Version May 2024
North American pit viper envenomation: Note: Initiate therapy as soon as possible and preferably within 6 hours after a North American pit viper bite in patients exhibiting any signs of envenomation (Anderson 2019; Greene 2021). Clinicians are encouraged to contact their local poison control center or clinical toxicologist for consultation when treating any envenomed patient. Although tourniquets are not recommended (Kanaan 2015), antivenin therapy should be initiated prior to tourniquet removal in patients who present with one in place. Tourniquet removal should only occur after the patient is tolerating the full infusion rate without signs of anaphylaxis (Bush 2015).
Initial: IV: 4 to 6 vials. Monitor for up to 1 hour following the infusion to determine if initial control has been achieved as evidenced by the arrest of local signs of envenomation (eg, leading edge of local injury is not progressing). Some clinicians recommend an initial dose of 8 to 12 vials for patients who present with immediately life-threatening effects (eg, shock, serious active bleeding) (Lavonas 2011b). Repeat with an additional 4 to 6 vials if control is not achieved with the initial dose. Continue to treat with 4- to 6-vial doses until local manifestations, coagulation tests, and systemic signs are normal. Maximum initial dose: 12 vials.
Maintenance: IV: Once initial control is achieved, administer 2 vials every 6 hours for up to 18 hours. Optimal dosing beyond 18 hours has not been established; however, treatment may be continued if deemed necessary based on the patient's condition.
Note: As needed dosing (as opposed to scheduled maintenance dosing) has been associated with a reduced length of stay and reduced antivenom used following rattlesnake envenomation (Spyres 2018); in patients envenomed by a copperhead, the use of scheduled maintenance doses may not be required based on patient presentation and response to treatment. Consultation with a poison control center or clinical toxicologist is recommended prior to using an as needed dosing strategy and/or prior to discontinuation of therapy (Greene 2021; Lavonas 2004; Lavonas 2011b).
Continuous infusion (off label): In cases of late hematological effects or in patients with medically significant bleeding complications from rattlesnake envenomation, the use of continuous IV infusion of antivenom may be of value. Reported rates of infusion has varied from 2 to 4 vials per 24 hours (Bush 2013).
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling.
Refer to adult dosing.
(For additional information see "Ovine polyvalent crotalidae North and South American snake antivenom: Pediatric drug information")
North American pit viper envenomation:
Note: Clinicians are encouraged to contact their local poison control center or clinical toxicologist for consultation when treating any envenomed patient. Although tourniquets are not recommended (Kanaan 2015), antivenin therapy should be initiated prior to tourniquet removal in patients who present with one in place. Tourniquet removal should only occur after the patient is tolerating the full infusion rate without signs of anaphylaxis (Bush 2015). Initiate therapy as soon as possible and preferably within 6 hours after a North American pit viper bite in patients exhibiting any signs of envenomation (Anderson 2019; Greene 2021).
Antivenom dosage is based on venom load and severity of symptoms and not on patient size; therefore, a reduced, weight-based antivenom dose in pediatric patients is not recommended (Behm 2003; Lavonas 2011a; Offerman 2002). Clinical trials included patients as young as 11 years of age. Use has been reported to be both safe and effective in children as young as 1 year of age (Johnson 2008; Schmidt 2005; Seifert 2009). Clinicians are encouraged to contact their local poison control center or clinical toxicologist for consultation when treating any envenomed patient, but especially pediatric patients.
Initial dose: Children and Adolescents: IV: 4 to 6 vials; monitor for 1 hour following infusion to determine if initial control has been achieved as evidenced by arrest of local signs of envenomation (eg, leading edge of local injury is not progressing). Some clinicians recommend an initial dose of 8 to 12 vials in patients presenting with immediately life-threatening effects (eg, shock, respiratory distress, cardiovascular collapse, significant hemorrhage, or severe neurologic toxicity) (Goto 2009; Lavonas 2011a). If control is not achieved, repeat with additional dose of 4 to 6 vials until initial control is achieved and local manifestations, coagulation tests and systemic signs are normal. Maximum initial dose: 12 vials.
