July 28, 2015
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Crofab

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Crofab

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Coagulopathy

Coagulopathy is a complication noted in many victims of viper envenomation that arises due to the ability of the snake venom to interfere with the blood coagulation cascade4, 8, 9, and is seen more frequently in severely envenomated patients. In clinical trials with CroFab®, recurrent coagulopathy (the return of a coagulation abnormality after it has been successfully treated with antivenin), characterized by decreased fibrinogen, decreased platelets, and elevated prothrombin time, occurred in approximately half of patients studied. The clinical significance of these recurrent abnormalities is not known. Recurrent coagulation abnormalities were observed only in patients who experienced coagulation abnormalities during their initial hospitalization, although coagulopathy can initially appear at any time before, during or after treatment. Optimal dosing to completely prevent recurrent coagulopathy has not been determined. Because CroFab® has a shorter persistence in the blood than crotalid venoms that can leak from depot sites over a prolonged period of time, repeat dosing to prevent or treat such recurrence may be necessary (see DOSAGE AND ADMINISTRATION).

Recurrent coagulopathy may persist for 1 to 2 weeks or more. 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 at the physician's discretion. During this period, the physician should carefully assess the need for retreatment with CroFab® and use of any type of anticoagulant or antiplatelet drug.

Because snake envenomation can cause coagulation abnormalities, the following conditions, which are also associated with coagulation defects, should be considered: cancer, collagen disease, congestive heart failure, diarrhea, elevated temperature, hepatic disorders, hyperthyroidism, poor nutritional state, steatorrhea, vitamin K deficiency.

Hypersensitivity Reactions

Severe hypersensitivity reactions may occur with CroFab®. In case of acute hypersensitivity reactions, including anaphylaxis and anaphylactoid reactions, discontinue infusion and institute appropriated emergency treatment.

CroFab® contains purified immunoglobulin fragments from the blood of sheep that have been immunized with snake venoms (see DESCRIPTION). Injection of heterologous animal proteins can cause severe acute and delayed hypersensitivity reactions (late serum reaction or serum sickness) and a possible febrile response to immune complexes formed by animal antibodies and neutralized venom components10].

Papain is used to cleave antibodies into fragments during the processing of CroFab®, and trace amounts of papain or inactivated papain residues may be present. Patients allergic to papain, chymopapain, other papaya extracts, or the pineapple enzyme bromelain may also have an allergic reaction to CroFab®. Some dust mite allergens and some latex allergens share antigenic structures with papain and patients with these allergies may be allergic to papain.

The following precautions should be used to manage hypersensitivity reactions:

Emergency medical care (e.g., epinephrine, intravenous antihistamines and/or albuterol) should be readily available.

Carefully monitored patients for signs and symptoms of an acute allergic reaction (e.g., urticaria, pruritus, erythema, angioedema, bronchospasm with wheezing or cough, stridor, laryngeal edema, hypotension, tachycardia).

Follow-up all patients for signs and symptoms of delayed allergic reactions or serum sickness (e.g., rash, fever, myalgia, arthralgia).

It has been noted in the literature with the use of other antibody therapies, that reactions during the infusion, such as fever, low back pain, wheezing and nausea are often related to the rate of infusion and can be controlled by decreasing the rate of administration of the solution11.

Patients who receive a course of treatment with a foreign protein such as CroFab® may become sensitized to it. Therefore, caution should be used when administering a repeat course of treatment with CroFab® for a subsequent envenomation episode.

Skin testing has not been used in clinical trials of CroFab® and is not required.

Mercury Toxicity

The final product contains up to 30 mcg or approximately 0.03 mg of mercury per vial, which amounts to no more than 0.6 mg of mercury per dose (based on the maximum dose of 18 vials studied in clinical trials of CroFab®). While there are no definitive data on the toxicity of ethyl mercury, literature suggests that information related to methyl mercury toxicities may be applicable.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Animal carcinogenicity and reproduction studies have not been conducted with CroFab®.

Use In Specific Populations

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with CroFab®. It is also not known whether CroFab® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CroFab® should be given to a pregnant woman only if clearly needed.

CroFab® contains mercury in the form of ethyl mercury from thimerosal (see WARNINGS AND PRECAUTIONS, Mercury). Although there are limited toxicology data on ethyl mercury, high dose and acute exposures to methyl mercury have been associated with neurological and renal toxicities. Developing fetuses and very young children are most susceptible and therefore, at greater risk

Nursing Mothers

It is not known whether CroFab® is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when CroFab® is administered to a nursing woman.

Pediatric Use

Specific studies in pediatric patients have not been conducted. Limited clinical experience has not shown that a dosage adjustment for age should be made.

CroFab® contains mercury in the form of ethyl mercury from thimerosal (see WARNINGS AND PRECAUTIONS, Mercury). Although there are limited toxicology data on ethyl mercury, high dose and acute exposures to methyl mercury have been associated with neurological and renal toxicities. Developing fetuses and very young children are most susceptible and therefore, at greater risk.

Geriatric Use

Specific studies in elderly patients have not been conducted.

REFERENCES

2. Dart RC, Hurlbut KM, Garcia R, Boren J. Validation of a severity score for the assessment of Crotalid snakebite. Ann Emerg Med 1996;27(3):321 326.

4. Lyons WJ. Profound thrombocytopenia associated with Crotalus ruber ruber envenomation: a clinical case. Toxicon 1971; 9:237 240.

8. Furlow TG, Brennan LV. Purpura following timber rattlesnake (Crotalus horridus horridus) envenomation. Cutis 1985; 35:234 236.

9. Budzynski AZ, Pandya BV, Rubin RN, Brizuela BS, Soszka T, Stewart GJ. Fibrinogenolytic afibrinogenemia after envenomation by western diamondback rattlesnake (Crotalus atrox). Blood 1984; 63(1):1 14.

10. Kojis FG. Serum sickness and anaphylaxis. Am J Dis Child 1997;93 350.

11. Kirkpatrick CH, The Digibind Study Advisory Panel. Allergic histories and reactions of patients treated with digoxin immune Fab (ovine) antibody. Am J Emerg Med 1991; 9(2 Suppl 1):7 10.

Last reviewed on RxList: 4/17/2015
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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