Crotalidae polyvalent immune Fab is an antivenin used in the management of North American crotalid envenomation (rattlesnakes, copperheads, and cottonmouths/water moccasins). It is produced by immunizing healthy sheep with one of the following North American snake venoms: Crotalus atrox (western diamondback rattlesnake), Crotalus adamanteus (eastern diamondback rattlesnake), Crotalus scutulatus (Mojave rattlesnake), and Agkistrodon piscivorus (cottonmouth or water moccasin). Venom-specific antibody fragments (Fab) of IgG are produced for each of the 4 venoms and are mixed to obtain the final antivenin product known as crotalidae polyvalent immune Fab. Since antivenin utilizes antibody fragments, which are smaller and lack the most immunogenic portions of the antibody, this formulation is less likely to induce an antibody response than products based on intact IgG. In addition, sheep-derived polyclonal antibodies are known to produce a decreased allergic response in humans when compared to equine-derived antibodies.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Administer the antivenin as soon as possible after crotalid snake bite in patients who develop any signs of envenomation (local injury, coagulation abnormality, systemic signs of envenomation). The antivenin has been shown to be effective when given within 6 hours of envenomation.
NOTE: Skin testing is not required prior to use of crotalidae polyvalent immune Fab.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The reconstituted product is opalescent.
Intravenous Administration
Reconstitution and Dilution
-Reconstitute each vial with 18 mL of 0.9% Sodium Chloride Injection, and mix by continuous manual inversion (1 to 2 inversions per second) until solid particles are no longer visible. Do not shake the vials as this will cause foaming.
-Dilute the contents of all the reconstituted vials to a total volume of 250 mL with 0.9% Sodium Chloride Injection. Mix by gentle swirling.
-Use the reconstituted and diluted product within 4 hours.
Intravenous infusion
-Administer the initial infusion slowly during the first 10 minutes at a rate of 25 to 50 mL/hour with careful observation for any allergic reaction.
-The infusion rate may be increased to 250 mL/hour until completion if no reaction occurs. Infusion-related reactions (fever, lower back pain, wheezing, nausea) may be controlled by decreasing the rate of administration. For individual treatment advice, consider contacting a poison control center.
-Following completion of the infusion, closely monitor for allergic reactions and progression of envenomation. Repeat doses may be required.
The safety of crotalidae polyvalent immune Fab has been evaluated in 289 patients. Of these 289 patients, 42 were from two prospective studies (age range: 11 to 76 years) and 247 were from a retrospective study of data collected during postmarketing use of the antivenin (age range: 1 to 91 years). Additionally, safety data are available from a literature review of nine publications involving 313 antivenin recipient.
Infusion-related reactions such as fever, low back pain, wheezing, and nausea may occur during administration of crotalidae polyvalent immune Fab, and can be controlled by decreasing the infusion rate. In the prospective clinical trials, 3 of the 42 antivenin recipients experienced nausea, 1 had anorexia, 1 had myalgia, and 2 had back pain. Some of these symptoms can be indicative of acute hypersensitivity or delayed serum reactions.
The most common adverse events reported in the crotalidae polyvalent immune Fab prospective clinical trials (n = 42) were dermatologic, including urticaria (n = 7), rash (n = 3), pruritus (n = 2), and subcutaneous nodules (n = 1). Early serum reactions were noted in 6 patients and consisted mainly of urticaria; 1 patient also experienced cough. Late serum reactions were noted in 4 patients and consisted of rash in 2, pruritus in 1, and urticaria in 1. Additionally, 2 of the 42 antivenin recipients experienced a severe reaction. The first patient developed severe urticaria and the other had a severe rash and pruritus. Both patients recovered following treatment with antihistamines and prednisone. In retrospective data from 247 patients, 12 patients had non-serious immediate symptoms such as rash, pruritus, urticaria, sinus tachycardia, tachypnea, erythema, swelling, hyperhidrosis, dizziness, headache, musculoskeletal chest pain, chills, feeling cold, and nervousness or anxiety. Tremor has been reported postmarketing.
