propofol injectable emulsion (contains benzyl alcohol) Warnings and Precautions

(propofol injectable emulsion (contains benzyl alcohol))

5 WARNINGS AND PRECAUTIONS

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 access parenteral product (single patient infusion vial) which contains benzyl alcohol 1.5 mg/mL and sodium benzoate 0.7 mg/mL to inhibit the rate of growth of microorganisms, for up to 12 hours, in the event of accidental extrinsic contamination. However, propofol injectable emulsion can still support the growth of microorganisms, as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling propofol injectable emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

Propofol injectable emulsion vials are never to be accessed more than once or used on more than one person.

There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and of the use of propofol vials intended for single use on multiple persons.

5.3 Risks of Pediatric Neurotoxicity

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Animal Toxicology and/or Pharmacology (13.2)].

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

5.4 Risks of Bradycardia, Asystole, and Cardiac Arrest

Propofol injectable emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with propofol injectable emulsion. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly.

The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.

5.5 Risk of Seizures

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

5.6 Neurosurgical Anesthesia

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

5.7 Cardiac Anesthesia

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

5.8 Use for Intensive Care Unit Sedation of Intubated, Mechanically Ventilated Adult Patients

The administration of propofol injectable emulsion should be initiated as a continuous infusion and changes in the rate of administration made slowly (>5 min) in order to minimize hypotension and avoid acute overdosage [see Overdosage (10) and Dosage and Administration (2.5)].

Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of propofol injectable emulsion, intravenous fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression.

As with other sedative medications, there is wide interpatient variability in propofol injectable emulsion dosage requirements, and these requirements may change with time.

Failure to reduce the infusion rate in patients receiving propofol injectable emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of propofol injectable emulsion infusion for ICU sedation, especially when it is used for long durations.

Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of propofol injectable emulsion should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilatory support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression.

Abrupt discontinuation of propofol injectable emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. It is therefore recommended that administration of propofol injectable emulsion be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes prior to extubation, at which time the infusion can be discontinued.

5.9 Risks of Propofol Infusion Syndrome in Patients with ICU Sedation

Use of propofol injectable emulsion infusions for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as Propofol Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes (Coved ST segment elevation -similar to ECG changes of the Brugada syndrome) and/or cardiac failure.

The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or prolonged, high-dose infusions of propofol (> 5 mg/kg/hour for > 48 hours). The syndrome has also been reported following large-dose, short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation, increasing propofol dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a propofol infusion, consideration should be given to using alternative means of sedation.

Prescribers should be alert to these events in patients with the above risk factors and immediately discontinue propofol when the above signs develop.

5.10 Risk of Elevations in Serum Triglycerides

Propofol injectable emulsion use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.

Since propofol injectable emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when propofol injectable emulsion is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of propofol injectable emulsion should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the propofol injectable emulsion formulation; 1 mL of propofol injectable emulsion contains approximately 0.1 g of fat (1.1 kcal).

5.11 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.

5.12 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.

5.13 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.

5.14 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.

5.15 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.

5.16 Risks of Perioperative Myoclonia

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

5.17 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.

5.18 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.

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Warnings and Precautions

5 WARNINGS AND PRECAUTIONS

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 access parenteral product (single patient infusion vial) which contains benzyl alcohol 1.5 mg/mL and sodium benzoate 0.7 mg/mL to inhibit the rate of growth of microorganisms, for up to 12 hours, in the event of accidental extrinsic contamination. However, propofol injectable emulsion can still support the growth of microorganisms, as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling propofol injectable emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

Propofol injectable emulsion vials are never to be accessed more than once or used on more than one person.

There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and of the use of propofol vials intended for single use on multiple persons.

5.3 Risks of Pediatric Neurotoxicity

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Animal Toxicology and/or Pharmacology (13.2)].

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

5.4 Risks of Bradycardia, Asystole, and Cardiac Arrest

Propofol injectable emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with propofol injectable emulsion. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly.

The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.

5.5 Risk of Seizures

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

5.6 Neurosurgical Anesthesia

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

5.7 Cardiac Anesthesia

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

5.8 Use for Intensive Care Unit Sedation of Intubated, Mechanically Ventilated Adult Patients

The administration of propofol injectable emulsion should be initiated as a continuous infusion and changes in the rate of administration made slowly (>5 min) in order to minimize hypotension and avoid acute overdosage [see Overdosage (10) and Dosage and Administration (2.5)].

Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of propofol injectable emulsion, intravenous fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression.

As with other sedative medications, there is wide interpatient variability in propofol injectable emulsion dosage requirements, and these requirements may change with time.

Failure to reduce the infusion rate in patients receiving propofol injectable emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of propofol injectable emulsion infusion for ICU sedation, especially when it is used for long durations.

Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of propofol injectable emulsion should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilatory support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression.

Abrupt discontinuation of propofol injectable emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. It is therefore recommended that administration of propofol injectable emulsion be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes prior to extubation, at which time the infusion can be discontinued.

5.9 Risks of Propofol Infusion Syndrome in Patients with ICU Sedation

Use of propofol injectable emulsion infusions for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as Propofol Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes (Coved ST segment elevation -similar to ECG changes of the Brugada syndrome) and/or cardiac failure.

The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or prolonged, high-dose infusions of propofol (> 5 mg/kg/hour for > 48 hours). The syndrome has also been reported following large-dose, short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation, increasing propofol dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a propofol infusion, consideration should be given to using alternative means of sedation.

Prescribers should be alert to these events in patients with the above risk factors and immediately discontinue propofol when the above signs develop.

5.10 Risk of Elevations in Serum Triglycerides

Propofol injectable emulsion use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.

Since propofol injectable emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when propofol injectable emulsion is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of propofol injectable emulsion should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the propofol injectable emulsion formulation; 1 mL of propofol injectable emulsion contains approximately 0.1 g of fat (1.1 kcal).

5.11 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.

5.12 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.

5.13 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.

5.14 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.

5.15 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.

5.16 Risks of Perioperative Myoclonia

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

5.17 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.

5.18 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.

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