Maintenance dose: Begin once control of envenomation achieved:
Intermittent dosing: Children and Adolescents: IV: 2 vials every 6 hours for up to 18 hours. Optimal dosing beyond 18 hours has not been established; however, treatment may be continued if deemed necessary based on patient condition. Note: Based on experience in adult patients, "as needed" dosing (as opposed to scheduled maintenance dosing) has been associated with reduced length of stay and reduced antivenom used (Spyres 2018); in patients envenomed by a copperhead, the use of scheduled maintenance doses may not be required based on patient presentation and response to treatment. Consultation with a poison control center or clinical toxicologist is recommended prior to using this dosing strategy and/or prior to discontinuation of therapy (Greene 2021; Lavonas 2004; Lavonas 2011b).
Continuous infusion: Adolescents ≥16 years: IV: Dosing regimens variable: Reported rates of infusion: 2 to 4 vials per 24 hours; a case series describing 5 patients (age range: 16 to 73 years) reported a mean dose: 3.1 ± 0.4 vials/day and mean duration of infusion: 6 ± 2 days (range: 4 to 14 days); in cases of late hematologic effects or in patients with medically significant bleeding complications from rattlesnake envenomation, the use of continuous intravenous infusion of antivenom may be of value. Consult poison control center or clinical toxicologist for use in pediatric patients (Bush 2013).
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions are derived from product labeling unless otherwise specified. Adverse reactions reported in children, adolescents, and adults.
Frequency not defined:
Dermatologic: Ecchymoses, pruritus, skin rash, subcutaneous nodule, urticaria
Gastrointestinal: Anorexia, nausea
Hypersensitivity: Hypersensitivity reaction, serum sickness
Nervous system: Nervousness
Neuromuscular & skeletal: Back pain, myalgia
Respiratory: Cough
Postmarketing:
Hypersensitivity: Angioedema, type I hypersensitivity reaction, type IV hypersensitivity reaction
Nervous system: Tremor
Hypersensitivity to any component of the formulation (including papaya or papain), unless the benefits outweigh the risks and appropriate management for anaphylaxis is readily available
Concern related to adverse effects:
• Hypersensitivity reactions: Derived from ovine (sheep) Fab immunoglobulin fragments; hypersensitivity reactions (eg, anaphylactic or anaphylactoid reactions, delayed allergic reactions) are possible. Patients with allergies to sheep proteins and patients with prior exposure to ovine antibodies or ovine Fab may be at a higher risk for anaphylactic reactions; however, the majority of early adverse reactions that occur following antivenom administration are de novo (reactions in individuals without prior exposure or sensitization) and are non-IgE mediated (Laustsen 2018). In patients who develop an anaphylactic reaction, discontinue the infusion immediately and administer emergency care. Immediate treatment (eg, epinephrine, corticosteroids, diphenhydramine) should be available (Campbell 2014).
- The incidence of acute hypersensitivity reactions appears to be lower than initially reported (Buchanan 2009; Cannon 2008; Khobrani 2019; Kleinschmidt 2018; Lavonas 2011b). Crotalidae polyvalent immune Fab (ovine) lacks the immunogenic Fc fragments and proteins found in the older equine-derived product.
- Crotalidae polyvalent immune Fab (ovine) is processed with papain and may cause hypersensitivity reactions in patients who are allergic to papaya, other papaya extracts, papain, chymopapain, or the pineapple-enzyme bromelain. There may also be cross allergenicity with dust mite and latex allergens. Galactose-α-1,3 galactose (α-gal), an allergen associated with IgE-mediated reactivity to mammalian meat, is present in Crotalidae polyvalent immune Fab (ovine) and several equine-derived antivenoms (Fischer 2017; Rizer 2017; Straesser 2021). The presence of α-gal may contribute to immediate hypersensitivity reactions to these antivenoms in patients with an underlying α-gal allergy (Fischer 2017; Rizer 2017; Straesser 2021).
Disease-related concerns:
• Crotalid envenomation: Antivenom should be used within 4 to 6 hours of the envenomation to prevent clinical deterioration and the development of coagulation abnormalities; however, the administration of antivenom may be beneficial even if treatment has been delayed (Bush 2013; Kelly 2022). Coagulation abnormalities are due directly to snake venom interference with the coagulation cascade. Recurrent coagulopathy occurs in ~50% of patients and may persist for 1 to 2 weeks or more; patients who have evidence of coagulopathy during the first 12 hours post antivenom treatment have an ~66% chance of recurrence, which typically occurs 2 to 14 days after completion of antivenom administration (Boyer 2001). Repeat dosing may be indicated (Miller 2010; Ruha 2011). Patients should be monitored for at least 1 week and evaluated for other preexisting conditions associated with bleeding disorders. In severe envenomation, a decrease in platelets may occur, lasting hours to several days. Blood products are generally ineffective as they are rapidly consumed by circulating venom.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
CroFab: (1 ea) [contains papain]
No
IV: Administer IV over 60 minutes at a rate of 25 to 50 mL/hour for the first 10 minutes. If no allergic reaction is observed, increase rate to 250 mL/hour. Monitor closely. Discontinue the infusion if any allergic reaction occurs and institute appropriate emergency treatment. Immediate treatment (eg, epinephrine, corticosteroids, diphenhydramine) should be available during the infusion of an antivenom (Campbell 2014; Lavonas 2011a). Decreasing the rate of infusion may help control some infusion-related adverse effects (eg, fever, low back pain, wheezing, nausea).
