Abstract
Promethazine has long been a cornerstone in the management of nausea and vomiting (N/V) in emergency medicine; however, its safety profile—including risks of severe tissue injury and respiratory depression—has prompted renewed scrutiny. Nausea and vomiting arise from complex interactions between central and peripheral pathways involving the chemoreceptor trigger zone, vagal afferents, and multiple neurotransmitter systems, including dopamine (D2), serotonin (5-HT3), histamine (H1), muscarinic (M1), and neurokinin-1 (NK1) receptors. This manuscript presents a focused narrative review and expert commentary examining the evolving role of promethazine in modern clinical practice. Drawing on regulatory guidance, contemporary literature, and institutional experience, we evaluate the risks associated with injectable promethazine and the rationale for transitioning toward safer alternatives. At our institution, removal of injectable promethazine from the formulary was guided by multidisciplinary consensus and aligned with updated safety recommendations. Alternative agents, including dopamine antagonists and 5-HT3 receptor antagonists, provide comparable or superior efficacy with improved safety profiles. Advances in antiemetic therapy now support a multimodal, receptor-targeted approach, combining agents that act on complementary pathways to improve symptom control while minimizing adverse effects. While clinical contexts such as chemotherapy-induced and postoperative nausea and vomiting differ in etiology and guideline-based management, they share overlapping receptor pathways that allow for a unified pharmacologic framework. Although intravenous promethazine remains in use in some settings, evolving safety data and regulatory guidance have led to progressive restriction and, in many institutions, elimination of its parenteral use. Given the availability of safer and more targeted therapies, the continued routine use of injectable promethazine warrants critical reassessment. This shift reflects a broader movement toward precision, safety, and evidence-based practice in antiemetic management and highlights the importance of aligning clinical practice with contemporary pharmacologic understanding.
Introduction
Major causes of nausea and vomiting.
Nausea and vomiting are mediated through complex interactions between central and peripheral pathways involving the chemoreceptor trigger zone (CTZ), nucleus tractus solitarius, vestibular system, and vagal afferents from the gastrointestinal tract. Multiple neurotransmitter systems contribute to this process, including dopamine (D2), serotonin (5-HT3), histamine (H1), muscarinic (M1), and neurokinin-1 (NK1) receptors. These pathways form the physiologic basis for targeted antiemetic therapies and support the rationale for multimodal treatment strategies.4–7
Historically, promethazine (Phenergan) has been a cornerstone in the treatment of nausea and vomiting in the emergency department. While effective, its sedative properties and the risk of tissue injury from extravasation have raised significant concerns among clinicians. As a result, modern antiemetic strategies have evolved, incorporating a broader spectrum of pharmacologic options such as serotonin receptor antagonists, dopamine receptor antagonists, and neurokinin-1 receptor antagonists.6,8–10 Herein, we detail the efficacy, safety, and clinical applications of these alternatives, providing a comprehensive framework for optimizing N/V management in the ED.
Recent updates to the product labeling of injectable promethazine, prompted by FDA and Institute for Safe Medication Practices (ISMP) scrutiny, alongside growing medical and legal concerns, have significantly impacted its use.11–13 Notably, in 2021, the ISMP had already recommended the removal of all injectable forms of promethazine due to safety risks. 12 In response, our institution made the difficult decision to remove injectable promethazine from our formulary—a choice that balanced its long-standing role as a cost-effective and effective antiemetic against mounting safety concerns. Eliminating the intravenous (IV) formulation mitigates the risk of inadvertent administration without proper safeguards such as dilution and administration in a large-bore vein. Consideration was given to retaining the intramuscular (IM) route, but similar safety risks led to its rejection.
To ensure an informed decision, multiple clinical services including anesthesia, adult and pediatric oncology, emergency medicine and pharmacy departments were consulted, and a consensus was reached that the safest course of action was to remove all injectable promethazine from the formulary. Nevertheless, oral and rectal formulations remain available, preserving treatment options for patients who benefit from this medication. This change also presents an opportunity to embrace newer, safer antiemetic agents, reflecting a shift in clinical practice toward evidence-based and patient-centered care.
This manuscript is intended as a focused narrative review and expert commentary examining the evolving role of promethazine in modern clinical practice. Rather than providing a comprehensive systematic review of all antiemetic therapies, the aim is to critically evaluate the safety profile of promethazine and to highlight the rationale for transitioning toward safer, mechanism-based, multimodal antiemetic strategies.
The central argument of this manuscript is that the continued use of promethazine, particularly in injectable form, is increasingly difficult to justify given its safety profile and the availability of more targeted and safer alternatives.6,12,13
Methods
This work represents a targeted narrative review informed by selective literature searches of PubMed, guideline repositories, and regulatory communications, including FDA and ISMP safety updates. Sources were chosen based on relevance to clinical practice, safety considerations, and contemporary antiemetic strategies. These findings were integrated with institutional formulary decisions and multidisciplinary expert consensus to provide a clinically grounded perspective.
