The cure is not worse than the disease

Dr. Spencer Greene explains why with modern snakebite antivenom ‘the cure is NOT worse than the disease’.

Spencer Greene, MD, MS, FACEP, FACMT, FAACT, FAAEM •

Snakebite victims frequently tell me that their physicians refused to treat them with antivenom because “the cure is worse than the disease.” This is dangerously incorrect information that can really prevent patients from receiving appropriate care.

I kind of understand why some people may believe this. Before 2000, the antivenom used to treat U.S. crotalid envenomations had a high incidence of acute adverse reactions, estimated to be between 25 – 56%. Additionally, the incidence of serum sickness was ~ 100% in patients treated with 10 or more vials. Other whole-IgG products have similar rates of adverse reactions.

CroFab, which has been on the market since 2000 and has been used to treat thousands of patients successfully, is not whole IgG. It’s a Fab fragment, meaning the Fc portion of the immunoglobin molecule, which is responsible for eliciting most allergic reactions, is not present in the final product. Additionally, CroFab is ovine (sheep)-derived. Most snake antivenoms are equine (horse)-derived, and physicians may be reluctant to use these products in patients who report a horse serum allergy. Sheep immune serum is less immunogenic than horse immune serum, which contains a highly immunogenic immunoglobulin G subclass. And the sheep used in its production are hearty, healthy Australian sheep!

Another neat thing about CroFab is that its production includes a unique step. Affinity purification removes unnecessary antibodies so that only venom-neutralizing antibodies remain. This increases specificity and minimizes nonspecific foreign proteins that can lead to adverse reactions.

Of course, every medication has the potential to cause an adverse reaction. Fortunately, the incidence of acute adverse reactions to CroFab is low and well understood. A study using data from the North American Snakebite Registry found the overall incidence of acute adverse reactions to be 2.7%.  More severe adverse reactions such as hypotension, bronchospasm, and/or angioedema occurred in 1.1% of patients. In a more recent study from the Arizona Poison and Drug Information Center, the incidence of acute adverse reactions in 1340 adult patients was 1.4%. Pruritis, urticaria, rash, and vomiting were most common. Dyspnea or wheezing was observed in 0.3% of patients. Hypotension occurred in 0.15% of patients. Significantly, none of the adverse reactions were considered life-threatening, and no patient required discontinuation of the CroFab infusion.

It’s important to remember that allergic reactions can be treated. Mild symptoms can usually be relieved with antihistamines, such as diphenhydramine. More serious reactions may require epinephrine. Nonetheless, the signs and symptoms can be managed. Antivenom is the definitive treatment for envenomation, and it can be continued for a significant envenomation if the adverse reaction is treated simultaneously. Antivenom should definitely not be withheld because of a fear of potential adverse reaction.

One other really important thing to know: it’s a total myth that once you receive antivenom you can never be treated with it again. I have successfully and safely used CroFab to treat multiple patients on multiple occasions. I treated one patient in Arizona for his 6th and 7th rattlesnake envenomations, and I hear he has been treated a few more times since I moved to Texas. There is also a cool case report by Eric Lavonas describing someone who has been treated with CroFab at least 19 times!

Just remember: crotalid envenomations can be serious, and the best treatment is antivenom. The incidence of adverse reactions to CroFab is low (1.4 – 2.7% in the two studies I mentioned above), and it’s even lower for serious adverse reactions. When it comes to snakebites, the cure is much, much better than the disease!

Dr. Greene is a paid consultant for BTG International Inc.

Spencer Greene, MD, MS, FACEP, FACMT, FAACT, FAAEM is a board-certified medical toxicologist and emergency physician. He currently serves as the Director of Toxicology and an attending emergency physician at HCA Houston Healthcare-Kingwood. He is a Clinical Professor at the University of Houston College of Medicine. Dr. Greene is a recognized expert in the management of snake envenomation in the US. He has treated more than 1000 snakebites at the bedside and has authored more than 50 scholarly articles and book chapters. He has also served as the course director for the Houston Venom Conference since 2013.

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CroFab® Crotalidae Polyvalent Immune Fab (Ovine) is a sheep-derived antivenin indicated for the management of adult and pediatric patients with North American crotalid envenomation. The term crotalid is used to describe the Crotalinae subfamily (formerly known as Crotalidae) of venomous snakes which includes rattlesnakes, copperheads and cottonmouths/water moccasins.



Do not administer CroFab® to patients with a known history of hypersensitivity to any of its components, or to papaya or papain unless the benefits outweigh the risks and appropriate management for anaphylactic reactions is readily available.


Coagulopathy: In clinical trials, recurrent coagulopathy (the return of a coagulation abnormality after it has been successfully treated with antivenin), characterized by decreased fibrinogen, decreased platelets, and elevated prothrombin time, occurred in approximately half of the patients studied; one patient required re-hospitalization and additional antivenin administration. Recurrent coagulopathy may persist for 1 to 2 weeks or more. Patients who experience coagulopathy due to snakebite should be monitored for recurrent coagulopathy for up to 1 week or longer. During this period, the physician should carefully assess the need for re-treatment with CroFab® and use of any type of anticoagulant or anti-platelet drug.

Hypersensitivity Reactions: Severe hypersensitivity reactions may occur with CroFab®. In case of acute hypersensitivity reactions, including anaphylaxis and anaphylactoid reactions, discontinue infusion and institute appropriate emergency treatment. Patients allergic to papain, chymopapain, other papaya extracts, or the pineapple enzyme bromelain may also have an allergic reaction to CroFab®. Follow-up all patients for signs and symptoms of delayed allergic reactions or serum sickness (e.g., rash, fever, myalgia, arthralgia).


The most common adverse reactions (incidence ≥ 5% of subjects) reported in the clinical studies were urticaria, rash, nausea, pruritus and back pain. Adverse reactions involving the skin and appendages (primarily rash, urticaria, and pruritus) were reported in 12 of the 42 patients. Two patients had a severe allergic reaction (severe hives and a severe rash and pruritus) following treatment and one patient discontinued CroFab® due to an allergic reaction. Recurrent coagulopathy due to envenomation and requiring additional treatment may occur.

Please see full Prescribing Information.

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