Propofol Injectable Emulsion

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 2months. MAC sedation in the pediatric population is not recommended propofol injectable emulsion is not indicated for use in Pediatric ICU sedation.

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 withdrawing propofol injectable emulsion from a vial, a sterile vent spike should be used. The syringe should be labelled with appropriate information including the date and time the vial was opened.Administration should commence promptly and be completed within 12 hours after the vial has been opened. Propofol injectable emulsion should be discarded and administration lines changed after 12 hours. [see Warnings and Precautions ( 5.2 )] Administration with Lidocaine If lidocaine is to be administered to minimize pain on injection of propofol injectable emulsion, it is recommended that it be administered prior to propofol injectable emulsion administration or that it be added to propofol injectable emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg propofol injectable emulsion. [see Warnings and Precautions ( 5.13 )] Compatibility and Stability Propofol injectable emulsion should not be mixed with other therapeutic agents prior to administration. Dilution Prior to Administration Propofol injectable emulsion is provided as a ready-to-use formulation. However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic). Administration with Other Fluids Compatibility of propofol injectable emulsion with the coadministration of blood/serum/plasma has not been established [see Warnings and Precautions ( 5.15 )]. When administered using a y-type infusion set, propofol injectable emulsion has been shown to be compatible with the following intravenous fluids: • 5% Dextrose Injection, USP • Lactated Ringers Injection, USP • Lactated Ringers and 5% Dextrose Injection • 5% Dextrose and 0.45% Sodium Chloride Injection, USP • 5% Dextrose and 0.2% Sodium Chloride Injection, USP. Administration with Pumps When administering propofol injectable emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates. When infusing propofol injectable emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical. Administration with Filters Clinical experience with the use of in-line filters and propofol injectable emulsion during anesthesia or ICU/MAC sedation is limited. Propofol injectable emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of propofol injectable emulsion and/or cause the breakdown of the emulsion. Filters should be used with caution and where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion. 2.2 Induction of General Anesthesia for Patients Greater than or Equal to 3 Years of Age Adult Patients Most adult patients under 65 years of age and classified as ASA-PS I or II require 2 mg/kg to 2.5 mg/kg of propofol injectable emulsion. For induction, whether administered by infusion or intravenous injection the dose of propofol injectable emulsion to the patient should be titrated against the response of the patient and until there are clinical signs consistent with the onset of anesthesia. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication may impact the dose of propofol injectable emulsion required for induction of general anesthesia. Elderly, Debilitated, or ASA-PS III or IV Patients Due to the reduced clearance and higher blood concentrations, most elderly, debilitated, or ASA-PS III or IV patients require approximately 1 mg/kg to 1.5 mg/kg of propofol injectable emulsion for induction of anesthesia. For induction, whether administered by infusion or intravenous injection the dose administration of propofol injectable emulsion to the patient should be titrated against the response of the patient and until there are clinical signs consistent with the onset of anesthesia. A rapid bolus may increase the likelihood of undesirable cardiorespiratory depression. [See Warnings and Precautions ( 5.12 )] Pediatric Patients Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 mg/kg to 3.5 mg/kg of propofol injectable emulsion for induction. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication may impact the dose of propofol injectable emulsion required for induction of general anesthesia. