2.1 Dose

• Administer CROFAB as soon as possible in patients who develop any signs of envenomation (e.g., local injury, coagulation abnormality or systemic signs of envenomation) to prevent clinical deterioration. CROFAB was shown in clinical studies to be effective when given within 6 hours of snakebite.
  
  
• Antivenin dosage requirements are contingent upon an individual patient’s response. Based on clinical experience with CROFAB, the recommended initial dose is 4 to 6 vials; however, the starting dose may vary from a minimum of 4 vials to a maximum of 12 vials based on clinical judgment and severity of envenomation [3].
  
  
• Observe the patient for up to 1 hour following completion of the first dose to determine if initial control of envenomation has been achieved. Initial control is achieved when local signs of envenomation are arrested (leading edge of local injury is not progressing), systemic symptoms are resolved and coagulation parameters have normalized or are trending toward normal. If initial control is not achieved by the first dose, an additional dose of 4 to 6 vials should be administered repeatedly until initial control of the envenomation syndrome has been achieved.
  
  
• Once initial control has been achieved, additional 2-vial doses of CROFAB every 6 hours for up to 18 hours (3 doses) are recommended. Optimal dosing following the 18-hour scheduled dose of CROFAB has not been determined. Additional 2-vial doses may be administered as deemed necessary by the treating physician, based on the patient’s clinical course.
  
  
• Infusion reactions, such as fever, low back pain, wheezing and nausea, may be related to the rate of infusion and can be controlled by decreasing the rate of administration of the solution [12]. Poison control centers are a helpful resource for individual treatment advice.

2.2 Preparation and Administration

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
  
  
• Reconstitute each vial of CROFAB with 18 mL of 0.9% Sodium Chloride (diluent not included) and mix by continuous manual inversion at the rate of one to two inversions per second until no solid material is visible in the vial (the fully reconstituted product will still be opalescent). Do not shake as this can cause foaming. Further dilute the contents of all of the reconstituted vials to a total volume of 250 mL with 0.9% Sodium Chloride and mix by gently swirling.
  
  
• Use the reconstituted and diluted product within 4 hours.
  
  
• Infuse the dose intravenously over 60 minutes. However, the infusion should proceed slowly over the first 10 minutes at a 25- 50 mL/hour rate with careful observation for any allergic reaction. If no such reaction occurs, the infusion rate may be increased to the full 250 mL/hour rate until completion. Close patient monitoring is necessary.
  
  

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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of CROFAB was evaluated in 289 patients who received CROFAB for crotalid envenomation. Forty-two patients were from two prospective clinical trials in patients who experienced mild to moderate crotalid envenomation; 247 patients were from a retrospective study in patients who experienced mild, moderate or severe envenomation. There also were safety information extracted from literature review of publications on CROFAB that contained patient exposure data.

Premarketing Prospective Clinical Trials

A total 42 patients received CROFAB for treatment of mild to moderate crotalid envenomation in two clinical studies. The patients were aged 11 to 76 years, and 34 were male and 8 were female. Nineteen patients experienced an adverse reaction for a total of 26 adverse reactions. Adverse reactions involving the skin and appendages (primarily rash, urticaria, and pruritus) were reported in 12 of the 42 patients (see Table 1). One patient discontinued CROFAB therapy due to an allergic reaction.

Of the 19 patients who experienced adverse reactions, 3 patients experienced severe or serious adverse reactions.

• 1 patient who experienced a serious adverse reaction had recurrent coagulopathy due to envenomation, which required re-hospitalization and additional antivenin administration. This patient eventually made a complete recovery.
• 2 patients had severe adverse reactions that consisted of 1 patient who developed severe urticaria following treatment and 1 patient who developed a severe rash and pruritus several days following treatment. Both patients recovered following treatment with antihistamines and prednisone.

Six of 42 patients experienced an adverse reaction associated with an early serum reaction and 4 experienced an adverse reaction associated with a late serum reaction. Two additional patients were considered to have experienced a late serum reaction by the investigator, although no associated adverse reaction was reported. Serum reactions are defined as reactions associated with CROFAB infusion. They consisted mainly of urticaria and rash, and all patients recovered without sequelae. Table 2 lists the incidence of early and late serum reactions. There were 7 events classified as early serum reactions and 5 events classified as late serum reactions; none was serious.

Postmarketing Retrospective Study

This was a retrospective study of data collected from postmarketing use of CROFAB to compare treatment and outcome characteristics between patients with severe envenomation to those with mild to moderate envenomation. A total of 247 patients received CROFAB for treatment of mild, moderate or severe crotalid envenomation. The patients were aged 1 to 91 years, and 206 were male and 41 were female. Of the 247 patients, 209 were classified as mild/moderate (n=181) or severe (n=28), while 38 patients did not have enough data to calculate an initial severity score.

