administration. The structural formula of propofol, USP is: Chemical name: 2,6 diisopropylphenol Molecular formula: C 12 H 18 O Molecular weight: 178.28 g/mol Propofol, USP is a clear, colorless to slightly yellowish liquid. It is very soluble in methanol and in ethanol, slightly soluble in cyclohexane and in isopropyl alcohol and very slightly soluble in water. The pKa is 11. The octanol/water partition coefficient for propofol is 6761:1 at a pH of 6.0 to 8.5. Each mL of propofol injectable emulsion, USP contains 10 mg propofol, USP; soybean oil, 100 mg; glycerol, 22.5 mg; egg phospholipids, 12 mg; disodium edetate anhydrous, 0.05 mg and sodium hydroxide to adjust pH, in water for injection. Propofol injectable emulsion, USP is isotonic and has a pH of 7.00 to 8.50. 1

AND USAGE

Induction of General Anesthesia for Patients Greater than or Equal to 3 Years of Age
Maintenance of General Anesthesia for Patients Greater than or Equal to 2 Months of Age
Initiation and Maintenance of Monitored Anesthesia Care (MAC) Sedation in Adult Patients
Sedation for Adult Patients in Combination with Regional Anesthesia
Intensive Care Unit (ICU) Sedation of Intubated, Mechanically Ventilated Adult Patients Propofol Injectable Emulsion is an intravenous general anesthetic and sedation drug indicated for: Induction of General Anesthesia for Patients Greater than or Equal to 3 Years of Age Maintenance of General Anesthesia for Patients Greater than or Equal to 2 Months of Age Initiation and Maintenance of Monitored Anesthesia Care (MAC) Sedation in Adult Patients Sedation for Adult Patients in Combination with Regional Anesthesia Intensive Care Unit (ICU) Sedation of Intubated, Mechanically Ventilated Adult Patients Limitations of Use Propofol Injectable Emulsion is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness have not been established in those populations [see Pediatric Use ( 8.4 )] . Safety, effectiveness and dosing guidelines for Propofol Injectable Emulsion have not been established for MAC sedation in the pediatric population; therefore, it is not recommended for this use [see Pediatric Use ( 8.4 )].

Propofol Injectable

Emulsion is not indicated for use in Pediatric ICU sedation since the safety of this regimen has not been established [see Pediatric Use ( 8.4 )].

Propofol Injectable

Emulsion is an intravenous general anesthetic and sedation drug indicated for: Induction of General Anesthesia for Patients Greater than or Equal to 3 Years of Age Maintenance of General Anesthesia for Patients Greater than or Equal to 2 Months of Age Initiation and Maintenance of Monitored Anesthesia Care (MAC) Sedation in Adult Patients Sedation for Adult Patients in Combination with Regional Anesthesia Intensive Care Unit (ICU) Sedation of Intubated, Mechanically Ventilated Adult Patients Limitations of Use : Propofol Injectable Emulsion is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months MAC sedation in the pediatric population is not recommended Propofol Injectable Emulsion is not indicated for use in Pediatric ICU sedation

DOSAGE AND ADMINISTRATION: Propofol blood concentrations at steady-state are generally proportional to infusion rates, especially in individual patients. Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate. An adequate interval (3 minutes to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects. Shake well before use. Do not use 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 should disappear after shaking, may be visible upon prolonged standing. When administering DIPRIVAN by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates. When infusing DIPRIVAN to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical. Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of DIPRIVAN. For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate DIPRIVAN infusion to provide satisfactory anesthesia. With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of DIPRIVAN and/or opioids should be increased in order to provide adequate anesthesia. Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN at rates higher than are clinically necessary. Generally, rates of 50 mcg/kg/min to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. Other drugs that cause CNS depression (e.g., sedatives, anesthetics, and opioids) can increase CNS depression induced by propofol. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. Induction of General Anesthesia Adult Patients Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 mg/kg to 2.5 mg/kg of DIPRIVAN for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, DIPRIVAN should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. As with other general anesthetics, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN. Elderly, Debilitated, or ASA-PS III or IV Patients It is important to be familiar and experienced with the intravenous use of DIPRIVAN before treating elderly, debilitated, or ASA-PS III or IV patients. Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 mg/kg to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN for induction of anesthesia according to their condition and responses. A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION ).

Pediatric Patients

Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 mg/kg to 3.5 mg/kg of DIPRIVAN for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients. As with other general anesthetics, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Attention should be paid to minimize pain on injection when administering DIPRIVAN to pediatric patients. Boluses of DIPRIVAN may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS , General ).

Neurosurgical Patients

Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower boluses or infusions of DIPRIVAN for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 mg/kg to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ).

Cardiac

Anesthesia DIPRIVAN has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited. As with other general anesthetics and sedation drugs, DIPRIVAN in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend upon the dose and speed of the induction and maintenance infusion rates. In addition, lower heart rates are observed during maintenance with DIPRIVAN, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated. As with other anesthetic agents, DIPRIVAN reduces myocardial oxygen consumption. Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. The rate of DIPRIVAN administration should be determined based on the patient's premedication and adjusted according to clinical responses. A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 mg/kg to 1.5 mg/kg) should be used. In order to assure adequate anesthesia, when DIPRIVAN is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an opioid is used as the primary agent, DIPRIVAN maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia. Higher doses of DIPRIVAN will reduce the opioid requirements (see Table 4). When DIPRIVAN is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia ).

Table

4.

Cardiac Anesthesia Techniques Primary Agent

Rate Secondary Agent/Rate (Following Induction with Primary Agent) DIPRIVAN OPIOID a /0.05 mcg/kg/min to 0.075 mcg/kg/min (no bolus)

Preinduction Anxiolysis

25 mcg/kg/min Induction 0.5 mg/kg to 1.5 mg/kg over 60 sec Maintenance (Titrated to Clinical Response) 100 mcg/kg/min to 150 mcg/kg/min OPIOID b DIPRIVAN /50 mcg/kg/min to 100 mcg/kg/min (no bolus)

Induction

25 mcg/kg to 50 mcg/kg Maintenance 0.2 mcg/kg/min to 0.3 mcg/kg/min a OPIOID is defined in terms of fentanyl equivalents, i.e., 1 mcg of fentanyl = 5 mcg of alfentanil (for bolus) = 10 mcg of alfentanil (for maintenance) or = 0.1 mcg of sufentanil b Care should be taken to ensure amnesia. Maintenance of General Anesthesia DIPRIVAN has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents. In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

Adult

Patients In adults, anesthesia can be maintained by administering DIPRIVAN by infusion or intermittent IV bolus injection. The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous

Infusion DIPRIVAN 100 mcg/kg/min to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of DIPRIVAN should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period following the induction dose, higher rates of infusion are generally required (150 mcg/kg/min to 200 mcg/kg/min) for the first 10 minutes to 15 minutes. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance. Generally, rates of 50 mcg/kg/min to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. Other drugs that cause CNS depression (e.g., sedatives, anesthetics, and opioids) can increase the CNS depression induced by propofol.

Intermittent Bolus

Increments of DIPRIVAN 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Pediatric

Patients DIPRIVAN administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia. In general, for the pediatric population, maintenance by infusion of DIPRIVAN at a rate of 200 mcg/kg/min to 300 mcg/kg/min should immediately follow the induction dose. Following the first half-hour of maintenance, infusion rates of 125 mcg/kg/min to 150 mcg/kg/min are typically needed. DIPRIVAN should be titrated to achieve the desired clinical effect. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients. (See Table 2 Clinical Trials.)

Monitored Anesthesia

Care (MAC)

Sedation Adult Patients

When DIPRIVAN is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of DIPRIVAN administration will be in the range of 25 mcg/kg/min to 75 mcg/kg/min. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS ). A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation. Initiation of MAC Sedation For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be initiated by infusing DIPRIVAN at 100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/h to 9 mg/kg/h) for a period of 3 minutes to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 minutes to 5 minutes and titrated to clinical responses. When DIPRIVAN is administered slowly over 3 minutes to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS ). The rate of administration should be over 3 minutes to 5 minutes and the dosage of DIPRIVAN should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION ). Maintenance of MAC Sedation For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require maintenance rates of 25 mcg/kg/min to 75 mcg/kg/min (1.5 mg/kg/h to 4.5 mg/kg/h) during the first 10 minutes to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 mcg/kg/min to 50 mcg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect. Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN at rates higher than are clinically necessary. If the intermittent bolus dose method is used, increments of DIPRIVAN 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS ). The rate of administration and the dosage of DIPRIVAN should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION ). DIPRIVAN can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When DIPRIVAN sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN and may also result in a slower recovery profile (see PRECAUTIONS , Drug Interactions ).

