The Poison Control Center

Crotalidae Polyvalent Immune Fab (Ovine)

Introduction

Wyeth-Ayerst's Antivenin Crotalidae Polyvalent (ACP) has been the gold standard of care for snakebite poisoning in the United States. Until recently, all venomous snakebites in the United States have been treated with this whole IgG antivenin. This product was successful at treating rattlesnake envenomation but had substantial adverse effects. These adverse events often included anaphylactoid reactions (23 percent) and serum sickness (50 percent).¹ Although most adverse events did not result in mortality when treated with appropriate medication, such complications are problematic and fueled the development of a less immunogenic antivenin. Biotechnological advances resulted in a new antivenin that purports to be less immunogenic than the standard antivenin.

In attempt to address these issues, Protherics Inc. developed a fragmented antivenin that only utilizes the Fab fragment of the antibody. Similar to the methods that were used to produce Digibind, Protherics was able to separate the Fab fragments from the Fc fragments which were assumed to be responsible for the allergic reaction.^2-3 Crofab and other Fab productions such as Digibind have been shown to be safe and effective in remarketing trials.⁸ Nevertheless, products that are derived from an animal source have the potential to precipitate an allergic reaction in humans.

Crofab is a mixture of Fab fragments produced by a sheep (ovine) where as ACP is derived from a horse (equine). This was accomplished by injecting separate flocks of sheep with venom from the following North American venomous snakes: Crotalus Atrox (Western Diamondback rattlesnake), Crotalus Adamanteus (Eastern Diamondback rattlesnake), Crotalus Scutulatus (Mojave rattlesnake) and Agkistrodon Picvorus (Cottonmouth or Water Moccasin). Then the four resulting antivenins are harvested. They are mixed and the serum is digested with papain. Finally, the Fab fragments are isolated by an ion exchange and affinity chromatography columns.⁴ Crofab is indicated for treatments of minimal to moderate cases of North American crotalid envenomation because the current studies were only documented for these conditions.⁴

Dosing

Protherics recommends that Crofab should be given on a scheduled basis: four to six vials as the initial dose (within six hours of snake bite) and with close patient monitoring for the first hour. If optimum control is not achieved, another four to six vials can be administered, followed by two vials every six hours for up to 18 hours. Crofab is supplied in a dry powder form that needs to be reconstituted. This can be accomplished in less then 45 minutes compared to 60 minutes with the Wyeth's Antivenin.⁷ Each vial should be diluted with 10 ml of sterile water and then the resulting solution diluted in 250 ml of saline for infusion. In addition, Protherics recommends infusion over 60 minutes. The first 10 minutes of infusion should be maintained at a rate of 25-50 ml/hour while examining the patient for any signs of allergies. If no such signs develop, the infusion can be increased to 250 ml/hr until completion, but epinephrine, antihistamines and supportive care should be readily available for prompt rescue if deemed necessary.

Based on a study done by Boyer et al, 20 out of 38 Crofab treated cases of North American crotalid envenomation resulted in recurrent coagulation abnormalities that may indicate the need for additional doses of Crofab.⁵ Another study done by Dart et al showed that additional doses are needed to fully control the envenomation.⁶ The study compared a single dose alone (as-needed group) to a scheduled group that received antivenin every six hours for 18 hours. Both groups had a decrease in their mean severity score (p=<0.001). However, eight of the 16 as-needed patients needed subsequent doses because of the recurrence of symptoms (p=0.002).

Adverse effects

The most common adverse effects of Crofab include urticaria, rash and serum sickness. The skin manifestation can be early signs of anaphylaxis that requires close monitoring with appropriate management. Crofab is contraindicated in patients who are allergic to sheep (ovine), papaya or papain unless the benefits outweigh the risks. According to Ruha et al, no acute hypersensitivity reaction was reported in the initial postmarketing experience with 28 patients who were admitted for rattlesnake envenomation. However, two patients had evidence of mild serum sickness after being treated with Crofab.⁸

Crofab has shown to be as effective as Wyeth's Antivenin and safer with regards to the side effects profile.⁹ In a case series study by Clark et al, Crofab was successful in treating neurotoxicity by C scutulatus (Mojave rattlesnake) in which ACP seemed ineffective.¹⁰ In the study, three patients who experienced weakness, paresthesia, and fasciculations completely recovered from the envenomation after being treated with Crofab. Compared to Wyeth's ACP, Crofab proved less immunogenic in preliminary trials and yet remained effective in treating minimal to moderate cases of snake bite poisoning.

