First-generation oral antihistamines long entrenched in pediatric care can be displaced with the safer alternative cetirizine through relatively simple system changes, according to new research published in Pediatrics.

Despite long-standing safety concerns, first-generation antihistamines such as diphenhydramine remain common in pediatric settings, even though second-generation agents are recommended as first-line therapy. The findings suggest that overuse of older, more sedating antihistamines may be less a matter of clinical necessity than of habit and system design.

“Health systems should strongly consider the use of quality improvement methodology to reduce the use of first-generation antihistamines in favor of second-generation antihistamines [SGAs],” said Katelyn Wong, MD, assistant professor in the Department of Pediatric Pulmonology, Allergy, Immunology and Sleep Medicine at the Yale School of Medicine in New Haven, Connecticut, who led the study. “These interventions are applicable to various clinical settings as they are not overly time- or resource-intensive.”

First-generation oral antihistamines (FGAs) such as diphenhydramine and hydroxyzine are associated with oversedation, coma, seizures, attention-deficit/hyperactivity disorder, and impaired learning in children. Meanwhile, SGA cetirizine has been shown to produce fewer side effects and remains safe even at high doses.

SGAs are the preferred antihistamine for allergic rhinitis, urticaria, and anaphylaxis, but FGAs remain overused.

The reduction was the result of clinician education, easier access to cetirizine, and updated clinical pathways to push prescribers toward the safer agent.

The study took place between 2022 and 2024 at a pediatric hospital among nearly 7000 patients aged 6 months to 21 years.

Implementation of the project occurred in two phases, beginning in the emergency department (ED) and expanding to inpatient units. In the ED, clinicians watched a 30-minute lecture on the efficacy of SGAs, time of onset, and indications. Wong and her team also posted informational flyers in high-traffic areas and sent email reminders about the availability of cetirizine.

Medication dispensing machines were preloaded with cetirizine, which previously required delivery from the central pharmacy, and clinical pathways were updated to make the drug the preferred antihistamine.

The intervention was tweaked when expanded to inpatient units. Education shifted to a series of 20-minute educational sessions. Resident and pharmacist champions delivered brief peer-to-peer education and gave individual feedback to clinicians who ordered FGAs.

Prescriptions for FGAs fell from 74% to 28% over a 2-year period in the pediatric ED and from 54% to 36% in inpatient units.

Rates of ED visits and length of stays stayed stable. The shift to the newer agent raised the monthly median antihistamine costs from $53 to $177 in the ED and from $57 to $104 in inpatient units.

Clinicians who completed pre- and post-education surveys showed a doubling in knowledge. Use of clinical pathways — optional, standardized workflows meant to guide treatment — increased after cetirizine was listed as the preferred antihistamine.

The biggest barriers to SGA use are often “habit and familiarity with diphenhydramine,” said Brian Johnston, MD, MPH, chief of pediatrics at Harborview Medical Center in Seattle, who was not associated with the study. “In addition, if second-generation drugs are not clearly favored in order sets, pathways, and dispensing cabinets, the path of least resistance remains the older medications.”

First-generation diphenhydramine is no longer used in the Division of Allergy and Immunology at Lurie Children’s Hospital in Chicago, where Sai Nimmagadda, MD, works as an attending physician. Nimmagadda was not involved with the study. He said hydroxyzine is sparingly used for patients with atopic dermatitis who have nocturnal itching.

Diphenhydramine “would probably not get approved today by the Food and Drug Administration, just due to the sedating effects,” Nimmagadda, also an associate professor of pediatrics at Northwestern University Feinberg School of Medicine in Chicago, said. “If there are drugs with less side effects, those are the ones we should be prescribing rather than sticking to an old habit. It’s always better to keep stepping up and improving our patient care.”

First-generation antihistamines for some conditions can be used selectively. For instance, hydroxyzine can be effective for treating anxiety. Diphenhydramine can also be used for cyclic vomiting, or acute agitation in children “where its sedating or antiemetic properties are being used deliberately,” Johnston said.

The study had no funding sources. The sources cited in the article reported having no conflicts of interest or disclosures.

Brittany Vargas is a journalist covering medicine, mental health, and wellness.