Products Affected - Description

• • Propofol intravenous emulsion injection, Hikma, 10 mg/mL, 100 mL vial, 10 count, NDC 00641-6196-10
  • Propofol intravenous emulsion injection, Hikma, 10 mg/mL, 20 mL vial, 10 count, NDC 00641-6194-10
  • Propofol intravenous emulsion injection, Hikma, 10 mg/mL, 50 mL vial, 20 count, NDC 00641-6195-20

Reason for the Shortage

• • Avet has propofol available.[1]
  • Dr. Reddy's has propofol available.[2]
  • Fresenius Kabi has Diprivan available. Check wholesaler for inventory.[3]
  • Hikma has propofol on shortage due to increased demand.[4]
  • Pfizer has propofol on shortage due to increased demand and manufacturing delays.[5]
  • Sagent has propofol available.[6]
  • Samson Medical Technologies is distributing Avet's propofol products. All presentations are available.[7]
  • Teva discontinued propofol in January 2023.[8]

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, Avet Pharmaceuticals, 10 mg/mL, 100 mL vial, 10 count, NDC 23155-0345-43
  • Propofol intravenous emulsion injection, Avet Pharmaceuticals, 10 mg/mL, 20 mL vial, 20 count, NDC 23155-0345-44
  • Propofol intravenous emulsion injection, Avet Pharmaceuticals, 10 mg/mL, 50 mL vial, 20 count, NDC 23155-0345-42
  • 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, 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 00069-0248-10
  • 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, 10 count, NDC 00069-0209-10
  • Propofol intravenous emulsion injection, Pfizer, 10 mg/mL, 50 mL vial, 20 count, NDC 00069-0234-20
  • 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, 20 mL vial, 25 count, NDC 25021-0608-20

• • Hikma has propofol 20 mL, 50 mL, and 100 mL vials on back order and the company cannot estimate a release date.[4]

• • 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.[9-10] 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/dose	Monitoring
  Propofol11
  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.
  Dexmedetomidine12
  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/dose	Monitoring
  Midazolam13
  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
  Lorazepam14
  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
  Diazepam15-16
  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/dose	Monitoring
  Ketamine17-18
  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
  Phenobarbital20-22
  Loading dose 7.5 mg/kg over 60 to 120 min	Drug-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

  
  

• 1. Avet (personal communication): July 18, October 31, 2022; and January 6, 2023.
  2. Dr. Reddy's (personal communication): April 14, and May 1, October 14 (FDA), December 16, 2020; August 12, 2021; February 22, May 12, July 19, September 22, December 14 and 20, 2022; April 4, and August 14, 2023.
  3. Fresenius Kabi (personal communication): April 24, May 1, 14, and 29, August 7 and 28, November 6, December 4 and 11, 2020; January 29, March 5 and 26, April 16, May 14 and 28, August 20, September 17, October 15 and 29, November 19, December 3, 2021; January 14 and 28, February 4, 11, and 25, March 11 and 25, May 6, June 3,August 19, October 28, December 2, 6, and 29, 2022; March 3 and 31, April 28, May 26, June 2, July 13, August 24, October 12, November 2, December 21, 2023; and April 4, 2024.
  4. Hikma (personal communications) December 16, 2020; February 3, March 3 and 31, April 21, May 12, June 2, August 18, September 15, October 20 and 27, November 24, December 1, 2021; January 12 and 26, February 16 and 23, March 9 and 23, May 4, June 1, July 6, August 17, October 26, December 1 and 14, 2022; January 4, March 2 and 29, April 26, May 25, June 1, July 20, August 23, October 11, November 1, December 20, 2023; and April 3, 2024.
  5. Pfizer (personal communication): April 24, May 5 and 19, and June 5, August 7 and 28, November 6, December 4 and 18, 2020; February 3, March 8 and 30, April 16, May 14 and 28, August 23, September 17, October 20 and 29, November 28, December 3, 2021; January 14 and 28, February 15 and 25, March 11 and 25, May 6, June 3, July 6, August 23, October 28, December 5 and 19, 2022; January 6, March 7, April 2 and 30, May 26, June 5, July 19, August 25, October 15, November 3, December 26, 2023; and April 4, 2024.
  6. Sagent (personal communication): April 23 and 30, May 14 and 28, August 6 and 27, November 5, December 3 and 17, 2020; February 3, March 5 and 25, April 15, May 13 and 27, August 19, September 16, October 14 and 28, November 18, 2021; January 14 and 27, February 10 and 24, March 10 and 24, May 5, June 3, July 7, August 18, October 27, December 1, 2022; January 6, March 2 and 29, April 27, May 19, June 1, July 13, October 12, November 3, December 21, 2023' and April 4, 2024.
  7. Samson Medical Technologies (personal communication): July 18, 2022.
  8. Teva (personal communication): April 27, and May 4 and 15, June 5, July 31, August 28, November 6, December 4 and 18, 2020; January 29, February 5, March 5 and 26, April 16, May 14 and 28, August 20, September 17, October 15 and 29, November 19, December 3, 2021; January 14 and 28, February 11 and 25, March 11, May 6, June 3, July 1, August 19, October 21, December 2, 2022; and January 2 and 9, 2023.
  9. 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.
  10. 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.
  11. Fresenius Kabi USA LLC, Diprivan (propofol injection, emulsion) [prescribing information], 2020, Fresenius Kabi USA, LLC: Lake Zurich, IL.
  12. Hospira Inc, Precedex (dexmedetomidine hydrochloride injection) [prescribing information], 2019, Hospira, Inc.: Lake Forest, IL.
  13. Fresenius Kabi USA LLC, Midazolam (midazolam hydrochloride injection) [prescribing information], 2020, Fresenius Kabi USA, LLC: Lake Zurich, IL.
  14. Hospira Inc, Lorazepam (lorazepam injection, solution) [prescribing information], 2019, Hospira Inc.: Lake Forest, IL.
  15. Hospira Inc, Diazepam (diazepam injection) [prescribing information], 2019, Hospira Inc.: Lake Forest, IL.
  16. Mylan Pharmaceuticals Inc, Diazepam (diazepam tablet) [prescribing information], 2018, Mylan Pharmaceuticals Inc.: Morgantown, WV.
  17. 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.
  18. Hospira Inc, Ketamine (ketamine hydrochloride injection, solution, concentrate) [prescribing information], 2018, Hospira Inc.: Lake Forest, IL.
  19. Garber, P.M., et al., Continuous Infusion Ketamine for Adjunctive Analgosedation in Mechanically Ventilated, Critically Ill Patients. Pharmacotherapy, 2019. 39(3): p. 288-296.
  20. 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.
  21. West-Ward Pharmaceuticals Corp, Phenobarbital (phenobarbital sodium injection) [prescribing information], 2011, West-Ward Pharmaceuticals Corp.: Eatontown, NJ.
  22. Par Pharmaceutical, Phenobarbital (phenobarbital tablet) [prescribing information], 2019, Par Pharmaceutical: Chesnut Ridge, NY.