Original Article

Adverse Events in the Efficacy of Crotalidae Polyvalent Immune Fab Antivenom vs Placebo in Recovery from Copperhead Snakebite Trial

Authors: Michael E. Mullins, MD, Charles J. Gerardo, MD, Sean P. Bush, MD, S. Rutherfoord Rose, PharmD, Spencer Greene, MD, Eugenia B. Quackenbush, MD, Brandon Lewis, DO, Victoria E. Anderson, MPH, Kurt C. Kleinschmidt, MD, Richard B. Schwarz, MD, Nathan P. Charlton, MD, Eric A. Toschlog, MD, Kapil Sharma, MD, David A. Denning, MD, Eric J. Lavonas, MD
diagnostic:283946

Abstract

Objective: To compare the incidence of hypersensitivity reactions following copperhead envenomation treated with Fab antivenom (FabAV) or placebo.

Methods: Patients with copperhead snakebites received treatment and follow-up in a prospective, randomized, double-blind, placebo-controlled trial of FabAV or placebo. The treatment allocation ratio was 2:1 (FabAV:placebo). All of the included patients received at least one dose of study treatment. We reviewed all treatment-emergent adverse events (AEs) using a previously published scale to classify likely hypersensitivity reactions as mild, moderate, or severe.

Results: We enrolled 74 patients at 13 sites. Forty-five patients received FabAV, and 29 patients received placebo. Five FabAV patients and 4 placebo patients had moderate envenomations; the rest were mild. Twenty-five FabAV patients and 8 placebo patients had at least 1 AE. Mild skin reactions occurred in 11 (24%) FabAV patients (pruritis, urticaria, rash, ecchymosis, erythema) and 1 (3%) placebo patient (pruritis). Moderate gastrointestinal AEs occurred in 7 (16%) FabAV patients (nausea, vomiting, constipation, diarrhea, oral paresthesia) and in 2 (7%) placebo patients (nausea). Respiratory AEs occurred in 3 (7%) FabAV patients (dyspnea, pulmonary embolism, nasal congestion, sneezing) and no placebo patients. Hypotension occurred in 1 patient in each group.

Conclusions: In a randomized controlled trial of FabAV for copperhead bites, the incidence of hypersensitivity reactions was low. Most reactions were mild skin reactions.

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References

1. Mowry JB, Spyker DA, Brooks DE, et al. 2015 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 33rd annual report. Clin Toxicol 2016;54:924-1109.
 
2. Schulte J, Domanski K, Smith EA, et al. Childhood victims of snakebites: 2000-2013. Pediatrics 2016;138:pii.e20160491.
 
3. Roth B, Sharma K, Onisko N, et al. Prospective evaluation of pain, swelling, and disability from copperhead envenomation. Clin Toxicol (Phila) 2016;54:271-276.
 
4. Abbey JM, Jaffar NA, Abugrara HL, et al. Epidemiologic characteristics, hospital course and outcome of snakebite victims in West Texas. Hosp Pract (1995) 2015;43:217-220.
 
5. Thorson A, Lavonas EJ, Rouse AM, et al. Copperhead envenomations in the Carolinas. J Toxicol Clin Toxicol 2003;41:29-35.
 
6. Lepak MR, Bochenek SH, Bush SP. Severe adverse drug reaction following Crotalidae polyvalent immune Fab (ovine) administration for copperhead snakebite. Ann Pharmacother 2015;49:145-149.
 
7. Holstege CP, Wu J, Baer AB. Immediate hypersensitivity reaction associated with the rapid infusion of Crotalidae polyvalent immune Fab (ovine). Ann Emerg Med 2002;39:677-679.
 
8. Schaeffer TH, Khatri V, Reifler LM, et al. Incidence of immediate hypersensitivity reaction and serum sickness following administration of Crotalidae polyvalent immune Fab antivenom: a meta-analysis. Acad Emerg Med 2012;19:121-131.
 