Icu

Sedation ( See WARNINGS and DOSAGE AND ADMINISTRATION , Handling Procedures . ) Abrupt discontinuation of DIPRIVAN prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of DIPRIVAN should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS ).

Adult Patients

For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION ). Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/h to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION ). With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation. These higher rates of administration may increase the likelihood of patients developing hypotension. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS ). Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient. The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS ). DIPRIVAN should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS , Intensive Care Unit Sedation ). For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 5 mcg/kg/min to 10 mcg/kg/min (0.3 mg/kg/h to 0.6 mg/kg/h) until the desired level of sedation is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect. Most adult patients require maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/h to 3 mg/kg/h) or higher. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS ). Dosages of DIPRIVAN should be reduced in patients who have received large dosages of narcotics. The DIPRIVAN dosage requirement may also be reduced by adequate management of pain with analgesic agents. As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES ). Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials , Intensive Care Unit (ICU) Sedation ). Bolus administration of 10 mg or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur. Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS ). SUMMARY OF DOSAGE GUIDELINES: Dosages and rates of administration in the following table should be individualized and titrated to clinical response. Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older. Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. For complete dosage information, see DOSAGE AND ADMINISTRATION .

Indication Dosage And Administration

Induction of General Anesthesia: Healthy Adults Less Than 55 Years of Age: 40 mg every 10 seconds until induction onset (2 mg/kg to 2.5 mg/kg). Elderly, Debilitated, or ASA-PS III or IV Patients: 20 mg every 10 seconds until induction onset (1 mg/kg to 1.5 mg/kg).

Cardiac

Anesthesia: 20 mg every 10 seconds until induction onset (0.5 mg/kg to 1.5 mg/kg).

Neurosurgical

Patients: 20 mg every 10 seconds until induction onset (1 mg/kg to 2 mg/kg).

Pediatric

Patients - healthy, from 3 years to 16 years of age: 2.5 mg/kg to 3.5 mg/kg administered over 20 seconds to 30 seconds. (see PRECAUTIONS , Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics ). Maintenance of General Anesthesia: Infusion Healthy Adults Less Than 55 Years of Age: 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/h to 12 mg/kg/h). Elderly, Debilitated, ASA-PS III or IV Patients: 50 mcg/kg/min to 100 mcg/kg/min (3 mg/kg/h to 6 mg/kg/h).

Cardiac

Anesthesia: Most patients require: Primary DIPRIVAN with Secondary Opioid – 100 mcg/kg/min to 150 mcg/kg/min. Low-Dose DIPRIVAN with Primary Opioid – 50 mcg/kg/min to 100 mcg/kg/min. (see DOSAGE AND ADMINISTRATION , Table 4).

Neurosurgical

Patients: 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/h to 12 mg/kg/h).

Pediatric

Patients - healthy, from 2 months of age to 16 years of age: 125 mcg/kg/min to 300 mcg/kg/min (7.5 mg/kg/h to 18 mg/kg/h). Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased. (see PRECAUTIONS , Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics ). Maintenance of General Anesthesia: Intermittent Bolus Healthy Adults Less Than 55 Years of Age: Increments of 20 mg to 50 mg as needed. Initiation of MAC Sedation: Healthy Adults Less Than 55 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Most patients require an infusion of 100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/h to 9 mg/kg/h) for 3 minutes to 5 minutes or a slow injection of 0.5 mg/kg over 3 minutes to 5 minutes followed immediately by a maintenance infusion. Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require dosages similar to healthy adults. Rapid boluses are to be avoided (see WARNINGS ). Maintenance of MAC Sedation: Healthy Adults Less Than 55 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique. Most patients require an infusion of 25 mcg/kg/min to 75 mcg/kg/min (1.5 mg/kg/h to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

In

Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require 80% of the usual adult dose. A rapid (single or repeated) bolus dose should not be used (see WARNINGS ). Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least 5 minutes. Subsequent increments of 5 mcg/kg/min to 10 mcg/kg/min (0.3 mg/kg/h to 0.6 mg/kg/h) over 5 minutes to 10 minutes may be used until desired clinical effect is achieved. Maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/h to 3 mg/kg/h) or higher may be required. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS ). Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation. The tubing and any unused DIPRIVAN drug product should be discarded after 12 hours because DIPRIVAN contains no preservatives and is capable of supporting growth of microorganisms (see WARNINGS and DOSAGE AND ADMINISTRATION ). Administration with Lidocaine If lidocaine is to be administered to minimize pain on injection of DIPRIVAN, it is recommended that it be administered prior to DIPRIVAN administration or that it be added to DIPRIVAN immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN. Compatibility and Stability DIPRIVAN should not be mixed with other therapeutic agents prior to administration.

Dilution

Prior to Administration DIPRIVAN is provided as a ready-to-use formulation. However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic). Administration with Other Fluids Compatibility of DIPRIVAN with the coadministration of blood/serum/plasma has not been established (see WARNINGS ). When administered using a y-type infusion set, DIPRIVAN has been shown to be compatible with the following intravenous fluids. - 5% Dextrose Injection, USP - Lactated Ringers Injection, USP - Lactated Ringers and 5% Dextrose Injection - 5% Dextrose and 0.45% Sodium Chloride Injection, USP - 5% Dextrose and 0.2% Sodium Chloride Injection, USP Handling Procedures General Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Clinical experience with the use of in-line filters and DIPRIVAN during anesthesia or ICU/MAC sedation is limited. DIPRIVAN should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN and/or cause the breakdown of the emulsion. Filters should be used with caution and where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion. Do not use if there is evidence of separation of the phases of the emulsion. Rare cases of self-administration of DIPRIVAN by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE ). Strict aseptic technique must always be maintained during handling. DIPRIVAN is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination. However, DIPRIVAN can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling DIPRIVAN was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death. There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons. DIPRIVAN vials are never to be accessed more than once or used on more than one person. Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms. Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation DIPRIVAN must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. DIPRIVAN should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN from vials, a sterile vent spike should be used. The syringe should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened. DIPRIVAN must be prepared for single-patient use only. Any unused DIPRIVAN drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN. Guidelines for Aseptic Technique for ICU Sedation DIPRIVAN must be prepared for single-patient use only. Strict aseptic techniques must be followed. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN. As with other lipid emulsions, the number of IV line manipulations should be minimized. Administration should commence promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused DIPRIVAN drug product must be discarded after 12 hours. If DIPRIVAN is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN from a vial, a sterile vent spike should be used. The syringe should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened. DIPRIVAN should be discarded and administration lines changed after 12 hours.

Induction of General Anesthesia Adult Patients Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 mg/kg to 2.5 mg/kg of DIPRIVAN for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, DIPRIVAN should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. As with other general anesthetics, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN. Elderly, Debilitated, or ASA-PS III or IV Patients It is important to be familiar and experienced with the intravenous use of DIPRIVAN before treating elderly, debilitated, or ASA-PS III or IV patients. Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 mg/kg to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN for induction of anesthesia according to their condition and responses. A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION ).

Pediatric Patients

Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 mg/kg to 3.5 mg/kg of DIPRIVAN for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients. As with other general anesthetics, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Attention should be paid to minimize pain on injection when administering DIPRIVAN to pediatric patients. Boluses of DIPRIVAN may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS , General ).

Neurosurgical Patients

Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower boluses or infusions of DIPRIVAN for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 mg/kg to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ).

Cardiac

Anesthesia DIPRIVAN has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited. As with other general anesthetics and sedation drugs, DIPRIVAN in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend upon the dose and speed of the induction and maintenance infusion rates. In addition, lower heart rates are observed during maintenance with DIPRIVAN, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated. As with other anesthetic agents, DIPRIVAN reduces myocardial oxygen consumption. Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. The rate of DIPRIVAN administration should be determined based on the patient's premedication and adjusted according to clinical responses. A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 mg/kg to 1.5 mg/kg) should be used. In order to assure adequate anesthesia, when DIPRIVAN is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an opioid is used as the primary agent, DIPRIVAN maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia. Higher doses of DIPRIVAN will reduce the opioid requirements (see Table 4). When DIPRIVAN is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia ).

