Comparing Antihistamine Premedication Regimens for Preventing Rituximab-Associated Infusion Reactions in Hemato-Oncology Patients: A Retrospective Analysis

Background: Rituximab, an anti-CD20 monoclonal antibody, is crucial in treating certain lymphoproliferative disorders, but up to 77% of patients may experience infusion-related reactions. Diphenhydramine, a first-generation antihistamine, is considered the standard of care for rituximab premedication but poses safety concerns, especially in older adults. The use of second-generation antihistamines, loratadine and cetirizine, have gained interest due to their improved tolerability and safety. However, antihistamine prescribing varies substantially and the relative effectiveness of antihistamines in reducing rituximab infusion reactions has not been previously assessed. Certain patient-specific risk factors, such as patients with more advanced disease, may also be associated with infusion-related reactions. Consideration of these variables would be necessary to better characterize potential factors contributing to a patient’s likelihood of experiencing an infusion reaction. Furthermore, despite generally having a longer duration of effect compared to first-generation antihistamines, it is not known whether taking an extra dose of second-generation antihistamine impacts the incidence infusion-related reactions. Examining different generations of antihistamines and how their dosing strategies compare in their ability to reduce rituximab infusion reactions may prove relevant to the provision of patient-centred care.

Objective(s): To evaluate antihistamine premedication prescribing practices for rituximab patients and to assess the incidence, severity, and symptoms of infusion reactions between antihistamine generations.

Methods: This is a retrospective chart review of 422 adult patients with B-cell malignancies who received first dose intravenous rituximab across four Alberta cancer sites over a 12-month period. Data on patient characteristics, premedications, and infusion reactions were collected. The severity of reaction was graded using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) grading scale. Chi-square and Fisher Exact tests were used to examine associations of infusion reactions with patient-specific factors. A multivariate logistic regression analysis was conducted to identify whether known risk factors were associated with infusion reactions among the different antihistamine groups.

Results: Three antihistamines were identified: diphenhydramine 50 mg, loratadine 10 mg, and cetirizine 10 mg. Among all eligible patients, 225 (53.3%) were given diphenhydramine, 160 (37.9%) received loratadine, and 37 (8.8%) got cetirizine. The overall incidence of infusion reactions was 27%. There was no significant difference in infusion reactions between first- and second- generation antihistamines (p=0.44). The incidence of reactions amongst patients who received one antihistamine dose (same day of infusion) was not different compared with patients given two separate doses (p=0.83). Approximately 91% of patients who experienced an infusion reaction were classified as grade 2 using the CTCAE grade scale. There were 251 total reported symptoms among the 115 patients who experienced infusion reactions. Chills/rigors (n=41) and throat irritation (n=28) were the two most prevalent symptom types. In terms of the spread of symptom types, 39.1% of patients experienced 1 symptom, 44.3% experienced 2-3 different symptoms and 16.5% experienced 4 or more symptom types. Age <65 was significantly associated with a higher risk of experiencing infusion reactions (OR = 2.0, 95% CI: 1.3-3.1, p=0.0031). This observation persisted even after accounting for other variables such as sex, staging of disease, other antihistamine premedication (i.e. histamine-2 receptor blockers, corticosteroid, acetaminophen), and diagnosis.

Conclusions: In hemato-oncology patients receiving first-time rituximab, infusion reactions did not differ by antihistamine choice. Using one dose of less sedating second-generation antihistamines may improve patient safety without compromising clinical efficacy. By recognizing second-generation antihistamines as a safer and equally efficacious option for rituximab premedication, standard antihistamine prescribing practices should be re-evaluated with the goal of optimizing patient safety and medication burden.