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Boluses of propofol injectable emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins [see Dosage and Administration ( 2.7 )] . Neurosurgical Patients Most adult neurosurgical patients require 1 mg/kg to 2 mg/kg of propofol injectable emulsion. Slower induction is recommended to allow for titration to achieve an adequate clinical response [see Warnings and Precautions ( 5.6 )] . Whether administered by infusion or an intravenous injection, the dose of propofol injectable emulsion to the patient should be titrated against the response of the patient and until there are clinical signs consistent with the onset of anesthesia. Cardiac Anesthesia Most adult cardiac patients require 0.5 mg/kg to 1.5 mg/kg of propofol injectable emulsion. Slower induction is recommended to allow for titration to clinical response and to prevent hemodynamic instability. Whether administered by infusion or intravenous injection, the dose of propofol injectable emulsion to the patient should be titrated against the response of the patient until the clinical signs show the onset of anesthesia. Other agents used in addition to propofol injectable emulsion for induction and maintenance of anesthesia may require propofol injectable emulsion doses to be titrated to ensure adequate sedation level. Propofol injectable emulsion has been well-studied in patients with coronary artery disease and in patients with hemodynamically significant valvular or congenital heart disease. No significant safety issues or changes to the induction of anesthesia is generally required for these patient groups. Dosing should be titrated based on depth of anesthesia. As with other anesthetic and sedative-hypnotic agents, propofol injectable emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend upon the dose and speed of the induction and maintenance infusion rates. In addition, lower heart rates are observed during maintenance with propofol injectable emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated. As with other anesthetic agents, propofol injectable emulsion reduces myocardial oxygen consumption. Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injectable emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. The rate of propofol injectable emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses. 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. Adult Patient s In adults, anesthesia can be maintained by administering propofol injectable emulsion by infusion or intermittent intravenous bolus injection. The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections. Continuous Infusion Propofol injectable emulsion 100 mcg/kg/min to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of propofol injectable emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period following the induction dose, higher rates of infusion are generally required (150 mcg/kg/min to 200 mcg/kg/min) for the first 10 minutes to 15 minutes. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance. Generally, rates of 50 mcg/kg/min to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol. Intermittent Bolus Increments of propofol injectable emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered in adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia. Cardiac Anesthesia The maintenance dose of propofol in adult cardiac patients should be administered as 25 to 100 mcg/kg/min, and should be adjusted according to the patient’s sedation level and clinical response. Pediatric Patients In children greater than or equal to 2 months of age, anesthesia can be maintained by administering propofol injectable emulsion by infusion or intermittent intravenous bolus injection. An initial bolus of between 1 to 4 mg/kg, followed by subsequent administration of smaller aliquots based on patients’ response (0.5 to 2 mg/kg). The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections. Continuous Infusion Propofol injectable emulsion administered as a variable rate infusion provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia. In general, for the pediatric population, maintenance by infusion of propofol injectable emulsion at a rate of 200 mcg/kg/min to 300 mcg/kg/min should immediately follow the induction dose. Following the first half-hour of maintenance, infusion rates of 125 mcg/kg/min to 150 mcg/kg/min are typically needed. Propofol injectable emulsion should be titrated to achieve the desired clinical effect. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients [see Clinical Studies ( 14.1 )]. Intermittent Bolus An initial bolus of 1 to 4 mg/kg should be administered, with additional 0.5 to 2 mg/kg doses as needed. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia. 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. Initiation of MAC Sedation in Adult Patients For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be initiated by infusing propofol injectable emulsion at 100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/hour to 9 mg/kg/hour) for a period of 3 minutes to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the slow injection method for initiation, patients will require approximatel y0.5 mg/kg administered over 3 minutes to 5 minutes and titrated to clinical responses. When propofol injectable emulsion is administered slowly over 3 minutes to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels. 