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Antivenin (Crotalidae Polyvalent Immune Fab Ovine Systemic)


VA CLASSIFICATION
Primary: AD500

Commonly used brand name(s): CroFab.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antivenin —

Indications

Accepted

Envenomation, pit viper (treatment)—Antivenin (Crotalidae) polyvalent immune Fab (ovine) is indicated for the treatment of minimal or moderate envenomation caused by bites of North American crotalid species, including the Western Diamondback rattlesnake (Crotalus atrox), Eastern Diamondback rattlesnake (C. adamanteus), Mojave rattlesnake ( C. scutulatus), and Cottonmouth or Water Moccasin ( Agkistrodon piscivorus).{01} This medication is most effective when it is administered within 6 hours after envenomation.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Antivenin (Crotalidae) polyvalent immune Fab (ovine) is a sterile, nonpyrogenic, purified, lyophilized preparation of ovine Fab (monovalent) immunoglobulin fragments obtained from the blood of healthy sheep flocks immunized with the venoms of one of the following crotalid snake species: Western Diamondback rattlesnake (Crotalus atrox ), Eastern Diamondback rattlesnake (C. adamanteus ), Mojave rattlesnake (C. scutulatus), and the Cottonmouth or Water Moccasin (Agkistrodon piscivorus ). Each monospecific antivenin is prepared by fractionating the immunoglobulin from the ovine serum, digesting it with papain, and isolating the venom-specific Fab fragments on ion exchange and affinity chromatography columns. To obtain the final product, the four different monospecific antivenins are mixed together.{01} The antivenin is standardized by biological assay on mice, based on its ability to neutralize the lethal action of each of the four immunogens.{01}

Mechanism of action/Effect:

Antivenin (Crotalidae ) polyvalent immune Fab (ovine) is a venom-specific Fab fragment of immunoglobulin G (IgG) that binds and neutralizes venom toxins, facilitating their redistribution away from target tissues and their elimination from the body. {01}

Half-life:

Elimination— 12 to 23 hours.{01}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to sheep or any product of ovine origin may be sensitive to antivenin (Crotalidae) polyvalent immune Fab (ovine) also.{01}

Carcinogenicity and mutagenicity

Studies have not been done in humans or animals.{01}

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans.{01} Antivenin (Crotalidae) polyvalent immune Fab (ovine) contains ethyl mercury from thimerosal.{01} Although there are limited toxicology data on ethyl mercury, high dose and acute exposure to methyl mercury have been associated with neurological and renal toxicity.{01} Developing fetuses are most at risk for toxicity.{01}

Studies have not been done in animals.{01}

FDA Pregnancy Category C.{01}

Breast-feeding

It is not known whether antivenin (Crotalidae) polyvalent immune Fab (ovine) is distributed into human breast milk.{01}

Pediatrics

Appropriate studies on the relationship of age to the effects of antivenin (Crotalidae) polyvalent immune Fab (ovine) have not been performed in the pediatric population.{01} However, no dosage adjustment for age should be made, since the absolute venom dose following a snakebite is expected to be the same in children and adults.{01} It should be noted that antivenin (Crotalidae ) polyvalent immune Fab (ovine) contains ethyl mercury from thimerosal.{01} Although there are limited toxicology data on ethyl mercury, high dose and acute exposure to methyl mercury have been associated with neurological and renal toxicity.{01} Very young children are most at risk for toxicity.{01}


Geriatrics


No information is available on the relationship of age to the effects of antivenin (Crotalidae) polyvalent immune Fab (ovine) in geriatric patients.{01}

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Envenomation, history of{01}    (treatment with antivenin [Crotalidae] polyvalent immune Fab [ovine] may cause sensitization due to antibody formation;{01} caution should be exercised when administering this medication to a patient who has previously been treated with it{01})


» Hypersensitivity to bromelain{01}    (these patients may have an increased risk of developing an allergic reaction{01})


