Based on data from studies in mice, CROFAB has relatively good cross-protection against

venoms not used in the immunization of flocks used to produce it. For C. v. helleri and C. m.

molossus, higher doses may be required based on historical data.

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.

Premarketing Prospective Studies

Two premarketing prospectively defined, open label, multi-center trials were conducted in otherwise healthy patients 11 years of age or older who had experienced minimal or moderate North American crotalid envenomation that showed evidence of progression. Progression was defined as the worsening of any evaluation parameter used in the grading of an envenomation: local injury, laboratory abnormality or symptoms and signs attributable to crotalid snake venom poisoning. Both clinical trials excluded patients with Copperhead envenomation.

Efficacy was determined using a Snakebite Severity Score (SSS) [2] (referred to as the efficacy score or ES) and an investigator's clinical assessment (ICA) of efficacy. The SSS is a tool used to measure the severity of envenomation based on six body categories: local wound (e.g., pain, swelling and ecchymosis), pulmonary, cardiovascular, gastrointestinal, hematological and nervous system effects. A higher score indicates worse symptoms.. 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:

Safety was assessed during CROFAB infusion by monitoring for early allergic events, such as anaphylaxis and early serum reactions, and late events, such as late serum reactions [see Adverse Reactions (6.1)]

In clinical study 1, 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. After initial clinical response, two patients demonstrated a need for additional antivenom to stem progressive or recurrent symptoms and signs; one patient received an additional 4 vials of CROFAB. No patient in this study experienced an anaphylactic or anaphylactoid response or evidence of an early or late serum reaction as a result of administration of CROFAB.

Based on observations from the first study, the second clinical study compared two different CROFAB 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 normalization of coagulation tests and systemic signs. 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 study, CROFAB was administered 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.

It has been noted in published literature accounts of rattlesnake bites, that a decrease in platelets can accompany moderately severe envenomation, that was not corrected by whole blood transfusions [3]. These reductions in platelet count have been observed to last from several hours and to several days following the venomous bite [3, 4, 5]. In clinical study 2, 6 patients had pre-dosing platelet counts below 100,000/mm3 (baseline average of 44,000/mm3). 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 Platelet Counts from Baseline to 36 Hours for Patients with Counts <100,000/mm3 at Baseline (Clinical Study 2)

Although the difference in the decrease in ES between the two treatment groups was not significant, the data suggest that Scheduled dosing may provide better control of envenomation symptoms caused by continued leakage 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 more patients in the PRN Group showed a reduction in platelet count after discharge than in the Scheduled Group (see Figure 2). The need to administer additional CROFAB to patients in the PRN Group after initial control suggests there is continued need of antivenin for adequate treatment.

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

Only patients showing a reduced platelet count after discharge are shown

Postmarketing Retrospective Study

Following marketing approval of CROFAB, a retrospective study was conducted to assess the efficacy of CROFAB in mild, moderate and severe crotalid envenomation. This study was a multi-center, retrospective chart review of medical records of snakebite patients treated with CROFAB that compared treatment and outcomes of severe envenomation with those of mild and moderate envenomation. 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 whom 28 were classified as severe.

Improvement in severity score was observed in all 28 severely envenomated patients. Improvement was noted for each severe venom effect studied, including limb pain and swelling; cardiovascular, respiratory, gastrointestinal and neurologic effects; and coagulopathy/defibrination syndrome, thrombocytopenia and significant/spontaneous bleeding. The median dose of CROFAB administered to treat these severe venom effects was 9 vials (median of 2 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, which occurred in 1 severe case. All 12 severe patients who did not achieve 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 achieve 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 or not they achieved initial control, experienced significant improvement of venom effects and decreased severity scores after receiving CROFAB. Among patients with severe envenomation who did not achieve initial control, median severity score improved from 5 (range: 5 - 6) before CROFAB administration to 2 (range: 1 - 4) at the last loading dose. No patient in this analysis had a severity score greater than 3 at time of final clinical assessment.