VOLUME 36, ISSUE 2

Stewart D. Caskey, D.O.

PGY-3 Anesthesiology Resident
Baylor-Scott & White Medical Center – Temple
Temple, TX

Tricia A. Meyer, PharmD, FASHP

Adjunct Professor of Anesthesiology
Texas A&M School of Medicine
Co-Chair-Anesthesia Patient Safety Foundation-Medication Safety
Temple, TX

Benjamin B. Vacula, M.D.

Clinical Professor of Anesthesiology
Baylor College of Medicine-Temple
Director of Medical Informatics-Baylor Scott & White-Temple
Temple, TX

Russell K. McAllister, M.D., FASA

TSA Newsletter Editor in Chief
Professor of Anesthesiology-Baylor College of Medicine-Temple
Chair of Anesthesiology-Baylor Scott & White Health-Central Texas
Temple, TX

Practice Updates with Regard to Intravenous Promethazine Hydrochloride

Promethazine and Tissue Injury

Promethazine hydrochloride is a phenothiazine derivative and a frequently administered medication among anesthesiologists for prophylaxis and management of post-operative nausea and vomiting (PONV) as well as for its histamine H1-blocking, anti-cholinergic, and anti-motion sickness effects. Intravenous (IV) administration is a common practice within many institutions and is in accordance with its labeling. However, with an acidic pH between 4.0 and 5.5 and formulation with the vesicant phenol, promethazine poses significant risk to the tunica intima of vasculature. This is of particular risk with high concentration injections and may result in severe tissue injury and ischemia with IV infiltration secondary to its vesicant properties. In the setting of peripheral IV extravasation, subcutaneous injection, or accidental arterial injection, promethazine may cause a vast range of complications from mild irritation on injection and local erythema to thrombophlebitis, paralysis, and tissue necrosis requiring fasciotomy or amputation.(2) While the frequency of injury is unknown, many reports of serious harm have been collected, prompting recent evaluation and amendment to the Food and Drug Administration’s

(FDA) administration guidelines. Intramuscular injection of promethazine appears to be safer, but itself is not without risk of tissue injury. While promethazine is an effective medication for the prophylaxis of PONV, risks and benefits as well as route of administration must be considered to enhance safe use and decrease the risk of adverse outcomes.

Tissue Injury Prevention

With accordance to the Institute for Safe Medication Practices (ISMP) and FDA recommendations, alternative medication use is a first line approach to prevent harm secondary to promethazine use. There are many options of available alternate medications to use from a wide variety of drug classes in place of promethazine. These include antiemetics from the same phenothiazine drug class (prochlorperazine) or from other drug classes such as 5-hydroxytryptamine antagonists (ondansetron), antihistamines (diphenhydramine), butyrophenones (droperidol, haloperidol), corticosteroids (dexamethasone), anticholinergic drugs (scopolamine), and neurokinin-1 antagonists (aprepitant).

When using IV promethazine, tissue injury prevention is of utmost importance. Adequate and confirmed patent IV access, preferably in larger or more central veins, is vital to keep patients safe and decrease risk of harm. Having the IV site in clear view during infusion can assist with early recognition of infiltration and avoidance of potential problems.

According to an August 2006 article by the ISMP, many tissue injury related adverse events following IV administration have been reported, prompting a suggested change in practice. Similarly, in 2009 and again in December 2023, the FDA released updated package inserts and a statement regarding the safety margin of intravenous promethazine hydrochloride administration and provided updated recommendations for its usage.