» Hypersensitivity to chymopapain{01} or
» Hypersensitivity to papain{01} or
» Hypersensitivity to papaya{01}    (papain is used to cleave the immunoglobulin into fragments, therefore, trace amounts of papain or residues of inactivated papain may be present in antivenin [Crotalidae] polyvalent immune Fab [ovine];{01} patients hypersensitive to papain or related compounds may have an increased risk of developing an allergic reaction;{01} use is not recommended unless the benefit outweighs the risk;{01} however, if used, appropriate management for anaphylactic reactions must be readily available{01})


» Hypersensitivity to dust mites{01} or
» Hypersensitivity to latex{01}    (these allergens are similar in structure to papain, which may be present in trace amounts in antivenin [Crotalidae] polyvalent immune Fab [ovine];{01} these patients may have an increased risk of developing an allergic reaction{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Allergic, anaphylactic, or anaphylactoid reaction{01}    (close monitoring is recommended for all patients receiving antivenin [Crotalidae] polyvalent immune Fab [ovine];{01} appropriate treatment, including albuterol and intravenous antihistamines and epinepherine, should be readily available to manage a reaction if one should occur{01})


» Coagulopathy, recurrent    (when initial envenomation leads to coagulopathy, patients should be monitored for symptoms of recurrent coagulopathy for 1 week or longer{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Note: Because antivenin (Crotalidae) polyvalent immune Fab (ovine) is derived from animal protein, it is possible that an anaphylactic, anaphylactoid, or allergic reaction or a febrile response to the immune complexes may occur following treatment.{01} Although during clinical trials, no patient experienced a severe anaphylactic reaction, it is recommended that all patients who receive this medication be closely monitored and that appropriate treatment be readily available to manage a reaction if one should occur.{01} If a reaction does occur, administration of antivenin (Crotalidae) polyvalent immune Fab (ovine) should be immediately discontinued and appropriate treatment given.{01}


Those indicating need for medical attention
Incidence more frequent
    
Coagulation disorder {01}(unexplained bleeding or bruising)

Incidence less frequent
    
Allergic reaction, acute, including angioedema (large, hive-like swellings on the eyelids, face, lips, mouth, and/or tongue)
    
bronchospasm with cough or wheezing
erythema (redness of skin), hypotension ( dizziness or lightheadedness), laryngeal edema (difficulty in swallowing), pruritus (itching of skin), stridor ( noisy breathing), tachycardia (fast heartbeat), urticaria (hives or welts; itching of skin; skin rash){01}
    
allergic reaction, delayed, including late serum reaction (pruritus ; skin rash; urticaria), serum sickness ( arthralgia; fever; myalgia; pruritus; skin rash){01}
    
asthma (difficulty in breathing; shortness of breath; wheezing){01}
    
cellulitis (chills; local pain, redness, and swelling; unusual tiredness or weakness){01}
    
chest pain {01}
    
ecchymosis (unusual bruising){01}
    
wound infection (chills; discharge from wound; pain, tenderness, and warmth at wound site; unusual tiredness or weakness){01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Nausea {01}
    
pruritus (itching of skin){01}
    
skin rash {01}
    
urticaria {01}(hives or welts; itching of skin; skin rash)

Incidence less frequent
    
Anorexia {01}(loss of appetite)
    
back pain {01}
    
chills {01}
    
cough {01}
    
hypotension {01}(dizziness or lightheadedness )
    
myalgia (muscle pain){01}
    
nervousness {01}
    
paresthesia {01}(burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings)—circumoral or generalized{01}
    
sputum, increased production {01}
    
subcutaneous nodules {01}(hard bumps under the skin )





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Antivenin, Pit Viper—Sheep-derived (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Hypersensitivity to bromelain (pineapple enzyme), chymopapain, dust mites, latex, papain, papaya, or sheep or ovine products
Other conditions, especially history of envenomation

