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8/31/2020

Propofol Emulsion Injection

Products Affected - Description

    • Propofol intravenous emulsion injection, Dr. Reddy's, 10 mg/mL, 100 mL vial, 10 count, NDC 43598-0549-10
    • Propofol intravenous emulsion injection, Dr. Reddy's, 10 mg/mL, 20 mL vial, 10 count, NDC 43598-0265-58
    • Propofol intravenous emulsion injection, Dr. Reddy's, 10 mg/mL, 20 mL vial, 25 count, NDC 43598-0265-25
    • Propofol intravenous emulsion injection, Dr. Reddy's, 10 mg/mL, 50 mL vial, 20 count, NDC 43598-0548-21
    • Propofol intravenous emulsion injection, Pfizer, 10 mg/mL, 100 mL vial, 10 count, NDC 00409-4699-24
    • Propofol intravenous emulsion injection, Pfizer, 10 mg/mL, 20 mL vial, 25 count, NDC 00409-4699-30
    • Propofol intravenous emulsion injection, Pfizer, 10 mg/mL, 50 mL vial, 20 count, NDC 00409-4699-33
    • Propofol intravenous emulsion injection, Sagent, 10 mg/mL, 100 mL vial, 10 count, NDC 25021-0608-51
    • Propofol intravenous emulsion injection, Sagent, 10 mg/mL, 50 mL vial, 20 count, NDC 25021-0608-50
    • Propofol intravenous emulsion injection, Teva, 10 mg/mL, 100 mL vial, 10 count, NDC 00591-2136-68
    • Propofol intravenous emulsion injection, Teva, 10 mg/mL, 20 mL vial, 25 count, NDC 00591-2136-95
    • Propofol intravenous emulsion injection, Teva, 10 mg/mL, 50 mL vial, 20 count, NDC 00591-2136-51

Reason for the Shortage

    • Dr. Reddy's has propofol on shortage due to increased demand.[1]
    • Fresenius Kabi has Diprivan available but may experience intermittent back order due to increased demand. Check wholesaler for inventory.[2]
    • Pfizer has propofol on shortage due to increased demand.[3]
    • Sagent has propofol on shortage due to increased demand.[4]
    • Teva has propofol on shortage due to shipping delays related to COVID-19.[5]

Available Products

    • Diprivan intravenous emulsion injection, Fresenius Kabi, 10 mg/mL, 10 mL vial, 10 count, NDC 63323-0269-10
    • Diprivan intravenous emulsion injection, Fresenius Kabi, 10 mg/mL, 100 mL vial, 10 count, NDC 63323-0269-65
    • Diprivan intravenous emulsion injection, Fresenius Kabi, 10 mg/mL, 20 mL vial, 10 count, NDC 63323-0269-29
    • Diprivan intravenous emulsion injection, Fresenius Kabi, 10 mg/mL, 50 mL vial, 20 count, NDC 63323-0269-50
    • Propofol intravenous emulsion injection, Sagent, 10 mg/mL, 20 mL vial, 25 count, NDC 25021-0608-20

Estimated Resupply Dates

    • Dr. Reddy has propofol 20 mL, 50 mL, and 100 mL vials available in limited supply. The next estimated release date is October 2020.[1]
    • Pfizer has propofol 20 mL, 50 mL, and 100 mL vials available in limited supply.[3]
    • Sagent has propofol 50 mL and 100 mL vials on limited allocation.[4]
    • Teva has propofol 20 mL, 50 mL, and 100 mL vials on allocation.[5]

Implications for Patient Care

    • These recommendations are in alignment with the Surviving Sepsis Campaign: Guidelines on the Management of the Critically Ill Adults with Coronavirus Disease 2019 (COVID-19) and 2018 PADIS clinical practice guidelines
    • 1. For mechanically ventilated adults with COVID-19 and moderate to severe ARDS - patients without persistent ventilator dyssynchrony, use of intermittent boluses of neuromuscular blocking agents (NMBAs) as needed over continuous infusions.
    • 2. For mechanically ventilated adults with COVID-19 and moderate to severe ARDS - patients with persistent ventilator dyssynchrony, use of continuous NMBAs up to 48 hours along with other lung recruiting measures.
    • 3. Critically ill patients requiring deep sedation should not use dexmedetomidine (with or without NMBAs).