Anaphylactic shock, anaphylactoid reactions, serum sickness, and fever are all possible due to the formation of immune complexes by animal antibodies and neutralized venom components. In the prospective clinical trials, 1 of the 42 antivenin recipients discontinued treatment due to an allergic reaction (urticaria, dyspnea, and wheezing) and 1 patient developed serum sickness (severe rash and pruritus). In retrospective data from 247 patients, 4 patients experienced immediate serious reactions including hypotension, tongue swelling, chest pain (unspecified), angioedema, bronchospasm, wheezing, tracheal edema, dyspnea, and lip swelling. Additionally, delayed hypersensitivity reactions were noted in 2 patients. The first developed non-serious symptoms described as hives, pruritus, and epigastric pressure occurring 6 days post-dosing. In the other patient, symptoms were not described in the medical records. A literature review of 9 publications involving 313 antivenin recipients identified 15 patients (4.8%) who developed an acute hypersensitivity reaction. The most common symptoms associated with these reactions were rash (n = 10) and wheezing (n = 3). Most of the reactions were mild, resolved with antihistamine therapy, and did not require discontinuation of the antivenin. No patient developed a life-threatening hypersensitivity reaction or suffered lasting ill-effects. The literature review also identified 10 delayed hypersensitivity reactions. Most were mild rash (n = 9) and fever (n =3), and were treated with antihistamines and steroids. If acute hypersensitivity reactions including anaphylaxis and anaphylactoid reactions occur, discontinue the infusion and institute appropriate emergency treatment. All patients should be followed up for signs and symptoms of delayed allergic reactions or serum sickness and treated appropriately if necessary. Because antibody formation may develop in patients who receive a course of treatment with a foreign protein such as crotalidae polyvalent immune Fab, caution should be taken when administering a repeat course of treatment for a subsequent envenomation episode.
In the crotalidae polyvalent immune Fab prospective clinical trials, 1 of the 42 antivenin recipients experienced a serious recurrent coagulopathy due to envenomation, which required re-hospitalization and additional antivenin administration. The patient eventually made a complete recovery. Additionally, ecchymosis was reported in 1 patient. In retrospective data from 247 patients, recurrent coagulopathy (including thrombocytopenia) developed in 5 severely envenomated patients and 6 patients with mild to moderate envenomation. Seven of the mild to moderate patients experienced delayed-onset coagulopathy, and 1 severely envenomated patient with recurrent coagulopathy developed medically significant bleeding.
Papain is used to cleave antibodies into fragments during the processing of crotalidae polyvalent immune Fab, and trace amounts of papain or inactivated papain residues may be present. The antivenin is contraindicated for use by patients with a known history of papaya hypersensitivity or papain hypersensitivity unless the benefits outweigh the risks and appropriate treatments for anaphylactic reactions (epinephrine, IV antihistamines, albuterol) are readily available. Patients with allergies to chymopapain, other papaya extracts, or the pineapple enzyme bromelain may also be at risk for an allergic reaction. In addition, some dust mite allergens and some latex allergens share antigenic structures with papain. Patients with latex hypersensitivity may be allergic to papain, and thus, demonstrate allergic reactions to crotalidae polyvalent immune Fab.
Crotalidae polyvalent immune Fab is derived from the blood of healthy sheep that have been immunized with snake venoms; therefore, caution is advised when considering use in patients with known ovine protein hypersensitivity. Administration of the antivenin can cause severe acute and delayed hypersensitivity reactions (serum sickness) and a possible febrile response to immune complexes formed by animal antibodies and neutralized venom components. Closely monitor drug recipients for signs of an acute allergic reaction (urticaria, pruritus, erythema, angioedema, bronchospasm with wheezing or cough, stridor, laryngeal edema, hypotension, tachycardia), and follow-up with all patients for delayed allergic reactions or serum sickness (rash, fever, myalgia, arthralgia). Ensure epinephrine, IV antihistamines, and albuterol are readily available during the infusion. Patients who have been treated previously with sheep-derived products may become sensitized to them. Use caution when administering a repeat course of treatment with crotalidae polyvalent immune Fab.
