Drug: Crofab

CroFab® [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 one of the following North American snake venoms: Crotalus atrox (Western Diamondback rattlesnake), Crotalus adamanteus (Eastern Diamondback rattlesnake), Crotalus scutulatus (Mojave rattlesnake), and Agkistrodon piscivorus (Cottonmouth or Water Moccasin). To obtain the final antivenin product, the four different monospecific antivenins are mixed. 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. CroFab® is standardized by its ability to neutralize the lethal action of each of the four venom immunogens following intravenous injection in mice. The potency of the product will vary from batch to batch; however, a minimum number of mouse LD50 neutralizing units against each of the four venoms is included in every vial of final product, as shown in Table 3. Table 3 : Minimum Mouse LD50 Neutralizing Units1 for Each Venom Component
Venom Minimum Potency per Vial of CroFab®2 Crotalus atrox ≥ 1270 Crotalus adamanteus ≥ 420 Crotalus scutulatus ≥ 5570 Agkistrodon piscivorus ≥ 780 1 One neutralizing unit is determined as the amount of the mixed monospecific Fab proteins necessary to neutralize one LD50 of each of the four venoms, where the LD50 is the amount of venom that would be lethal in 50% of mice.
2 As of 2008, the potency assay has been optimized for a new strain of mice, which has resulted in changes to the minimum mouse LD50 neutralizing units. These changes do not reflect any change in product potency, but only a different biological response of the mouse strain to the venom. Each vial of CroFab® contains up to 1 g of total protein and sodium phosphate buffer consisting of dibasic sodium phosphate USP and sodium chloride USP. Thimerosal is used as a preservative in the manufacturing process, and as such, mercury is carried over into the final product at an amount no greater than 30 mcg per vial, which amounts to no more than 0.6 mg of mercury per dose (based on the maximum dose of 18 vials used in clinical studies of CroFab®). The product is intended for intravenous administration after reconstitution with 18 mL of 0.9% Saline. Last reviewed on RxList: 4/17/2015
This monograph has been modified to include the generic and brand name in many instances.

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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 trails of another drug and may not reflect the rates observed in clinical practice.
  • The most common adverse events reported in the clinical studies were urticaria and rash. Adverse events involving the skin and appendages (primarily rash, urticaria, and pruritus) were reported in 14 of the 42 patients (Table 1).
  • Of the 25 patients who experienced adverse reactions, 3 patients experienced severe or serious adverse reactions.
    • The 1 patient who experienced a serious adverse event had a recurrent coagulopathy due to envenomation, which required re-hospitalization and additional antivenin administration. This patient eventually made a complete recovery.
    • The other 2 had severe adverse reactions that consisted of 1 patient who developed severe hives 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.
  • One patient discontinued CroFab® therapy due to an allergic reaction.
Table 1 : Incidence of Clinical Adverse Events in Studies of CroFab® by Body System
Adverse Events n=42*
Number of Events Body as a Whole Back pain 2 Chest pain 1 Cellulitis 1 Wound infection 1 Chills 1 Allergic reaction† 1 Serum sickness 1 Skin and Appendages Urticaria 7 Rash 5 Pruritus 3 Subcutaneous nodule 1 Cardiovascular System Hypotension 1 Respiratory System Asthma 1 Cough 1 Increased sputum 1 Digestive System Nausea 3 Anorexia 1 Hematologic/Lymphatic Coagulation disorder 3 Ecchymosis 1 Musculoskeletal Myalgia 1 Nervous System Circumoral paresthesia 1 General paresthesia 1 Nervousness 1 * Of the 42 patients receiving CroFab® in the clinical studies, 25 experienced an adverse event. A total of 40 adverse events was experienced by these 25 patients.
† Allergic reaction consisted of urticaria, dyspnea and wheezing in 1 patient. In the 42 patients treated with CroFab® for minimal or moderate crotalid envenomations, there were 7 events classified as early serum reactions and 5 events classified as late serum reactions, and none were serious (Table 2). In the clinical studies, serum reactions consisted mainly of urticaria and rash, and all patients recovered without sequelae. Table 2 : Incidence of Early and Late Serum Reactions (Reactions Associated with CroFab® Infusion)
  n=42*
Number of Events Early Serum Reactions Urticaria 5 Cough 1 Allergic reaction** 1 Late Serum Reactions Rash 2 Pruritus 1 Urticaria 1 Serum sickness† 1 * 6 of 42 patients experienced an adverse event associated with an early serum reaction and 4 experienced an adverse event associated with a late serum reaction. Two additional patients were considered to have a late serum reaction by the investigator, although no associated adverse event was reported.
** Allergic reaction consisted of urticaria, dyspnea and wheezing in 1 patient.
† Serum sickness consisted of severe rash and pruritus in 1 patient. Post-marketing Experience The following 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:
  • Acute allergic reactions including anaphylaxis or anaphylactoid type reactions during or shortly following CroFab® infusion, manifested by one or more of the following: anxiety, bronchospasm, chills, edema, fever, hypotension, pruritis, rash, urticaria, voice alteration, and/or wheezing
  • 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
  • Nausea
  • Tremor
  • Worsening eye sight
  • Treatment failure resulting in death
A retrospective study of data collected by the Rocky Mountain Poison and Drug Center for post-marketing use of CroFab® was conducted (13.2).
  • There were a total of 36 immediate adverse drug reactions reported in 6.1% (15/247) of patients in the post-marketing retrospective study, including one patient in the severely envenomated group (3.6%, n = 28) and 13 patients in the mild/moderate severity group (7.2%, n = 181) (not significantly different rates).
    • 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 pruritis, 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 the symptoms occurred 6 days post-dosing, were not serious, and described as hives, itching and epigastric pressure. In the second patient symptoms were not described in the medical records and were therefore 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® containing 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 and 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. Read the Crofab (crotalidae polyvalent immune fab ovine) Side Effects Center for a complete guide to possible side effectsLearn More »