9. Ruha AM, Curry SC, Beuhler M, et al. Initial postmarketing experience with crotalidae polyvalent immune Fab for treatment of rattlesnake envenomation. Ann Emerg Med 2002;39:609-615.
 
10. Lavonas EJ, Gerardo CJ, O’ G, et al. Initial experience with Crotalidae polyvalent immune Fab (ovine) antivenom in the treatment of copperhead snakebite. Ann Emerg Med 2004;43:200-206.
 
11. Corneille MG, Larson S, Stewart RM, et al. A large single-center experience with treatment of patients with crotalid envenomations: outcomes with and evolution of antivenin therapy. Am J Surg 2006;192:848-852.
 
12. Pizon AF, Riley BD, LoVecchio F, et al. Safety and efficacy of Crotalidae polyvalent immune Fab in pediatric crotaline envenomations. Acad Emerg Med 2007;14:373-376.
 
13. Cannon R, Ruha AM, Kashani J. Acute hypersensitivity reactions associated with administration of crotalidae polyvalent immune Fab antivenom. Ann Emerg Med 2008;51:407-411.
 
14. Nazim MH, Gupta S, Hashmi S, et al. Retrospective review of snake bite victims. W V Med J 2008;104:30-34.
 
15. Lavonas EJ, Kokko J, Schaeffer TH, et al. Short-term outcomes after Fab antivenom therapy for severe crotaline snakebite. Ann Emerg Med 2011;57:128-137.e3.
 
16. Gilbert EH, Lowenstein SR, Koziol-McLain J, et al. Chart reviews in emergency medicine research: where are the methods? Ann Emerg Med 1996;27:305-308.
 
17. Worster A, Haines T. Advanced statistics: understanding medical record review (MRR) studies. Acad Emerg Med 2004;11:187-192.
 
18. O’ ME, Mack KA, Gilchrist J, et al. Snakebite injuries treated in United States emergency departments, 2001-2004. Wilderness Environ Med 2007;18:281-287.
 
19. Gerardo CJ, Quackenbush E, Lewis B, et al. The efficacy of crotalidae polyvalent immune Fab (ovine) antivenom versus placebo plus optional rescue therapy on recovery from copperhead snake envenomation: a randomized, double-blind, placebo-controlled, clinical trial. Ann Emerg Med 2017;70:233-244.e3.
 
20. Baber N. International conference on harmonisation of technical requirements for registration of pharmaceutical for human use (ICH). Br J Clin Pharmacol 1994;37:401-404.
 
21. Code of Federal Regulations 21 CFR Section 321.32(a). https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32. Accessed October 5, 2018.
 
22. Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114:371-376.
 
23. Isbister GK, Brown SG, MacDonald E, et al. Current use of Australian snake antivenoms and freqency of immediate-type hypersensitivity reactions and anaphylaxis. Med J Aust 2008;188:473-476.
 
24. Wilson L. Repeated administrations of crotalid Fab antivenin in the same patient. Am J Emerg Med 2002;20:572.
 
25. Lavonas EJ, Benson BE, Seifert SA. Failure to develop sensitization despite repeated administration of ovine fab snake antivenom: update of a single-patient, multicenter case series. Ann Emerg Med 2013;61:371-372.
 
26. Abdelmalek D, Arroyo-Plasencia A, Schwarz ES, et al. Factitious snake envenomation and narcotic-seeking behavior. Am J Emerg Med 2015;33:1331.e5-1331.e6.
 
27. Gale SC, Peters JA, Allen L, et al. FabAV antivenin use after copperhead snakebite: clinically indicated or knee-jerk reaction? J Venom Anim Toxins Incl Trop Dis 2016;22:2.
 
28. Kleinschmidt K, Ruha AM, Campleman S, et al. Acute adverse events associated with the administration of Crotalidae polyvalent immune Fab antivenom within the North American Snakebite Registry. Clin Toxicol (Phila) 2018;1-6.
 
29. Bush SP, Ruha AM, Seifert SA, et al. Comparison of F(ab′)2 versus Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial. Clin Toxicol (Phila) 2015;54:37-45.