Conclusion

Wyeth-Ayerst's decision to continue production of Antivenin Crotalidae Polyvalent (ACP) and the availability of Crofab will allow for comparative studies. Protheric's Crofab will continue to challenge the standard of care for North American crotalid envenomation.

Clinical reviewers' comments

The lack of experience/information on the use of Crofab. in severe envenomations does not preclude its use.

References

1. Jurkovich GJ, Luterman A, Mcculler K, Ramenofsky ML, Curreri PW. Complications of Crotalidae antivenin therapy [Abstract]. J Trauma 1988;28(7):1032-7.
2. Dart RC, Seifert SA, Carroll L, Clark RF, Hall E, Boyer-Hassen LV, Curry SC, Kitchens CS, Garcia RA. Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for treatment of crotalid venom poisoning. Ann Emerg Med 1997;30(1):33-9.
3. Clark RF, McKinney PE, Chase PB, Walter FG. Immediate and delayed allergic reactions to Crotalidae polyvalent immune Fab (ovine) antivenom [In Process Citation]. Ann Emerg Med 2002;39:671-6.
4. Crofab.: Crotalidae Polyvalent Immune Fab (Ovine), in Packet Insert. 2000, Savage Laboratories.
5. Boyer LV, Seifert SA, Clark RF, McNally JT, Williams SR, Nordt SP, Walter FG, Dart RC. Recurrent and persistent coagulopathy following pit viper envenomation. Arch Inter Med 1999;159:706-10.
6. Dart RC, Seifert SA, Boyer LV, Clark RF, Hall E, McKinney P, McNally J, Kitchens CS, Curry SC, Bogdan GM, Ward SB, Porter RS. A randomized Multicenter trial of crotalidae polyvalent immune Fab (ovine) antivenin for the treatment for crotaline snakebite in the United States [Abstract]. Arch Intern Med 2001;161(16):2030-6.
7. Hill RE, Bogdan GM, Dart RC. Time to reconstitution: purified Fab antivenom vs unpurified IgG antivenom [Abstract]. Toxicon 2001;39:729-31.
8. Ruha AM, Curry SC, Beuhler M, Katz K, Brooks DE, Graeme KA, Wallace K, Gerkin R, Lovecchio F, Wax P, Selden B. Initial postmarketing experience with crotalidae immune Fab for treatment of rattlesnake envenomation [In Process Citation]. Ann Emerg Med 2002;39(6):609-15.
9. Dart RC, McNally J. Efficacy, Safety, and Use of Snake Antivenoms in the United States [Abstract]. Ann Emerg Med 2001;37:181-8.
10. Clark RF, William SR, Nordt SP, Boyer-Hassen LV. Successful treatment of crotid-induced neurotoxicity with a new polyspecific crotalid Fab antivenom. Ann Emerg Med 1997;30(1):54-7.
11. Seifert SA, Boyer LV. Recurrence Phenomena after Immunoglobulin Therapy for Snake Envenomations: Part 1. Pharmacokinetics and Pharmacodynamics of Immunoglobulin antivenoms and related Antibodies [Abstract]. Ann Emerg Med 2001;37(2):189-95.
12. Boyer LV, Seifert SA, Cain JS. Recurrence phenomena after immunoglobulin therapy for snake envenomations: part 2. Guidelines for clinical management with crotaline fab antivenom. Ann Emerg Med 2001;37(2):196-201.

Author

Daniel K. Le, PharmD candidate, Temple University, June 2002

Clinical reviewers at The Poison Control Center

A. Muller, S. Sheen