Proper use of this medication

» Proper dosing


Side/adverse effects
Signs of potential side effects, especially coagulation disorder, acute allergic reaction, delayed allergic reaction, asthma, cellulitis, chest pain, ecchymosis, and wound infection


General Dosing Information
In the management of poisonous snakebite, the following should be considered. Cooling may predispose tissues already jeopardized by the snake venom enzymes to severe necrosis when rewarmed. Therefore, under no circumstances should the affected area be cooled, and so-called cryotherapy is contraindicated. A tourniquet should not be applied as a first-aid measure,{02} and excisional therapy is not recommended. Fasciotomy also should not be considered unless there is objective evidence of true compartment syndrome, in which case a surgical consultation should be obtained.{03} For more information on the management of snake envenomation, contact a Poison Control Center (see Poison Control Center Listing.{01}

Effectiveness of antivenin (Crotalidae) polyvalent immune Fab (ovine) is maximized when it is given within 6 hours of envenomation.{01}

Skin testing is not required prior to administration of antivenin (Crotalidae) polyvalent immune Fab (ovine).{01}

The initial intravenous infusion of antivenin (Crotalidae ) polyvalent immune Fab (ovine) should proceed slowly over the first 10 minutes at a rate of 25 to 50 mL per hour (mL/hour), with careful observation for any sign of allergic reaction.{01} If no reaction occurs, the infusion rate should be increased to 250 mL/hour until completion of the infusion.{01}


Parenteral Dosage Forms

ANTIVENIN (CROTALIDAE) POLYVALENT IMMUNE FAB (OVINE)

Usual Adult Dose
Pit viper envenomation
Initial: Intravenous, four to six vials over sixty minutes (at a rate of 25 to 50 mL per hour with close observation for an allergic reaction during the first ten minutes; if no allergic reaction develops, the rate may be increased to 250 mL per hour).{01} Additional four- to six-vial doses should be given until control of the envenomation has been achieved.{01}

Maintenance: Intravenous, two vials every six hours for up to eighteen hours (three doses).{01} Additional two-vial doses may be given, if necessary.{01}

Note: Initial control of the envenomation is defined as complete arrest of local manifestations and return of coagulation tests and systemic signs to normal.{01}



Usual Pediatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—


One vial of antivenin neutralizes not less than 1350 mouse LD 50 of Crotalus atrox (Western diamondback rattlesnake) venom; 800 mouse LD 50 of Crotalus adamanteus (Eastern diamondback rattlesnake) venom; 5210 mouse LD 50 of Crotalus scutulatus (Mojave rattlesnake) venom; and 460 mouse LD 50of Agkistrodon piscivorus(Cottonmouth or Water Moccasin) venom (Rx) [CroFab (dibasic sodium phosphate) (sodium chloride) (thimerosal [mercury £ 104.5 mcg]){01}]

Packaging and storage:
Store between 2 and 8°C (36 and 46°F).{01} Do not freeze.{01}

Preparation of dosage form:
Each vial of antivenin (Crotalidae) polyvalent immune Fab (ovine) should be reconstituted with 10 mL of sterile water for injection.{01} To avoid foaming, the contents of the vial should be mixed by gently swirling rather than by shaking.{01} The reconstituted solution should be further diluted in 250 mL of 0.9% sodium chloride injection.{01}

Stability:
The reconstituted and diluted solutions should be used within 4 hours.{01}



Developed: 07/5/2001



References
  1. Product Information: CroFab™, Crotalidae polyvalent immune Fab (ovine). Protherics, Nashville, TN (PI revised 12/2000), reviewed 5/2001.
  1. Smith TA II, Figge HL. Treatment of snakebite poisoning. Am J Hosp Pharm 1991; 48: 2190-6.
  1. Hogan DE, Dire DJ. Anaphylactic shock secondary to rattlesnake bite. Ann Emerg Med 1990; 19: 814-6.
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