ASHP INJECTABLE DRUG INFORMATION 1351

Propofol AHFS 28:04.92

Products Stability Propofol is available as a ready-to-use oil-in-water emulsion in Propofol injection is a white, oil-in-water emulsion.3499 3500 3501 20-, 50-, and 100-mL vials.3499 3500 3501 3502 3503 Each mL contains 3502 3503 Intact containers should be stored at 4 to 25°C3499 3500 propofol 10 mg along with soybean oil 100 mg, 22.5 3502 3503 or 20 to 25°C.3501 Vials should not be frozen.3499 3500 3501 mg, egg lecithin or phospholipids 12 mg, and hydroxide 3502 3503 The emulsion should not be used if there is evidence of to adjust the pH.3499 3500 3501 3502 3503 Propofol products are not excessive creaming or aggregation, if large droplets are visible, identical.3499 3500 3501 3502 3503 Diprivan products contain disodium or if other forms of phase separation indicating compromised edetate 0.05 mg/mL (0.005%) as an antimicrobial agent.3499 stability are present.3499 3500 3501 3502 3503 Generic propofol formulations may contain benzyl alcohol 1.5 Because propofol undergoes oxidative degradation when 3500 mg/mL, benzyl alcohol 1.5 mg/mL and sodium benzoate 0.7 exposed to oxygen, intact containers are packaged under 3501 3502 mg/mL, sodium metabisulfite 0.25 mg/mL, or sodium nitrogen to avoid oxygen exposure.3499 3500 3501 3502 3503 Whether 3503 benzoate 1 mg/mL as an antimicrobial agent. Additionally, propofol is administered directly from the vial or drawn into a Diprivan and some generic propofol formulations have differing syringe, administration should begin immediately and should be pH values (see Products: pH), which also may contribute to completed within 12 hours after the vial is spiked.3499 3500 3501 3502 2336 differing compatibility results among the products. 3503 The tubing and any unused propofol should be discarded Compatibility information for propofol with other drugs after 12 hours.3499 3500 3501 3502 3503 established using the Diprivan formulation should not be Propofol formulated with sodium metabisulfite antioxi- extrapolated to generic propofol products because of formula- dant is subject to a differing decomposition reaction compared 2336 tion differences. with the edetate-containing Diprivan formulation. Exposure to pH air results in the formation of a yellow discoloration in about 6 to 7 hours, which does not occur with Diprivan. The yellow Diprivan has a pH ranging from 7 to 8.5.3499 discoloration is a result of the formation of oxidized propofol The metabisulfite-containing formulation of propofol has a dimer quinone from radicals that form in the generic 3502 pH ranging from 4.5 to 6.6. The benzyl alcohol-containing product and may be associated with increased adverse effects. 3500 formulation has a pH ranging from 5.5 to 7.4. The benzyl This oxidation product does not form in Diprivan containing alcohol- and sodium benzoate-containing formulation and edetate.2344 2575 2576 Stability information for propofol estab- the sodium benzoate-containing formulations both have a pH lished using the Diprivan formulation should not be extrapo- 3501 3503 ranging from 6 to 8.5. lated to generic formulations.2336 2344 Tonicity The physical stability of both Diprivan and propofol Propofol 10 mg/mL injectable emulsion is isotonic.3499 3500 3501 containing sodium metabisulfite was evaluated. The formula- 3502 3503 tion differences, principally pH, resulted in a much higher zeta potential for Diprivan, making it a more rugged emulsion and Trade Name(s) less subject to damage from physical agitation and thermal Diprivan insult. Physical agitation resulted in no increase in fat droplet size in Diprivan after 16 hours, but a substantial increase in fat Administration droplets larger than 5 μm occurred in as little as 4 hours in the 2445 Before use, propofol should be shaken well.3499 3500 3501 3502 3503 sodium metabisulfite-containing formulation. Propofol is administered by intravenous injection or infusion; One benzyl alcohol-containing formulation of propofol had the if necessary, propofol may be diluted with dextrose 5% to a same pH as Diprivan (pH 7 to 8.5) and exhibited the same degree of concentration not less than 2 mg/mL.3499 3500 3501 3502 3503 ruggedness and resistance to emulsion disruption as Diprivan.2659 Numerous outbreaks of serious postoperative infections In another study, propofol (Diprivan) was again reported to be have resulted from inadvertent contamination of propofol.1930 a more rugged emulsion than the generic formulation containing 3499 3500 3501 3502 3503 The contamination resulted from risky prepa- sodium metabisulfite. Diprivan had a very low quantity of fat glob- ration practices and lapses in aseptic technique.1930 The lipid ules exceeding 5 μm throughout its shelf life. The sodium metabi- base supports microbiological growth.1930 3499 3500 3501 3502 3503 The sulfite-containing formulation formed much greater amounts of disodium edetate, sodium metabisulfite, or benzyl alcohol and/ globules of 5 μm or larger within a few months after manufacture or sodium benzoate in the formulations can retard the growth and well before the expiration date. This 5-μm or larger globule size of microorganisms for up to 12 hours, but the products can is an important threshold because globules of this size may occlude still support growth and are not antimicrobially preserved.3499 capillaries and lead to embolic syndrome. The safety of using this 3500 3501 3502 3503 Strict aseptic procedures are required during sodium metabisulfite-containing formulation of propofol, especially handling.3499 3500 3501 3502 3503 as the product nears its expiration date, was questioned.2589

