1. 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.
2. Crotalid envenomation’s can cause broad range of adverse effects, including local tissue, hematologic, and/or systemic effects including shock and life-threatening bleeding.
3. 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.
4. Patients can develop delayed or recurrent hematologic symptoms up to a week after treatment cessation, especially following a severe envenomation.
|Crotalidae Polyvalent Immune Fab (Ovine) (Crofab®)||Crotalidae Immune F(ab’)2 (Equine) (Anavip®)|
|Mechanism of Action||Fab fragment of IgG antibody isolated from sheep serum; antibody binds to venom and removes it from tissue||F(ab’)2 fragment of IgG antibody isolated from horse serum; antibody binds to venom and removes it from tissue|
|Dose||• Initial Dose o Progressing tissue/hematologic effects: 4 – 6 vials o Systemic effects including shock: 8 – 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 achieve||• Initial dose: 10 vials o 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|
|Administration||• Inject ≥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|
|Formulation||IV only; each box contains 2 vials (~$5000/box)||IV only; each vial costs ~$1220|
|PK/PD||T½: 12 – 23 hours||T½: ~5.5 days|
|Adverse Effects||• Hypersensitivity 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 Interactions||No known drug interactions||No known drug interactions|
|Compatibility||NS or SWFI for reconstitution; NS for infusion||NS|
|Comments||Approved for treatment of any North American crotalid envenomation||Approved for treatment of North American rattlesnake envenomations only|
Overview of Evidence
|Author, year||Design/ sample size||Intervention & Comparison||Outcome|
|Dart RC, 1997||Prospective, multicenter trial (n = 11)||Patients received 4 vials of Crofab® for initial control of symptoms following minimal or moderate crotalid envenomation||Ten of 11 patients were deemed to have a clinical response and reduction in snakebite severity score; one patient required 4 addition vials|
|Dart RC, 2001||Multicenter, 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 hours||No statistical difference between groups in snakebite severity score; Overall severity was reduced from 4.35 to 2.39 (p < 0.001)|
|Boyer LV, 2013||Phase 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 envenomation||Venom 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, 2015||RCT at 18 sites in the US (n = 123)||Crofab® vs Anavip® for the prevention of late coagulopathy following crotalid envenomation||More patients in the Crofab® group vs the Anavip group ® experienced late coagulopathy versus • 29.7% vs 10.3% • p < 0.05, NNT = 5|
|Gerardo CJ, 2017||RCT in 18 ED in the US (n = 74)||Crofab® versus placebo to measure limb function 14 days after envenomation using Patient-Specific Functional Scale||Crofab 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 – 2.3; p = 0.04)|
• 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.
• It is important to note that at present, Anavip® is only FDA approved for North American rattlesnake envenomations, even though it is expected that it is safe and effective to use for copperhead and water moccasin envenomations as well.
1. Lavonas et al. BMC Emerg Med. 2011;11:2.
2. Cocchio C, et alAm J Health Syst Pharm. 2020;77(3):175-187.
3. Crotalidae Polyvalent Immune FAB (Ovine). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed April 28, 2020.
4. Crofab® [package insert]. West Conshohocken, PA: BTG International Inc; 2000.
5. 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.
6. Anavip® [package insert]. Franklin, TN: Instituto Bioclon, S.A. de C.V.; 2015.
7. Dart RC, et al. Ann Emerg Med. 1997;30(1):33-9.
8. Dart RC, et al. Arch Intern Med. 2001;161(16):2030-6.
9. Boyer LV, et al. Toxicon. 2013;74:101-8.
10. Bush SP, et al. Clin Toxicol (Phila). 2015;53(1):37-45. 11. Gerardo CJ, et al. Ann Emerg Med. 2017;70(2):233-244.e3.