Prophylactic antihistamines in adverse reactions to snake antivenom. A systematic review of randomized controlled trials

Background. Snakebite envenoming is a neglected tropical disease that kills thousands and leaves many more with permanent disabilities every year, especially in rural areas of low- and middle-income countries. Antivenom remains the only specific and truly effective treatment, but early adverse reactions, often anaphylactoid or allergic, are common and have led many clinicians to routinely give H1 antihistamines as premedication, even though solid evidence for doing so is lacking. This systematic review looks at whether prophylactic H1 antihistamines, compared with placebo or no premedication, actually reduce the risk of early, severe, or delayed reactions, as well as mortality, in patients receiving antivenom for snakebite envenoming. Methods. We conducted a systematic review following PRISMA 2020 guidelines. We searched PubMed/MEDLINE, Cochrane CENTRAL, LILACS, SCOPUS, EMBASE, and grey literature sources from October 14 to December 20, 2025. Only randomized controlled trials comparing prophylactic H1 antihistamines against control were included. Risk of bias was assessed using RoB 2, and certainty of evidence using GRADE. The protocol was prospectively registered on OSF. Results. Three RCTs were included (total n=1160 participants). Promethazine alone did not reduce early reactions (RR ≈0.96–1.00) or severe reactions (RR ≈0.93–1.00). Chlorpheniramine, given only together with hydrocortisone, appeared to lower reactions in one small trial, but the antihistamine’s independent effect could not be isolated. No studies systematically reported delayed reactions (serum sickness). Mortality was low overall and showed no clear differences linked to antihistamines. Evidence certainty was low for early and severe reactions, and very low for mortality and delayed reactions. Conclusions. Current evidence does not support routine use of H1 antihistamines alone as premedication to prevent antivenom reactions. Efforts should focus instead on high-quality antivenoms, close monitoring during infusion, and prompt treatment of reactions (especially with adrenaline when needed).