2.1 Important Dosage and Administration Information

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

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. Do not use if there is evidence of separation of the phases of the emulsion.

Propofol injectable emulsion with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms. Product is packaged under nitrogen.

For general anesthesia or monitored anesthesia care (MAC) sedation, propofol injectable emulsion should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously monitored, and equipment for maintaining a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV patients.

For sedation of intubated, mechanically ventilated adult patients in the Intensive Care Unit, propofol injectable emulsion should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.

2.2 Induction of General Anesthesia for Patients Greater than or Equal to 3 Years of Age

2.3 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.

2.4 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. 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 and Precautions (5.12)]. A rapid bolus injection may result in undesirable cardiorespiratory depression.

2.5 Clinical Responses and Dose Titrations

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 propofol injectable emulsion.

For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate propofol injectable emulsion 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 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. 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.

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.

2.6 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.

Propofol injectable emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs [see Warnings and Precautions (5.8, 5.9, and 5.10)]. 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. When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/hour). The infusion rate should be increased by increments of 5 mcg/kg/min to 10 mcg/kg/min (0.3 mg/kg/hour to 0.6 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.

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/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. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks [see Warnings and Precautions (5.8)].

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. The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses [see Warnings and Precautions (5.12)].

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. As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time [see Dosage and Administration (2.6)].

Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of propofol injectable emulsion required for sedation [see Clinical Studies (14.4)]. 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. Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension [see Warnings and Precautions (5.4)].

Abrupt discontinuation of propofol injectable emulsion prior to weaning or for daily evaluation of sedation levels should be avoided [see Warnings and Precautions (5.8)].

2.7 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.

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 0.005% disodium edetate (EDTA) 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 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.

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 propofol injectable emulsion.

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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Postmarketing Experience

During the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of propofol injectable emulsion [see Warnings and Precautions (5.14)].

Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (<1%).

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of propofol injectable emulsion 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.

In pediatric patients, administration of fentanyl concomitantly with propofol injectable emulsion may result in serious bradycardia [see Warnings and Precautions (5.4)].

Propofol injectable emulsion 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 propofol injectable emulsion 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 propofol injectable emulsion (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality was not established in this study, propofol injectable emulsion is not indicated for ICU sedation in pediatric patients until further studies have been performed to document its safety in that population [see Clinical Pharmacology (12.3) and Dosage and Administration (2.1 and 2.2)]. However, propofol infusions are routinely used to provide safe sedation to critically ill pediatric patients in ICUs.

In pediatric patients, abrupt discontinuation of propofol injectable emulsion 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 propofol injectable emulsion, 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 and Precautions (5.3), Pregnancy (8.1), and Animal Toxicology and/or Pharmacology (13.2)].

8.5 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 propofol injectable emulsion 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. All dosing should be titrated according to patient condition and response [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

The long-term administration of propofol injectable emulsion to patients with hepatic insufficiency has not been evaluated.

The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis compared to adults with normal hepatic function. The effects of acute hepatic failure on the pharmacokinetics of propofol have not been studied.

8.7 Renal Impairment

Studies to date in patients with normal or impaired renal function have not shown any alteration in renal function with propofol injectable emulsion 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.

Propofol injectable emulsion contains 0.005% disodium edetate. At high doses (2 to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules.

The long-term administration of propofol injectable emulsion to patients with renal failure has not been evaluated.

The pharmacokinetics of propofol do not appear to be different in people with chronic renal impairment compared to adults with normal renal function. The effects of acute renal failure on the pharmacokinetics of propofol have not been studied.

9.2 Abuse

There are reports of the abuse of propofol for recreational and other improper purposes, which have resulted in fatalities and other injuries. Instances of self-administration of propofol injectable emulsion by health care professionals have also been reported, which have resulted in fatalities and other injuries. Inventories of propofol injectable emulsion should be stored and managed to prevent the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting.

10.1 Symptoms

Overdosage is likely to cause cardiorespiratory depression.

10.2 Treatment

If overdosage occurs, propofol injectable emulsion administration should be discontinued immediately.

Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.

12.1 Mechanism of Action

The mechanism of action, like all general anesthetics, is poorly understood. However, propofol is thought to produce its sedative/anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAA receptors.

12.2 Pharmacodynamics

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.

The hemodynamic effects of propofol injectable emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of propofol injectable emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of propofol injectable emulsion during induction of anesthesia are generally more pronounced than with other intravenous induction agents.

Induction of anesthesia with propofol injectable emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received propofol injectable emulsion (2 mg/kg to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 seconds to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of propofol injectable emulsion (1 mg/kg to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 seconds to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, propofol injectable emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of propofol injectable emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of propofol injectable emulsion. 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 administration in order to minimize undesirable cardiorespiratory effects. 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 and Precautions (5.12)].

