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Introduction

Around 9,000 Americans are treated for snake bites and 5 die each year. Most are bitten by members of the Crotalinae subfamily (a.k.a. crotalids) of the pit viper family which includes copperheads, water moccasins, and rattlesnakes.

Crotalid envenomation’s can cause a broad range of adverse effects, including local tissue, hematologic, and/or systemic effects including shock and life-threatening bleeding.

  • Use symptom progression such as swelling beyond 1 major joint or hematologic effects (decreased fibrinogen, thrombocytopenia, or increased PT) as an indicator for initial or additional doses of antivenom.
  • Identification of the snake can be helpful but should not determine decision to initiate or continue therapy in place of symptom progression.
  • Patients can develop delayed or recurrent hematologic symptoms up to a week after treatment cessation, especially following a severe envenomation.

PHARMACOLOGY

Crotalidae Polyvalent Immune Fab (Ovine)
(Crofab®)

Crotalidae Immune F(ab’)2 (Equine)
(Anavip®)

Mechanism of Action

Fab fragment of IgG antibody isolated from sheep serum; antibody binds to venom and removes it from tissue

  • F(ab’)2 fragment of IgG antibody isolated from horse serum; antibody binds to venom and removes it from tissue

Dose

  • Initial Dose
    • Progressing tissue/hematologic effects: 4 – 6 vials
    • Systemic effects including shock: 8 – 12 vials
    • May repeat every hour as needed until initial control of local, hematological, and systemic symptoms is achieved
  • Maintenance
    • 2 vials q6h x 3 after control is achieve
  • Initial dose:
    • 10 vials
      • May repeat every hour as needed until initial control of local, hematological, and systemic symptoms is achieved

  • Maintenance
    • 4 vials as needed; may administer for any re-emerging symptoms

Administration

  • Inject ≥18 mL NS (or SWFI) into each vial; more volume will speed up the dissolution
  • Gently swirl or roll vials in hand or combine all vials in the bag to roll simultaneously; DO NOT SHAKE
  • Add/QS solution to 250 mL bag of NS admin over 1 hour
  • NOTE: Many clinicians choose a slower initial rate to allow for assessment of allergic reaction
  • Reconstitute each vial with 10 mL NS
  • Gently swirl or roll vials in hand or combine all vials in bag to roll simultaneously; DO NOT SHAKE
  • Solution should be clear to yellow/green and opalescent; do not use if otherwise discolored
  • Add/QS solution to 250 mL bag of NS
  • Administer total volume over 1 hour
  • NOTE: Many clinicians choose a slower initial rate to allow for assessment of allergic reaction

PK/PD

T½: 12 – 23 hours

T½: ~5.5 days

Adverse Effects

  • Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis
  • Serum sickness (rare
  • Nausea (23%), arthralgia (11%), peripheral edema (8%)
  • Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis
  • Serum sickness (rare)

Drug Interactions

No known drug interactions

No known drug interactions

Compatibility

NS or SWFI for reconstitution; NS for infusion

NS

Comments

Approved for the treatment of any North American crotalid envenomation

Recently approved any North American crotalid envenomation

Review of Evidence

Author, yearDesign/ sample sizeIntervention & ComparisonOutcome
Dart RC,
1997
Prospective, multicenter trial
(n = 11)
Patients received 4 vials of Crofab® for initial control of symptoms following minimal or moderate crotalid envenomationTen of 11 patients were deemed to have a clinical response and reduction in snakebite severity score; one patient required 4 additional vials
Dart RC,
2001
Multicenter, randomized, prospective, open-label trial

(n = 31)
Initial 6 vials of Crofab® patients were randomized to receive either 2 vials PRN vs 2 vials Q6h x 18 hoursNo statistical difference between groups in snakebite severity score;

Overall severity was reduced from 4.35 to 2.39 (p < 0.001)
Boyer LV,
2013
Phase 2, RCT for rattlesnake bites in Tuscon, AZ

(n = 12)
Crofab® vs Anavip® for a reduction in serum venom levels at various pre-defined times following crotalid envenomationVenom levels were insignificantly lower following initial control in the Crofab® group, but significantly lower following maintenance and during follow-up in the Anavip® group (p = 0.004);

No difference between groups in safety outcomes
Bush SP,
2015
RCT at 18 sites in the US
(n = 123)
Crofab® vs Anavip® for the prevention of late coagulopathy following crotalid envenomationMore patients in the Crofab® group vs the Anavip group ® experienced late coagulopathy versus
• 29.7% vs 10.3%
• p < 0.05, NNT = 5
Gerardo CJ,
2017
RCT in 18 ED in the US
(n = 74)
Crofab® versus placebo to measure limb function 14 days after envenomation using Patient-Specific Functional ScaleCrofab reduced limb disability measured by the Patient-Specific Functional Scale 14 days after copperhead envenomation.
• 8.6 in the treatment group vs 7.4 in the control group (95% CI 0.1 – 2.3; p = 0.04)
Gerardo CJ, 2020Post-hoc analysis
(N=21)
Group 1: Anavip 10 Vials + Anavip 4 vials q6 x 3

Group 2: Anavip 10 vials + Placebo

Group 3: Crofab 5 vials + 2 vials q6h x 3
In Copperhead bites (n=21) there was no difference between Anavip® and Crofab® in
o Time to achieve initials control
o Patient requiring PRN or unscheduled doses
Review of Studies for Crotalid Envenomation

Conclusions

Crofab® and Anavip® seem to be comparable for initial symptom control, although due to the longer half-life, Anavip® may have a larger role in the prevention of late-onset or recurrent coagulopathy

Each health system will likely need to make a formulary decision on which agent to use. This decision should be based on which snake species are endemic to that region, preparation time, agent costs, and the prevalence of recurring coagulopathy in their patient population.

