Propofol: Package Insert and Label Information (Page 2 of 6)

INDICATIONS AND USAGE

Propofol Injectable Emulsion is an IV general anesthetic and sedation drug that can be used as described in the table below.

Table 3. Indications for Propofol Injectable Emulsion

Indication

Approved Patient Population

Initiation and maintenance of Monitored Anesthesia Care (MAC) sedation

Adults only

Combined sedation and regional anesthesia

Adults only (see PRECAUTIONS)

Induction of General Anesthesia

Patients greater than or equal to 3 years of age

Maintenance of General Anesthesia

Patients greater than or equal to 2 months of age

Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients

Adults only

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 PRECAUTIONS, Pediatric 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.

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 is not indicated for use in Pediatric ICU sedation since the safety of this regimen has not been established (see PRECAUTIONS, Pediatric Use).

Propofol Injectable Emulsion is not recommended for obstetrics, including Cesarean section deliveries. Propofol Injectable Emulsion crosses the placenta, and as with other general anesthetic agents, the administration of Propofol Injectable Emulsion may be associated with neonatal depression (see PRECAUTIONS).

Propofol Injectable Emulsion is not recommended for use in nursing mothers because propofol has been reported to be excreted in human milk, and the effects of oral absorption of small amounts of propofol are not known (see PRECAUTIONS).

CONTRAINDICATIONS

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 allergies to eggs, egg products, soybeans or soy products.

WARNINGS

Use of Propofol Injectable Emulsion has been associated with both fatal and life-threatening anaphylactic and anaphylactoid reactions.

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 facilities for maintenance of 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 patients in the Intensive Care Unit (ICU), 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.

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* 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 (greater than 5 mg/kg/h for greater than 48h). 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.

*Coved ST segment elevation (similar to ECG changes of the Brugada syndrome).

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. Infusions of Propofol Injectable Emulsion should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level (see PRECAUTIONS).

Propofol Injectable Emulsion should not be coadministered through the same IV 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.

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 death. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits (see DOSAGE AND ADMINISTRATION, Handling Procedures).

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. Propofol Injectable Emulsion vial is never to be accessed more than once or used on more than one person.

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 PRECAUTIONS, Pregnancy, Pediatric Use; ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).

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.

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. Propofol Injectable Emulsion 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 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.

When Propofol Injectable Emulsion 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 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 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 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.

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 postmarketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of Propofol Injectable Emulsion.

Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with Propofol Injectable Emulsion administration.

Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following Propofol Injectable Emulsion administration.

There have been rare reports of pulmonary edema in temporal relationship to the administration of Propofol Injectable Emulsion, although a causal relationship is unknown.

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.

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.

Intensive Care Unit Sedation

Adult Patients

(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.) The administration of Propofol Injectable Emulsion 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 Propofol Injectable Emulsion, 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 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. Because of the rapid clearance of Propofol Injectable Emulsion, 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 Propofol Injectable Emulsion 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 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).

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 Propofol Injectable Emulsion to patients with renal failure and/or hepatic insufficiency has not been evaluated.

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