A Historical Look at Phenergan (Promethazine)
First developed in the 1940s and approved for medical use in the U.S. in 1951, promethazine (sold under the brand name Phenergan) is a first-generation antihistamine belonging to the phenothiazine family of medications [1.8.3, 1.8.2]. For decades, it was a versatile and widely used drug for treating a variety of conditions, including:
- Allergic reactions like hay fever and hives [1.7.1]
- Nausea and vomiting, especially from motion sickness or after surgery [1.7.1]
- Sedation before and after surgical procedures [1.7.1]
Its effectiveness comes from its ability to block several chemical messengers in the body, including histamine and dopamine [1.6.3, 1.8.4]. While the brand name Phenergan has been discontinued in the United States, generic promethazine remains available [1.3.2, 1.3.3]. However, its use has become much more restricted and cautious over the years.
The FDA Black Box Warning: A Major Turning Point
A primary reason for the dramatic shift in Phenergan's use was the issuance of a black box warning by the U.S. Food and Drug Administration (FDA)—the most serious warning the agency can require.
Risk of Fatal Respiratory Depression in Children
The most critical warning concerns its use in pediatric patients. Promethazine is contraindicated in children under two years of age because it can cause severe and potentially fatal respiratory depression (slowed or stopped breathing) [1.5.2, 1.9.5]. The FDA received numerous reports of life-threatening adverse events in this age group, prompting the contraindication [1.4.5]. For children two years and older, it must be used with extreme caution at the lowest possible effective dose, and co-administration with other respiratory depressant drugs should be avoided [1.7.1]. In some countries, like Australia, official advice has been updated to state that oral promethazine should not be used in children under six [1.7.3].
Risk of Severe Tissue Injury
Another black box warning highlights the risk of severe tissue injury when the injectable form is administered improperly [1.4.1, 1.4.2]. The drug is a vesicant, meaning it can cause severe chemical irritation and damage if it leaks out of the vein or is accidentally injected into an artery [1.4.3, 1.9.1]. These events have led to reports of tissue necrosis (death) and gangrene, sometimes requiring skin grafts or even amputation [1.4.1, 1.9.5]. Due to these risks, deep intramuscular injection is the preferred route of administration, and intravenous (IV) use is highly discouraged unless absolutely necessary and performed with extreme care [1.4.2, 1.9.2].
Other Significant Side Effects and Concerns
Beyond the black box warnings, Phenergan carries a range of other risks that have contributed to its decline in favor of newer medications:
- Profound Sedation: As a first-generation antihistamine, it readily crosses the blood-brain barrier, causing significant drowsiness, confusion, and disorientation that can impair mental and physical abilities [1.5.4, 1.7.2]. This effect is amplified by alcohol and other CNS depressants [1.9.5].
- Elderly Patient Risks: Older adults are particularly sensitive to promethazine's side effects, such as confusion and severe drowsiness [1.7.4]. The American Geriatric Society Beers Criteria lists it as a potentially inappropriate medication for this population due to its strong anticholinergic effects [1.5.4].
- Neuroleptic Malignant Syndrome (NMS): Though rare, promethazine use is associated with NMS, a life-threatening reaction characterized by high fever, muscle rigidity, and altered mental status [1.5.1, 1.5.4].
- Abuse Potential: The formulation of promethazine with codeine became popular for recreational use, often mixed into a drink called "purple drank" or "sizzurp" [1.2.3]. This led the manufacturer Actavis to pull the prescription cough syrup from the market in 2014 to curb abuse [1.2.1].
Comparison Table: Phenergan vs. Modern Alternatives
The development of newer medications with better safety profiles has provided clinicians with safer options for treating conditions once commonly managed with Phenergan. A key example is the rise of serotonin 5-HT3 antagonists like ondansetron (Zofran).
| Feature | Phenergan (Promethazine) | Ondansetron (Zofran) |
|---|---|---|
| Drug Class | 1st Gen Antihistamine, Phenothiazine [1.3.2] | Serotonin 5-HT3 Antagonist [1.6.3] |
| Primary Use | Allergies, motion sickness, nausea/vomiting, sedation [1.3.2] | Nausea/vomiting from chemotherapy, radiation, surgery [1.6.3] |
| Key Side Effects | Significant drowsiness, dry mouth, confusion, blurred vision [1.3.2] | Headache, constipation, diarrhea, fatigue [1.6.2, 1.6.3] |
| Pediatric Use | Contraindicated under 2 years; caution in older children [1.9.5] | Can be used in children as young as one month old [1.6.3] |
| Serious Risks | Respiratory depression, severe tissue injury (injection), NMS [1.5.4] | Potential for irregular heart rhythm, especially when combined with other drugs [1.6.3] |
The Rise of Safer Alternatives
For nausea and vomiting, especially related to chemotherapy and post-operative care, drugs like ondansetron (Zofran) are now frequently used [1.6.2]. While both can be effective, Zofran does not cause the profound sedation associated with Phenergan, making it a much safer option for many patients [1.6.3]. Other alternatives for nausea include metoclopramide and prochlorperazine [1.6.2].
For allergies, newer second-generation antihistamines (e.g., loratadine, cetirizine) are preferred because they do not readily cross the blood-brain barrier and therefore cause little to no drowsiness.
Conclusion: A Shift Towards Safer Pharmacology
The story of Phenergan is a clear example of the evolution of medical and pharmacological standards. While it was once a go-to medication, a deeper understanding of its significant risks—particularly fatal respiratory depression in children and severe tissue damage—has rightfully led to its decline. It has not been completely removed from use, but its application is now highly specific and cautious. The medical community has largely stopped using Phenergan as a routine treatment, embracing safer, more targeted, and better-tolerated alternatives that reflect a modern commitment to patient safety.