Discussion
The problem
Promethazine is a phenothiazine derivative with antiemetic, sedative, antihistamine, and anticholinergic properties. Its antiemetic effects are believed to result from dopamine antagonism in the chemoreceptor trigger zone. Promethazine injection is formulated with phenol and has a pH between 4 and 5.5, increasing the risk of tissue injury when administered parenterally, such as via intramuscular (IM) or intravenous (IV) routes. 14 The manufacturer’s product labeling describes promethazine as an irritant drug that can be highly caustic to the intima of blood vessels and surrounding tissue. Because of these risks, deep intramuscular injection into a large muscle is the preferred route of administration. However, product labeling also permits slow IV push administration, which remains the typical method in many hospitals11,15
Inadvertent subcutaneous, intra-arterial, or extravasated intravenous administration of promethazine carries a significantly increased risk of severe complications. Reported injuries include local pain, burning, erythema, induration, and edema, as well as more serious outcomes such as vascular spasm, venous thrombosis, nerve damage, paralysis, abscess formation, tissue necrosis, and gangrene.11,16–18 Case reports further illustrate the severity of these events, including inadvertent intra-arterial injection leading to immediate vascular compromise and progressive tissue necrosis requiring surgical intervention, such as fasciotomy or amputation. Additional reports describe severe extravasation injuries resulting in long-term functional impairment. Although these complications are relatively uncommon, their severity is disproportionate to the therapeutic benefit of the drug and has prompted multiple safety alerts and regulatory warnings.
Promethazine was approved in 1951 and quickly became widely used due to its broad applications. Over time, familiarity with its use led to decreased vigilance regarding its limitations. Promethazine has been used for sedation and anxiolysis, as an adjunct in treating acute allergic reactions and anaphylaxis, and for nausea and vomiting across a range of clinical conditions, including gastrointestinal disorders, motion sickness, headaches, and perioperative care. Its popularity stemmed from its cost-effectiveness and efficiency. 16 Clinical effects are typically observed within five minutes after IV administration and 20 minutes after IM administration in adults, with a duration of action of four to six hours. However, overconfidence in its safety profile contributed to diminished awareness of its risks. 15
Concerns regarding injectable formulations began to mount in the 1990s as case reports linked IV administration of promethazine to severe tissue injuries, including thrombosis, nerve damage, tissue necrosis, and gangrene, sometimes requiring surgical intervention such as skin grafting, fasciotomy, or amputation.15–17
Adverse effects of promethazine have been particularly concerning in pediatric patients. Children under six years old are at increased risk for psychiatric and central nervous system side effects, including hyperactivity, aggression, and hallucinations. In 2005, the FDA strengthened labeling to highlight the risk of respiratory depression in pediatric patients, including a boxed warning and contraindication for children younger than two years.19,20
The central nervous system toxicity of promethazine in pediatric patients is thought to result from a combination of potent H1 receptor antagonism, anticholinergic effects, and phenothiazine-related dopaminergic modulation within the central nervous system. These mechanisms may lead to both central respiratory depression and paradoxical excitation. Clinically, this may manifest as excessive sedation, confusion, or respiratory compromise, but children may also exhibit agitation, hyperactivity, aggression, and hallucinations.14–21
While precise incidence rates are difficult to determine due to reliance on postmarketing data, FDA safety reviews identified multiple cases of severe respiratory depression in young children, including fatal outcomes, leading to a boxed warning and contraindication in children younger than two years. These findings underscore the heightened vulnerability of pediatric patients to central and respiratory toxicities associated with promethazine.19,20
In 2009, the FDA mandated additional boxed warning language emphasizing the risk of severe tissue injury, including gangrene and amputation, associated with parenteral administration. More recently, in 2023, the FDA required further labeling updates to reduce the risk of severe chemical irritation and tissue damage associated with intravenous administration.11,13,19
Current FDA labeling emphasizes that the risks associated with injectable promethazine are closely tied to the challenges of safe administration. Recommended precautions include deep intramuscular injection when possible, dilution in compatible fluids for intravenous use, administration through a large-bore vein, and slow infusion rates with close monitoring for pain or signs of extravasation. Despite these precautions, the risk of severe tissue injury cannot be fully eliminated, highlighting the inherent limitations of safe parenteral use.
