Antivenom for Rattlesnake Envenomation

Take Home Points

• Both ANAVIP^® and CroFab^® are FDA approved for the treatment of North American pit viper envenomation.^9,10
• The use of antivenom is indicated for any patient with progressive local tissue effects, hematologic venom effects, systemic signs attributable to venom, and bites with swelling of hands or airway.⁵
• Dosing is based on initial control and will differ based on patient presentation and management requirements.⁹
• Patients should be monitored for 18 – 24 hours after the initial envenomation and labs assessing for coagulation abnormalities should be taken 6 – 12 hours after initial control, prior to discharge, and two times after discharge.⁵

Pit Viper Envenomation

In 2022, 7,016 cases of possible snake envenomation were documented by the National Poison Data System.¹ Of the documented snakebites in the United States, 98% of venomous bites are from North American pit vipers which includes copperheads, cottonmouths, and rattlesnakes.² Envenomations from these snakes have the potential to lead to life and limb threatening conditions. Copperhead and cottonmouth (water moccasin) snakes are commonly found in the southeast region of the United States, while rattlesnake species are found in all lower 48 states. There are 7 rattlesnake species native to Utah with the Great Basin rattlesnake being the most common.³ 

Snake venom contains a unique mixture of pro- and anticoagulants, neurotoxins, cytotoxins, cardiotoxins, and hemotoxins.⁴ These toxins have individual and synergistic activity resulting in acute, local effects as well as prolonged, systemic, and hematologic effects.⁴ Local effects commonly include edema, ecchymosis, vesiculations, bullae, and skin necrosis while systemic effects may include headache, diarrhea, nausea/vomiting, abdominal pain, hypo- or hypertension, tachycardia, and paralysis. Hematologic effects may include decreased fibrinogen, elevated international normalized ratio (INR) and prothrombin time (PT), thrombocytopenia, and diffuse bleeding. Due to a variety of these effects, snake envenomation can rarely lead to limb loss and death making rapid evaluation and treatment of the bite of the utmost importance. However, not all snake bites require treatment with antivenom.⁵

Envenomation Treatment Indications

The unified treatment algorithm regarding the management of snake envenomation was published by Lavonas and colleagues in 2011. This algorithm can be applied to human patients who have been bitten by pit viper snakes, including those in the family Viperidae, subfamily Crotalinae, genus Crotalus, Sistrurus, and Agkistrodon. It is important to mention that while native to several states in the US, the algorithm does not apply to coral snakes or other non-indigenous snakes.⁵

Treatment with antivenom is indicated if there are progressive local tissue effects, like progressive edema, ecchymosis, or blebs, hematologic effects such as abnormal prothrombin time, fibrinogen, or platelet count, and/or systemic effects including hypotension, systemic bleeding, or any degree of neurotoxicity. Treatment with antivenom is also indicated if there is any swelling of the hand or impact to the airway. 

There are two Crotalide antivenom products currently available, Crotalidae polyvalent immune Fab (ovine), known as CroFab^® and Crotalidae immune F(ab’)₂ (equine), known as ANAVIP^®. Both products are FDA approved for the treatment of North American pit viper envenomation, however dosing, monitoring, and cost varies between the two products.

Product	WAC price per unit6,7	WAC price per vial	Cost/Initial Treatment
CroFab®	$6,396.00	$3,198.00	$19,188 (6 vials)
Anavip®	$1,320.00	$1,320.00	$13,200 (10 vials)

CroFab^® | Crotalidae polyvalent immune Fab (ovine)

CroFab^® was approved for use in 2000 and is made from the venom for four North American pit vipers including the Cottonmouth/water moccasin, Mojave rattlesnake, Eastern diamondback, and Western diamondback. Australian sheep are envenomated with the venom of these four snakes to produce specific antibodies/whole IgG against the toxins. During the manufacturing process, the Fc fragment of the antibody is removed to reduce hypersensitivity. The remaining Fab fragments are further purified to increase venom specificity and reduce adverse reactions.^5,8 After the purification process, a single active Fab fragment remains.

When used for the treatment of envenomation, the Fab fragments bind and neutralize venom toxins. This neutralization process halts local tissue effects, systemic effects, and promotes resolution of hematologic derangements. The Fab-toxin complex is then cleared from the body.^5,8

Dosing

There is no “one-size fits all” dosing scheme for antivenom, rather dosing strategies are based on effect and are titrated to clinical response.⁵ The goal of antivenom administration is to stop progression of soft tissue swelling and improve coagulopathy. Antivenom cannot reverse soft tissue swelling.

