Introduction

  • Around 9,000 Americans are treated for snake bites and 5 die each year. Most are bitten by members of the Crotalinae subfamily (a.k.a.

    • crotalids) of the pit viper family which includes copperheads, water moccasins, and rattlesnakes.

  • Crotalid envenomation's can cause broad range of adverse effects, including local tissue, hematologic, and/or systemic effects including shock and life-threatening bleeding.
  • Use symptom progression such as swelling beyond 1 major joint or hematologic effects (decreased fibrinogen, thrombocytopenia, or increased PT) as an indicator for initial or additional doses of antivenom. Identification of the snake can be helpful but should not determine decision to initiate or continue therapy in place of symptom progression.
  • Patients can develop delayed or recurrent hematologic symptoms up to a week after treatment cessation, especially following a severe envenomation.

Clinical Detail

AttributeCrotalidae Polyvalent Immune Fab (Ovine)
(Crofab®)		Crotalidae Immune F(ab')2 (Equine)
(Anavip®)
Mechanism of ActionFab fragment of IgG antibody isolated from sheep serum; antibody binds to venom and removes it from tissueF(ab')2 fragment of IgG antibody isolated from horse serum; antibody binds to venom and removes it from tissue
DoseInitial Dose:
• Progressing tissue/hematologic effects: 4 to 6 vials
• Systemic effects including shock: 8 to 12 vials
  May repeat every hour as needed until initial control of local, hematological, and systemic symptoms is achieved
Maintenance: 2 vials q6h x 3 after control is achieved		Initial dose: 10 vials
  May repeat every hour as needed until initial control of local, hematological, and systemic symptoms is achieved
Maintenance: 4 vials as needed; may administer for any re-emerging symptoms
AdministrationInject ≥18 mL NS (or SWFI) into each vial; more volume will speed up dissolution
Gently swirl or roll vials in hand or combine all vials in bag to roll simultaneously; DO NOT SHAKE
Add/QS solution to 250 mL bag of NS admin over 1 hour
NOTE: Many clinicians choose a slower initial rate to allow for assessment of allergic reaction		Reconstitute each vial with 10 mL NS
Gently swirl or roll vials in hand or combine all vials in bag to roll simultaneously; DO NOT SHAKE
Solution should be clear to yellow/green and opalescent; do not use if otherwise discolored
Add/QS solution to 250 mL bag of NS
Administer total volume over 1 hour
NOTE: Many clinicians choose a slower initial rate to allow for assessment of allergic reaction
FormulationIV only; each box contains 2 vials (~$5000/box)IV only; each vial costs ~$1220
PK/PDT½: 12 to 23 hoursT½: ~5.5 days
Adverse EffectsHypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis
Serum sickness (rare)		Nausea (23%), arthralgia (11%), peripheral edema (8%)
Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis
Serum sickness (rare)
Drug InteractionsNo known drug interactionsNo known drug interactions
CompatibilityNS or SWFI for reconstitution; NS for infusionNS
CommentsApproved for treatment of any North American crotalid envenomationRecently approved any North American crotalid envenomation

Evidence

Author, YearDesign/Sample SizeIntervention & ComparisonOutcome
Dart RC, 1997Prospective, multicenter trial (n = 11)Patients received 4 vials of Crofab® for initial control of symptoms following minimal or moderate crotalid envenomationTen of 11 patients were deemed to have a clinical response and reduction in snakebite severity score; one patient required 4 addition vials
Dart RC, 2001Multicenter, randomized, prospective, open-label trial (n = 31)Initial 6 vials of Crofab® patients were randomized to receive either 2 vials PRN vs 2 vials Q6h x 18 hoursNo statistical difference between groups in snakebite severity score; overall severity was reduced from 4.35 to 2.39 (p < 0.001)
Boyer LV, 2013Phase 2, RCT for rattlesnake bites in Tuscon, AZ (n = 12)Crofab® vs Anavip® for reduction in serum venom levels at various pre-defined times following crotalid envenomationVenom levels were insignificantly lower following initial control in the Crofab® group, but significantly lower following maintenance and during follow-up in the Anavip® group (p = 0.004); no difference between groups in safety outcomes
Bush SP, 2015RCT at 18 sites in the US (n = 123)Crofab® vs Anavip® for the prevention of late coagulopathy following crotalid envenomationMore patients in the Crofab® group vs the Anavip® group experienced late coagulopathy: 29.7% vs 10.3% (p < 0.05, NNT = 5)
Gerardo CJ, 2017RCT in 18 ED in the US (n = 74)Crofab® versus placebo to measure limb function 14 days after envenomation using Patient-Specific Functional ScaleCrofab reduced limb disability measured by the Patient-Specific Functional Scale 14 days after copperhead envenomation: 8.6 in the treatment group vs 7.4 in the control group (95% CI 0.1 to 2.3; p = 0.04)
Gerardo CJ, 2020Post hoc analysis (N = 21)Group 1: Anavip 10 vials + Anavip 4 vials q6 x 3
Group 2: Anavip 10 vials + Placebo
Group 3: Crofab 5 vials + 2 vials q6h x 3		In Copperhead bites (n = 21) there was no difference between Anavip® and Crofab® in:
• Time to achieve initial control
• Patients requiring PRN or unscheduled doses

Conclusions

  • Crofab® and Anavip® seem to be comparable for initial symptom control, although due to the longer half-life, Anavip® may have a larger role in prevention of late-onset or recurrent coagulopathy.
  • Each health-system will likely need to make a formulary decision on which agent to use. This decision should be based on which snake species are endemic to that region, preparation time, agent costs, and the prevalence of recurring coagulopathy in their patient population.

References

  • Lavonas et al. BMC Emerg Med. 2011;11:2.
  • Cocchio C, et alAm J Health Syst Pharm. 2020;77(3):175-187.
  • Crotalidae Polyvalent Immune FAB (Ovine). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available
  • at: http://online.lexi.com. Accessed April 28, 2020.
  • Crofab® [package insert]. West Conshohocken, PA: BTG International Inc; 2000.
  • Crotalidae Immune F(ab')2 (Equine). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at:
  • http://online.lexi.com. Accessed April 28, 2020.
  • Anavip® [package insert]. Franklin, TN: Instituto Bioclon, S.A. de C.V.; 2015.
  • Dart RC, et al. Ann Emerg Med. 1997;30(1):33-9.
  • Dart RC, et al. Arch Intern Med. 2001;161(16):2030-6.
  • Boyer LV, et al. Toxicon. 2013;74:101-8.
  • Bush SP, et al. Clin Toxicol (Phila). 2015;53(1):37-45.
  • Gerardo CJ, et al. Ann Emerg Med. 2017;70(2):233-244.e3.
  • Gerardo CJ, Keyler DE, Rapp-Olsson AM, Schwarz J III, Dart RC. Post Hoc Analysis of the RCT Comparing F(ab')2 to Fab Antivenom:

    • Control of Venom-Induced Tissue Injury in Copperhead Snakebite Patients. Annals of Emergency Medicine 76(4) Supp:S29Dec;26(4):472-

Tags:crotalid snake bite antivenom envenomation