twiddling with [150),:<0.0001) and when the patient's condition was at its worst (r=0.70, p> <0.0001). In this study, the condition of 87/108 patients worsened during hospitalization. Changes in the physicians' assessment of condition correlated well with changes in SSS. Crofab was required to prevent an increase in the ES in order to demonstrate efficacy. The ICA was based on the investigator s clinical judgment as to whether the patient had a: Clinical response (pre-treatment signs and symptoms of envenomation were arrested or improved after treatment) Partial response (signs and symptoms of envenomation worsened, but at a slower rate than expected after treatment) Non-response (the patient s condition was not favorably affected by the treatment). Safety was assessed by monitoring for early allergic events, such as anaphylaxis and early serum reactions during Crofab infusion, and late events, such as late serum reactions. TAb001: In the first clinical study of Crofab, 11 patients received an intravenous dose of 4 vials of Crofab over 60 minutes. An additional 4-vial dose of Crofab was administered after completion of the first Crofab infusion, if deemed necessary by the investigator. At the 1-hour assessment, 10 out of 11 patients had no change or a decrease in their ES. Ten of 11 patients were also judged to have a clinical response by the ICA. Several patients, after initial clinical response, subsequently required additional vials of Crofab to stem progressive or recurrent symptoms and signs. No patient in this first study experienced an anaphylactic or anaphylactoid response or evidence of an early or late serum reaction as a result of administration of Crofab. TAb002: Based on observations from the first study, the second clinical study of Crofab compared two different dosage schedules. Patients were given an initial intravenous dose of 6 vials of Crofab with an option to retreat with an additional 6 vials, if needed, to achieve initial control of the envenomation syndrome. Initial control was defined as complete arrest of local manifestations, and return of coagulation tests and systemic signs to normal. Once initial control was achieved, patients were randomized to receive additional Crofab either every 6 hours for 18 hours (Scheduled Group) or as needed (PRN Group). In this trial, Crofab was administered safely to 31 patients with minimal or moderate crotalid envenomation. All 31 patients enrolled in the study achieved initial control of their envenomation with Crofab, and 30, 25 and 26 of the 31 patients achieved a clinical response based on the ICA at 1, 6 and 12 hours respectively following initial control. Additionally, the mean ES was significantly decreased across the patient groups by the 12-hour evaluation time point (p=0.05 for the Scheduled Group; p=0.05 for the PRN Group) (see Table 6 ). There was no statistically significant difference between the Scheduled Group and the PRN Group with regard to the decrease in ES. Table 6 Summary of Patient Efficacy Scores for Scheduled and PRN Groups * No change or a decline in the Efficacy Score was considered an indication of clinical response and a sign of efficacy. ** For both the Scheduled and the PRN Groups, differences in the Efficacy Score at the four post-baseline assessment times were statistically decreased from baseline by Friedman s test (p> < 0.001). Time Period Scheduled Group (n=15) Efficacy Score * Mean SD PRN Group (n=16) Efficacy Score * Mean SD Baseline 4.0 1.3 4.7 2.5 End of Initial Control Antivenin Infusion(s) 3.2 1.4 3.3 1.3 1 hour after Initial Control achieved 3.1 1.3 3.2 0.9 6 hours after Initial Control achieved 2.6 1.5 2.6 1.3 12 hours after Initial Control achieved 2.4 1.1 ** 2.4 1.2 ** In published literature accounts of rattlesnake bites, it has been noted that a decrease in platelets can accompany moderately severe envenomation, which whole blood transfusions could not correct [ 3 ]. These platelet count decreases have been observed to last for many hours and often several days following the venomous bite [ 3, 4, 5 ]. In this clinical study, 6 patients had pre-dosing platelet counts below 100,000/mm3 (baseline average of 44,000/mm3). Of note, the platelet counts for all 6 patients increased to normal levels (average 209,000/ mm3) at 1 hour following initial control dosing with Crofab (see Figure 1 ). Figure 1 Graph of Platelet Counts from Baseline to 36 Hours for Patients with Counts <100,000/mm3 at Baseline (Study TAb002) Although there was no significant difference in the decrease in ES between the two treatment groups, the data suggest that Scheduled dosing may provide better control of envenomation symptoms caused by the continued leaking of venom from depot sites. Scheduled patients experienced a lower incidence of coagulation abnormalities at follow up compared with PRN patients (see Table 7 and Figure 2 ). In addition, the need to administer additional Crofab to patients in the PRN Group after initial control suggests that there is a continued need for antivenin for adequate treatment. Table 7 Lower Incidence of Recurrence of Coagulopathies at Follow-Up in Scheduled and PRN Dosing Groups ^ Numbers are expressed as percent of patients that had a follow-up platelet count that was less than the count at hospital discharge, or a fibrinogen level less than 50% of the level at hospital discharge. * Follow-up data not available for one patient. ** Statistically significant difference, p=0.04 by Fisher s Exact test. Scheduled Group (n=14) * (percent of patients with abnormal values) ^ PRN Group (n=16) (percent of patients with abnormal values) ^ Platelet 2/14 (14%) ** 9/16 (56%) ** Fibrinogen 2/14 (14%) 7/16 (44%) Figure 2 Change in Platelet Counts in Individual Patients between Follow-Up Visits and Discharge Patients in the Scheduled and PRN Groups are plotted separately. More