Based on CroFab^® prescribing information, the following algorithm is recommended, however, more or less antivenom can/should be used based on initial and maintained control.

Initial:

• 4 – 6 vials x 1. If initial control is not achieved in approximately 1 hour, administer an additional 4 – 6 vials.

Maintenance:

• Once initial control is achieved, administer an additional 2 vial every 6 hours x 3 doses.

Each vial of CroFab^® is to be reconstituted with 18 mL of 0.9% normal saline. The vial should be rotated, not shaken until no dry matter remains. All necessary vials can then be pooled together and further diluted with 0.9% normal saline to a total volume of 250 mL. Each pooled dose should be administered via intravenous infusion. To limit possible hypersensitivity reactions, the infusion should be started at 25 – 50 mL/hr for the first ten minutes. If no reaction is noted, the remainder of the infusion can be run over 60 minutes. 

Pharmacokinetics

Studies evaluating the pharmacokinetics of CroFab^® are limited, however the elimination half-life is estimated to be between 12 – 23 hours.⁹

ANAVIP^® | Crotalidae immune F(ab’)2 (equine)

ANAVIP^® was developed in 2015 and available for use in 2018. Unlike CroFab^®, ANAVIP® is directed against the Terciopelo, a species of pit viper found in Mexico and Central America and the Central American rattlesnake. While the snakes used for this antivenom are not found in the continental United States, the product retains activity against North American species.¹⁰ To produce ANAVIP^®, horses are envenomated to produce specific whole IgG antibodies. The Fc fragment of the antibody is then removed, however ANAVIP^® is a F(ab’)₂ agent meaning both antibody binding sites are retained after the purification process. This difference in structure has been hypothesized to contribute to the product’s longer elimination half-life.¹¹

Dosing

Based on ANAVIP^® prescribing information, the following algorithm is recommended:

Initial:

• 10 vials x 1, if initial control is not achieved in approximately 1 hour, administer an additional 10 vials.

Symptom re-emergence:

• Patients should be observed for 18 hours after treatment. If symptoms return during the observation window, administer an additional 4 vial dose.

Each vial of ANAVIP^® is to be reconstituted with 10 mL of 0.9% normal saline. The vial should be rotated, not shaken until no dry matter remains. All vials can then be pooled together and further diluted with 0.9% normal saline to a total volume of 250 mL. Each pooled dose should be administered via intravenous infusion. To limit possible hypersensitivity reactions, the infusion should be started at 25 – 50 mL/hr for the first ten minutes. If no reaction is noted, the remainder of the infusion can be run over 60 minutes.¹⁰

Pharmacokinetics

The elimination half-life of ANAVIP^® is estimated to be 5.5 days.¹⁰ This prolonged circulation time is postulated to result in a decreased risk of late coagulopathy and reduced need for repeat/maintenance dosing.¹³

Contraindications

CroFab^®/ANAVIP^® should not be administered to patients with a known hypersensitivity to its components, papaya, or papain (CroFab^® specifically). However, clinicians should weigh risks/benefit of antivenom use and ensure materials for the management of severe reactions are readily available.

Monitoring

Patients should be monitored for 8 – 24 hours after initial control to ensure there is no further progression. Additional labs to monitor for ongoing coagulopathy should be obtained 6–12 hours after initial control, prior to discharge, and twice after discharge (on day 2 – 3 and 5 – 7 days after discharge). 

• Labs should include CBC, platelet, INR/PT, PTT, and fibrinogen.

Comparison of CroFab^® and AVAVIP^®

Since the development and release of the two unique antivenoms, there has been ongoing debate regarding which product is more efficacious when treating pit viper envenomation. Several trials have been published comparing the two products including a Phase 2, prospective, randomized control trial (RCT) published by Boyer and colleagues in 2013.¹² This trial compared 12 patients with rattlesnake envenomation in Tucson, AZ who were randomly assigned to receive either CroFab^® or ANAVIP^® for treatment. The primary efficacy endpoint was quantitative serum venom levels evaluated with venom ELISA testing. Secondary endpoints included presence of coagulopathies such as platelet count and fibrinogen levels. Patients were evaluated after the first dose, at initial control, after each maintenance dose, daily through day 5, and at each additional follow-up visit for 2 weeks. In both groups, response to treatment was rapid with platelet and fibrinogen counts normalizing by the end of the maintenance period without differences between groups. However, in patients treated with CroFab^®, 67% of patients demonstrated a resurgence of plasma venom levels along with recurrent coagulopathies by follow-up day 6 while those treated with ANAVAP® did not experience any recurrence in plasma venom or coagulopathy. 