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)] . The rate of administration should be over 3 minutes to 5 minutes and the dosage of propofol injectable emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs. Maintenance of MAC Sedation in Adult Patients For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require maintenance rates of 25 mcg/kg/min to 75 mcg/kg/min (1.5 mg/kg/hour to 4.5 mg/kg/hour) during the first 10 minutes to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 mcg/kg/min to 50 mcg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect. Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of propofol injectable emulsion at rates higher than are clinically necessary. If the intermittent bolus dose method is used, increments of propofol injectable emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery. 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 )]. The rate of administration and the dosage of propofol injectable emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs. Propofol injectable emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When propofol injectable emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of propofol injectable emulsion and may also result in a slower recovery profile [see Drug Interactions ( 7 )]. 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 steadystate 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. Table 1. Summary of Dosage Guidelines for Different Indications INDICATION DOSAGE AND ADMINISTRATION Induction of General Anesthesia: Healthy Adults Less Than 65 Years of Age: 2 mg/kg to 2.5 mg/kg until induction onset, as determined by clinical response of the patient. Elderly, Debilitated, or ASA-PS III or IV Patients: 1 mg/kg to 1.5 mg/kg until induction onset, as determined by clinical response to the onset of anesthesia. Cardiac Anesthesia: 0.5 mg/kg to 1.5 mg/kg until induction onset, as determined by clinical response of the patient. Neurosurgical Patients: 1 mg/kg to 2 mg/kg until induction onset, as determined by clinical response of the patient. Pediatric Patients – healthy, from 3 years to 16 years of age: 2.5 mg/kg to 3.5 mg/kg administered until induction onset, as determined by clinical response of the patient [see Pediatric Use ( 8.4 ) and Clinical Pharmacology ( 12.2 )]. Maintenance of General Anesthesia: Infusion Healthy Adults Less Than 65 Years of Age: Infusion of 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/hour to 12 mg/kg/hour). Elderly, Debilitated, ASA-PS III or IV Patients: Infusion of 50 mcg/kg/min to 100 mcg/kg/min (3 mg/kg/hour to 6 mg/kg/hour). Cardiac Anesthesia: Infusion of 25 mcg/kg/min to 100 mcg/kg/min Neurosurgical Patients: Infusion of 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/hour to 12 mg/kg/hour). Pediatric Patients - healthy, from2 months of age to 16 yearsof age: Infusion of125 mcg/kg/min to 300 mcg/kg/min (7.5 mg/kg/hour to 18 mg/kg/hour). Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased [see Pediatric Use ( 8.4 ) and Clinical Pharmacology ( 12.2 )] Intermittent Bolus Healthy Adults Less Than 65 Years of Age: Increments of 20 mg to 50 mg as needed. Initiation of MAC Sedation: Healthy Adults Less Than 65 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Most patients require an infusion of100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/hour to 9 mg/kg/hour) for 3 minutes to 5 minutes or a slow injection of 0.5 mg/kg over 3 minutes to 5 minutes foll followed immediately by a maintenance infusion. Elderly, Debilitated, Neurosurgical, or ASA-PSIII or IV Patients: Most patients require dosages similar to healthy adults. Rapid boluses are to be avoided [see Warnings and Precautions ( 5.12 )]. Maintenance of MAC Sedation: Healthy Adults Less Than 65 Years of Age: A variable rateinfusion technique is preferable over an intermittent bolus technique. Most patients requirean infusion of 25 mcg/kg/min to 75 mcg/kg/min (1.5 mg/kg/hour to 4.5 mg/kg/hour) or incremental bolus dosesof 10 mg or 20 mg. In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require 80% of the usualadult dose. A rapid (single or repeated) bolusdose should not be used [see Warnings and Precautions ( 5.12 )]. Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated Adult Patients: Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/hour) for at least 5 minutes. Subsequent increments of Subsequent increments of 5 mcg/kg/min to 10 mcg/kg/min (0.3 mg/kg/hour to 0.6 mg/kg/hour) over 5 minutes to 10 minutes may be used until desired clinical effect is achieved. Maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/hour to 3 mg/kg/hour) or higher may be required. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks [see Warnings and Precautions ( 5.8 )] . Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of propofol injectable emulsion required for sedation. The tubing and any unused propofol injectable emulsion drug product should be discarded after 12 hours because propofol injectable emulsion contains no preservatives and is capable of supporting growth of microorganisms [see Dosage and Administration ( 2.7 ) and Warnings and Precautions ( 5.2 )].

