Propofol

Administration should commence promptly and be completed within 12 hours after the vial has been opened. Propofol injectable emulsion must be prepared for single dose only. Any unused propofol injectable emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing propofol injectable emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.

The intravenous line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual propofol injectable emulsion. 2 )] . Guidelines for Aseptic Technique for ICU Sedation Propofol injectable emulsion must be prepared for single dose 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 propofol injectable emulsion. As with other lipid emulsions, the number of intravenous 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 propofol injectable emulsion drug product must be discarded after 12 hours. If propofol injectable emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened.

When withdrawing propofol injectable emulsion from a vial, a sterile vent spike should be used. The syringe should be labelled 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.

Propofol injectable emulsion should be discarded and administration lines changed after 12 hours. 2 )] Administration with Lidocaine If lidocaine is to be administered to minimize pain on injection of propofol injectable emulsion, it is recommended that it 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.

13 )] Compatibility and Stability Propofol injectable emulsion should not be mixed with other therapeutic agents prior to administration. Dilution Prior to Administration Propofol injectable emulsion 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).

15 )] . 2% Sodium Chloride Injection, USP. Administration with Pumps When administering propofol injectable emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates. When infusing propofol injectable emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

Administration with Filters Clinical experience with the use of in-line filters and propofol injectable emulsion during anesthesia or ICU/MAC sedation is limited. Propofol injectable emulsion 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 propofol injectable emulsion 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. 5 mg/kg of propofol injectable emulsion. For induction, whether administered by infusion or intravenous injection the dose of propofol injectable emulsion to the patient should be titrated against the response of the patient and until there are clinical signs consistent with the onset of anesthesia.

As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication may impact the dose of propofol injectable emulsion required for induction of general anesthesia. 5 mg/kg of propofol injectable emulsion for induction of anesthesia.

For induction, whether administered by infusion or intravenous injection the dose administration of propofol injectable emulsion to the patient should be titrated against the response of the patient and until there are clinical signs consistent with the onset of anesthesia.

A rapid bolus may increase the likelihood of undesirable cardiorespiratory depression. 5 mg/kg of propofol injectable emulsion for induction. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.

As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication may impact the dose of propofol injectable emulsion required for induction of general anesthesia. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.

7 )] . Neurosurgical Patients Most adult neurosurgical patients require 1 mg/kg to 2 mg/kg of propofol injectable emulsion. Slower induction is recommended to allow for titration to achieve an adequate clinical response. 6 )] . Whether administered by infusion or an intravenous injection, the dose of propofol injectable emulsion to the patient should be titrated against the response of the patient and until there are clinical signs consistent with the onset of anesthesia.

5 mg/kg of propofol injectable emulsion. Slower induction is recommended to allow for titration to clinical response and to prevent hemodynamic instability. Whether administered by infusion or intravenous injection, the dose of propofol injectable emulsion to the patient should be titrated against the response of the patient until the clinical signs show the onset of anesthesia.

Other agents used in addition to propofol injectable emulsion for induction and maintenance of anesthesia may require propofol injectable emulsion doses to be titrated to ensure adequate sedation level. Propofol injectable emulsion has been well-studied in patients with coronary artery disease and in patients with hemodynamically significant valvular or congenital heart disease.

No significant safety issues or changes to the induction of anesthesia is generally required for these patient groups. Dosing should be titrated based on depth of anesthesia. As with other anesthetic and sedative-hypnotic agents, propofol injectable emulsion 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 propofol injectable emulsion, 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, propofol injectable emulsion 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.

15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injectable emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.

The rate of propofol injectable emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses. 3 Maintenance of General Anesthesia for Patients Greater than or Equal to 2 Months of Age Propofol injectable emulsion 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 the likelihood of undesirable cardiorespiratory depression. Adult Patients In adults, anesthesia can be maintained by administering propofol injectable emulsion by infusion or intermittent intravenous bolus injection.

The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections Continuous Infusion Propofol injectable emulsion 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 propofol injectable emulsion 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 (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol. 5 mL) to 50 mg (5 mL) may be administered 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. Cardiac Anesthesia The maintenance dose of propofol in adult cardiac patients should be administered as 25 to 100 mcg/kg/min, and should be adjusted according to the patient's sedation level and clinical response.

Pediatric Patients In children greater than or equal to 2 months of age, anesthesia can be maintained by administering propofol injectable emulsion by infusion or intermittent intravenous bolus injection. 5 to 2 mg/kg). The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous Infusion Propofol injectable emulsion administered as a variable rate infusion 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 propofol injectable emulsion 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. Propofol injectable emulsion should be titrated to achieve the desired clinical effect. 1 )] . 5 to 2 mg/kg doses as needed.

The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia. 4 Initiation and Maintenance of Monitored Anesthesia Care (MAC) Sedation in Adult Patients When propofol injectable emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.