Table

4.

Cardiac Anesthesia Techniques Primary Agent

Rate Secondary Agent/Rate (Following Induction with Primary Agent) DIPRIVAN OPIOID a /0.05 mcg/kg/min to 0.075 mcg/kg/min (no bolus)

Preinduction Anxiolysis

25 mcg/kg/min Induction 0.5 mg/kg to 1.5 mg/kg over 60 sec Maintenance (Titrated to Clinical Response) 100 mcg/kg/min to 150 mcg/kg/min OPIOID b DIPRIVAN /50 mcg/kg/min to 100 mcg/kg/min (no bolus)

Induction

25 mcg/kg to 50 mcg/kg Maintenance 0.2 mcg/kg/min to 0.3 mcg/kg/min a OPIOID is defined in terms of fentanyl equivalents, i.e., 1 mcg of fentanyl = 5 mcg of alfentanil (for bolus) = 10 mcg of alfentanil (for maintenance) or = 0.1 mcg of sufentanil b Care should be taken to ensure amnesia.

Maintenance of General Anesthesia DIPRIVAN has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents. In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

Adult

Patients In adults, anesthesia can be maintained by administering DIPRIVAN by infusion or intermittent IV bolus injection. The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous

Infusion DIPRIVAN 100 mcg/kg/min to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of DIPRIVAN should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period following the induction dose, higher rates of infusion are generally required (150 mcg/kg/min to 200 mcg/kg/min) for the first 10 minutes to 15 minutes. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance. Generally, rates of 50 mcg/kg/min to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. Other drugs that cause CNS depression (e.g., sedatives, anesthetics, and opioids) can increase the CNS depression induced by propofol.

Intermittent Bolus

Increments of DIPRIVAN 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Pediatric

Patients DIPRIVAN administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia. In general, for the pediatric population, maintenance by infusion of DIPRIVAN at a rate of 200 mcg/kg/min to 300 mcg/kg/min should immediately follow the induction dose. Following the first half-hour of maintenance, infusion rates of 125 mcg/kg/min to 150 mcg/kg/min are typically needed. DIPRIVAN should be titrated to achieve the desired clinical effect. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients. (See Table 2 Clinical Trials.)

Monitored Anesthesia

Care (MAC)

Sedation Adult Patients

When DIPRIVAN is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of DIPRIVAN administration will be in the range of 25 mcg/kg/min to 75 mcg/kg/min. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS ). A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation. Initiation of MAC Sedation For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be initiated by infusing DIPRIVAN at 100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/h to 9 mg/kg/h) for a period of 3 minutes to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 minutes to 5 minutes and titrated to clinical responses. When DIPRIVAN is administered slowly over 3 minutes to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS ). The rate of administration should be over 3 minutes to 5 minutes and the dosage of DIPRIVAN should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION ). Maintenance of MAC Sedation For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require maintenance rates of 25 mcg/kg/min to 75 mcg/kg/min (1.5 mg/kg/h to 4.5 mg/kg/h) during the first 10 minutes to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 mcg/kg/min to 50 mcg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect. Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN at rates higher than are clinically necessary. If the intermittent bolus dose method is used, increments of DIPRIVAN 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS ). The rate of administration and the dosage of DIPRIVAN should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION ). DIPRIVAN can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When DIPRIVAN sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN and may also result in a slower recovery profile (see PRECAUTIONS , Drug Interactions ).

Icu

Sedation ( See WARNINGS and DOSAGE AND ADMINISTRATION , Handling Procedures . ) Abrupt discontinuation of DIPRIVAN prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of DIPRIVAN should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS ).

Adult Patients

For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION ). Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/h to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION ). With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation. These higher rates of administration may increase the likelihood of patients developing hypotension. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS ). Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient. The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS ). DIPRIVAN should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS , Intensive Care Unit Sedation ). For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 5 mcg/kg/min to 10 mcg/kg/min (0.3 mg/kg/h to 0.6 mg/kg/h) until the desired level of sedation is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect. Most adult patients require maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/h to 3 mg/kg/h) or higher. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS ). Dosages of DIPRIVAN should be reduced in patients who have received large dosages of narcotics. The DIPRIVAN dosage requirement may also be reduced by adequate management of pain with analgesic agents. As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES ). Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials , Intensive Care Unit (ICU) Sedation ). Bolus administration of 10 mg or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur. Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS ). SUMMARY OF DOSAGE GUIDELINES: Dosages and rates of administration in the following table should be individualized and titrated to clinical response. Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older. Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. For complete dosage information, see DOSAGE AND ADMINISTRATION .

Indication Dosage And Administration

Induction of General Anesthesia: Healthy Adults Less Than 55 Years of Age: 40 mg every 10 seconds until induction onset (2 mg/kg to 2.5 mg/kg). Elderly, Debilitated, or ASA-PS III or IV Patients: 20 mg every 10 seconds until induction onset (1 mg/kg to 1.5 mg/kg).

Cardiac

Anesthesia: 20 mg every 10 seconds until induction onset (0.5 mg/kg to 1.5 mg/kg).

Neurosurgical

Patients: 20 mg every 10 seconds until induction onset (1 mg/kg to 2 mg/kg).

Pediatric

Patients - healthy, from 3 years to 16 years of age: 2.5 mg/kg to 3.5 mg/kg administered over 20 seconds to 30 seconds. (see PRECAUTIONS , Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics ). Maintenance of General Anesthesia: Infusion Healthy Adults Less Than 55 Years of Age: 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/h to 12 mg/kg/h). Elderly, Debilitated, ASA-PS III or IV Patients: 50 mcg/kg/min to 100 mcg/kg/min (3 mg/kg/h to 6 mg/kg/h).

Cardiac

Anesthesia: Most patients require: Primary DIPRIVAN with Secondary Opioid – 100 mcg/kg/min to 150 mcg/kg/min. Low-Dose DIPRIVAN with Primary Opioid – 50 mcg/kg/min to 100 mcg/kg/min. (see DOSAGE AND ADMINISTRATION , Table 4).

Neurosurgical

Patients: 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/h to 12 mg/kg/h).

Pediatric

Patients - healthy, from 2 months of age to 16 years of age: 125 mcg/kg/min to 300 mcg/kg/min (7.5 mg/kg/h to 18 mg/kg/h). Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased. (see PRECAUTIONS , Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics ). Maintenance of General Anesthesia: Intermittent Bolus Healthy Adults Less Than 55 Years of Age: Increments of 20 mg to 50 mg as needed. Initiation of MAC Sedation: Healthy Adults Less Than 55 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Most patients require an infusion of 100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/h to 9 mg/kg/h) for 3 minutes to 5 minutes or a slow injection of 0.5 mg/kg over 3 minutes to 5 minutes followed immediately by a maintenance infusion. Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require dosages similar to healthy adults. Rapid boluses are to be avoided (see WARNINGS ). Maintenance of MAC Sedation: Healthy Adults Less Than 55 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique. Most patients require an infusion of 25 mcg/kg/min to 75 mcg/kg/min (1.5 mg/kg/h to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

In

Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require 80% of the usual adult dose. A rapid (single or repeated) bolus dose should not be used (see WARNINGS ). Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least 5 minutes. Subsequent increments of 5 mcg/kg/min to 10 mcg/kg/min (0.3 mg/kg/h to 0.6 mg/kg/h) over 5 minutes to 10 minutes may be used until desired clinical effect is achieved. Maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/h to 3 mg/kg/h) or higher may be required. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS ). Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation. The tubing and any unused DIPRIVAN drug product should be discarded after 12 hours because DIPRIVAN contains no preservatives and is capable of supporting growth of microorganisms (see WARNINGS and DOSAGE AND ADMINISTRATION ). Administration with Lidocaine If lidocaine is to be administered to minimize pain on injection of DIPRIVAN, it is recommended that it be administered prior to DIPRIVAN administration or that it be added to DIPRIVAN immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN. Compatibility and Stability DIPRIVAN should not be mixed with other therapeutic agents prior to administration.