Source: http://www.rxlist.com

For Intravenous Use after Reconstitution Dosage
  • Antivenin dosage requirements are contingent upon an individual patient's response; however, based on clinical experience with CroFab®, the recommended initial dose is 4 to 6 vials.
  • Administration of antivenin should be initiated as soon as possible after crotalid snakebite in patients who develop signs of progressive envenomation (e.g., worsening local injury, coagulation abnormality, or systemic signs of envenomation). CroFab® was shown in the clinical studies to be effective when given within 6 hours of snakebite.
  • The patient should be observed for up to 1 hour following the completion of this first dose to determine if initial control of the envenomation has been achieved (as defined by complete arrest of local manifestations, and return of coagulation tests and systemic signs to normal). If initial control is not achieved by the first dose, an additional dose of 4 to 6 vials should be repeated until initial control of the envenomation syndrome has been achieved.
  • After initial control has been established, additional 2-vial doses of CroFab® every 6 hours for up to 18 hours (3 doses) is 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.
  • Additional Patient Care (Supportive and Adjunctive Therapy): Supportive measures are often utilized to treat certain manifestations of crotalid snake envenomation, such as pain, swelling, hypotension, and wound infection. Poison control centers are a helpful resource for individual treatment advice.
Preparation And Administration
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
  • Each vial of CroFab® should be reconstituted with 18 mL of 0.9% Saline (diluent not included) and mixed by continuous manual inversion until no solid material is visible in the vial. Do not shake. The contents of all of the reconstituted vials should be further diluted in 250 mL of 0.9% Sodium Chloride USP and mixed by gently swirling.
  • The initial dose of CroFab® diluted in 250 mL of saline should be infused 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.
  • The reconstituted and diluted product should be used within 4 hours.

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Studies of drug interactions have not been conducted with CroFab®. Last reviewed on RxList: 4/17/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

CroFab® is indicated for the management of patients with North American crotalid envenomation (see Table 5 in Clinical Studies section for definitions). The term crotalid is used to describe the Crotalinae subfamily (formerly known as Crotalidae) of venomous snakes which includes rattlesnakes, copperheads and cottonmouths/water moccasins. Early use of CroFab® (within 6 hours of snakebite) is advised to prevent clinical deterioration and the occurrence of systemic coagulation abnormalities.

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CroFab® should not be administered to patients with a known history of hypersensitivity to papaya or papain unless the benefits outweigh the risks and appropriate management for anaphylactic reactions is readily available. Last reviewed on RxList: 4/17/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

The maximum amount of CroFab® that can safely be administered in single or multiple doses has not been determined. Doses of up to 18 vials (approximately 13.5 g of protein) have been administered without any observed direct toxic effect.

Source: http://www.rxlist.com

Dosage Forms And Strengths CroFab® is supplied as a sterile, nonpyrogenic, purified, lyophilized powder. Each vial contains up to 1 gram of total protein, a maximum of 0.03 mg of mercury, and not less than the indicated number of mouse LD50 neutralizing units*: Snake Species Used for Antivenin Component Minimum mouse LD50 Units per vial C. atrox (Western Diamondback rattlesnake) 1270 C. adamanteus (Eastern Diamondback rattlesnake) 420 C. scutulatus (Mojave rattlesnake) 5570 A. piscivorus (Cottonmouth or Water Moccasin) 780 * As of 2008, the potency assay has been optimized for a new strain of mice, which has resulted in changes to the minimum mouse LD50 neutralizing units. These changes do not reflect any change in product potency, but only a different biological response of the mouse strain to the venom. Storage And Handling CroFab® is supplied as a carton that contains 2 vials of product (diluent not included). Each vial of CroFab® contains up to 1 gram of lyophilized total protein and not less than the indicated number of mouse LD50 neutralizing units: Snake Species Used for Antivenin Component Minimum mouse LD50 Units per vial C. atrox (Western Diamondback rattlesnake) 1270 C. adamanteus (Eastern Diamondback rattlesnake) 420 C. scutulatus (Mojave rattlesnake) 5570 A. piscivorus (Cottonmouth or Water Moccasin) 780 NDC 50633-110-12
  • Store at 2° to 8°C (36° to 46°F).
  • Do not freeze.
  • Use within 4 hours after reconstitution.
REFERENCES 6. Quarre JP, Lecomte J, Lauwers D, Gilbert P, Thiriaux J. Allergy to latex and papain. J Allergy Clin Immunol 1995; 95(4):922. 7. Baur X, Chen Z, Rozynek P, Düser D, Raulf Heimsoth M. Cross reacting IgE antibodies recognizing latex allergens, including Hev b 1, as well as papain. Allergy 1995; 50(7):604 609. Manufactured for: and distributed by: BTG International Inc., West Conshohocken, PA 19428. Revised March 2012 Last reviewed on RxList: 4/17/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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.

Source: http://www.rxlist.com

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