Snake envenomation may cause coagulation abnormalities; therefore, caution is advised when administering crotalidae polyvalent immune Fab to patients with preexisting conditions associated with coagulation defects. These include neoplastic disease, collagen vascular disease, congestive heart failure, diarrhea or steatorrhea, fever, hepatic disease, hyperthyroidism, malnutrition, and vitamin K deficiency. Recurrent coagulopathy (the return of a coagulation abnormality after it has been successfully treated with antivenin), characterized by decreased fibrinogen, thrombocytopenia, and elevated prothrombin time, occurred in approximately half of the patients studied in clinical trials. Patients who experience coagulopathy due to snakebite during hospitalization for initial treatment should be monitored for signs and symptoms of recurrent coagulopathy for up to 1 week or longer.
No adequate and well-controlled studies have been conducted to evaluate the use of crotalidae polyvalent immune Fab during pregnancy; thus, the ability of the antivenin to cause fetal harm or to affect reproduction capacity is unknown. Consider use of the antivenin in pregnant patients only if clearly needed.
Data are limited regarding use of crotalidae polyvalent immune Fab during breast-feeding and the excretion in breast milk is unknown. The manufacturer recommends caution when administering to lactating patients. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-fed infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the management of North American crotalid snake bite (rattlesnakes, copperheads, and cottonmouths/water moccasins):
NOTE: Administer the antivenin as soon as possible after crotalid snake bite in patients who develop any signs of envenomation (local injury, coagulation abnormality, systemic signs of envenomation). The antivenin has been shown to be effective when given within 6 hours of envenomation.
NOTE: The total dose of antivenin required is variable and depends upon the individual patient's response.
Intravenous dosage:
Adults: 4 to 6 vials via IV infusion over 60 minutes is the recommended starting dose; however, the starting dose may vary from 4 to 12 vials based on severity of envenomation. Start the infusion slowly at 25 to 50 mL/hour for the first 10 minutes with careful observation for any allergic reaction. If no reactions occur, the infusion rate may be increased to the full 250 mL/hour until completion. Once the infusion is complete, monitor the patient for at least 1 hour to determine that local signs of envenomation are not progressing, systemic symptoms are resolved, and coagulation parameters are trending towards normal. If control is not achieved, give additional 4- to 6-vial doses repeatedly until successful. After initial control has been achieved, give additional 2-vial doses IV every 6 hours for up to 18 hours (3 doses). Optimal dosing after this 18-hour schedule has not been determined; additional 2-vial doses may be given as deemed necessary based on patient's clinical course.
Adolescents: 4 to 6 vials via IV infusion over 60 minutes is the recommended starting dose; however, the starting dose may vary from 4 to 12 vials based on severity of envenomation. Start the infusion slowly at 25 to 50 mL/hour for the first 10 minutes with careful observation for any allergic reaction. If no reactions occur, the infusion rate may be increased to the full 250 mL/hour until completion. Once the infusion is complete, monitor the patient for at least 1 hour to determine that local signs of envenomation are not progressing, systemic symptoms are resolved, and coagulation parameters are trending towards normal. If control is not achieved, give additional 4- to 6-vial doses repeatedly until successful. After initial control has been achieved, give additional 2-vial doses IV every 6 hours for up to 18 hours (3 doses). Optimal dosing after this 18-hour schedule has not been determined; additional 2-vial doses may be given as deemed necessary based on patient's clinical course.
Infants and Children: Although data are limited, published clinical experience in children has shown that a dosage adjustment for age is not necessary. 4 to 6 vials via IV infusion over 60 minutes is the recommended starting dose; however, the starting dose may vary from 4 to 12 vials based on severity of envenomation. Start the infusion slowly at 25 to 50 mL/hour for the first 10 minutes with careful observation for any allergic reaction. If no reactions occur, the infusion rate may be increased to the full 250 mL/hour until completion. Once the infusion is complete, monitor the patient for at least 1 hour to determine that local signs of envenomation are not progressing, systemic symptoms are resolved, and coagulation parameters are trending towards normal. If control is not achieved, give additional 4- to 6-vial doses repeatedly until successful. After initial control has been achieved, give additional 2-vial doses IV every 6 hours for up to 18 hours (3 doses). Optimal dosing after this 18-hour schedule has not been determined; additional 2-vial doses may be given as deemed necessary based on patient's clinical course.
