Crotalidae immune F(ab')2 (Anavip) is a parenteral antivenin indicated for neutralizing the toxic effects of crotalid snake bites, specifically North American pit vipers. It is prepared by fractionating and purifying specific venom-neutralizing immunoglobulins obtained from the serum of healthy horses immunized against the venoms of Bothrops asper (Terciopelo or Fer-de-lance) and Crotalus simus (Central American Rattlesnake). The FDA approved initial dose for all patients consists of 10 vials; however, the total amount of antivenin required is highly variable and dependent on venom burden, potency of the venom, and the time to healthcare presentation. Gauge response to therapy and need for repeated dosing on the results of laboratory tests taken at baseline and at regular intervals during treatment. Following initial control of envenomation, patients must be closely monitored for at least 18 hours in order to identify re-emerging symptoms, immediate hypersensitivity reactions, and the development of delayed serum sickness.
Administration
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).
NOTE: Prior to administering the antivenin and at regular intervals during therapy, perform laboratory tests (complete blood count, platelet count, PT, PTT, serum fibrinogen concentration, serum chemistry) to assess response and need for additional doses.
NOTE: Certain manifestations of the envenomation (pain, swelling, hypotension, wound infection) may require use of supportive measures. Contact the local poison control center for addition individual treatment advice.
Route-Specific Administration
Injectable Administration
-Administer only by intravenous infusion.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The reconstituted solution is clear to yellow or green and opalescent; discard if discolored or turbid.
Intravenous Administration
Reconstitution and Dilution
-Reconstitute each vial with 10 mL of 0.9% Sodium Chloride Injection. Mix via continuous gentle swirling until solid particles are no longer visible; do not shake. Average reconstitution time is 11.8 seconds per vial (range: 8 to 26 seconds).
-Promptly combine the contents of the reconstituted vials and further dilute with 0.9% Sodium Chloride Injection to a total volume of 250 mL. Pediatric patients may require adjustments in total fluid volumes; consider contacting the Poison Control Center (800-222-1222) for individual treatment advise.
-Administer the diluted product as soon as possible, and within 6 hours. Discard partially or unused reconstituted and diluted product.
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 incrementally increased to 250 mL/hour until completion if no reaction occurs.
-Discontinue the infusion and institute appropriate emergency care if any allergic reaction occurs during treatment.
-Following completion of the infusion, continue to monitor for allergic reactions and progression of envenomation for at least 60 minutes. Repeat doses may be required.
The safety of crotalidae immune F(ab')2 was assessed in a total of 86 drug recipients ranging in age from 2 to 80 years. Potential adverse reactions of the antivenin were evaluated during the infusion and for up to 22 days after the infusion, with 76% (n = 65) of patients reporting at least one adverse reaction. In general, the safety profile of the antivenin was similar in pediatric and adult populations.
Local dermatologic reactions are common with crotalidae immune F(ab')2 administration. During clinical trials, pruritus (43%), rash (12%), blister (5%), and erythema (4%) were reported in drug recipients. If a systemic hypersensitivity reaction (e.g., urticaria, rash, wheezing, hypotension, chest tightness) develops during treatment, discontinue the infusion immediately and institute appropriate treatment. Reassess risk to benefit before continuing the infusion. Patients with follow-up visits should be monitored for signs and symptoms of delayed allergic reactions or serum sickness (e.g., pyrexia, rash, muscle aches, joint pain, pruritus, urticarial rash); administer appropriate treatment, as needed, should either occur.
Arthralgia (11%), myalgia (7%), and pain in the extremities (6%) have been reported in crotalidae immune F(ab')2 recipients during clinical trials. Of note, the injectable excipient used during the manufacturing process, cresol, has been associated with cases of generalized myalgia and localized reaction. According to the manufacturer, the final product contains trace amounts of cresol.
Nausea and vomiting were reported by 23% and 6%, respectively, of crotalidae immune F(ab')2 recipients during clinical trials.
Neurologic adverse events reported by patients treated with crotalidae immune F(ab')2 during clinical trials included headache (6%), anxiety (2%), and insomnia (2%).
Peripheral edema (8%), fever (5%), and chills (4%) have been associated with crotalidae immune F(ab')2 infusion during clinical trials.
Dehydration (2%), dyspnea (1%), and thrombocytopenia (1%) were observed in patients receiving crotalidae immune F(ab')2 during clinical trials.
