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Department: Clinical Queries

Why remove injectable promethazine from the formulary?

Moodley, Jenna M. PharmD; Gardner, Julia C. PharmD; Sheridan, Daniel J. MS, RPh, CPPS

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doi: 10.1097/01.NURSE.0000668464.68553.00
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My hospital is removing injectable promethazine from the formulary because of safety concerns. What is the reason for this?—S.N., MO.

Jenna M. Moodley, PharmD, Julia C. Gardner, PharmD, and Daniel J. Sheridan, MS, RPh, CPPS, reply: Promethazine is a phenothiazine derivative and H1 receptor blocking agent with antihistaminic, sedative, antimotion-sickness, antiemetic, and anticholinergic effects.1 This medication blocks many receptors in the body, including dopamine and alpha-adrenergic receptors. It is commonly used in both inpatient and outpatient settings to treat nausea and vomiting, allergies, and motion sickness. Central nervous system depressant effects such as drowsiness are the most common adverse reactions associated with this drug.1

Promethazine can be administered orally, rectally, or parenterally via I.M. or slow I.V. bolus injection. The preferred parenteral route is deep I.M. injection.1 Inadvertent administration into an artery or subcutaneous tissue may result in soft tissue damage, leading to tissue necrosis and, in some cases, gangrene and amputation.2 Injectable promethazine has been on the Institute for Safe Medication Practices (ISMP) List of High-Alert Medications in Acute Care Settings since 2007.3

In 2009, the FDA required promethazine manufacturers to label the drug with a boxed warning about the potential for adverse reactions associated with injectable promethazine, regardless of the administration route.1,4 The boxed warning states that “severe tissue injury can occur from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration. Adverse reactions include burning, pain, thrombophlebitis, tissue necrosis, and gangrene. In some cases, surgical intervention, including fasciotomy, skin graft and/or amputation have been required.” The boxed warning also describes the risk of fatal respiratory depression in pediatric patients.1

Because of the high risk for error and serious complications, ISMP considers completely removing injectable promethazine from formularies a best practice for hospitals, noting that even deep I.M. administration can lead to tissue damage if the drug is accidentally injected intra-arterially.5 ISMP recommends use of safer alternatives such as the 5-HT3 antagonist ondansetron. At one time, alternative drugs were significantly more costly than promethazine, but with the current availability of generic versions, they have become significantly less expensive. Today, a dose of injectable ondansetron is less expensive than a dose of promethazine, making it a viable and cost-effective alternative.5 Other medications that can be used to treat nausea and vomiting include metoclopramide and prochlorperazine.

Promethazine is also available in safer formulations, including oral tablets and solutions and a rectal suppository, which can be substituted for the parenteral formulation. Although these alternative administration routes have a slightly longer onset of action, they do not carry the risk of tissue damage associated with the injectable formulation.

Many hospitals have weighed the risks and benefits of injectable promethazine and attempted to mitigate the risks by limiting administration to the deep I.M. route, reducing the dose, or further diluting the drug's concentration.2 However, these strategies do not eliminate the risk. Because of this, hospitals should follow ISMP's recommendation to remove injectable promethazine from the formulary and offer clinicians safer alternatives. Unfortunately, in a 2019 survey of 347 large US hospitals, ISMP found that only 32% were fully compliant with this best practice.6

REFERENCES

1. Promethazine hydrochloride injection, USP. Prescribing information. www.accessdata.fda.gov/drugsatfda_docs/nda/2009/040454_s006_promethazine_hydrochloride_injection.pdf.
2. Grissinger M. Preventing serious tissue injury with intravenous promethazine (Phenergan). P T. 2009;34(4):175–176.
3. Institute for Safe Medication Practices. ISMP List of High-Alert Medications in Acute Care Settings. https://forms.ismp.org/Tools/institutionalhighAlert.asp.
4. Rebelo K. FDA adds boxed warning to injectable promethazine. Medscape. 2009. www.medscape.com/viewarticle/709055.
5. Institute for Safe Medication Practices. 2020-2021 ISMP Targeted Medication Safety Best Practices for Hospitals. www.ismp.org/guidelines/best-practices-hospitals.
6. Institute for Safe Medication Practices. Two new best practices in the 2020-2021 targeted medication safety best practices for hospitals. ISMP Medication Safety Alert! 2020;25(4):4.
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