Propofol
Dosing in kidney impairment
Renal Impairment Studies to date in patients with normal or impaired renal function have not shown any alteration in renal function with propofol injectable emulsion containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation.
Propofol injectable emulsion contains 0.005% disodium edetate. At high doses (2 to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules. The long-term administration of propofol injectable emulsion to patients with renal failure has not been evaluated. The pharmacokinetics of propofol do not appear to be different in people with chronic renal impairment compared to adults with normal renal function.
The effects of acute renal failure on the pharmacokinetics of propofol have not been studied.
Dosing in liver impairment
Hepatic Impairment The long-term administration of propofol injectable emulsion to patients with hepatic insufficiency has not been evaluated. The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis compared to adults with normal hepatic function. The effects of acute hepatic failure on the pharmacokinetics of propofol have not been studied.
Preparation and administration
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 ] .
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 ] .
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 ] .
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 ] .
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.
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. [See table below.]
| 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, from 2 months of age to 16 years of age: Infusion of 125 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 of 100 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 followed immediately by a maintenance infusion. Elderly, Debilitated, Neurosurgical, or ASA-PS III 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 rate infusion technique is preferable over an intermittent bolus technique. Most patients require an 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 doses of 10 mg or 20 mg. In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require 80% of the usual adult dose. A rapid (single or repeated) bolus dose 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 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)]. |