Dilution

Prior to Administration DIPRIVAN is provided as a ready-to-use formulation. However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic). Administration with Other Fluids Compatibility of DIPRIVAN with the coadministration of blood/serum/plasma has not been established (see WARNINGS ). When administered using a y-type infusion set, DIPRIVAN has been shown to be compatible with the following intravenous fluids. - 5% Dextrose Injection, USP - Lactated Ringers Injection, USP - Lactated Ringers and 5% Dextrose Injection - 5% Dextrose and 0.45% Sodium Chloride Injection, USP - 5% Dextrose and 0.2% Sodium Chloride Injection, USP

Handling Procedures General Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Clinical experience with the use of in-line filters and DIPRIVAN during anesthesia or ICU/MAC sedation is limited. DIPRIVAN should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN and/or cause the breakdown of the emulsion. Filters should be used with caution and where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion. Do not use if there is evidence of separation of the phases of the emulsion. Rare cases of self-administration of DIPRIVAN by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE ). Strict aseptic technique must always be maintained during handling. DIPRIVAN is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination. However, DIPRIVAN can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling DIPRIVAN was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death. There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons. DIPRIVAN vials are never to be accessed more than once or used on more than one person. Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms. Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation DIPRIVAN must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. DIPRIVAN should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN from vials, a sterile vent spike should be used. The syringe should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened. DIPRIVAN must be prepared for single-patient use only. Any unused DIPRIVAN drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN. Guidelines for Aseptic Technique for ICU Sedation DIPRIVAN must be prepared for single-patient use only. Strict aseptic techniques must be followed. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN. As with other lipid emulsions, the number of IV line manipulations should be minimized. Administration should commence promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused DIPRIVAN drug product must be discarded after 12 hours. If DIPRIVAN is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN from a vial, a sterile vent spike should be used. The syringe should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened. DIPRIVAN should be discarded and administration lines changed after 12 hours.

Propofol injectable emulsion is contraindicated in patients with a known hypersensitivity to propofol or any of propofol injectable emulsion components. Propofol injectable emulsion is contraindicated in patients with a history of anaphylaxis to eggs, egg products, soybeans or soy products. Known hypersensitivity to propofol, egg or soybean. ( 4 )

ADVERSE REACTIONS: To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

General

Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient. Anesthesia and MAC Sedation in Adults The following estimates of adverse events for DIPRIVAN include data from clinical trials in general anesthesia/MAC sedation (N=2,889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with DIPRIVAN was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship. The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with DIPRIVAN during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea. Anesthesia in Pediatric Patients Generally the adverse experience profile from reports of 506 DIPRIVAN pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with DIPRIVAN during anesthesia in adults (see Pediatric percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

Icu

Sedation in Adults The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship. Incidence greater than 1% - Probably Causally Related Anesthesia/MAC Sedation ICU Sedation Cardiovascular: Bradycardia Bradycardia Decreased Cardiac Output Hypotension 26% Arrhythmia [Peds: 1.2%]

Tachycardia

Nodal [Peds: 1.6%] Hypotension* [Peds: 17%](see also CLINICAL PHARMACOLOGY ) Hypertension [Peds: 8%]

Central Nervous

System: Movement* [Peds: 17%]

Injection

Site: Burning/Stinging or Pain, 17.6% [Peds:10%] Metabolic/Nutritional: Hyperlipemia* Respiratory: Apnea (see also CLINICAL PHARMACOLOGY )

Respiratory Acidosis During

Weaning* Skin and Appendages: Rash [Peds: 5%] Pruritus [Peds: 2%] Events without an * or % had an incidence of 1% to 3% *Incidence of events 3% to 10% Incidence less than 1% - Probably Causally Related Anesthesia MAC Sedation ICU Sedation Body as a Whole: Anaphylaxis/Anaphylactoid Reaction Perinatal Disorder Tachycardia Bigeminy Bradycardia Premature Ventricular Contractions Hemorrhage ECG Abnormal Arrhythmia Atrial Fever Extremities Pain Anticholinergic Syndrome Cardiovascular: Premature Atrial Contractions Syncope Central Nervous System: Hypertonia/Dystonia, Paresthesia Agitation Digestive: Hypersalivation Nausea Hemic/Lymphatic: Leukocytosis Injection Site: Phlebitis Pruritus Metabolic: Hypomagnesemia Musculoskeletal: Myalgia Nervous: Dizziness Agitation Chills Somnolence Delirium Respiratory: Wheezing Cough Laryngospasm Hypoxia Decreased Lung Function Skin and Appendages: Flushing, Pruritus Special Senses: Amblyopia Vision Abnormal Urogenital: Cloudy Urine Green Urine Incidence less than 1% - Causal Relationship Unknown Anesthesia/MAC Sedation ICU Sedation Body as a Whole: Asthenia, Awareness, Chest Pain, Extremities Pain, Fever, Increased Drug Effect, Neck Rigidity/Stiffness, Trunk Pain Fever, Sepsis, Trunk Pain, Whole Body Weakness Cardiovascular: Arrhythmia, Atrial Fibrillation, Atrioventricular Heart Block, Bigeminy, Bleeding, Bundle Branch Block, Cardiac Arrest, ECG Abnormal, Edema, Extrasystole, Heart Block, Hypertension, Myocardial Infarction, Myocardial Ischemia, Premature Ventricular Contractions, ST Segment Depression, Supraventricular Tachycardia, Tachycardia, Ventricular Fibrillation Arrhythmia, Atrial Fibrillation, Bigeminy, Cardiac Arrest, Extrasystole, Right Heart Failure, Ventricular Tachycardia Central Nervous System: Abnormal Dreams, Agitation, Amorous Behavior, Anxiety, Bucking/Jerking/Thrashing, Chills/Shivering/Clonic/Myoclonic Movement, Combativeness, Confusion, Delirium, Depression, Dizziness, Emotional Lability, Euphoria, Fatigue, Hallucinations, Headache, Hypotonia, Hysteria, Insomnia, Moaning, Neuropathy, Opisthotonos, Rigidity, Seizures, Somnolence, Tremor, Twitching Chills/Shivering, Intracranial Hypertension, Seizures, Somnolence, Thinking Abnormal Digestive: Cramping, Diarrhea, Dry Mouth, Enlarged Parotid, Nausea, Swallowing,Vomiting Ileus, Liver Function Abnormal Hematologic/Lymphatic: Coagulation Disorder, Leukocytosis Injection Site: Hives/Itching, Phlebitis, Redness/Discoloration Metabolic/Nutritional: Hyperkalemia, Hyperlipemia BUN Increased, Creatinine Increased, Dehydration, Hyperglycemia, Metabolic Acidosis, Osmolality Increased Respiratory: Bronchospasm, Burning in Throat, Cough, Dyspnea, Hiccough, Hyperventilation, Hypoventilation, Hypoxia, Laryngospasm, Pharyngitis, Sneezing, Tachypnea, Upper Airway Obstruction Hypoxia Skin and Appendages: Conjunctival Hyperemia, Diaphoresis, Urticaria Rash Special Senses: Diplopia, Ear Pain, Eye Pain, Nystagmus, Taste Perversion, Tinnitus Urogenital: Oliguria, Urine Retention Kidney Failure

General Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

Anesthesia and MAC Sedation in Adults The following estimates of adverse events for DIPRIVAN include data from clinical trials in general anesthesia/MAC sedation (N=2,889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with DIPRIVAN was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship. The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with DIPRIVAN during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.