References

  1. Lavonas et al. BMC Emerg Med. 2011;11:2.
  1. Cocchio C, et alAm J Health Syst Pharm. 2020;77(3):175-187.
  2. Crotalidae Polyvalent Immune FAB (Ovine). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed April 28, 2020.
  3. Crofab® [package insert]. West Conshohocken, PA: BTG International Inc; 2000.
  4. Crotalidae Immune F(ab’)2 (Equine). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed April 28, 2020.
  5. Anavip® [package insert]. Franklin, TN: Instituto Bioclon, S.A. de C.V.; 2015.
  6. Dart RC, et al. Ann Emerg Med. 1997;30(1):33-9.
  7. Dart RC, et al. Arch Intern Med. 2001;161(16):2030-6.
  8. Boyer LV, et al. Toxicon. 2013;74:101-8.
  9. Bush SP, et al. Clin Toxicol (Phila). 2015;53(1):37-45.
  10. Gerardo CJ, et al. Ann Emerg Med. 2017;70(2):233-244.e3.
  11. Gerardo CJ, Keyler DE, Rapp-Olsson AM, Schwarz J III, Dart RC. Post Hoc Analysis of the RCT Comparing F(ab’)2 to Fab Antivenom: Control of Venom-Induced Tissue Injury in Copperhead Snakebite Patients. Annals of Emergency Medicine 76(4) Supp:S29Dec;26(4):472-87.
crotalid-envenomation-Pharmacy-Friday.-jp3.-7-15-21

Transcript

Jimmy

What’s good fam? It’s your host, Jimmy Pruitt aka PharmD in the ED and I’m bringing you another episode of the Pharm So Hard Podcast.Today is going to be one of our shorter episodes, we’re going to be having our Pharmacy Friday Pearl.

So happy Pharmacy Friday to all of you guys out there.

And today, we’re going to talk about snake bites. And particularly talking about the management of snake bites using two agents, Crofab and Anavip.

So what we know about snake bites is about 9000 Americans are treated for each year, and about five of them die, and most are bitten by the Pit Vipers.

And a good bit of them are gonna be local tissue, hematological, and it can be systemic, including shock and life threatening bleeding.

When figuring out if we’re going to give the initial dose or additional doses of anti venom, we’re gonna use things like swelling beyond one major joint, or hematological effects like decreased fibrinogen, thrombocytopenia, or an increase PT and INR. But the very interesting thing is that patients can develop delayed or recurrent hematological symptom up to one week after we finished treatment, especially falling less severe envenomation.

Alright, so let’s move on to these two agents, Crofab and Anavip. So when looking at Crofab, the mechanism of action is that the fab fragment of the IgG antibody is isolated from sheep serum. And these antibodies bind to the venom removed from the tissue.

While looking at the initial dose of Crofab, we’re gonna see for progressing tissue or hematological effects, you can start with four to six vials of Crofab. But if you have systemic effects, including shock, you’re going to do eight to 12 vials, and it may be repeated every hour as needed until initial control of local, hematological and systemic effects are achieved. Once you get there, then you move on to their maintenance, and that’s gonna be two vials every six hours times three, you should be good to go. All my pharmacists out there can attest to the fact that mixing Crofab is a mofo. You it takes forever, of gently rolling and swirling in your hand. And then you’re going to do that for 10 to 20 minutes depending on how many vials you’re using. And once you are able to reconstitute that with sterile water or normal saline, then you’re gonna put all that in a normal saline bag of 250 and administer that over one hour. However, you have to watch out for the fact that you can have some infusion related reactions. So, you’re going to want to slow that bag way down and drop that infusion rate so the patient can tolerate it. One thing that I talked about that scenario doesn’t matter most of the time, but actually do in this particular scenario is the half-life, it’s going to be for Crofab, 12 to 23 hours. And that’s going to make a big difference when we’re talking about the other agent, Anavip. Until very recently, it was the only FDA approved agent for the treatment of any North American pit viper envenomation.

The other agent that we have is Anavip, and it’s gonna be Crotalidae Immune F(ab’)2 or Anavip as most of us call it, and it’s going to work by that F(ab’)2 fragment of the IgG antibody, going to be isolated from horse serum.

And then that antibody itself is going to bind to the venom and remove it from the tissue. The initial dose is going to be 10 vials. You may repeat that every hour until you get the initial control of the local, hematological, or systemic symptoms. And after that there’s no scheduled dose like for Crofab, but you may get four vials as needed for any reemerging symptoms. The reconstitution can be a little easier. And you should be able to reconstitute each vial at 10 ml. So, ns it didn’t put that into a 250 bag of saline and administer that over one hour.