Moving beyond promethazine
Safety concerns necessitating a new FDA boxed warning allowed us to revisit our antiemetic usage. In December of 2023, the Pharmacy and Therapeutic Committee in conjunction with the Formulary Subcommittee of UF Health voted unanimously to eliminate injectable promethazine from our formulary based on the recommendations of expert opinion, consults held with key stakeholders within our health care system, and new FDA warnings.11,19,22
The transition to eliminating injectable promethazine was facilitated by replacing promethazine injectable with prochlorperazine—another dopamine receptor blocker—and by removing some restrictions with regard to newer antiemetic agents. Updated guidelines and a list of currently available antiemetic agents on our formulary were distributed electronically to all providers. Thus, armed with strong clinical evidence and a clear rationale, removing injectable promethazine from our formulary—after using it for so many years—was met with little resistance, and the transition has since been seamless.10,23
Medication classes with mechanisms of action, use and safety data.
CINV = chemotherapy induced nausea and vomiting; PONV = postoperative nausea and vomiting. CTZ = chemoreceptor trigger zone; EPS = extrapyramidal symptoms.
Overview of antiemetic classes and their clinical applications
A multimodal approach to nausea and vomiting management involves targeting multiple emetic pathways simultaneously to improve efficacy while minimizing reliance on any single agent. Common strategies include combining a 5-HT3 receptor antagonist with a dopamine antagonist, with the addition of corticosteroids or NK1 receptor antagonists in higher-risk or refractory cases. Compared with promethazine, these combinations provide more targeted therapy with reduced risks of sedation, tissue injury, and respiratory compromise.5–9
Medication classifications with common examples and relative costs (USD). a
aEstimated U.S. average drug costs derived from representative pricing sources (e.g., NADAC and GoodRx); costs are approximate and may vary by formulation, dose, payer, and clinical setting.
Outpatient prescription data for antiemetics (United States, 2022). a
aData source: https://clincalc.com/DrugStats/Top300Drugs.aspx
Although chemotherapy-induced, postoperative, and emergency department-related nausea and vomiting arise from distinct clinical contexts, they share overlapping neuroreceptor pathways, allowing for a unified pharmacologic framework based on receptor-targeted therapy.4,7
While guideline recommendations differ across clinical contexts—such as chemotherapy-induced and postoperative nausea—these differences largely reflect variations in risk stratification and prophylactic strategies rather than fundamentally distinct pharmacologic targets.8,9
5-HT3 receptor antagonists (e.g., ondansetron, granisetron)
5-HT3 receptor antagonists selectively block serotonin (5-HT3) receptors located in the gastrointestinal tract and chemoreceptor trigger zone (CTZ). This mechanism underpins their efficacy in treating chemotherapy-induced nausea and vomiting (CINV), postoperative nausea and vomiting (PONV), and radiation-induced nausea. These agents offer a more targeted and effective approach compared to older antiemetics like promethazine, with fewer sedative side effects. However, their use is associated with a risk of QT interval prolongation, which requires monitoring in patients with predisposing conditions. The superior safety profile and efficacy of 5-HT3 antagonists have made them first-line therapies in oncology and postoperative care.8,9,25 They are often used in combination with corticosteroids or NK1 receptor antagonists for enhanced symptom control. Landmark studies underscore their pivotal role in modern antiemetic regimens. 25
NK1 receptor antagonists (e.g., aprepitant, fosaprepitant)
NK1 receptor antagonists block neurokinin-1 (NK1) receptors to inhibit the action of substance P, a key neurotransmitter in emesis. They are particularly effective for prophylaxis in delayed-phase CINV, where serotonin antagonists often fall short. With minimal sedative and anticholinergic side effects, these agents are integral components of guideline-based regimens for highly emetogenic chemotherapy. When used in combination with 5-HT3 antagonists and corticosteroids, NK1 receptor antagonists significantly improve control of both acute and delayed nausea and vomiting, enhancing overall patient outcomes.17,26 However, NK1 receptor antagonists are not effective for aborting established nausea and vomiting and are best utilized as prophylactic agents.
Dopamine-D2 receptor antagonists (e.g., amisulpride, metoclopramide, prochlorperazine)
These agents block dopamine receptors in the CTZ and are versatile options for N/V associated with migraines, gastroparesis, and PONV. Metoclopramide also offers prokinetic benefits, making it particularly effective for gastroparesis-related nausea. Although these medications are effective and cost-efficient, their use is often limited by the risk of extrapyramidal symptoms (EPS), such as dystonia and akathisia, especially with high doses or prolonged use.2,27 Prochlorperazine is commonly employed in acute settings but requires careful monitoring for side effects, including sedation and hypotension.