Maximum Dosage Limits:
-Adults
There is no known maximum dose; dosage must be individualized to the envenomation.
-Geriatric
There is no known maximum dose; dosage must be individualized to the envenomation.
-Adolescents
There is no known maximum dose; dosage must be individualized to the envenomation.
-Children
There is no known maximum dose; dosage must be individualized to the envenomation.
-Infants
There is no known maximum dose; dosage must be individualized to the envenomation.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Do not give immune globulin including varicella zoster immune globulin concurrently with the varicella-zoster virus vaccine, live. Because of the potential inhibition of the immune response to vaccination by passively transferred antibodies, it is advisable not to give varicella-zoster virus vaccine, live to any patient who has received blood (except washed red blood cells), plasma transfusions, or immunoglobulins within the previous 5 months. After varicella vaccination, the CDC recommends that immune globulin products should not be given for 3 weeks, unless the benefit outweighs the risk; the manufacturer recommends waiting 2 months before administering immunoglobulins. In the case that IgG products are administered within 3 weeks of vaccination, the vaccinee should be either revaccinated at 5 months or tested for immunity and revaccinated if seronegative. Consult current CDC guidelines for recommendations.
Varicella-Zoster Virus Vaccine, Live: (Major) Do not give immune globulin including varicella zoster immune globulin concurrently with the varicella-zoster virus vaccine, live. Because of the potential inhibition of the immune response to vaccination by passively transferred antibodies, it is advisable not to give varicella-zoster virus vaccine, live to any patient who has received blood (except washed red blood cells), plasma transfusions, or immunoglobulins within the previous 5 months. After varicella vaccination, the CDC recommends that immune globulin products should not be given for 3 weeks, unless the benefit outweighs the risk; the manufacturer recommends waiting 2 months before administering immunoglobulins. In the case that IgG products are administered within 3 weeks of vaccination, the vaccinee should be either revaccinated at 5 months or tested for immunity and revaccinated if seronegative. Consult current CDC guidelines for recommendations.
Crotalidae polyvalent immune Fab binds and neutralizes venom toxins from North American crotalids (rattlesnakes, copperheads, cottonmouth/water moccasins), facilitating their redistribution away from target tissues and their elimination from the body. Potency is based on mouse LD50 (lethal dose) neutralizing units. The minimum potency units per vial is as follows:
-1,270-times the LD50 of Crotalus atrox (Western Diamondback Rattlesnake) venom
-420-times the LD50 of Crotalus adamanteus (Eastern Diamondback Rattlesnake) venom
-5,570-times the LD50 of Crotalus scutulatus (Mohave Rattlesnake) venom
-780-times the LD50 of Agkistrodon piscivorus (Cottonmouth or Water Moccasin) venom
Crotalidae polyvalent immune Fab is administered intravenously. Pharmacokinetic data are limited to a study of 3 patients. The elimination half-life for total Fab ranged approximately 12 to 23 hours. The manufacturer's product literature offers additional perspective on crotalidae polyvalent immune Fab pharmacokinetics by drawing comparisons with an analogous ovine Fab product (digoxin immune Fab). This product was shown to have a volume of distribution of 0.3 L/kg, a systemic clearance of 32 mL/minute (approximately 0.4 mL/minute/kg), and an elimination half-life of approximately 15 hours; however, these data were based on only 8 patients.
Information on the pharmacokinetics of the Fab-venom complexes is also very limited. Due to the large molecular weight of venom components, it is likely that the Fab-venom complexes are not excreted in the urine, but removed by the reticuloendothelial system. Thus, the plasma half-life of the Fab-venom complex is expected to be longer than that for unbound Fab. Theoretically, the Fab-venom complex could dissociate after all the unbound Fab has been eliminated, allowing recurrence of toxic effects such as coagulopathy.
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Intravenous Route
Crotalidae polyvalent immune Fab pharmacokinetic data are limited to a study of 3 patients. The pharmacodynamics of crotalidae polyvalent immune Fab have not been described. Based on the available data from clinical studies, the onset of action appears to be rapid. The majority of patients treated with the antivenin in clinical studies achieved initial control of symptoms at 1 hour after the end of the infusion. However, prolonged and repeated administration is often needed.