† 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 cascade [4,8,9].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. 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 re-treatment with CroFab and use of any type of anticoagulant or anti-platelet drug.

† Papain is used to cleave the whole antibody into Fab and Fc fragments, and trace amounts of papain or inactivated papain residues may be present in CroFab. Patients with allergies to papain, chymopapain, other papaya extracts, or the pineapple enzyme bromelain may also be at risk for an allergic reaction to CroFab. In addition, it has been noted in the literature that some dust mite allergens and some latex allergens share antigenic structures with papain and patients with these allergies may be allergic to papain [6,7] (see CONTRAINDICATIONS).

General

CroFab contains mercury in the form of ethyl mercury from thimerosal.The final product contains up to 104.5 mcg or approximately 0.11 mg of mercury per vial, which amounts to no more than 1.9 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.

Anaphylaxis,Anaphylactoid Reactions and Allergic Reactions

† The possible risks and side-effects that attend the administration of heterologous animal proteins in humans include ana-phylactic and anaphylactoid reactions, delayed allergic reactions (late serum reaction or serum sickness) and a possible febrile response to immune complexes formed by animal antibodies and neutralized venom components [10].Although no patient in the clinical studies of CroFab has experienced a severe anaphylactic reaction,the possibility of an anaphylactic reaction should be considered. The patient should be informed of the possibility of an anaphylactic reaction and close patient monitoring and readiness with intravenous therapy using epinephrine and diphenhydramine hydrochloride is recommended during the infusion of CroFab. If an anaphylactic reaction occurs during the infusion, CroFab administration should be terminated at once and appropriate treatment administered. Patients with known allergies to sheep protein would be particularly at risk for an anaphylactic reaction.

† All patients treated with antivenin should be carefully monitored 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) and treated with appropriate emergency medical care (e.g., epinephrine, intravenous antihistamines and/or albuterol).

† All patients should be followed-up for signs and symptoms of delayed allergic reactions or serum sickness (e.g.,rash, fever, myalgia, arthralgia) and treated appropriately if necessary.

† 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 solution [11].

† 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.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

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

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 PRECAUTIONS, General). 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.

Geriatric Use:

Specific studies in elderly patients have not been conducted.

Pediatric Use:

Specific studies in pediatric patients have not been conducted. The absolute venom dose following snakebite is expected to be the same in children and adults, therefore, no dosage adjustment for age should be made.

CroFab contains mercury in the form of ethyl mercury from thimerosal (see PRECAUTIONS, General). 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.

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