Dosage / Administration
Crotalidae polyvalent immune fab (ovine); brand name CroFab

• For management of North American crotalid envenomation.
• Snake species used for antivenin component: Crotalus atrox, Crotalus adamanteus, Crotalus scutulatus, and Agkistrodon piscivorus.
• Recommended dosage: 4-6 vials as needed to achieve control, then 2 vials every 6 hours for 3 doses.

Crotalidae Immune F(ab')₂ (equine); brand name Anavip

• For management of North American crotalid envenomation.
• Snake species used for antivenin component: Bothrops asper and Crotalus durissus.
• Recommended dosing: 10 vials repeated as needed to achieve control.

North American coral snake antivenin (NACSA); brand name Antivenin

• For management of eastern coral snake and Texas coral snake envenomation.
• Snake species used for antivenin component: Micrurus fulvius.
• Recommended dosing: 3-4 vials repeated as needed for clinical improvement.

All 3 antivenoms are packaged in vials as a powder that must be reconstituted by filling each vial with 18 mL of sterile water, then gently inverting them by hand to mix at a rate of 2 inversions per second until no solid material remains. Do not shake, as this causes foaming. The reconstituted antivenom is further diluted into 250 mL of 0.9% saline.

CroFab: The initial recommended dose of CroFab antibody is 4-6 vials mixed in 250 mL 0.9% saline and given over 1 hour. If the patient presents in cardiovascular collapse, the initial recommended dose is 8-12 vials. The exact concentration of antivenom is not critical.

Infusion rate: Infuse the initial dose at a rate of 10 mL/hour while the patient is closely observed. Have airway equipment at the bedside. After 5 minutes, if no adverse reactions are noted, the infusion rate is doubled every few minutes as tolerated, with the goal of infusing the first dose over 1 hour. If the initial dose is tolerated, subsequent doses can be given at 250 mL/hour without titration.

Anavip: The initial recommended dose of Anavip is 10 vials, again mixed in 250 mL 0.9% saline and administered over 1 hour. For the first 10 minutes, the infusion rate should be 25-50 mL/hour, then increased to the full 250 mL/hour until completion. Repeat doses of 10 vials are recommended until control is achieved. Clinical trials suggest no maintenance dosing is needed, but package inserts recommend 4 vials as needed for recurrent effects and 18 hours of monitoring once control is achieved.

NACSA: Mix by preparing each vial with 10 mL sterile water, then gently hand roll the vials for 1 minute. Initial recommended dose is 3-5 vials, mixed in 250 mL 0.9% saline and administered over 1 hour. Up to 10 vials can be administered. For access to NACSA, contact local poison control. In the United States, call 800-222-1222.

Pediatric dosing: The total volume of fluid in which the antivenom is diluted can be decreased when necessary for pediatric patients. There are no dosing adjustments for children because the amount of venom requiring neutralization is not dependent on the patient's weight.

Indications
Indications for CroFab and Anavip antivenom administration after confirmed crotalid envenomation:

• Progression of swelling
• Significant coagulopathy or thrombocytopenia (eg, if prothrombin time is elevated or if fibrinogen or platelet counts are decreased)
• Neuromuscular toxicity (eg, muscle fasciculations, weakness)
• Hemodynamic compromise (eg, shock)

When one or more of the above indications are met, give antivenom as soon as possible to prevent progression of swelling or coagulopathy. Early administration will not reverse swelling and tissue necrosis, but it may reduce pain, protect against future loss of function of the extremity, and reverse systemic effects such as coagulopathies.

Indications for NACSA administration after confirmed envenomation by the eastern coral snake (Micrurus fulvius) or the Texas coral snake (Micrurus tener): Neurologic abnormalities, including slurred speech, paresthesias, ptosis, diplopia, dysphagia, stridor, muscle weakness, fasciculation, and paralysis.

Empiric treatment in the absence of true signs of envenomation is not recommended.

Without antivenom, the mainstay of treatment for North American coral snake bites is supportive care. Respiratory failure may result from muscle weakness, and patients may require prolonged mechanical ventilation until their neurologic recovery. Paralysis typically takes weeks to months to completely resolve.

Contraindications
Do not give antivenom prophylactically to individuals without evidence of envenomation. Do not give antivenom for localized tissue swelling without other signs of envenomation. For example, localized swelling only around the bite site or swelling that does not cross a major joint (wrist, elbow, ankle, knee) does not require antivenom administration.

Do not give CroFab to patients with papaya or papain allergies unless the benefits of administration outweigh the risks of the allergic reaction. Note that patients with latex allergy or allergy to certain fruits (ie, banana, avocado, kiwi, apricot, chestnut, grape, passion fruit, and pineapple) may have cross-reactivity reactions with papain. Administration should be cautioned in these patients.