Anesthesia in Pediatric Patients Generally the adverse experience profile from reports of 506 DIPRIVAN pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with DIPRIVAN during anesthesia in adults (see Pediatric percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

Icu

Sedation in Adults The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship. Incidence greater than 1% - Probably Causally Related Anesthesia/MAC Sedation ICU Sedation Cardiovascular: Bradycardia Bradycardia Decreased Cardiac Output Hypotension 26% Arrhythmia [Peds: 1.2%]

Tachycardia

Nodal [Peds: 1.6%] Hypotension* [Peds: 17%](see also CLINICAL PHARMACOLOGY ) Hypertension [Peds: 8%]

Central Nervous

System: Movement* [Peds: 17%]

Injection

Site: Burning/Stinging or Pain, 17.6% [Peds:10%] Metabolic/Nutritional: Hyperlipemia* Respiratory: Apnea (see also CLINICAL PHARMACOLOGY )

Respiratory Acidosis During

Weaning* Skin and Appendages: Rash [Peds: 5%] Pruritus [Peds: 2%] Events without an * or % had an incidence of 1% to 3% *Incidence of events 3% to 10% Incidence less than 1% - Probably Causally Related Anesthesia MAC Sedation ICU Sedation Body as a Whole: Anaphylaxis/Anaphylactoid Reaction Perinatal Disorder Tachycardia Bigeminy Bradycardia Premature Ventricular Contractions Hemorrhage ECG Abnormal Arrhythmia Atrial Fever Extremities Pain Anticholinergic Syndrome Cardiovascular: Premature Atrial Contractions Syncope Central Nervous System: Hypertonia/Dystonia, Paresthesia Agitation Digestive: Hypersalivation Nausea Hemic/Lymphatic: Leukocytosis Injection Site: Phlebitis Pruritus Metabolic: Hypomagnesemia Musculoskeletal: Myalgia Nervous: Dizziness Agitation Chills Somnolence Delirium Respiratory: Wheezing Cough Laryngospasm Hypoxia Decreased Lung Function Skin and Appendages: Flushing, Pruritus Special Senses: Amblyopia Vision Abnormal Urogenital: Cloudy Urine Green Urine Incidence less than 1% - Causal Relationship Unknown Anesthesia/MAC Sedation ICU Sedation Body as a Whole: Asthenia, Awareness, Chest Pain, Extremities Pain, Fever, Increased Drug Effect, Neck Rigidity/Stiffness, Trunk Pain Fever, Sepsis, Trunk Pain, Whole Body Weakness Cardiovascular: Arrhythmia, Atrial Fibrillation, Atrioventricular Heart Block, Bigeminy, Bleeding, Bundle Branch Block, Cardiac Arrest, ECG Abnormal, Edema, Extrasystole, Heart Block, Hypertension, Myocardial Infarction, Myocardial Ischemia, Premature Ventricular Contractions, ST Segment Depression, Supraventricular Tachycardia, Tachycardia, Ventricular Fibrillation Arrhythmia, Atrial Fibrillation, Bigeminy, Cardiac Arrest, Extrasystole, Right Heart Failure, Ventricular Tachycardia Central Nervous System: Abnormal Dreams, Agitation, Amorous Behavior, Anxiety, Bucking/Jerking/Thrashing, Chills/Shivering/Clonic/Myoclonic Movement, Combativeness, Confusion, Delirium, Depression, Dizziness, Emotional Lability, Euphoria, Fatigue, Hallucinations, Headache, Hypotonia, Hysteria, Insomnia, Moaning, Neuropathy, Opisthotonos, Rigidity, Seizures, Somnolence, Tremor, Twitching Chills/Shivering, Intracranial Hypertension, Seizures, Somnolence, Thinking Abnormal Digestive: Cramping, Diarrhea, Dry Mouth, Enlarged Parotid, Nausea, Swallowing,Vomiting Ileus, Liver Function Abnormal Hematologic/Lymphatic: Coagulation Disorder, Leukocytosis Injection Site: Hives/Itching, Phlebitis, Redness/Discoloration Metabolic/Nutritional: Hyperkalemia, Hyperlipemia BUN Increased, Creatinine Increased, Dehydration, Hyperglycemia, Metabolic Acidosis, Osmolality Increased Respiratory: Bronchospasm, Burning in Throat, Cough, Dyspnea, Hiccough, Hyperventilation, Hypoventilation, Hypoxia, Laryngospasm, Pharyngitis, Sneezing, Tachypnea, Upper Airway Obstruction Hypoxia Skin and Appendages: Conjunctival Hyperemia, Diaphoresis, Urticaria Rash Special Senses: Diplopia, Ear Pain, Eye Pain, Nystagmus, Taste Perversion, Tinnitus Urogenital: Oliguria, Urine Retention Kidney Failure

AND PRECAUTIONS Hypersensitivity Reactions : Serious and sometimes fatal reactions ( 5.1 )

Microbial

Contamination : Strict aseptic technique must be maintained during handling. Propofol injectable emulsion vials are never to be accessed more than once or used on more than one person. Administration should commence promptly and be completed within 12 hours after the vial has been opened. Discard unused drug product. Do not use if contamination is suspected ( 5.2 )

Cardiovascular

Depression : Cases of bradycardia, asystole, and cardiac arrest have been reported. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly ( 5.4 )

5.1 Anaphylactic and Anaphylactoid Reactions Use of propofol injectable emulsion has been associated with both fatal and life threatening anaphylactic and anaphylactoid reactions. Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following propofol injectable emulsion administration.

5.2 Risks of Microbial Contamination Strict aseptic technique must always be maintained during handling. Propofol injectable emulsion is a single-dose parenteral product (single patient infusion vial) which contains benzyl alcohol 1.5 mg/mL and sodium benzoate 0.7 mg/mL to inhibit the rate of growth of microorganisms, for up to 12 hours, in the event of accidental extrinsic contamination. However, propofol injectable emulsion can still support the growth of microorganisms, as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling propofol injectable emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death. Propofol injectable emulsion vials are never to be accessed more than once or used on more than one person. There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and of the use of propofol vials intended for single use on multiple persons.

5.3 Risks of Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Animal Toxicology and/or Pharmacology (13.2) ] . Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

5.4 Risks of Bradycardia, Asystole, and Cardiac Arrest Propofol injectable emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with propofol injectable emulsion. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.

5.5 Risk of Seizures When propofol injectable emulsion is administered to an epileptic patient, there is a risk of seizure during the recovery phase.

5.6 Neurosurgical Anesthesia When propofol injectable emulsion is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus should be utilized instead of rapid, more frequent, and/or larger boluses of propofol injectable emulsion. Slower induction, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 mg/kg to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of propofol injectable emulsion [see Dosage and Administration (2.1) ] .

5.7 Cardiac Anesthesia Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Fluid deficits should be corrected prior to administration of propofol injectable emulsion. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with propofol injectable emulsion.

5.8 Use for Intensive Care Unit Sedation of Intubated, Mechanically Ventilated Adult Patients The administration of propofol injectable emulsion should be initiated as a continuous infusion and changes in the rate of administration made slowly (>5 min) in order to minimize hypotension and avoid acute overdosage [see Overdosage (10) and Dosage and Administration (2.5) ] . Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of propofol injectable emulsion, intravenous fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression. As with other sedative medications, there is wide interpatient variability in propofol injectable emulsion dosage requirements, and these requirements may change with time. Failure to reduce the infusion rate in patients receiving propofol injectable emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of propofol injectable emulsion infusion for ICU sedation, especially when it is used for long durations. Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of propofol injectable emulsion should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilatory support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression. Abrupt discontinuation of propofol injectable emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. It is therefore recommended that administration of propofol injectable emulsion be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes prior to extubation, at which time the infusion can be discontinued.

5.9 Risks of Propofol Infusion Syndrome in Patients with ICU Sedation Use of propofol injectable emulsion infusions for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as Propofol Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes (Coved ST segment elevation -similar to ECG changes of the Brugada syndrome) and/or cardiac failure. The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or prolonged, high-dose infusions of propofol (> 5 mg/kg/hour for > 48 hours). The syndrome has also been reported following large-dose, short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation, increasing propofol dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a propofol infusion, consideration should be given to using alternative means of sedation. Prescribers should be alert to these events in patients with the above risk factors and immediately discontinue propofol when the above signs develop.

5.10 Risk of Elevations in Serum Triglycerides Propofol injectable emulsion use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis. Since propofol injectable emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when propofol injectable emulsion is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of propofol injectable emulsion should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the propofol injectable emulsion formulation; 1 mL of propofol injectable emulsion contains approximately 0.1 g of fat (1.1 kcal).

5.11 Risk of Serious Adverse Reactions in Neonates and Infants due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including propofol injectable emulsion. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing propofol injectable emulsion in infants consider the combined daily metabolic load of benzyl alcohol from all sources including propofol injectable emulsion (contains 1.5 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.4) ].

5.12 Use in the Elderly, Debilitated, or ASA-PS III or IV Patients A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients [see Dosage and Administration (2) ] . Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds.