Both the ISMP and FDA’s recommendations include significant overlap regarding methods to minimize risk when using IV promethazine. In combination, they overall recommend:

  • Alternative medication use whenever clinically feasible
  • Alternative routes of administration when appropriate
  • Limitation of total parenteral dosing to 6.25mg to 12.5mg
  • Dilution in only 0.9% sodium chloride to reduce vesicant effects
  • Administration via larger and central venous sites to avoid the risk of extravasation or arterial injection
  • Use of an IV port that is more proximal to the venous access poin
  • Slow administration over ten to forty minutes.(1,2)

Additional recommendations by the ISMP highlight the value of education and communication with patients prior to administration, with instructions for patients to verbalize any pain on injection to allow for discontinuation of the infusion if present. Further, in an effort to create halts in workflow and prompt consideration of treatment options, they recommend creation of updated package instructions for administration and an alert system to be integrated into medication administration records (MAR) to highlight risks when dispensing promethazine for parenteral use. This electronic medical record alert would include a message which recommends considering alternative medication use and alerting the provider to potential hazards of intravenous administration. Other recommendations include hospital-wide removal of parenteral formulations of promethazine.(2)

In accordance with the above guidelines, the FDA adds recommendations to avoid mixing promethazine with other drugs as well as avoiding concentrations of greater than 1mg/mL. Their dilution recommendations for the pediatric population include up to 25mg promethazine hydrochloride in 25mL 0.9% sodium chloride.

If giving an increased dose of 25-50mg promethazine hydrochloride, this should be diluted in 50mL 0.9% sodium chloride. Regardless of these concentrations, the recommended maximum rate of infusion is 1.25 mL/minute. With regard to the adult population, 12.5mg to 50mg promethazine hydrochloride should be diluted in 50mL 0.9% sodium chloride and infused at a maximum rate of 2.5 mL/minute. This will allow for a safer concentration to be given and for prevention of severe injury if extravasation does occur.(1)

Overall, the combined recommendations by the ISMP and FDA suggest using the lowest effective dose, a slowed infusion rate, administration via a central venous catheter, and a dilute concentration to minimize the risk of adverse events if an IV route of administration must be used.

Tissue Injury Treatment

If IV promethazine is used and tissue injury is suspected, there is no official manufacturer recommendation for treatment. However, if this occurs, first, stop the infusion and then work to diminish harm from extravasation by vasodilating vasculature in the affected area. Treatment options may be modeled after the suggested treatments for accidental intra-arterial injection of harmful medications (e.g. epinephrine), as the treatment goals are similar. Therefore, treatment considerations include local injection of heparin to decrease the risk of thrombus formation and giving direct vasodilators (e.g. papaverine) as well as alpha adrenergic blockers (e.g. phentolamine). Further management includes local anesthetic infiltration in the area to prevent reflex vasospasm, and, finally, sympathetic blockade (e.g. stellate ganglion block). Since the damage can be rapid and severe, these treatments should be undertaken with urgency.(3)

Summary

With the known risks, it is important for the anesthesiologist to consider alternative routes of promethazine administration or even alternative medications when clinically reasonable. With accordance to the above guidelines, patient harm may be minimized and adverse events reduced. Patient safety and vigilance remain important considerations for anesthesiologists and, while each decision we make is with consideration of the risk of harm weighed against potential benefits, following these guidelines can decrease the risk of a devastating necrosis or ischemic injury in patients treated with promethazine.

References:

  1. FDA requires updates to labeling for promethazine hydrochloride injection products. U.S. Food and Drug Administration. 27, December 2023. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-updates-labeling-promethazine-hydrochloride-injection-products#:~:text=FDA%20recommends%20health%20care%20professionals,administration%20instead%20of%20intravenous%20administration
  2. Action Needed to Prevent Serious Tissue Injury with IV Promethazine. (10, August 2006). Institute for Safe Medication Practices. https://www.ismp.org/resources/action-needed-prevent-serious-tissue-injury-iv-promethazine
  3. Sen S, Chini EN, Brown MJ. Complications after unintentional intra-arterial injection of drugs: risks, outcomes, and management strategies. Mayo Clin Proc. 2005 Jun;80(6):783-95. doi: 10.1016/S0025-6196(11)61533-4. PMID: 15945530.

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