The half-life is going to be interesting to me 5.5 days,

and that’s going to be pretty cool when we start getting into some of the data. And the adverse effects are very mild with nausea, arthralgia and peripheral edema listed to some of the studies and hypersensitivity reactions can happen with any drug. But with these two agents, that’s something that we look at. And if you do have them, you can just dilute the drug a little bit more and slow down the infusion rate. And a very cool thing about Anavip is that until recently, and I’m talking about April 1st, it did not have an FDA indication for some of the other snakes in this family like copperheads. And now Anavip is FDA approved for any North American crotalid envenomation.

Alright, guys, let’s jump into some evidence. One of the first studies that looked at Crofab was then in  1997 by Dart and colleagues. And it was a randomized controlled trial with only 11 patients. But what they did was look at patients that had minimal or moderate crotalid envenomation. And they use 4 vials of Crofab for the initial control of those symptoms. And what they found was that 10 of the 11 patients were deemed to have a clinical response and reduce snake severity score. And some later studies again, repeated those same results showing that Crofab did a phenomenal job in reducing the symptoms of patients that had crotalid envenomation. Now, the controversy is not really there. The controversy comes when talking about using Crofab or just your fab compared to Anavip F(ab’)2. In a study done by Boyer and colleagues, it was a phase 2 randomized controlled trial looking at rattlesnake bites in Arizona, and it was Crofab vs Anavip. And this was going to be for the reduction in serum venom levels at various predefined times following crotalid envenomation. And what they found was that venom levels were insignificantly lower following initial control in the Crofab group, but significantly lower following maintenance and follow up in Anavip group. So looking at all that they also found that there is no major difference in safety outcomes between these patients. So the last study I want to talk about is this Bush and colleague study that was put out in 2015, which is an RCT at 18 sites in the US, it had 123 patients. They looked at the use of Crofab vs Anavip for prevention of late coagulopathy following crotalid envenomation. And what they found was more patients in the Crofab group, compared to Anavip group experienced late coagulopathy. It’s about 29.7% in Crofab group, compared to just 10.3% in the Anavip group, and what they found that is worth physically significant. It was a number needed to treat a five for this group of no bring the original review and approval of antibiotics. The FDA made the decision to exclude copperheads patients since late coagulopathy are more commonly observed in rattlesnake envenomations. And FDA is focused on rattlesnake data at the time also led to exclusion of copperhead envenomation as the indication for Anavip. This is cool because the original Anavip clinical trial still included Copperhead data, which was recently reviewed in a Post hoc analysis that looked at two groups of Anavip with the initial 10-vial group with maintenance therapy after that, 4 vials Q6 times three. It also looked at Anavip with the initial 10 vials by itself plus placebo. And they compare that to Crofab 5 vials up front and then two vials Q6 times three, and what they found in those 21 patients that there is no major difference between Anavip and Crofab, we’re looking at time to initial control, patients requiring PRN, or unscheduled doses. And the study concluded that Anavip was non inferior to Crofab for the treatment of Copperhead envenomations. So when looking at all of this, this post hoc analysis, and some animal studies showing that Anavip actually neutralize venom from Copperhead and cottonmouth, and mice in human case report information. This all led to the FDA giving a knock to Anavip for all crotalid envenomations.

 So get ready for all of your committee meetings, when it comes to whether you should add Anavip to your formulary, replace it or have it in combination and use it for just rattlesnake bites, that’s going to be something that really comes to what you and your site is seeing. And the other thing to consider is the cost component because at one period of time, depending on if you need to get additional vials of Anavip compared to Crofab, people were saving like $15,000. So that was going to be a huge, huge, huge cost savings. But the word from the streets is that Crofab realizes what’s going on. And it’s going to drop those prices quite a bit. So reach out to your buyers see the actual prices because I’ve heard from mine, that the price of Crofab drops tremendously. So for me guys, I can be solved inAnavip. Initially, I wasn’t when I didn’t see that post hoc data, but now I’m kind of onboard and if the pricing benefit is still there, I’m pretty good with adding it to formulary. If it’s just up to me. My doctors seem to want it on formulary as well. So I’m going to go ahead and try to get that push forward and let me guys know what you guys are doing. Many people are talking about this right now. Love to hear what you and your shopper doing. But as we close out, don’t forget to go over to our sister site, pharmacy-pearls.com where you can type in pharmacyfriday.com, it’s going to take you to the website. Go ahead and click and subscribe to that email list so you never miss the latest and greatest when it comes to acute care pharmacotherapy. If you haven’t already, go ahead and click on that subscribe button in your Spotify, your Apple podcasts, YouTube, whatever you’re listening to this podcast on. Go ahead and give us some support and subscribe to that podcast. Hit me up on Twitter @PharmD_intheEd and let me know what you think about this podcast. You guys know how it ended every single time. Just know you don’t have to be a pharmacist.

You don’t have to work in ED, but everything you do, make sure you Pharm So Hard.

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