5.13 Risk of Transient Local Pain Attention should be paid to minimize pain on administration of propofol injectable emulsion. Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous injection may also be reduced by prior injection of intravenous lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to propofol injectable emulsion in quantities greater than 20 mg lidocaine/200 mg propofol injectable emulsion results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it is recommended that lidocaine be administered prior to propofol injectable emulsion administration or that it be added to propofol injectable emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg propofol injectable emulsion.

5.14 Risks of Local Reactions Phlebitis or venous thrombosis has been reported. In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction. Accidental intra-arterial injection has been reported in patients, and, other than pain, there were no major sequelae.

5.15 Risks of Aggregation if Administered through the Same Intravenous Catheter with Blood or Plasma Propofol injectable emulsion should not be coadministered through the same intravenous catheter with blood or plasma because compatibility has not been established. In vitro tests have shown that aggregates of the globular component of the emulsion vehicle have occurred with blood/plasma/serum from humans and animals. The clinical significance of these findings is not known.

5.16 Risk of Postoperative Unconsciousness Very rarely the use of propofol injectable emulsion may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness. Recovery is spontaneous.

5.17 Risks of Perioperative Myoclonia Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with propofol injectable emulsion administration.

5.18 Risks of Pulmonary Edema There have been rare reports of pulmonary edema in temporal relationship to the administration of propofol injectable emulsion, although a causal relationship is unknown.

5.19 Risks of Unexplained Postoperative Pancreatitis Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which propofol injectable emulsion was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to propofol injectable emulsion is unclear.

PRECAUTIONS: General Adult and Pediatric Patients A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients (see DOSAGE AND ADMINISTRATION ). Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds. DIPRIVAN use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis. Very rarely the use of DIPRIVAN may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness. Recovery is spontaneous. When DIPRIVAN is administered to an epileptic patient, there is a risk of seizure during the recovery phase. Attention should be paid to minimize pain on administration of DIPRIVAN. Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous injection may also be reduced by prior injection of IV lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to DIPRIVAN in quantities greater than 20 mg lidocaine/200 mg DIPRIVAN results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it is recommended that lidocaine be administered prior to DIPRIVAN administration or that it be added to DIPRIVAN immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN. Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (less than 1%). In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction. Intra-arterial injection in animals did not induce local tissue effects. Accidental intra-arterial injection has been reported in patients, and, other than pain, there were no major sequelae. Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of DIPRIVAN. Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with DIPRIVAN administration. Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following DIPRIVAN administration. There have been rare reports of pulmonary edema in temporal relationship to the administration of DIPRIVAN, although a causal relationship is unknown. Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which DIPRIVAN was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to DIPRIVAN is unclear. DIPRIVAN has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with DIPRIVAN. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.

Intensive Care Unit Sedation Adult

Patients ( See WARNINGS and DOSAGE AND ADMINISTRATION , Handling Procedures . ) The administration of DIPRIVAN should be initiated as a continuous infusion and changes in the rate of administration made slowly (greater than 5 min) in order to minimize hypotension and avoid acute overdosage (see DOSAGE AND ADMINISTRATION ). Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of DIPRIVAN, IV fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression, including hypotension, apnea, airway obstruction, and oxygen desaturation. As with other sedative medications, there is wide interpatient variability in DIPRIVAN dosage requirements, and these requirements may change with time. Failure to reduce the infusion rate in patients receiving DIPRIVAN for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of DIPRIVAN infusion for ICU sedation, especially when it is used for long durations. Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of DIPRIVAN should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilatory support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression. Because of the rapid clearance of DIPRIVAN, abrupt discontinuation of a patient's infusion may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of DIPRIVAN be continued in order to maintain a light level of sedation throughout the weaning process until 10 minutes to 15 minutes prior to extubation, at which time the infusion can be discontinued. Since DIPRIVAN is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when DIPRIVAN is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of DIPRIVAN should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the DIPRIVAN formulation; 1 mL of DIPRIVAN contains approximately 0.1 g of fat (1.1 kcal). EDTA is a strong chelator of trace metals – including zinc. Although with DIPRIVAN there are no reports of decreased zinc levels or zinc deficiency-related adverse events, DIPRIVAN should not be infused for longer than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses. In clinical trials mean urinary zinc loss was approximately 2.5 mg/day to 3 mg/day in adult patients and 1.5 mg/day to 2 mg/day in pediatric patients. In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major sepsis, the need for supplemental zinc should be considered during prolonged therapy with DIPRIVAN. At high doses (2 grams to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules. Studies to date in patients with normal or impaired renal function have not shown any alteration in renal function with DIPRIVAN containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation. The long-term administration of DIPRIVAN to patients with renal failure and/or hepatic insufficiency has not been evaluated.

Neurosurgical Anesthesia

When DIPRIVAN is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus of approximately 20 mg every 10 seconds should be utilized instead of rapid, more frequent, and/or larger boluses of DIPRIVAN. Slower induction, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 mg/kg to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of DIPRIVAN (see DOSAGE AND ADMINISTRATION ).

Cardiac Anesthesia

Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Fluid deficits should be corrected prior to administration of DIPRIVAN. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with DIPRIVAN. Information for Patients Risk of Drowsiness Patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle, or hazardous machinery or signing legal documents may be impaired for some time after general anesthesia or sedation. Effect of Anesthetic and Sedation Drugs on Early Brain Development Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs (see WARNINGS, Pediatric Neurotoxicity ).

Drug Interactions

The induction dose requirements of DIPRIVAN may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (e.g., morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (e.g., nitrous oxide or opioids). The concurrent administration of potent inhalational agents (e.g., isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN. The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce the dose of propofol when co-administering with valproate. Monitor patients closely for signs of increased sedation or cardiorespiratory depression. DIPRIVAN does not cause a clinically significant change in onset, intensity or duration of action of the commonly used neuromuscular blocking agents (e.g., succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed in adults. In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN may result in serious bradycardia. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of propofol.

Mutagenesis

Propofol was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. Propofol was not mutagenic in either the gene mutation/gene conversion test using Saccharomyces cerevisiae, or in vitro cytogenetic studies in Chinese hamsters. In the in vivo mouse micronucleus assay with Chinese hamsters propofol administration did not produce chromosome aberrations. Impairment of Fertility Female Wistar rats administered either 0, 10, or 15 mg/kg/day propofol intravenously from 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility (0.65 and 1 times the human induction dose of 2.5 mg/kg based on body surface area). Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.

Pregnancy Risk Summary

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, decreased pup survival concurrent with increased maternal mortality was observed with intravenous administration of propofol to pregnant rats either prior to mating and during early gestation or during late gestation and early lactation at exposures less than the human induction dose of 2.5 mg/kg. In pregnant rats administered 15 mg/kg/day intravenous propofol (equivalent to the human induction dose) from two weeks prior to mating to early in gestation (Gestation Day 7), offspring that were allowed to mate had increased postimplantation losses. The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [See Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Animal Data

Pregnant rats were administered propofol intravenously at 0, 5, 10, and 15 mg/kg/day (0.3, 0.65, and 1 times the human induction dose of 2.5 mg/kg based on body surface area) during organogenesis (Gestational Days 6-15). Propofol did not cause adverse effects to the fetus at exposures up to 1 times the human induction dose despite evidence of maternal toxicity (decreased weight gain in all groups). Pregnant rabbits were administered propofol intravenously at 0, 5, 10, and 15 mg/kg/day (0.65, 1.3, 2 times the human induction dose of 2.5 mg/kg based on body surface area comparison) during organogenesis (Gestation Days 6-18). Propofol treatment decreased total numbers of corpora lutea in all treatment groups but did not cause fetal malformations at any dose despite maternal toxicity (one maternal death from anesthesia-related respiratory depression in the high dose group). Pregnant rats were administered propofol intravenously at 0, 10, and 15 mg/kg/day (0.65 and 1 times the human induction dose of 2.5 mg/kg based on body surface area) from late gestation through lactation (Gestation Day 16 to Lactation Day 22). Decreased pup survival was noted at all doses in the presence of maternal toxicity (deaths from anesthesia-induced respiratory depression). This study did not evaluate neurobehavioral function including learning and memory in the pups. Pregnant rats were administered propofol intravenously at 0, 10, or 15 mg/kg/day (0.3 and 1 times the human induction dose of 2.5 mg/kg based on body surface area) from 2 weeks prior to mating to Gestational Day 7. Pup (F1) survival was decreased on Day 15 and 22 of lactation at maternally toxic doses of 10 and 15 mg/kg/day. When F1 offspring were allowed to mate, postimplantation losses were increased in the 15 mg/kg/day treatment group. In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits (see WARNINGS; Pediatric Neurotoxicity , PRECAUTIONS ; Pediatric Use , and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). Labor and Delivery DIPRIVAN is not recommended for obstetrics, including cesarean section deliveries. DIPRIVAN crosses the placenta, and as with other general anesthetic agents, the administration of DIPRIVAN may be associated with neonatal depression.