A second trial, published by Bush and colleagues in 2015 also compared the efficacy of CroFab^® and ANAVIP^® for the treatment of pit viper envenomation.¹³ This trial was a prospective, blinded, multicenter, RCT that included 121 patients who were randomly assigned to receive with CroFab^® with CroFab^® for maintenance dosing (CroFab^®/CroFab^®), ANAVIP® with ANAVIP^® for maintenance dosing (ANAVIP^®/ANAVIP^®) or ANAVIP^® with placebo for maintenance dosing (ANAVIP^®/placebo). The primary outcome was coagulopathy between the end of the maintenance dosing period and study day 8. For this trial, coagulopathy was defined as a platelet count < 150,000/mm³, fibrinogen < 150 mg/dL, or the use of antivenom to treat a coagulation abnormality prior to study day 5. Four (10%) of the patients in the ANAVIP®/ANAVIP® group experienced late coagulopathy compared to 11 (30%) of those in the CroFab^®/CroFab^® group. This was a statistically significant difference. This trial, along with the trial discussed above demonstrate that ANAVIP® may have a lower risk of late coagulopathy and decreased requirement for ongoing maintenance dosing.^12,13

While these two products differ in their production, pharmacokinetics, and incidence of late coagulopathy, both are safe and effective for the treatment of pit viper envenomation and clinicians should utilize whichever product is stocked by their hospital pharmacy. 

References

1. Gummin, D.D., Mowry, J.B., Beuhler, M.C., Spyker, D.A., Rivers, L.J., Feldman, R., Brown, K., Pham, N.P., Bronstein, A.C. and DesLauriers, C., 2023. 2022 Annual Report of the National Poison Data System^®(NPDS) from America’s Poison Centers^®: 40th Annual Report. Clinical Toxicology, 61(10), pp.717-939.
2. Gummin, D.D., Mowry, J.B., Beuhler, M.C., Spyker, D.A., Brooks, D.E., Dibert, K.W., Rivers, L.J., Pham, N.P. and Ryan, M.L., 2020. 2019 Annual report of the American Association of poison control centers’ National Poison Data System (NPDS): 37th annual report. Clinical toxicology, 58(12), pp.1360-1541.
3. Snakes in Your State. https://crofab.com/envenomation-education/snakes-in-your-state.html
4. Munawar, A., Ali, S.A., Akrem, A. and Betzel, C., 2018. Snake venom peptides: Tools of biodiscovery. Toxins, 10(11), p.474.
5. Lavonas, E.J., Ruha, A.M., Banner, W., Bebarta, V., Bernstein, J.N., Bush, S.P., Kerns, W.P., Richardson, W.H., Seifert, S.A., Tanen, D.A. and Curry, S.C., 2011. Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop. BMC emergency medicine, 11(1), pp.1-16.
6. Active Ingredient: CroFab^®. REDBOOK Online. IBM Micromedex [database online]. Truven Health Analytics/IBM Watson Health; 2024. https://www.micromedexsolutions.com
7. Active Ingredient: ANAVIP^®. REDBOOK Online. IBM Micromedex [database online]. Truven Health Analytics/IBM Watson Health; 2024. https://www.micromedexsolutions.com
8. Manufacturing. https://crofab.com/about-crofab/manufacturing.html
9. CroFab^®. Prescribing information. BTG International Inc.; August 2018.
10. ANAVIP^®. Prescribing Information. Rare Disease Therapeutics, Inc.; June 2021.
11. Summary Brochure. https://anavip-us.com/downloads/
12. Boyer, L.V., Chase, P.B., Degan, J.A., Figge, G., Buelna-Romero, A., Luchetti, C. and Alagón, A., 2013. Subacute coagulopathy in a randomized, comparative trial of Fab and F (ab′) 2 antivenoms. Toxicon, 74, pp.101-108.
13. Bush, S.P., Ruha, A.M., Seifert, S.A., Morgan, D.L., Lewis, B.J., Arnold, T.C., Clark, R.F., Meggs, W.J., Toschlog, E.A., Borron, S.W. and Figge, G.R., 2015. Comparison of F (ab’) 2 versus Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial. Clinical Toxicology, 53(1), pp.37-45.