Safety

    • FDA is allowing temporary importation of propofol 2% emulsion, Propoven, supplied by Fresenius Kabi. The major differences with this product are the double strength (2% versus the 1% emulsion available in the US) and the lack of ethylenediaminetetraacetic acid (EDTA) compared with Diprivan. FDA has a side by side comparison available at https://www.fda.gov/media/137891/download.
    • FDA has specific guidance on how Propoven should be used. The main points are this should be used in patients >16 years of age in an ICU setting. It should not be used in pregnant patients unless FDA-approved products are unavailable. The fact sheet can be located at https://www.fda.gov/media/137889/download.

Alternative Agents & Management

    • Historically, providers commonly used benzodiazepines to sedate critically ill patients. Practice has shifted over the last decade to lighter sedation and the minimization of benzodiazepine use due to an association with prolonged mechanical ventilation.[7-8] In a time of drug shortages and supply delays, ICU providers may have to resort to older sedation practices that are out of favor. The tables below contain sedation and monitoring strategies to targeted sedation goals (eg, RIKER) for mechanically intubated adults.
    • Summary of sedative use considerations:
    • Propofol is preferred over benzodiazepines, especially in the setting of prolonged intubation and deep sedation.
    • An elevated triglyceride is not considered a strict exclusion to propofol use, but continued monitoring and strategies for dose-reduction are encouraged if triglyceride is >400 mg/dL to minimize risk of pancreatitis.
    • Due to limited supply or other contraindications to propofol, a benzodiazepine may be an alternative agent.
    • If midazolam supply is limited, consider allocating to patients with moderate to severe renal or hepatic dysfunction. For all others, consider lorazepam as the benzodiazepine of choice to preserve midazolam supply.
    • Midazolam has a higher propensity than lorazepam to accumulate metabolites that produce CNS depression and altered mental status. Half-life elimination is especially prolonged in cirrhosis, CHF, and obesity.
    • There is little use for dexmedetomidine as a primary sedative agent when patients require deep sedation for ventilator compliance.
    • Ketamine and phenobarbital may be considered as adjunctive agents for sedation, but not as primary sedatives for ICU sedation.
    • Consider the use of scheduled atypical anti-psychotic agents for hyperactive delirium.
    • Intravenous agents are preferred in the setting of NMBA use due to concern over impaired absorption of enteral agents.
    • Narcotics and paralytics put patients at high risk for ileus and aggressive bowel regimens should addressed.
    Table 1. Non-benzodiazepine Use in Critically Ill patients
    Drug/doseMonitoring
    Propofol9
    Common maintenance dose range:
    5 to 50 mcg/kg/min, adjusted to targeted sedation level. Doses may be titrated > 50 mcg/kg/min to achieved desired sedation.
    -Triglycerides (TG) at least weekly. Consider decreasing propofol doses if TGs trend > 400 mg/dL; these concentrations may be associated with pancreatitis.
    -Formulated in lipids, which should be accounted for in nutrition (~1.1 kcal/mL)
    -Hypotension > bradycardia, green urine (NOT harmful)
    -Metabolic acidosis, rhabdomyolysis, and other signs of propofol related infusion syndrome (PRIS)
    Note: PRIS is very rare, usually occurs with high doses for prolonged periods.