Nursing

Mothers DIPRIVAN is not recommended for use in nursing mothers because DIPRIVAN has been reported to be excreted in human milk and the effects of oral absorption of small amounts of propofol are not known.

Pediatric Use

The safety and effectiveness of DIPRIVAN have been established for induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2 months and older. DIPRIVAN is not recommended for the induction of anesthesia in patients younger than 3 years of age and for the maintenance of anesthesia in patients younger than 2 months of age as safety and effectiveness have not been established. In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN may result in serious bradycardia (see PRECAUTIONS , General ). DIPRIVAN is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established. There have been anecdotal reports of serious adverse events and death in pediatric patients with upper respiratory tract infections receiving DIPRIVAN for ICU sedation. In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received DIPRIVAN (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality has not been established, DIPRIVAN is not indicated for sedation in pediatric patients until further studies have been performed to document its safety in that population (see CLINICAL PHARMACOLOGY , Pharmacokinetics , Pediatric Patients and DOSAGE AND ADMINISTRATION ). In pediatric patients, abrupt discontinuation of DIPRIVAN following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed. Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as DIPRIVAN, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans. In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data (see WARNINGS , Pediatric Neurotoxicity , Pregnancy , ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ).

Geriatric Use

The effect of age on induction dose requirements for propofol was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age. A lower induction dose and a slower maintenance rate of administration of DIPRIVAN should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response (see DOSAGE AND ADMINISTRATION, Elderly, Debilitated or ASA-PS III or IV Patients and CLINICAL PHARMACOLOGY, Geriatrics ).

General

Adult and Pediatric Patients A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients (see DOSAGE AND ADMINISTRATION ). Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds. DIPRIVAN use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis. Very rarely the use of DIPRIVAN may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness. Recovery is spontaneous. When DIPRIVAN is administered to an epileptic patient, there is a risk of seizure during the recovery phase. Attention should be paid to minimize pain on administration of DIPRIVAN. Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous injection may also be reduced by prior injection of IV lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to DIPRIVAN in quantities greater than 20 mg lidocaine/200 mg DIPRIVAN results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it is recommended that lidocaine be administered prior to DIPRIVAN administration or that it be added to DIPRIVAN immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN. Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (less than 1%). In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction. Intra-arterial injection in animals did not induce local tissue effects. Accidental intra-arterial injection has been reported in patients, and, other than pain, there were no major sequelae. Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of DIPRIVAN. Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with DIPRIVAN administration. Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following DIPRIVAN administration. There have been rare reports of pulmonary edema in temporal relationship to the administration of DIPRIVAN, although a causal relationship is unknown. Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which DIPRIVAN was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to DIPRIVAN is unclear. DIPRIVAN has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with DIPRIVAN. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.

Intensive Care Unit Sedation Adult

Patients ( See WARNINGS and DOSAGE AND ADMINISTRATION , Handling Procedures . ) The administration of DIPRIVAN should be initiated as a continuous infusion and changes in the rate of administration made slowly (greater than 5 min) in order to minimize hypotension and avoid acute overdosage (see DOSAGE AND ADMINISTRATION ). Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of DIPRIVAN, IV fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression, including hypotension, apnea, airway obstruction, and oxygen desaturation. As with other sedative medications, there is wide interpatient variability in DIPRIVAN dosage requirements, and these requirements may change with time. Failure to reduce the infusion rate in patients receiving DIPRIVAN for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of DIPRIVAN infusion for ICU sedation, especially when it is used for long durations. Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of DIPRIVAN should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilatory support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression. Because of the rapid clearance of DIPRIVAN, abrupt discontinuation of a patient's infusion may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of DIPRIVAN be continued in order to maintain a light level of sedation throughout the weaning process until 10 minutes to 15 minutes prior to extubation, at which time the infusion can be discontinued. Since DIPRIVAN is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when DIPRIVAN is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of DIPRIVAN should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the DIPRIVAN formulation; 1 mL of DIPRIVAN contains approximately 0.1 g of fat (1.1 kcal). EDTA is a strong chelator of trace metals – including zinc. Although with DIPRIVAN there are no reports of decreased zinc levels or zinc deficiency-related adverse events, DIPRIVAN should not be infused for longer than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses. In clinical trials mean urinary zinc loss was approximately 2.5 mg/day to 3 mg/day in adult patients and 1.5 mg/day to 2 mg/day in pediatric patients. In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major sepsis, the need for supplemental zinc should be considered during prolonged therapy with DIPRIVAN. At high doses (2 grams to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules. Studies to date in patients with normal or impaired renal function have not shown any alteration in renal function with DIPRIVAN containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation. The long-term administration of DIPRIVAN to patients with renal failure and/or hepatic insufficiency has not been evaluated.

Neurosurgical Anesthesia

When DIPRIVAN is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus of approximately 20 mg every 10 seconds should be utilized instead of rapid, more frequent, and/or larger boluses of DIPRIVAN. Slower induction, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 mg/kg to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of DIPRIVAN (see DOSAGE AND ADMINISTRATION ).

Cardiac Anesthesia

Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Fluid deficits should be corrected prior to administration of DIPRIVAN. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with DIPRIVAN.

Information for Patients Risk of Drowsiness Patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle, or hazardous machinery or signing legal documents may be impaired for some time after general anesthesia or sedation. Effect of Anesthetic and Sedation Drugs on Early Brain Development Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs (see WARNINGS, Pediatric Neurotoxicity ).

Drug Interactions

The induction dose requirements of DIPRIVAN may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (e.g., morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (e.g., nitrous oxide or opioids). The concurrent administration of potent inhalational agents (e.g., isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN. The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce the dose of propofol when co-administering with valproate. Monitor patients closely for signs of increased sedation or cardiorespiratory depression. DIPRIVAN does not cause a clinically significant change in onset, intensity or duration of action of the commonly used neuromuscular blocking agents (e.g., succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed in adults. In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN may result in serious bradycardia.

Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of propofol.

Mutagenesis

Propofol was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. Propofol was not mutagenic in either the gene mutation/gene conversion test using Saccharomyces cerevisiae, or in vitro cytogenetic studies in Chinese hamsters. In the in vivo mouse micronucleus assay with Chinese hamsters propofol administration did not produce chromosome aberrations. Impairment of Fertility Female Wistar rats administered either 0, 10, or 15 mg/kg/day propofol intravenously from 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility (0.65 and 1 times the human induction dose of 2.5 mg/kg based on body surface area). Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.

