July 29, 2015
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Crofab

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Crofab

CLINICAL PHARMACOLOGY

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.

Pharmacokinetics

The pharmacokinetic study of CroFab® was not adequately performed. A limited number of samples were collected from three patients. 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 Protherics 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.

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.

Table 4 : Average ED50 Values for CroFab® in Mice

Study Objective & Design Endpoint Measured Major Findings and Conclusions
To determine the cross-neutralizing ability of CroFab®to protect mice from the lethal effects of venom from clinically important species.

Separate groups of mice were injected with increasing doses of CroFab® premixed with two LD50 of each venom tested.
ED50 for each venom (Note: Lower numbers represent increased potency against venoms listed)
Challenge Venom ED50
C. atrox 3
C. adamanteus 18
C. scutulatus 18
A. piscivorus 4
C. h. atricaudatus 11
C. v. helleri 6
C. m. molossus 5
A. c. contortrix 8
S. m. barbouri 12
C. h. horridus 6

Based on data from studies in mice, CroFab® has relatively good crossprotection 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.

Clinical Studies

No clinical studies have been conducted comparing CroFab® with other antivenins, therefore, no comparisons can be made between CroFab® and other antivenins.

Pre-marketing Studies

Two prospective clinical trials using CroFab® have been conducted. They were prospectively defined, open label, multi-center trials conducted in otherwise healthy patients 11 years of age or older who had suffered from minimal or moderate (as defined in Table 5) 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.

Table 5 : Definition of Minimal, Moderate, and Severe Envenomation in Clinical Studies of CroFab®

Envenomation Category 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 < 150), and tachypnea;
Coagulation parameters may be abnormal, but no clinical evidence of bleeding present. Minor hematuria, gum bleeding and nosebleeds are allowed if they are not considered severe in the investigator’s judgment.
Severe Swelling, pain, and ecchymosis involving more than an entire extremity or threatening the airway;
Systemic signs and symptoms are markedly abnormal, including severe alteration of mental status, severe hypotension, severe tachycardia, tachypnea, or respiratory insufficiency;
Coagulation parameters are abnormal, with serious bleeding or severe threat of bleeding.

In both clinical studies, efficacy was determined using a Snakebite Severity Score (SSS)2 (referred to as the efficacy score or ES in these clinical studies) and an investigator's clinical assessment (ICA) of efficacy. The SSS (referred to as the ES) 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. In a retrospective study using medical records of 108 snakebite victims2, the SSS has been shown to correlate well with physicians' assessment of the patient's condition at presentation (Pearson correlation coefficient: r=0.63, p < 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

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**
* 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).

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 correct3. These platelet count decreases have been observed to last for many hours and often several days following the venomous bite3, 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)

Graph of Platelet Counts from Baseline to 36 Hours for Patients with Counts < 100,000/mm³ at Baseline - Illustration

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

  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%)
^ 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.

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.

Figure 2 - Change in Platelet Counts in Individual Patients between Follow-Up Visits and Discharge

Change in Platelet Counts in Individual Patients between Follow-Up Visits and Discharge - Illustration

Post-marketing 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

1. 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.

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.

3. La Grange RG and Russell FE. Blood platelet studies in man and rabbits following Crotalus envenomation. Proc West Pharmacol Soc 1970;13:99-105.

4. Lyons WJ. Profound thrombocytopenia associated with Crotalus ruber ruber envenomation: a clinical case. Toxicon 1971; 9:237 240.

5. Tallon RW, Koch KL, Barnes SG, Ballard JO. Letter to Editor. N Engl J Med 1981;305:1347.

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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