    Dexmedetomidine10
    Common maintenance dose range: 0.2 to 1.5 mcg/kg/h, adjusted to targeted sedation level-Bradycardia > hypotension, cardiac arrhythmia
    -Note: Loading dose may be associated with a greater incidence of bradycardia and hypotension
    -Half-life elimination prolonged in hepatic dysfunction
    -Also has benefit of anxiolysis


    Table 2. Benzodiazepine Use in Critically Ill Patients (associated with increased mortality, delirium, and prolonged ventilator requirements as well as prolonged ICU length of stay. The sedation guidelines recommend nonbenzodiazepine agents be used before starting benzodiazepines unless the patient has a strong history of alcoholism. If benzodiazepine sedation is required, patients must have a sedation holiday once daily unless otherwise directed by the attending physician.)
    Drug/doseMonitoring
    Midazolam11
    Loading dose: 0.01 to 0.05 mg/kg over 2 min-Hypotension, bradycardia
    -Note: Maximize bolus dose approach before increasing infusion rate to decrease the chance of undesired prolonged sedation and time on mechanical ventilation.
    -Half-life of midazolam and metabolites may be prolonged in renal impairment. Patients with severe renal impairment may not eliminate the active hydroxylated metabolites and can contribute to prolonged sedation.
    -Half-life elimination can be prolonged with renal dysfunction.
    -Expect longer duration of sedation and accumulation, dosage reduction might be necessary. Metabolized extensively by CYP3A4 then biotransformed to active metabolite. Half-life elimination is prolonged in cirrhosis, CHF and obesity

    Common maintenance dose range: 2 to 10 mg/hr, maximum of 15 mg/h x 4 h with attending physician approval. Recommended starting dose at 5 mg/hr
    Lorazepam12
    Common intermittent dose: As-needed injections of 1 to 2 mg every 4 to 6 h
    Continuous 0.5 mg/hr with a max dose of 2 mg/h x 4 h. NO more than 24 mg of lorazepam per 24 hr period
    -Electrolyte abnormalities, metabolic acidosis, renal failure, and other signs of propylene glycol toxicity
    -Note: propylene glycol toxicity rare, most likely to occur in renal failure or prolonged continuous infusion use
    Use not recommended for severe hepatic impairment or failure.
    -Intermittent dosing preferred to continuous infusion. Enteral route may be considered to reduce risk for developing propylene glycol toxicity

    Diazepam13-14
    Common maintenance dose range: 5 to 10 mg every 6 hours-Serum propylene glycol, serum osmolality, electrolyte abnormalities, serum lactate, metabolic acidosis, renal failure, and other signs of propylene glycol toxicity
    -May have risk of withdrawal symptoms upon cessation, a taper may be necessary.
    -Half-life is prolonged in hepatic dysfunction due to presence of active metabolites


    Table 3. Adjunctive Sedative Agents
    Drug/doseMonitoring
    Ketamine15-16
    Analgesia: 0.1 to 0.2 mg/kg/h, max dose 20 mg/hr. May be used for non-intubated patients.
    Sedation: 0.2 to 0.4 mg/kg/hr, max 1 mg/kg/hr. May give 0.5 to 1 mg/kg as bolus for acute agitation.
    -Hypertension, cardiac arrhythmias
    -Concern for heart failure exacerbations
    -Hallucinations, emergence reactions (especially at high doses, BZDs mediate this)
    -Hypersalivation (mediated by suctioning) -Caution in hepatic disease
    -Hyperreflexia (not a seizure)
    -Contraindicated in pregnancy

    Phenobarbital18-20
    Loading dose 7.5 mg/kg over 60 to 120 minDrug-drug interactions, liver function tests, serum phenobarbital levels, bradycardia, hypotension, Steven-Johnson Syndrome, may have risk of withdrawal symptoms upon cessation, a taper may be necessary.
    Common maintenance dose range: 1 to 2 mg/kg/day given in 2 or 3 divided doses per 24 h

