Propofol

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

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 GABA A receptors.

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for detailed dosing instructions. 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. Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation Propofol injectable emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. Propofol injectable emulsion should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing propofol injectable emulsion from vials, a sterile vent spike should be used. The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened. Propofol injectable emulsion must be prepared for single dose only. Any unused propofol injectable emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing propofol injectable emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The intravenous line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual propofol injectable emulsion. [see Warnings and Precautions ( 5.2 )] . Guidelines for Aseptic Technique for ICU Sedation Propofol injectable emulsion must be prepared for single dose only. Strict aseptic techniques must be followed. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of propofol injectable emulsion. As with other lipid emulsions, the number of intravenous line manipulations should be minimized. Administration should commence promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused propofol injectable emulsion drug product must be discarded after 12 hours. If propofol injectable emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened. When with

6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling: Hypersensitivity reaction [see Warnings and Precautions ( 5.1 )] Hypotension and/or bradycardia [see Warnings and Precautions ( 5.4 )] Propofol Infusion Syndrome [see Warnings and Precautions ( 5.9 )] In the description below, rates of the more common events represent US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient. 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. Anesthesia and MAC Sedation in Adults The following estimates of adverse events for propofol injectable emulsion include data from clinical trials in general anesthesia/MAC sedation (N=2,889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with propofol injectable emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship. The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with propofol injectable emulsion during anesthesia (see Table 3 below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea. Anesthesia in Pediatric Patients Generally, the adverse experience profile from reports of 506 propofol injectable emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with propofol injectable emulsion during anesthesia in adults. Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients. ICU Sedation in Adults The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship. Table 2. Treatment Emergent Adverse Events Observed from Clinical Trials Anesthesia/MAC Sedation ICU Sedation Body as a Whole: Anaphylaxis/Anaphylactoid reaction perinatal disorder, tachycardia, bigeminy, bradycardia, premature ventricular contractions, hemorrhage, ECG abnormal arrhythmia atrial, fever, extremities pain , anticholinergic syndrome, asthenia, awareness, chest pain, extremities pain, fever, increased drug effect, neck rigidity/stiffness, trunk pain Fever, sepsis, trunk pain, whole body weakness Cardiovascular: Premature atrial contractions Syncope, hypotension [see also Clinical Pharmacology ( 12 )], t achycardia Nodal, arrhythmia Bradycardia, arrhythmia, atrial fibrillation, atrioventricular heart block, bigeminy, bleeding, bundle branch block, cardiac arrest, ECG abnormal, ed

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Serious and sometimes fatal reactions ( 5.1 ) Microbial Contamination : Strict aseptic technique must be maintained during handling. Propofol injectable emulsion vials are never to be accessed more than once or used on more than one person. Administration should commence promptly and be completed within 12 hours after the vial has been opened. Discard unused drug product. Do not use if contamination is suspected ( 5.2 ) Cardiovascular depression : Cases of bradycardia, asystole, and cardiac arrest have been reported. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly ( 5.4 ) 5.1 Anaphylactic and Anaphylactoid Reactions Use of propofol injectable emulsion has been associated with both fatal and life threatening anaphylactic and anaphylactoid reactions. Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following propofol injectable emulsion administration. 5.2 Risks of Microbial Contamination Strict aseptic technique must always be maintained during handling. Propofol injectable emulsion is a single-dose parenteral product (single patient infusion vial) which contains 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 propof

4 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 a history of anaphylaxis to eggs, egg products, soybeans or soy products. Known hypersensitivity to propofol, egg or soybean ( 4 )

10 OVERDOSAGE 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.