Avoid NACSA in patients with known horse serum allergy.

Pregnant patients who meet the criteria for CroFab or Anavip administration should receive it. They are currently listed as category C and have been safely used in pregnancy. Continuous fetal and maternal monitoring is recommended. It is unknown if either of these antivenoms are excreted in breastmilk. There are no reports of administration of NACSA in pregnancy, and knowledge of its safety in these patients is unknown, but given the severe morbidity associated with coral snake envenomation, administration to pregnant patients who meet criteria is recommended.

There are no specific contraindications to patient medications or past medical history, aside from those listed previously.

Monitoring
After each dose of 4-6 vials, prothrombin time, fibrinogen, and platelet counts should be measured. The patient should be re-examined at this interval as well. Note that multiple doses may be required to achieve control.

A retrospective study analyzing rattlesnake envenomations in the North American Snakebite Registry compared CroFab and Anavip for the total number of dose administrations required to achieve control of swelling. The study found that 3% of patients who received CroFab needed a fourth administration, while 14.5% of patients who received Anavip needed a fifth administration, suggesting that those treated with CroFab required fewer vials and fewer administrations of the antivenom. In contrast, another retrospective study at a single center compared total vials needed to achieve control in patients with confirmed copperhead envenomation and found no significant difference in total vials administered (11.4 of CroFab versus 10.7 of Anavip) and that Anavip was more cost effective.

If repeat dosing is needed to control swelling but laboratory tests remain normal, there is no need to repeat the laboratory work after each dose. The laboratory work should be repeated at 2-3 days and again at 5-7 days after hospital discharge to ensure that late recurrent hematologic effects do not develop.

Consultation with regional poison control centers for local practices and specific recommendations is recommended. In the United States, call 800-222-1222.

Adverse Effects
Acute and delayed hypersensitivity reactions, such as urticaria, rash, bronchospasm, pruritus, angioedema, anaphylaxis, and delayed serum sickness, are associated with all 3 antivenoms.

If antivenom is administered too rapidly, anaphylactoid reactions can occur. Most patients can tolerate 4-6 vials per hour without developing a reaction, but if the antivenom needs to be given more rapidly because of the severity of envenomation, histamine receptor antagonists and epinephrine infusion should be readily available.

For acute anaphylactic reactions, stop the antivenom and manage the reaction with aggressive supportive care. Start intravenous (IV) epinephrine at 2-4 mcg/minute (0.03-0.06 mcg/kg/minute for children) and titrate to effect. Corticosteroids and histamine receptor antagonists should be administered. If symptoms of the hypersensitivity resolve and there is high risk of morbidity and mortality from envenomation, restart the antivenom infusion at 1-2 mL/hour while continuing the epinephrine infusion and slowly increase the rate of antivenom infusion as tolerated, with constant physician monitoring at the bedside.

Toxicity
The initial dose of antivenom should be given in an emergency department or ICU setting with close monitoring and airway equipment at the bedside. Once the first dose is tolerated without adverse reaction, the remaining doses can be given in an inpatient step down or floor setting.

Mechanism of Action
Regardless of preparation, the antivenoms work the same: antibody fragments bind and neutralize venom components. Smaller antibody fragments penetrate tissues and redistribute the venom away from its original target.

Production
CroFab: Crotalidae polyvalent immune fab (ovine) is produced by inoculating sheep with the venom from the following species:

• Eastern diamondback rattlesnake (Crotalus adamanteus)
• Western diamondback rattlesnake (Crotalus atrox)
• Cottonmouth (Agkistrodon piscivorus)
• Mojave rattlesnake (Crotalus scutulatus)

The immunoglobulin G (IgG) antibodies are then isolated from the sheep serum and digested with papain, a protease derived from papayas. The venom-specific antibodies are isolated by affinity purification, which eliminates most of the sheep proteins. All 4 species-specific antivenoms are combined to form the final product.

Anavip: Crotalidae immune F(ab')₂ (equine) is produced by immunizing horses with the venom of the following snakes:

• Fer-de-lance (Bothrops asper)
• South American rattlesnake (Crotalus durissus)

The horse serum is prepared by pepsin digestion, as opposed to papain, and the antibody fragments are isolated by nanofiltration and ammonium sulfate precipitation. Anavip has a longer duration of action than CroFab and a slower clearance, more similar to that of actual venom.

NACSA: NACSA is produced by immunizing healthy horses with venom from the eastern coral snake (Micrurus fulvius). It is purified and concentrated but remains a whole IgG product, unlike CroFab and Anavip.