CroFab: Package Insert and Label Information (Page 2 of 3)

6.2 Postmarketing Experience

The following additional 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:

  • 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
  • Tremor
  • Treatment failure resulting in death

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk SummaryAnimal 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary 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.

8.4 Pediatric Use

Thirty-two percent (78/247) of patients studied in a post-marketing retrospective study of CROFAB were 16 years of age or younger (median 8.5 years [range 1 to 16 years]). Initial control of envenomation was achieved in 64/72 (89%) of pediatric patients, which was similar to the initial control rate in adults (103/128, 80%). Changes in severity score, recurrence and incidence adverse reactions were similar between pediatric and adult patients, indicating safety and efficacy in the pediatric population are comparable to that in adults. Limited published clinical experience has not shown that a dosage adjustment for age should be made [14, 15].

8.5 Geriatric Use

Five percent (13/247) of patients studied in a post-marketing retrospective study of CROFAB were over 65 years of age (median 72 years [range 67 to 91 years]). The efficacy and safety of CROFAB in the geriatric population appears comparable to the overall population.

11 DESCRIPTION

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
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.
Venom Minimum Potency per Vial of CROFAB2
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

12.1 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.

12.3 Pharmacokinetics

A limited number of samples were collected from three patients in the pharmacokinetic study of CROFAB. 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 BTG International 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.

13 NONCLINICAL TOXICOLOGY

13.2 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 pre-mixed with two LD50 of each venom tested. ED50 for each venom (Note: Lower numbers represent increased potency against venoms listed) Challenge VenomED50 (mg antivenin/mg venom)C. atrox 3 C. adamanteus 18 C. scutulatus 8 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 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.

14 CLINICAL STUDIES

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
MinimalSwelling, pain, and ecchymosis limited to the immediate bite site; Systemic signs and symptoms absent; Coagulation parameters normal with no clinical evidence of bleeding
ModerateSwelling, 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)
SevereSwelling, 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

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:

  • 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 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.

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 ± SDPRN Group(n=16)Efficacy Score* Mean ± SD
Baseline4.0 ± 1.34.7 ± 2.5
End of Initial Control Antivenin Infusion(s)3.2 ± 1.43.3 ± 1.3
1 hour after Initial Control achieved3.1 ± 1.33.2 ± 0.9
6 hours after Initial Control achieved2.6 ± 1.52.6 ± 1.3
12 hours after Initial Control achieved2.4 ± 1.1** 2.4 ± 1.2**

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)

figure1
(click image for full-size original)

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.

Table 7 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

figure2
(click image for full-size original)

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.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2022. All Rights Reserved.