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Charleston, SC

jimmy@pharmacyfridaypeals.com

Pharmacologic Management of Crotalid Envenomation

Introduction 

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.

Pharmacology

Crotalidae 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
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  achieveInitial 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 reactionReconstitute 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  envenomationApproved for treatment of North American rattlesnake  envenomations only

Overview of Evidence

Author, year Design/ sample size Intervention & Comparison Outcome
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 versus • 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 – 2.3; p = 0.04)

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.

• 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.

References 

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.

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