Adverse events reported during postmarketing use of crotalidae immune F(ab')2 include chest pain (unspecified), flushing, hypersensitivity, late thrombocytopenia, tissue necrosis, prolonged prothrombin time, sinus tachycardia, urticaria, and treatment failure resulting in death. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Crotalidae immune F(ab')2 is derived from equine (horse) plasma; thus, this product must be used cautiously in patients with known equine protein hypersensitivity. Caution is also advised when administering to patients with known cresol hypersensitivity, as cresol is used during the manufacturing process and trace amounts are present in the final product. If a hypersensitivity reaction (i.e., urticaria, rash, wheezing, hypotension, chest tightness) develops during treatment, immediately stop the infusion and administer appropriate therapy. In addition, healthcare providers are advised to monitor patients for signs and symptoms of delayed allergic reactions or serum sickness (i.e., fever, rash, myalgia, arthralgia, pruritus, urticarial rash); administer appropriate treatment, as needed, should a delayed reaction or serum sickness develop.
As with other products derived from or purified with blood components, the possibility of transmitting a viral infection exists in patients receiving crotalidae immune F(ab')2. The manufacturing processes (including pepsin digestion, ammonium sulfate precipitation, heat treatment, nanofiltration) are designed to reduce the risk of transmitting viral infection; however, none of the processes are completely effective. There is also the possibility that unknown infectious agents may be present in this product.
Coagulation abnormalities may develop following snake envenomation; therefore, close monitoring of laboratory parameters (including platelet count, PT, PTT, serum fibrinogen concentration) is advised for all patients before and during treatment with crotalidae immune F(ab')2. Particular caution is advised when administering the antivenin to patients with preexisting conditions associated with coagulation defects (such as coagulopathy, neoplastic disease, hepatic disease, malnutrition, and vitamin K deficiency) as these patients may be at increased risk for adverse events.
No adequate and well-controlled studies have been conducted to evaluate the use of crotalidae immune F(ab')2 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.
No data are available regarding excretion of crotalidae immune F(ab')2 in human breast milk, the effects on a breast-fed infant, nor the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated maternal 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 crotalid snake bite (North American pit viper envenomation):
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).
NOTE: Prior to administering the antivenin and at regular intervals during therapy, perform laboratory tests (complete blood count, platelet count, PT, PTT, serum fibrinogen concentration, serum chemistry) to assess response and need for additional doses.
NOTE: The total dose of antivenin required is highly variable and depends on venom burden, potency of the venom, and the time to healthcare presentation.
Intravenous dosage:
Adults: 10 vials via IV infusion over 60 minutes. 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 incrementally increased to the full 250 mL/hour until completion. If there is an allergic reaction at any time, stop the infusion and treat accordingly. Once the infusion is complete, monitor the patient for at least 1 hour for allergic reactions and 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, administer additional 10-vial doses every hour until successful; there is no maximum dose. After initial control has been achieved, monitor the patient in a healthcare setting for at least 18 hours. Suppress any re-emerging symptoms by administering additional 4-vial doses as needed.
Infants, Children, and Adolescents: 10 vials via IV infusion over 60 minutes. 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 incrementally increased to the full 250 mL/hour until completion. If there is an allergic reaction at any time, stop the infusion and treat accordingly. Once the infusion is complete, monitor the patient for at least 1 hour for allergic reactions and 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, administer additional 10-vial doses every hour until successful; there is no maximum dose. After initial control has been achieved, monitor the patient in a healthcare setting for at least 18 hours. Suppress any re-emerging symptoms by administering additional 4-vial doses as needed.
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
There are no drug interactions associated with Crotaline Antivenin, Crotalidae products.
Crotalidae immune F(ab')2 binds and neutralizes venom toxins from North American pit vipers, 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:
-780-times the LD50 of Bothrops asper (Terciopelo or Fer-de-lance) venom
-790-times the LD50 of Crotalus simus (Central American Rattlesnake) venom
-244-times the LD50 of Crotalus adamanteus (Eastern Diamondback Rattlesnake) venom
-147-times the LD50 of Crotalus atrox (Western Diamondback Rattlesnake) venom
-185-times the LD50 of Crotalus scutulatus (Mohave Rattlesnake) venom
-28-times the LD50 of Agkistrodon contortrix (Copperhead) venom
-61-times the LD50 of Agkistrodon piscivorus (Cottonmouth or Water Moccasin) venom
Crotalidae immune F(ab')2 is administered by intravenous infusion. Pharmacokinetic data are available from a study involving 13 healthy volunteers who were administered a single one-vial intravenous dose (81.86 mg) of antivenin. After the infusion, blood samples were collected from each volunteer at 15 specific time points (range 5 to 480 minutes after infusion). Additional samples were collected just prior to discharge on Day 1, and on Days 3, 5, 7, 9, 11, and 21. Data from these blood samples suggests a 2-compartment model with the following mean pharmacokinetic values: 3.3 L steady-state volume of distribution, 4,144 mcg x hour/mL systemic exposure (AUC), 22 mL/hour total clearance, and an elimination half-life of 133 hours.
Affected cytochrome P450 isoenzymes: none