Clinical and preclinical studies suggest that propofol injectable emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that propofol injectable emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that propofol injectable emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. Propofol injectable emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension [see Clinical Studies (14.2)].

Clinical studies indicate that propofol injectable emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of propofol injectable emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving propofol injectable emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

12.3 Pharmacokinetics

The pharmacokinetics of propofol are well described by a three- compartment linear model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.

Following an intravenous bolus dose, there is rapid equilibration between the plasma and the brain, accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. Distribution accounts for about half of this decline following a bolus of propofol. However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion. When equilibration occurs there is no longer a net transfer of propofol between tissues and plasma.

Discontinuation of the recommended doses of propofol injectable emulsion after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and the time to awakening is increased.

By daily titration of propofol injectable emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, propofol redistribution from fat and muscle to the plasma can be significant and slow recovery.

The figure below illustrates the fall of plasma propofol levels following infusions of various durations to provide ICU sedation.

The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief infusions means that after very long infusions a reduction in the infusion rate is appropriate by as much as half the initial infusion rate in order to maintain a constant plasma level. Therefore, 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Intra-arterial injection in animals did not induce local tissue effects. Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction.

Published studies in animals demonstrate that the use of anesthetic agents 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 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 an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but 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 neonates and young children who require procedures against the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.3), Pregnancy (8.1), and Pediatric Use (8.4)].

14.1 Pediatric Anesthesia

Propofol injectable emulsion was studied in clinical trials which included cardiac surgical patients. Most patients were 3 years of age or older. The majority of the patients were healthy ASA-PS I or II patients. The range of doses in these studies are described in Tables 3 and 4.

14.2 Neuroanesthesia

Propofol injectable emulsion was studied in patients undergoing craniotomy for supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior × lateral) was 31 mm × 32 mm in one trial and 55 mm × 42 mm in the other trial respectively. Anesthesia was induced with a median propofol injectable emulsion dose of 1.4 mg/kg (range: 0.9 mg/kg to 6.9 mg/kg) and maintained with a median maintenance propofol injectable emulsion dose of 146 mcg/kg/min (range: 68 mcg/kg/min to 425 mcg/kg/min). The median duration of the propofol injectable emulsion maintenance infusion was 285 minutes (range: 48 minutes to 622 minutes).

Propofol injectable emulsion was administered by infusion in a controlled clinical trial to evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17% (mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), propofol injectable emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.

14.3 Cardiac Anesthesia

Propofol injectable emulsion was evaluated in clinical trials involving patients undergoing coronary artery bypass graft (CABG).

In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving propofol injectable emulsion required 35% less nitroprusside than midazolam patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular effects in patients with severely compromised ventricular function.

14.4 Intensive Care Unit (ICU) Sedation in Adult Patients

Propofol injectable emulsion was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received propofol injectable emulsion and comprise the overall safety database for ICU sedation.

Across all clinical studies, the mean infusion maintenance rate for all propofol injectable emulsion patients was 27 ± 21 mcg/kg/min. The maintenance infusion rates required to maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for analgesia. Some patients also received benzodiazepines and/or neuromuscular blocking agents. During long-term maintenance of sedation, some ICU patients were awakened once or twice every 24 hours for assessment of neurologic or respiratory function.

In Medical and Postsurgical ICU studies comparing propofol injectable emulsion to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators, propofol injectable emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect that propofol injectable emulsion has been used safely in patients with a history of porphyria or malignant hyperthermia.

In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, adequate sedation was maintained with propofol injectable emulsion or morphine. There were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery between the treatment groups. In literature reports of severely head injured patients in Neurosurgical ICUs, propofol injectable emulsion infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion pressure.

Propofol injectable emulsion was found to be effective in status epilepticus which was refractory to the standard anticonvulsant therapies. For these patients, as well as for ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill patient populations.

14.5 Intensive Care Unit (ICU) Sedation in Pediatric Patients

A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of propofol injectable emulsion versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either propofol injectable emulsion 2%, (113 patients), propofol injectable emulsion 1%, (109 patients), or an SSA (e.g, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). Propofol injectable emulsion therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The results of the study showed an increase in the number of deaths in patients treated with propofol injectable emulsion as compared to SSAs. Of the 25 patients who died during the trial or within the 28-day follow up period: 12 (11% were) in the propofol injectable emulsion 2% treatment group, 9 (8% were) in the propofol injectable emulsion 1% treatment group, and 4% were (4%) in the SSA treatment group. The differences in mortality rate between the groups were not statistically significant. Review of the deaths failed to reveal a correlation with underlying disease status or a correlation to the drug or a definitive pattern to the causes of death.

17.1 Impaired Mental Alertness

Advise patients 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.

17.2 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.

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November 2024