Parenteral: IV:
Intermittent doses: IV infusion: Administer at an initial rate of 25 to 50 mL/hour for the first 10 minutes; if tolerated and no allergic reaction observed, then increase rate so that total dose infuses over 60 minutes, usually to 250 mL/hour. Continue to monitor closely; discontinue the infusion if any allergic reaction occurs and institute appropriate emergency treatment. Immediate treatment (eg, epinephrine, corticosteroids, diphenhydramine) should be available during the infusion of an antivenom (Campbell 2014; Lavonas 2011a). Decreasing the rate of infusion may help control some infusion-related adverse effects, such as fever, nausea, low back pain, and wheezing.
Continuous IV infusion: Limited data available: In a case series, infusion rates were individualized and calculated based on delivery of vial doses over the day accounting for stability of preparations (Bush 2013).
North American pit viper envenomation: Management of adult and pediatric patients with North American crotalid envenomations (eg, rattlesnakes [Crotalus, Sistrurus], copperheads, and cottonmouth/water moccasins [Agkistrodon]).
Crotalid envenomation (other species [eg, South American rattlesnake])
None known.
There are no known significant interactions.
Information related to the use of crotalidae polyvalent immune FAB (ovine) in pregnancy is limited (Brown 2013; Ghosh 2018; Kravitz 2006; Moore 2019; Yano 2019).
In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant patients if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).
Available evidence suggests the main adverse pregnancy outcomes associated with a venomous snakebite (eg, fetal loss, placental abruption, preterm labor) are due to the direct effects of the toxin and resulting maternal illness. Antivenom administration in pregnancy should be considered when otherwise clinically indicated using a venom-specific approach, extended fetal and maternal monitoring, supportive care, and treatment of anaphylaxis if needed (Brown 2013; Kanaan 2015).
It is not known if this product is present in breast milk. The manufacturer recommends caution be used if administered to a breastfeeding patient.
Vital signs; CBC, platelet count, prothrombin time, aPTT, fibrinogen levels, fibrin split products, clot retraction, bleeding and coagulation times, BUN, electrolytes, bilirubin; measure the diameter (and circumference depending on the anatomical site) of the bite area/extremity at the leading edge of swelling and discoloration (repeat every 15 to 30 minutes); intake and output; signs and symptoms of anaphylaxis/allergy; signs and symptoms of delayed allergic reaction or serum sickness (rash, fever, myalgia, arthralgia). CBC, platelet counts, and clotting studies are evaluated at 6-hour intervals until patient is stable; patients who experience coagulopathy during hospitalization for initial treatment should be monitored ≥1 week to determine need for retreatment.
A venom-specific fragment of IgG, which binds and neutralizes venom toxin, helping to remove the toxin from the target tissue and eliminate it from the body.
Note: CroFab (Crotalidae polyvalent immune FAB [ovine]) originates from sheep immunized with the venom from the pit vipers Crotalus atrox (Western diamondback rattlesnake), Crotalus adamanteus (Eastern diamondback rattlesnake), Crotalus scutulatus (Mojave rattlesnake), and Agkistrodon piscivorus (cottonmouth/water moccasin).
Onset of action: Stability of patient or reduction in symptoms may be seen within 1 hour of administration.
Distribution: Vd: Unbound Fab: 110 mL/kg (Seifert 2001).
Half-life elimination: 12 to 23 hours (based on limited data).
Excretion: Excretion of the venom:antibody complex is speculated to occur via the reticuloendothelial system (Dart 1997). The excretion of Crotalidae polyvalent immune FAB antivenom that is not bound (free) to venom components is eliminated via renal excretion (Gutiérrez 2003).
Clearance: Unbound Fab: 5.9 mL/h/kg (Seifert 2001).
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