warnings and cautions
5 WARNINGS AND PRECAUTIONS Monitor patients for recurrent coagulopathy for one week or longer following treatment of the bite ( 5.1 ) Hypersensitivity reactions, including anaphylaxis, may occur. Patients allergic to papain, chymopapain, papaya extracts, or bromelain (pineapple enzyme), may react to CROFAB ( 5.2 ) Treatment with the maximum dose of CROFAB used in clinical trials (18 vials) will deliver up to 0.6 mg of ethyl mercury (thimerosol) to a patient ( 5.3 ) 5.1 Coagulopathy Coagulopathy is a complication noted in many victims of crotalid envenomation that arises due to the ability of the snake venom to interfere with the blood coagulation cascad [ 5 , 9 , 10 ], 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; however, one systematic review of the literature showed that medically significant bleeding following treatment of Crotaline snake envenomation is uncommon, occurring with an estimated frequency of 0.5% [ 13 ]. 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 the snake 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 ( 2 )] . 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 re-treatment with CROFAB and use of any type of anticoagulant or anti-platelet 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. 5.2 Hypersensitivity Reactions Severe hypersensitivity reactions may occur with CROFAB. In case of acute hypersensitivity reactions, including anaphylaxis and anaphylactoid reactions, discontinue infusion and institute appropriate emergency treatment. CROFAB contains purified immunoglobulin fragments from the blood of sheep that have been immunized with snake venoms [see Description ( 11 )] . 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 components [ 11 ]. 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 [ 7 , 8 ]. Use the following precautions to manage hypersensitivity reactions: Emergency medical care (e.g., epinephrine, intravenous antihistamines and/or albuterol) should be readily available. Carefully monitor 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). 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. 5.3 Mercury Toxicity The final product contains up to 30 mcg or approximately 0.03 mg of mercury per vial, which amounts up 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.