patients in the PRN Group showed a reduction in platelet count after discharge than in the Scheduled Group. Only patients showing a reduced platelet count after discharge are shown. Postmarketing Studies Following marketing approval of Crofab a retrospective study was conducted to assess the efficacy of Crofab in severe envenomation. This study was a multi-center retrospective chart review of medical records of snakebite patients treated with Crofab and compared treatment and outcomes of severe envenomations to those of mild and moderate envenomations. The primary efficacy variable was severity of envenomation as determined by a 7-point severity score. Patients were classified as having mild, moderate, or severe envenomation based on their scores just prior to receiving antivenom. Those subjects with a severity score of 5 or 6 at the start of antivenom therapy were a priori defined as severe envenomations; those with a score of 3 or 4 were defined as moderate envenomations, and those with a score of 1 or 2 were defined as mild envenomations (see Table 5 ). A total of 247 patients of all severities were included in the study. Patients with enough data to determine baseline severity were included in the efficacy evaluation; this comprised a cohort of 209 patients, of which 28 were classified as severe. Improvement in the severity score was observed in all 28 severely envenomated patients. Improvement was noted in every one of the severe venom effects studied, including limb pain and swelling, cardiovascular, respiratory, gastrointestinal and neurologic effects, as well as coagulopathy/defibrination syndrome, thrombocytopenia, and significant/spontaneous bleeding. The median dose of Crofab administered to control these severe venom effects was 9.0 vials (median of 2.0 doses). Initial control of envenomation was achieved in 57% (16/28) of severely envenomated patients and 87% (158/181) of mild/moderate envenomated patients. In both groups failure to achieve initial control was most commonly attributable to persistent coagulopathy and/or thrombocytopenia, although medically significant bleeding has been reported (occurring in only 1 severe patient that did not reach initial control). All 12 severe patients who did not reach initial control received only one bolus dose of 4 to 6 vials to try to achieve initial control of envenomation. Of the 23 mild/moderate cases who did not reach initial control, 19 did not follow recommended dosing for number of doses and vials. Whether initial control could have been achieved with larger initial doses of antivenom cannot be determined from this retrospective study. All patients, whether they achieved initial control or not, experienced significant improvement of venom effects and decreased severity scores after receiving Crofab. Among the patients with severe envenomation who did not achieve initial control, the median severity score improved from 5.0 (range: 5.0 6.0) before Crofab administration to 2.0 (range: 1.0 4.0) at the last loading dose. No patient in this analysis had a severity score greater than 3.0 at the time of final clinical assessment. REFERENCES 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. How Supplied/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 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 NDC 50633-110-12 Store at 2 to 8 C (36 to 46 F). Do not freeze. Use within 4 hours after reconstitution. Patient Counseling Information 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. Revised March 2012 P11012C PRINCIPAL DISPLAY PANEL - NDC 50633-110-12 - Vial Label PRINCIPAL DISPLAY PANEL - NDC 50633-110-12 - Carton Label Crofab ovine crotalidae venoms immune fab injection, powder, lyophilized, for solution Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:50633-110 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CROTALUS ATROX IMMUNE FAB ANTIVENIN (OVINE) (CROTALUS ATROX IMMUNE FAB ANTIVENIN (OVINE)) CROTALUS ATROX IMMUNE FAB ANTIVENIN (OVINE) 1 g AGKISTRODON PISCIVORUS IMMUNE FAB ANTIVENIN (OVINE) (AGKISTRODON PISCIVORUS IMMUNE FAB ANTIVENIN (OVINE)) AGKISTRODON PISCIVORUS IMMUNE FAB ANTIVENIN (OVINE) 1 g CROTALUS SCUTULATUS IMMUNE FAB ANTIVENIN (OVINE) (CROTALUS SCUTULATUS IMMUNE FAB ANTIVENIN (OVINE)) CROTALUS SCUTULATUS IMMUNE FAB ANTIVENIN (OVINE) 1 g CROTALUS ADAMANTEUS IMMUNE FAB ANTIVENIN (OVINE) (CROTALUS ADAMANTEUS IMMUNE FAB ANTIVENIN (OVINE)) CROTALUS ADAMANTEUS IMMUNE FAB ANTIVENIN (OVINE) 1 g Inactive Ingredients Ingredient Name Strength SODIUM PHOSPHATE, DIBASIC, ANHYDROUS SODIUM CHLORIDE Packaging # Item Code Package Description 1 NDC:50633-110-12 2 VIAL, GLASS in 1 CARTON 1 1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, GLASS Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103788 02/10/2000 Labeler - BTG International Inc. (617382395) Establishment Name Address ID/FEI Operations Cangene bioPhamra Inc. 050783398 MANUFACTURE(50633-110) Establishment Name Address ID/FEI Operations Protherics UK Limited 536591589 API MANUFACTURE(50633-110) Revised: 07/2016 BTG International Inc. Next Interactions Print this page Add to My Med List More about CroFab (antivenin (crotalidae) polyvalent) Side Effects During Pregnancy Dosage Information Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: antitoxins and antivenins Consumer resources CroFab Crofab (Advanced Reading) Related treatment guides Venomous Snake Bite> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out N/A CSA Schedule Not a controlled drug Drug Class Antitoxins and antivenins Related Drugs antitoxins and antivenins Anascorp , diphtheria antitoxin , Anavip , antivenin (crotalidae) polyvalent , botulism antitoxin Venomous Snake Bite Anavip , antivenin (crotalidae) polyvalent , More... CroFab Rating No Reviews - Be the first! No Reviews - Be the first! 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