Pregnancy Risk Summary

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, decreased pup survival concurrent with increased maternal mortality was observed with intravenous administration of propofol to pregnant rats either prior to mating and during early gestation or during late gestation and early lactation at exposures less than the human induction dose of 2.5 mg/kg. In pregnant rats administered 15 mg/kg/day intravenous propofol (equivalent to the human induction dose) from two weeks prior to mating to early in gestation (Gestation Day 7), offspring that were allowed to mate had increased postimplantation losses. The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [See Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Animal Data

Pregnant rats were administered propofol intravenously at 0, 5, 10, and 15 mg/kg/day (0.3, 0.65, and 1 times the human induction dose of 2.5 mg/kg based on body surface area) during organogenesis (Gestational Days 6-15). Propofol did not cause adverse effects to the fetus at exposures up to 1 times the human induction dose despite evidence of maternal toxicity (decreased weight gain in all groups). Pregnant rabbits were administered propofol intravenously at 0, 5, 10, and 15 mg/kg/day (0.65, 1.3, 2 times the human induction dose of 2.5 mg/kg based on body surface area comparison) during organogenesis (Gestation Days 6-18). Propofol treatment decreased total numbers of corpora lutea in all treatment groups but did not cause fetal malformations at any dose despite maternal toxicity (one maternal death from anesthesia-related respiratory depression in the high dose group). Pregnant rats were administered propofol intravenously at 0, 10, and 15 mg/kg/day (0.65 and 1 times the human induction dose of 2.5 mg/kg based on body surface area) from late gestation through lactation (Gestation Day 16 to Lactation Day 22). Decreased pup survival was noted at all doses in the presence of maternal toxicity (deaths from anesthesia-induced respiratory depression). This study did not evaluate neurobehavioral function including learning and memory in the pups. Pregnant rats were administered propofol intravenously at 0, 10, or 15 mg/kg/day (0.3 and 1 times the human induction dose of 2.5 mg/kg based on body surface area) from 2 weeks prior to mating to Gestational Day 7. Pup (F1) survival was decreased on Day 15 and 22 of lactation at maternally toxic doses of 10 and 15 mg/kg/day. When F1 offspring were allowed to mate, postimplantation losses were increased in the 15 mg/kg/day treatment group. In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits (see WARNINGS; Pediatric Neurotoxicity , PRECAUTIONS ; Pediatric Use , and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ).

Labor and Delivery DIPRIVAN is not recommended for obstetrics, including cesarean section deliveries. DIPRIVAN crosses the placenta, and as with other general anesthetic agents, the administration of DIPRIVAN may be associated with neonatal depression.

Nursing

Mothers DIPRIVAN is not recommended for use in nursing mothers because DIPRIVAN has been reported to be excreted in human milk and the effects of oral absorption of small amounts of propofol are not known.

Pediatric Use

The safety and effectiveness of DIPRIVAN have been established for induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2 months and older. DIPRIVAN is not recommended for the induction of anesthesia in patients younger than 3 years of age and for the maintenance of anesthesia in patients younger than 2 months of age as safety and effectiveness have not been established. In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN may result in serious bradycardia (see PRECAUTIONS , General ). DIPRIVAN is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established. There have been anecdotal reports of serious adverse events and death in pediatric patients with upper respiratory tract infections receiving DIPRIVAN for ICU sedation. In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received DIPRIVAN (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality has not been established, DIPRIVAN is not indicated for sedation in pediatric patients until further studies have been performed to document its safety in that population (see CLINICAL PHARMACOLOGY , Pharmacokinetics , Pediatric Patients and DOSAGE AND ADMINISTRATION ). In pediatric patients, abrupt discontinuation of DIPRIVAN following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed. Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as DIPRIVAN, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans. In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data (see WARNINGS , Pediatric Neurotoxicity , Pregnancy , ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ).

Geriatric Use

The effect of age on induction dose requirements for propofol was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age. A lower induction dose and a slower maintenance rate of administration of DIPRIVAN should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response (see DOSAGE AND ADMINISTRATION, Elderly, Debilitated or ASA-PS III or IV Patients and CLINICAL PHARMACOLOGY, Geriatrics ).

INTERACTIONS Opioids, Sedatives or Other Analgesic Agents : May increase the anesthetic/sedative and cardiorespiratory effects ( 7 ) Valproate : May lead to increased blood levels of propofol ( 7 ) Opioids and Sedatives The induction dose requirements of propofol injectable emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with opioids (e.g., morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of propofol injectable emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. In pediatric patients, administration of fentanyl concomitantly with propofol injectable emulsion may result in serious bradycardia.

Analgesic Agents

During maintenance of anesthesia or sedation, the rate of propofol injectable emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (e.g., nitrous oxide or opioids). The concurrent administration of potent inhalational agents (e.g., isoflurane, sevoflurane, desflurane, enflurane, and halothane) during maintenance with propofol injectable emulsion are routinely used. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of propofol injectable emulsion.

Valproate

The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce the dose of propofol when co-administering with valproate. Monitor patients closely for signs of increased sedation or cardiorespiratory depression.

Common Neuromuscular Blocking Agents

Propofol injectable emulsion does not cause a clinically significant change in onset, intensity or duration of action of the commonly used neuromuscular blocking agents (e.g., succinylcholine and nondepolarizing muscle relaxants).

Common Drugs

Used as Premedication or Drugs Used During Anesthesia or Sedation No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed in adults.

Side Effect	Reports	% of Total	Deaths	Hosp.
Drug ineffective	1,627	10.1%	298	841
Anaphylactic shock	1,494	9.3%	72	424
Hypotension	1,388	8.6%	117	646
Off label use	889	5.5%	211	483
Anaphylactic reaction	862	5.4%	37	312
Cardiac arrest	758	4.7%	293	325
Bradycardia	470	2.9%	56	205
Tachycardia	464	2.9%	38	212
Propofol infusion syndrome	420	2.6%	169	193
Foetal exposure during pregnancy	389	2.4%	58	101
Toxicity to various agents	381	2.4%	245	191
Product use in unapproved indication	367	2.3%	55	155
Rhabdomyolysis	365	2.3%	75	207
Bronchospasm	356	2.2%	15	112
Rash	354	2.2%	27	173
Condition aggravated	340	2.1%	104	159
Maternal exposure during pregnancy	340	2.1%	21	140
Oxygen saturation decreased	336	2.1%	28	150
Pyrexia	335	2.1%	70	209
Drug interaction	307	1.9%	37	177

Year	Reports	Deaths	Hosp.
2000	5	3	0
2001	15	4	6
2002	15	14	10
2003	6	2	2
2004	5	0	2
2005	8	4	4
2006	63	0	16
2007	3	0	2
2008	11	4	4
2009	29	11	12
2010	39	7	16
2011	39	7	18
2012	81	5	46
2013	128	21	53
2014	397	34	171
2015	469	34	186
2016	534	82	204
2017	525	40	210
2018	722	42	297
2019	717	29	301
2020	784	152	380
2021	592	77	246
2022	531	60	206
2023	698	64	274
2024	538	26	202
2025	410	25	135

Indication	Reports
Anaesthesia	2,503
General anaesthesia	2,292
Product used for unknown indication	2,240
Induction of anaesthesia	2,072
Sedation	1,714
Sedative therapy	904
Status epilepticus	752
Maintenance of anaesthesia	247
Seizure	234
Anaesthesia procedure	215

PROPOFOL: 16,061 Adverse Event Reports & Safety Profile

What Are the Most Common PROPOFOL Side Effects?

All PROPOFOL Side Effects by Frequency

Who Reports PROPOFOL Side Effects? Age & Gender Data

Is PROPOFOL Getting Safer? Reports by Year

What Is PROPOFOL Used For?

PROPOFOL vs Alternatives: Which Is Safer?

Other Drugs in Same Class: General Anesthesia [PE]

Official FDA Label for PROPOFOL

Drug Description

FDA Approved Uses (Indications)

Propofol Injectable

Propofol Injectable

Dosage & Administration

Pediatric Patients

Neurosurgical Patients

Cardiac

Table

Cardiac Anesthesia Techniques Primary Agent

Preinduction Anxiolysis

Induction

Adult

Continuous

Intermittent Bolus

Pediatric

Monitored Anesthesia

Sedation Adult Patients

Icu

Adult Patients

Indication Dosage And Administration

Cardiac

Neurosurgical

Pediatric

Cardiac

Neurosurgical

Pediatric

In

Dilution

Pediatric Patients

Neurosurgical Patients

Cardiac

Table

Cardiac Anesthesia Techniques Primary Agent

Preinduction Anxiolysis

Induction

Adult

Continuous

Intermittent Bolus

Pediatric

Monitored Anesthesia

Sedation Adult Patients

Icu

Adult Patients

Indication Dosage And Administration

Cardiac

Neurosurgical

Pediatric

Cardiac

Neurosurgical

Pediatric

In

Dilution

Contraindications

Known Adverse Reactions

General

Icu

Tachycardia

Central Nervous

Injection

Respiratory Acidosis During

Icu

Tachycardia

Central Nervous

Injection

Respiratory Acidosis During

Warnings

Microbial

Cardiovascular

5.5 Risk of Seizures When propofol injectable emulsion is administered to an epileptic patient, there is a risk of seizure during the recovery phase.

5.17 Risks of Perioperative Myoclonia Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with propofol injectable emulsion administration.