In most patients, the rates of propofol injectable emulsion 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. 12 )] . A rapid bolus injection may result in undesirable cardiorespiratory depression. Initiation of MAC Sedation in Adult Patients 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 propofol injectable emulsion at 100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/hour to 9 mg/kg/hour) for a period of 3 minutes to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.

5 mg/kg administered over 3 minutes to 5 minutes and titrated to clinical responses. When propofol injectable emulsion 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.

12 )]. The rate of administration should be over 3 minutes to 5 minutes and the dosage of propofol injectable emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs.

Maintenance of MAC Sedation in Adult Patients For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. 5 mg/kg/hour) 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 propofol injectable emulsion at rates higher than are clinically necessary.

If the intermittent bolus dose method is used, increments of propofol injectable emulsion 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.

12 )] . The rate of administration and the dosage of propofol injectable emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs.

Propofol injectable emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When propofol injectable emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of propofol injectable emulsion and may also result in a slower recovery profile [see Drug Interactions ( 7 )].

5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of propofol injectable emulsion. , body surface) nitrous oxide (60% to 70%) can be combined with a variable rate propofol injectable emulsion infusion to provide satisfactory anesthesia.

, intra- abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of propofol injectable emulsion 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 in order to avoid administration of propofol injectable emulsion 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 (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by propofol.

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. 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.

6 Intensive Care Unit (ICU) Sedation of Intubated, Mechanically Ventilated Adult Patients In the Intensive Care Unit (ICU), propofol injectable emulsion can be administered to intubated, mechanically ventilated adult patients to provide continuous sedation and control of stress responses only by persons skilled in the medical management of critically ill patients and trained in cardiovascular resuscitation and airway management.

10 ) ]. 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. 3 mg/kg/hour).

6 mg/kg/hour) 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. 3 mg/kg/hour to 3 mg/kg/hour) titrated to desired level of clinical response.

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.

8 )] . 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.

12 )] . Dosages of propofol injectable emulsion should be reduced in patients who have received large dosages of opioids. The propofol injectable emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.

6 )] . 4 )] . 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. 4 )] . 8 )] . 7 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.

Table 1. 5 mg/kg until induction onset, as determined by clinical response of the patient. 5 mg/kg until induction onset, as determined by clinical response to the onset of anesthesia. 5 mg/kg until induction onset, as determined by clinical response of the patient.

Neurosurgical Patients: 1 mg/kg to 2 mg/kg until induction onset, as determined by clinical response of the patient. 2 )] .

Maintenance of General Anesthesia:

Infusion Healthy Adults Less Than 65 Years of Age: Infusion of 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/hour to 12 mg/kg/hour).

Elderly, Debilitated, ASA-PS III or IV Patients:

Infusion of 50 mcg/kg/min to 100 mcg/kg/min (3 mg/kg/hour to 6 mg/kg/hour).

Cardiac Anesthesia:

Infusion of 25 mcg/kg/min to 100 mcg/kg/min Neurosurgical Patients: Infusion of 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/hour to 12 mg/kg/hour). 5 mg/kg/hour to 18 mg/kg/hour). 2 )] Intermittent Bolus Healthy Adults Less Than 65 Years of Age: Increments of 20 mg to 50 mg as needed.

Initiation of MAC Sedation:

Healthy Adults Less Than 65 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. 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. 12 )] .

Maintenance of MAC Sedation:

Healthy Adults Less Than 65 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique. 5 mg/kg/hour) 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. 12 )] . 3 mg/kg/hour) for at least 5 minutes. 6 mg/kg/hour) over 5 minutes to 10 minutes may be used until desired clinical effect is achieved. 3 mg/kg/hour to 3 mg/kg/hour) or higher may be required.

8 )] . Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of propofol injectable emulsion required for sedation. 2 )] .

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. Table 2. 14 )]. , phlebitis or thrombosis, have been reported rarely (<1%).

The most common adverse reactions >1% were bradycardia, arrhythmia, tachycardia, hypotension, hypertension, decreased cardiac output, movement, apnea, respiratory acidosis during weaning, rash, pruritus, burning/stinging or pain at injection site, and hyperlipemia ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc.

gov/medwatch

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. 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. 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. , succinylcholine) or surgical stimuli.

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

1 )] . 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.

, 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 )] . 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.

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. 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. 1 kcal). 11 Risks of Zinc Losses EDTA is a strong chelator of trace metals – including zinc. Although with propofol injectable emulsion there are no reports of decreased zinc levels or zinc deficiency-related adverse events, propofol injectable emulsion should not be infused for longer than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses.

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 propofol injectable emulsion.

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. 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.

14 Risk 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.

15 Risk 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. 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. 17 Risks of Perioperative Myoclonia Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with propofol injectable emulsion administration.

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. 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.