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 U.S/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 include data from clinical trials in general anesthesia/MAC sedation (N=2889 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 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 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 pediatric patients from 6 days through 16 years of age in the U.S/Canadian anesthesia clinical trials is similar to the profile established with propofol 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, trunkpain, whole body weakness Cardiovascular: Premature atrial contractions Syncope, hypotension [see also Clinical Pharmacology ( 12 )], tachycardia Nodal,arrhythmia Bradycardia, arrhythmia, atrial fibrillation, atrioventricular heart block, bigeminy, bleeding, bundle branch block, cardiac arrest, ECG abnormal, edema, extrasystole, heart block, hypertension, myocardial infarction, myocardial ischemia, premature ventricular contractions, ST segment depression, supraventricular tachycardia, tachycardia, ventricular fibrillation Bradycardia, decreased cardiac output, arrhythmia, atrial fibrillation, bigeminy, cardiac arrest, extrasystole, rightheart failure, ventricular tachycardia Central Nervous System: Hypertonia/Dystonia, paresthesia, movement, abnormal dreams, agitation, amorous behavior, anxiety, bucking/jerking/thrashing, chills/shivering/clonic/myoclonic movement, combativeness, confusion, delirium, depression, dizziness, emotional lability, euphoria, fatigue, hallucinations, headache, hypotonia, hysteria, insomnia, moaning, neuropathy, opisthotonos, rigidity, seizures, somnolence, tremor, twitching Agitation, hypotension, hills/shivering, intracranial hypertension, seizures, somnolence, thinking abnormal Digestive: Hypersalivation, nausea, cramping, diarrhea, dry mouth, enlarged parotid, nausea, swallowing, vomiting Ileus, liver function abnormal Hemic/Lymphatic: Leukocytosis, coagulation disorder, leukocytosis Injection Site: Phlebitis, pruritus, burning/Stinging or pain, hives/itching, phlebitis, redness/discoloration Metabolic/Nutritional: hypomagnesemia, hyperkalemia, hyperlipemia BUN increased, creatinine increased, dehydration, hyperglycemia, metabolic acidosis, osmolality increased, hyperlipemia Musculoskeletal: Myalgia Nervous: Dizziness, agitation, chills, somnolenceDelirium Respiratory: Wheezing, cough, laryngospasm, hypoxia, apnea, bronchospasm, burning in throat,dyspnea, hiccough, hyperventilation, hypoventilation, pharyngitis, sneezing, tachypnea, upper airway obstruction Decreased lung function, respiratory acidosis during weaning, hypoxia Skin and Appendages: Flushing, Pruritus, rash,conjunctival hyperemia, diaphoresis, urticaria Rash Special Senses: Amblyopia, vision abnormal, diplopia, ear pain, eye pain, nystagmus, taste perversion, tinnitus Urogenital: Cloudy urine, oliguria, urine retention Green urine, kidneyfailure 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%). The most common adverse reactions >1% were bradycardia, arrhythmia, tachycardia, hypotension, hypertension, decreased cardiac output, movement, apnea, respiratory acidosis during weaning, rash, pruritus, burning/stinging or pain at injection site, and hyperlipemia ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 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 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 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 infusion for ICU sedation. Adults Propofol clearance ranges from 23 mL/kg/min to 50 mL/kg/min (1.6 L/min to 3.4 L/min in 70 kg adults). It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. Propofol has a steady-state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not been observed. The terminal half-life of propofol after a 10-day infusion is 1 day to 3 days. Geriatrics With increasing patient age, the dose of propofol needed to achieve a defined anesthetic end point (dose-requirement) decreases. This does not appear to be an age-related change in pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing patient age, pharmacokinetic changes are such that, for a given intravenous bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or arterial oxygen desaturation. The higher plasma levels reflect an age-related decrease in volume of distribution and intercompartmental clearance. Lower doses are therefore recommended for initiation and maintenance of sedation and anesthesia in elderly patients [see Dosage and Administration ( 2 )] . Pediatrics The pharmacokinetics of propofol were studied in children between 3 years and 12 years of age who received propofol for periods of approximately 1 to 2 hours. The observed distribution and clearance of propofol in these children were similar to adults. Organ Failure The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of acute hepatic or renal failure on the pharmacokinetics of propofol have not been studied [See Specific Populations ( 8.6 ) and ( 8.7 ) ].