DOI: 10.37573/9781585286850.329 1352 Propofol ASHP INJECTABLE DRUG INFORMATION

Propofol emulsion is a single-access product and can support storage for 2 hours. In simulated infusions using the same initial the growth of microorganisms.1930 3499 3500 3501 3502 3503 In one concentration, administration through 72-inch PVC administra- study, propofol strongly supported the growth of Esche- tion sets at a rate of 1.75 mL/min resulted in an average propofol richia coli and Candida albicans.2411 Strict adherence to proper loss of 7.7% over the 2-hour period.2057 aseptic procedures, including disinfecting the vial stopper with When tested undiluted at 10 mg/mL, propofol (Diprivan) 3499 3500 3501 3502 3503 isopropyl alcohol 70%, is required. Use of the sorption to administration tubing composed principally of PVC 2411 drug within 6 hours has been recommended. did not represent a substantial portion of the total amount of Plastic and Glass Containers drug delivered. Any losses that did occur were within the error of the method and were not clinically relevant.2297 Diluted in dextrose 5%, propofol has been shown to be more stable in glass than in plastic containers; manufacturers indicate Propofol (Diprivan) was delivered at rates of 1 and 10 mL/hr that only 95% of the drug remains after only 2 hours of a running through PVC tubing. Little loss occurred at the higher rate of infusion in plastic (material unspecified).3499 3500 3501 3502 3503 delivery. However, at the slower rate, up to 6% propofol loss due to sorption occurred.2468 Syringes Propofol (Diprivan) 10 mg/mL was repackaged into 60-mL Plasticizer Leaching polypropylene syringes (Monoject, Sherwood Medical) and As happens with surfactant-containing drug formulations, stored at 23°C under fluorescent light and at 4°C protected propofol emulsion also has been shown to leach diethylhexyl from light. No visually apparent changes occurred to the phthalate (DEHP) plasticizer from PVC equipment such as emulsion under either storage condition. Propofol losses administration sets. The use of non-PVC administration sets has were 7% in 5 days and 12% in 7 days in the room-temperature been recommended.2424 samples. No propofol losses occurred in 13 days in the refrig- erated samples.1984 Filtration Propofol (Diprivan) 1% was repackaged into 2- and 10-mL When filtration is clinically appropriate, manufacturers recom- Plastipak (Becton Dickinson) and 2-mL Injekt (B. Braun) plastic mend that propofol be administered with caution only through syringes and was stored at 5°C. Propofol losses were about 7 to a filter with a pore size of 5 μm or greater, unless the filter has 8% in the Plastipak syringes and about 2% in the Injekt syringes demonstrated no effects on flow and/or breakdown of the emul- 3499 3500 3501 3502 3503 Continuous monitoring for restricted flow after 28 days of refrigerated storage.2118 sion. and/or emulsion breakdown is necessary if a filter is used.3499 3500 Sorption 3501 3502 3503 Filters with a pore size less than 5 μm should not be 3499 3500 3501 3502 3503 Propofol (Diprivan) injection was diluted to 2 mg/mL with used. dextrose 5% and stored in polyvinyl chloride (PVC) tubing (Kend- Propofol (Diprivan) 1% 10 mL filtered through a 5-μm filter all-McGaw). A propofol loss exceeding 31% occurred after static needle (Burron Medical) underwent no loss.2057

Compatibility Information Solution Compatibility

Propofol

Test Soln Name Mfr Mfr Conc/L or % Remarks Ref C/I

Dextrose 5% in Ringer’s injection, lactated FRKa Compatible via Y-site administration 3499 C

Dextrose 5% in Ringer’s injection, lactated b Compatible via Y-site administration 3500, 3501, 3502, 3503 C

Dextrose 5% in 0.2% FRKa Compatible via Y-site administration 3499 C

Dextrose 5% in sodium chloride 0.2% b Compatible via Y-site administration 3500, 3501, 3502, 3503 C

Dextrose 5% in sodium chloride 0.45% FRKa Compatible via Y-site administration 3499 C

Dextrose 5% in sodium chloride 0.45% b Compatible via Y-site administration 3500, 3501, 3502, 3503 C

Dextrose 5% FRKa Compatible 3499 C

Dextrose 5% b Compatible 3500, 3501, 3502, 3503 C

Ringer’s injection, lactated FRKa Compatible via Y-site administration 3499 C

Ringer’s injection, lactated b Compatible via Y-site administration 3500, 3501, 3502, 3503 C a Test performed using the formulation WITH edetate disodium. b Test performed using the formulation WITHOUT edetate disodium.