    Max: 400 mg/day

References

    1. Dr. Reddy's (personal communication): April 14, and May 1, 2020.
    2. Fresenius Kabi (personal communication): April 24, May 1, 14, and 29, and August 7 and 28, 2020.
    3. Pfizer (personal communication): April 24, May 5 and 19, and June 5, and August 7 and 28, 2020.
    4. Sagent (personal communication): April 23 and 30, May 14 and 28, and August 6 and 27, 2020.
    5. Teva (personal communication): April 27, and May 4 and 15, June 5, July 31, and August 28, 2020.
    6. Waleed Alhazzani, M.H.M., Yaseen M. Arabi, Mark Loeb, Michelle Ng Gong, Eddy Fan, Simon Oczkowski, Mitchell M. Levy, Lennie Derde, and B.D. Amy Dzierba, Michael Aboodi, Hannah Wunsch, Maurizio Cecconi,Younsuck Koh, Daniel S. Chertow, Kathryn Maitland, Fayez Alshamsi, Emilie Belle-Cote, Massimiliano Greco, Matthew Laundy, Jill S. Morgan, Jozef Kesecioglu, Allison McGeer, Leonard Merme, Manoj J. Mammen, Paul E. Alexander, Amy Arrington, John E. Centofanti, Giuseppe Citerio, Bandar Baw, Ziad A. Memish, Naomi Hammond, Frederick G. Hayden, Laura Evans, Andrew Rhodes, Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). Critical Care Medicine, 2020.
    7. Devlin, J.W., et al., Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med, 2018. 46(9): p. e825-e873.
    8. Barr, J., et al., Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med, 2013. 41(1): p. 263-306.
    9. Fresenius Kabi USA LLC, Diprivan (propofol injection, emulsion) [prescribing information], 2020, Fresenius Kabi USA, LLC: Lake Zurich, IL.
    10. Hospira Inc, Precedex (dexmedetomidine hydrochloride injection) [prescribing information], 2019, Hospira, Inc.: Lake Forest, IL.
    11. Fresenius Kabi USA LLC, Midazolam (midazolam hydrochloride injection) [prescribing information], 2020, Fresenius Kabi USA, LLC: Lake Zurich, IL.
    12. Hospira Inc, Lorazepam (lorazepam injection, solution) [prescribing information], 2019, Hospira Inc.: Lake Forest, IL.
    13. Hospira Inc, Diazepam (diazepam injection) [prescribing information], 2019, Hospira Inc.: Lake Forest, IL.
    14. Mylan Pharmaceuticals Inc, Diazepam (diazepam tablet) [prescribing information], 2018, Mylan Pharmaceuticals Inc.: Morgantown, WV.
    15. Cohen, S.P., et al., Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med, 2018. 43(5): p. 521-546.
    16. Hospira Inc, Ketamine (ketamine hydrochloride injection, solution, concentrate) [prescribing information], 2018, Hospira Inc.: Lake Forest, IL.
    17. Garber, P.M., et al., Continuous Infusion Ketamine for Adjunctive Analgosedation in Mechanically Ventilated, Critically Ill Patients. Pharmacotherapy, 2019. 39(3): p. 288-296.
    18. Gagnon, D.J., et al., Repurposing Valproate, Enteral Clonidine, and Phenobarbital for Comfort in Adult ICU Patients: A Literature Review with Practical Considerations. Pharmacotherapy, 2017. 37(10): p. 1309-1321.
    19. West-Ward Pharmaceuticals Corp, Phenobarbital (phenobarbital sodium injection) [prescribing information], 2011, West-Ward Pharmaceuticals Corp.: Eatontown, NJ.
    20. Par Pharmaceutical, Phenobarbital (phenobarbital tablet) [prescribing information], 2019, Par Pharmaceutical: Chesnut Ridge, NY.

Updated

Updated August 31, 2020 by Michelle Wheeler, PharmD, Drug Information Specialist. Created April 2, 2020 by Michelle Wheeler, PharmD, Drug Information Specialist. © 2020, Drug Information Service, University of Utah, Salt Lake City, UT.

Disclaimer

Drug Shortage Bulletins are copyrighted by the Drug Information Service of the University of Utah and provided by ASHP as its exclusive authorized distributor. ASHP and the University of Utah make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information, and specifically disclaim all such warranties. Users of this information are advised that decisions regarding the use of drugs and drug therapies are complex medical decisions and that in using this information, each user must exercise his or her own independent professional judgment. Neither ASHP nor the University of Utah assumes any liability for persons administering or receiving drugs or other medical care in reliance upon this information, or otherwise in connection with this Bulletin. Neither ASHP nor the University of Utah endorses or recommends the use of any particular drug. Any application of this information for any purpose shall be limited to personal, non-commercial use.

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