Haloperidol (Haldol) and droperidol are butyrophenone derivatives primarily known for their antipsychotic effects. However, their role as antiemetics has gained recognition, particularly in emergency medicine and perioperative care. Both agents alleviate nausea and vomiting by antagonizing dopamine-D2 receptors in the chemoreceptor trigger zone (CTZ) of the brain, making them effective in managing refractory cases. It is important to note that droperidol carries a boxed warning for QTc prolongation prompting recommendations for baseline ECG assessment and post-administration monitoring in accordance with boxed warnings.28,29
Corticosteroids (e.g., dexamethasone)
Corticosteroids play a critical role in combination regimens for CINV and PONV. These agents modulate emetic signals and reduce inflammation, enhancing the efficacy of other antiemetics, particularly for delayed-phase CINV. Dexamethasone is a cost-effective option with a long duration of action, making it ideal for oncology and perioperative settings.18,25 While generally well-tolerated, potential side effects, including hyperglycemia and insomnia, should be considered, particularly in patients with diabetes or those requiring prolonged use. The precise mechanisms of glucocorticoids in preventing emesis may involve anti-inflammatory effects, modulation of serotonin and tachykinin pathways, and regulation of the hypothalamic-pituitary-adrenal axis.
Anticholinergics (e.g., scopolamine)
Targeting muscarinic receptors, anticholinergics are particularly effective for motion sickness and vestibular-origin nausea. Scopolamine’s transdermal patch offers sustained symptom control, improving patient compliance compared to oral options. Although side effects such as dry mouth, blurred vision, and mild sedation may occur, they are generally less severe than those associated with older anticholinergic agents. Scopolamine is also effective for preventing PONV in high-risk patients and managing vertigo. 22
Benzodiazepines (e.g., lorazepam)
Although not primary antiemetics, benzodiazepines are invaluable for managing anticipatory nausea and vomiting, particularly in oncology patients whose symptoms are triggered by psychological factors. By enhancing GABAergic inhibition, lorazepam reduces anxiety-driven emetic responses. While highly effective in this context, its use is limited by potential side effects, including sedation, respiratory depression, and dependence with prolonged administration.30,31
Cannabinoids (e.g., dronabinol, nabilone)
Cannabinoids activate CB1 receptors in the central nervous system, modulating pathways involved in nausea and vomiting. These agents are primarily reserved for refractory nausea and vomiting, particularly in CINV patients who have not responded to standard therapies. Additionally, cannabinoids can stimulate appetite, benefiting patients with cachexia or significant weight loss due to chronic conditions like cancer or HIV/AIDS. While side effects such as dizziness, euphoria, and dry mouth are common, cannabinoids remain a valuable option for specific patient populations.32,33
Limitations
This manuscript represents a focused narrative review and expert commentary rather than a formal systematic review; therefore, it does not employ comprehensive search strategies or PRISMA methodology, and selection of included sources may reflect author perspective. While the discussion integrates current literature, regulatory guidance, and institutional experience, it is not intended to provide an exhaustive evaluation of all antiemetic therapies or clinical contexts. Additionally, the conclusions are informed in part by single-institution practice changes, which may limit generalizability to other settings with differing resources, formularies, or patient populations. Finally, much of the safety data related to promethazine is derived from case reports and postmarketing surveillance, which may underestimate true incidence while emphasizing severe outcomes.
Conclusion
The global use of intravenous promethazine reflects a transitional moment in antiemetic care. While many healthcare systems—particularly in the United States—have reduced or eliminated its use in favor of safer alternatives, it persists in some settings due to cost considerations, formulary inertia, and clinical familiarity. Ongoing reports of tissue injury and other adverse events underscore that its risks remain clinically relevant. As such, current practice is best characterized not by universal discontinuation, but by progressive restriction—highlighting the need for continued emphasis on safer, evidence-based strategies.
At the same time, modern management of nausea and vomiting (N/V) has evolved toward a multimodal, receptor-targeted approach that improves both efficacy and safety. By addressing key emetic pathways—including serotonin (5-HT3), dopamine (D2), neurokinin-1 (NK1), and histamine (H1)—clinicians can tailor therapy to underlying etiologies and clinical context. The availability of effective, often low-cost generic agents supports broad access, while newer therapies offer expanded options for high-risk and refractory cases.34,35
Despite these advances, important challenges remain. Access to certain highly effective agents, such as NK1 receptor antagonists, may be limited by cost, and all antiemetic classes carry potential adverse effects requiring thoughtful, patient-centered application. Within this evolving landscape, promethazine serves as a clear example of a legacy medication whose continued injectable use is increasingly difficult to justify given its safety profile and the availability of safer alternatives.
Transitioning away from injectable promethazine is both a practical and achievable step toward modernizing care. More broadly, optimizing N/V management requires balancing efficacy, safety, and access while aligning clinical practice with contemporary pharmacologic understanding. Embracing targeted, multimodal strategies represents a meaningful opportunity to improve patient safety and advance the standard of care.
Footnotes
Acknowledgements
The authors would like to thank the clinical and pharmacy teams at UF Health for their collaboration and input during the formulary review process that informed this work.
Author contributions
MFR drafted the manuscript, and both authors contributed substantially to its revision. MFR takes responsibility for the paper as a whole.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.