There were a total of 36 immediate adverse drug reactions reported in 15 patients (6.1%, n = 247).

• There were 11 immediate serious adverse events related to CROFAB administration reported in four patients. The events included two episodes each of hypotension and tongue swelling, and one episode each of chest discomfort, angioedema, bronchospasm, wheezing, tracheal edema, dyspnea, and lip swelling.
• There were 22 immediate non-serious adverse events related to CROFAB administration reported in 12 patients. The events included four episodes each of rash and pruritus, three episodes of urticaria and one episode each of tachycardia, tachypnea, erythema, swelling, hyperhidrosis, dizziness, headache, musculoskeletal chest pain, chills, feeling cold and nervousness.

Delayed hypersensitivity reactions were reported for two patients. In one patient, symptoms described as hives, itching and epigastric pressure occurred 6 days post-dosing and were not serious. In the second patient, symptoms were not described in the medical records and therefore were not captured in this study.

Recurrent coagulopathy developed in 5 severely envenomated patients and in 6 mild/moderate envenomated patients. In addition, 7 mild/moderate patients experienced delayed-onset coagulopathy. One severely envenomated patient with recurrent coagulopathy experienced medically significant bleeding.

Additional Published Clinical Studies Experience

From a literature review of nine publications on CROFAB that contained patient exposure data, 15 of 313 (4.8%) patients receiving CROFAB experienced acute hypersensitivity reactions. The most common signs and symptoms associated with these reactions were rash (10 patients) and wheezing (3 patients). Most reactions were mild, resolved after antihistamine therapy, and did not require discontinuation of antivenom therapy. No patient developed a life-threatening hypersensitivity reaction, required intubation, suffered lasting ill-effect or died as a result of CROFAB administration.

Follow up data (minimum of six days after treatment) were available in 94 of the 313 patients. Delayed hypersensitivity reactions were reported in 10 cases. The most common signs and symptoms of delayed hypersensitivity were rash (9 patients) and fever (3 patients). Most were mild and treated with antihistamines and steroids.

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during the post approval use of CROFAB. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure:

• Delayed allergic reaction manifested by fever, pruritis and/or rash
• Delayed or recurrent coagulopathy or thrombocytopenia
• Failure to achieve initial control
• Recurrent swelling refractory to treatment
• Thrombocytopenia refractory to treatment
• Prolonged hospitalization
• Bleeding
• Tremor
• Treatment failure resulting in death

8.1 Pregnancy

Risk Summary
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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary
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.

8.4 Pediatric Use

Thirty-two percent (78/247) of patients studied in a post-marketing retrospective study of CROFAB were 16 years of age or younger (median 8.5 years [range 1 to 16 years]). Initial control of envenomation was achieved in 64/72 (89%) of pediatric patients, which was similar to the initial control rate in adults (103/128, 80%). Changes in severity score, recurrence and incidence adverse reactions were similar between pediatric and adult patients, indicating safety and efficacy in the pediatric population are comparable to that in adults. Limited published clinical experience has not shown that a dosage adjustment for age should be made [14, 15].

8.5 Geriatric Use

Five percent (13/247) of patients studied in a post-marketing retrospective study of CROFAB were over 65 years of age (median 72 years [range 67 to 91 years]). The efficacy and safety of CROFAB in the geriatric population appears comparable to the overall population.

12.1 Mechanism of Action

CROFAB is a venom-specific Fab fragment of immunoglobulin G (IgG) that works by binding and neutralizing venom toxins, facilitating their redistribution away from target tissues and their elimination from the body.

12.3 Pharmacokinetics

A limited number of samples were collected from three patients in the pharmacokinetic study of CROFAB. Based on these data, estimates of elimination half-life were made. The elimination half life for total Fab ranged from approximately 12 to 23 hours. These limited pharmacokinetic estimates of half-life are augmented by data obtained with an analogous ovine Fab product produced by BTG International Inc. using a similar production process. In that study, 8 healthy subjects were given 1 mg of intravenous digoxin followed by an approximately equimolar neutralizing dose of 76 mg of digoxin immune Fab (ovine). Total Fab was shown to have a volume of distribution of 0.3 L/kg, a systemic clearance of 32 mL/min (approximately 0.4 mL/min/kg) and an elimination half-life of approximately 15 hours.

13.2 Animal Toxicology and/or Pharmacology

CROFAB was effective in neutralizing the venoms of 10 clinically important North American crotalid snakes in a murine lethality model (see Table 4) [1]. In addition, preliminary data from experiments in mice using whole IgG from the sheep immunized for CROFAB production suggest that CROFAB might possess antigenic cross-reactivity against the venoms of some Middle Eastern and North African snakes; however, there are no clinical data available to confirm these findings.