Complete SPL Sections
1 INDICATIONS AND USAGE
INDICATIONS & USAGE SECTION
CROFAB is indicated for the management of adult and pediatric patients with North American crotalid envenomation. 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.
2 DOSAGE AND ADMINISTRATION
DOSAGE & ADMINISTRATION SECTION
For intravenous use only
3 DOSAGE FORMS AND STRENGTHS
DOSAGE FORMS & STRENGTHS SECTION
CROFAB is available as a sterile, nonpyrogenic, purified, lyophilized powder. Each vial contains up to 1 gram of total protein and not less than the indicated number of mouse LD 50 neutralizing units * : * As of 2008, the potency assay has been optimized for a new strain of mice, which has resulted in changes to the minimum mouse LD 50 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. Snake Species Used for Antivenin Component Minimum mouse LD 50 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
4 CONTRAINDICATIONS
CONTRAINDICATIONS SECTION
Do not administer CROFAB 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.
5 WARNINGS AND PRECAUTIONS
WARNINGS AND PRECAUTIONS SECTION
6 ADVERSE REACTIONS
ADVERSE REACTIONS SECTION
Most common adverse reactions (incidence ≥5% of subjects) were urticaria, rash, nausea, pruritus and back pain. The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )]
8 USE IN SPECIFIC POPULATIONS
USE IN SPECIFIC POPULATIONS SECTION
11 DESCRIPTION
DESCRIPTION SECTION
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 LD 50 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 LD 50 Neutralizing Units 1 for Each Venom Component 1 One neutralizing unit is determined as the amount of the mixed monospecific Fab proteins necessary to neutralize one LD 50 of each of the four venoms, where the LD 50 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 LD 50 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. Venom Minimum Potency per Vial of CROFAB 2 Crotalus atrox ≥ 1270 Crotalus adamanteus ≥ 420 Crotalus scutulatus ≥ 5570 Agkistrodon piscivorus ≥ 780 Each vial of CROFAB contains up to 1 gram of total protein and sodium phosphate buffer consisting of dibasic sodium phosphate USP and sodium chloride USP. The product is intended for intravenous administration after reconstitution with 18 mL of 0.9% Sodium Chloride.
12 CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY SECTION
13 NONCLINICAL TOXICOLOGY
NONCLINICAL TOXICOLOGY SECTION
14 CLINICAL STUDIES
CLINICAL STUDIES SECTION
The safety and efficacy of CROFAB in crotalid envenomation were evaluated in two premarketing prospective and one postmarketing retrospective studies. The prospective studies evaluated patients suffering from minimal to moderate North American crotalid envenomation. The postmarketing study evaluated patients suffering from mild, moderate or severe envenomation. The definition of minimal, moderate, and severe envenomation in clinical studies of CROFAB is provided in Table 5 . Table 5 Definition of Minimal, Moderate, and Severe Crotalid Envenomation Envenomation Severity Definition Minimal Swelling, pain, and ecchymosis limited to the immediate bite site; Systemic signs and symptoms absent; Coagulation parameters normal with no clinical evidence of bleeding Moderate Swelling, pain, and ecchymosis involving less than a full extremity or, if bite was sustained on the trunk, head or neck, extending less than 50 cm; Systemic signs and symptoms may be present but not life threatening, including but not limited to nausea, vomiting, oral paresthesia or unusual tastes, mild hypotension (systolic blood pressure >90 mmHg), mild tachycardia (heart rate
15 REFERENCES
REFERENCES SECTION
Consroe P, Egen NB, Russell FE, Gerrish K, Smith DC, Sidki A, et al. Comparison of a new ovine antigen binding fragment (Fab) antivenin for United States Crotalidae with the commercial antivenin for protection against venom induced lethality in mice. J Trop Med Hyg 1995; 53(5):507 510. 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. Lavonas EJ, Ruha AM, Banner W, Bebarta V, Bernstein JN, Bush SP, Kerns WP, Richardson WH, Seifert SA, Tanen DA, Curry SC, Dart RC. Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop. BMC Emerg Med February 3 2011;11:2 ( http://www.biomedcentral.com/1471-227X/11/2 ). La Grange RG and Russell FE. Blood platelet studies in man and rabbits following Crotalus envenomation. Proc West Pharmacol Soc 1970;13:99-105. Lyons WJ. Profound thrombocytopenia associated with Crotalus ruber ruber envenomation: a clinical case. Toxicon 1971; 9:237 240. Tallon RW, Koch KL, Barnes SG, Ballard JO. Letter to Editor. N Engl J Med 1981;305:1347. Quarre JP, Lecomte J, Lauwers D, Gilbert P, Thiriaux J. Allergy to latex and papain. J Allergy Clin Immunol 1995; 95(4):922. 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. Furlow TG, Brennan LV. Purpura following timber rattlesnake (Crotalus horridus horridus) envenomation. Cutis 1985; 35:234 236. 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. Kojis FG. Serum sickness and anaphylaxis. Am J Dis Child 1997;93 350. 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. Lavonas EJ, Khatri V, Daugherty C, Bucher-Bartelson B, King T, Dart RC. Medically significant late bleeding after treated Crotaline envenomation: A systematic review. Ann Emerg Med 2014;63(1):71-78. Pizon AF, Riley BD, LoVecchio F, and Gill R. Safety and Efficacy of Crotalidae Polyvalent Immune Fab in Pediatric Crotaline Envenomations. Acad Emerg Med 2007;14:373-376. Offerman SR, Bush SP, Moynihan JA, Clark RF. Crotaline Fab Antivenom for the Treatment of Children with Rattlesnake Envenomation. Pediatrics 2002; 110(5):968-971.
16 HOW SUPPLIED/STORAGE AND HANDLING
HOW SUPPLIED SECTION
How Supplied CROFAB is supplied as a carton that contains 2 vials of product (diluent not included) [NDC 50633-110-12]. Each vial of CROFAB contains up to 1 gram of lyophilized total protein and not less than the indicated number of mouse LD 50 neutralizing units: Snake Species Used for Antivenin Component Minimum mouse LD 50 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 Storage and Handling Store vials at 2° to 8°C (36° to 46°F). A temperature excursion for no longer than 7 days within the range of -20° to 25°C (-4° to 77°F) is permitted. Do not freeze. Use within 4 hours after reconstitution.
17 PATIENT COUNSELING INFORMATION
INFORMATION FOR PATIENTS SECTION
Advise patients to contact their physician immediately if they experience unusual bruising or bleeding (e.g., nosebleeds, excessive bleeding after brushing teeth, the appearance of blood in stools or urine, excessive menstrual bleeding, petechiae, excessive bruising or persistent oozing from superficial injuries) after hospital discharge.Such bruising or bleeding may occur for up to 1 week or longer following initial treatment. Advise patients to contact their physician immediately if they experience any signs and symptoms of delayed allergic reactions or serum sickness (e.g., rash, pruritus, urticaria) after hospital discharge. Manufactured for and distributed by: BTG International Inc. West Conshohocken, PA 19428 U.S. License No. 1861 CroFab® is a registered trademark of BTG International Inc. BTG and the BTG roundel logo are registered trademarks of BTG International Ltd. P11012F
PRINCIPAL DISPLAY PANEL - NDC 50633-110-11 - Vial Label
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL - NDC 50633-110-12 - Carton Label
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL