Anavip: is the juice worth the squeeze

Authors:

Scott Dietrich, PharmD, BCCCP, @PCC_PharmD

Ryan Rogoszewski, PharmD, BCCCP, @RyanRogoPharmD

Craig Cocchio, PharmD, BCPS, DABAT, @iEMPharmD

Background 

Over 5,000 snakebites are reported to US poison centers each year.[1] The vast majority of snakebites in the US result from the Viperidae (aka “pit viper”) family of snakes. The sub-family most commonly found in the US includes the Crotalids which are made up of rattlesnakes, Cottonmouths (water moccasins), and Copperheads. Crotalide snake venom contains upwards of 50-100 toxic proteins which can cause local tissue injury, systemic toxicity, neuropathies, and coagulopathies.[2] The venom composition widely varies and is based on many factors, including age/sex of snake, geographic location, and species. Differences in amounts and composition of venom proteins have even been identified within the same species of snake.[3] As a result, there is wide variability in the severity of snake envenomations seen in clinical practice owing to many different factors. 

The first antivenom available in the US, Antivenin (Crotalide) Polyvalent, was available beginning in 1953 and produced by Wyeth. This product was derived via equine serum, and many times, was more dangerous than the actual venom itself. The Wyeth antivenom had a very long half-life but came with frequent and severe adverse effects (acute allergic reactions, some resulting in death, and frequent serum sickness).[4] These adverse effects, unfortunately, led to a “Wait and See” approach, where instead of treating and neutralizing the venom immediately, providers waited until severe symptoms arose before initiating treatment. These adverse effects led to the exploration of other animal species to create safer antivenoms and were the rationale for the manufacturer to obtain their antivenom from an ovine source for Crofab. Crofab became commercially available in the US in October of 2000 and has been a mainstay of treatment of moderate to severe snake envenomations ever since.[5] However, in 2015 a new antivenom, Anavip, was FDA approved and is now, in 2019, becoming commercially available for use in the US. 

Antivenom Comparison         

Crofab is a fragmented- antigen-binding (Fab) immunoglobulin fragment obtained from sheep serum immunized with venom from four North American Crotalide snakes: Western diamondback rattlesnake (Crotalus atrox), Eastern diamondback rattlesnake (Crotalus adamanteus), Mojave rattlesnake (Crotalus scutulatus ), and Cottonmouth/Water moccasin (Agkistrodon piscivorus ).[3] While Anavip is also a Fab immunoglobulin, it is obtained via equine serum immunized with venom from two Crotalidae snakes: Fer-de-lance / Lancehead (Bothrops asper) and Tropical rattlesnake (Crotalus durissus) both of which are not native to the U.S.[6] The Fer-de-lance snake is found in southern Mexico and northern South America, while the Tropical rattlesnake is exclusively located in South America. 

While both agents are made from, and neutralize, Crotalidae snake venom, as a result of using different species for production, each antivenom product displays different pharmacokinetic parameters most notably differences in half-life elimination. In eight healthy volunteers, Crofab displayed a mean half-life of 15 hours, with a range of 12-23 hours.[5] Anavip, when studied in fourteen healthy volunteers, showed a half-life of 133 hours (i.e., 5.5 days).[6] As a result of the variability in half-life, each agent is dosed differently for snakebite envenomation. 

Package insert dosing for Crofab recommends an initial dose of 4-6 vials, potentially up to 12+ vials in severe cases, repeated as needed until initial control of the envenomation is achieved. Following initial control, patients are to receive 2 vials every 6 hours for three doses as part of maintenance therapy.[5] Package insert dosing for Anavip recommends all patients receive an initial dose of 10 vials, repeated as necessary to achieve control of envenomation, with no subsequent maintenance dosing required owing to the extremely long half-life.[6] Additionally, per the package insert, Anavip dissolves in solution in approximately one minute compared to the notoriously slow reconstitution of Crofab.[6] However, more recent data suggest alternative ways to reconstitute Crofab with a much faster time (~3 minutes), although product labeling has not reflected these changes.[7]

Aside from the previously mentioned differences between Crofab and Anavip, the main reason Anavip is coming up is the cost difference between agents. The average wholesale price (AWP) of 1 vial of Crofab is $3,316.[8] Based on an initial dose of 6 vials followed by 6 vials of maintenance dosing, a conservative estimate of drug cost would be approximately $39,792 per patient. However, severe envenomations have required 50+ vials of Crofab per course which corresponds to a total cost of therapy of more than $165,000.[9] Anavip has an AWP of $1,120 per vial in which a conservative 10 vial course would cost approximately $11,200. It is unclear at this time how many vials of Anavip will be required in severe envenomations, but multiple doses will likely be required increasing the cost of therapy in severe cases. Some idea of total antivenom usage can be inferred from a phase 2 clinical trial of Anavip compared to Crofab for pit viper envenomations in Tucson, Arizona. Patients were randomized to open-label Anavip or Crofab at standard doses. A total of 12 patients were received either Anavip or Crofab with patients in the Anavip group receiving an average of 35.3 (+/- 12.1) vials versus 15.7 (+/- 2.6) vials in the Crofab group.[10]

In-vivo Data

There is one head-to-head comparison of Crofab and Anavip in humans worth discussing.[11] A prospective, blinded, randomized trial conducted among 18 clinical sites in the US compared Anavip (n= 81) against Crofab (n=40) for the treatment of Crotalid snake envenomations. Anavip patients received 10 vials every two hours until initial control was achieved and Crofab patients received 5 vials every two hours until initial control was achieved. After control, the Anavip arm was further split into two groups: 1 group received placebo (n=40, Anavip/Placebo), the other group an additional 4 vials of Anavip (n=41, Anavip/Anavip). The Crofab patients received the standard 2 vials every 6 hours for three doses after control. At any time during the study and at the discretion of the treating physician, patients could receive an additional 4 vials of Anavip or 2 vials of Crofab to treat ongoing signs of envenomation. 

Interestingly, the primary efficacy outcome was late-onset coagulopathy defined as “coagulopathy between the end of maintenance dosing and study day 8.” Coagulopathy was defined as a platelet count less than 150,000/mm^3 , fibrinogen less than 150 mg/dL, or use of antivenom to treat a coagulation abnormality between the end of maintenance dosing and study day five. 

While the selection of a surrogate outcome for clinically relevant bleeding would have been desirable, it is not necessarily ideal in this scenario. This is largely due to the observed incidence of clinically relevant recurrent or persistent bleeding is less than 1% among North American pit viper envenomations.[12] Albeit rare, this outcome is likely dependent on the geographic location, snake species, and severity of envenomation. The challenge is predicting who will have clinically relevant recurrent bleeding. At this time, there is no reliable predictor to identify these patients at the highest risk. Therefore, selecting an antivenom product that could measurably lower a surrogate for this outcome, and is potentially less expensive, can be a reasonable study objective. 

Additionally, the definition of “initial control” was slightly different than that used in the initial Crofab studies (see Table 1).

Table 1: Differences in study definitions of “initial control”

 Initial Crofab Studies[13,14]Anavip vs Crofab Study[11]
Local EffectsNo further progression of local effectsLeading edge of local injury was not progressing more than 1 inch per hour
Systemic EffectsSystemic effects are resolved (hypotension, neurotoxicity resolved or clearly improving)Not mentioned in study
Coagulation AbnormalitiesCoagulation parameters normalized or are trending towards normalPlatelet count, serum fibrinogen level, prothrombin time (PT), and partial thromboplastin time (PTT) were either normal or returning toward normal.

Not surprisingly, late coagulopathy was decreased in both Anavip arms compared to Crofab (10.3% in Anavip/Anavip vs 5.3% in Anavip/Placebo vs 29.7% in the Crofab arm). The authors noted that all six of the late coagulopathies seen in the Anavip groups occurred at one single site in southern California compared to Crofab which saw late coagulopathies spread among seven different study sites. 

Mean total antivenom doses were similar between the Anavip/Placebo and Crofab groups receiving a mean dose of 16 and 14 vials, respectively, but higher in the Anavip/Anavip group at 27 vials. Given the minimum dose, the Anavip/Anavip group should have received was 14 vials, an extra 13 vials were administered which is almost equivalent to the entire treatment course for the Anavip/Placebo arm (mean 16 vials). Unfortunately, it is unclear when these extra doses were required, as it would be nice to know if it was early in the treatment course or later if it was isolated to a specific study site, and/or which types of snakes bit these patients.Not surprisingly, late coagulopathy was decreased in both Anavip arms compared to Crofab (10.3% in Anavip/Anavip vs 5.3% in Anavip/Placebo vs 29.7% in the Crofab arm). The authors noted that all six of the late coagulopathies seen in the Anavip groups occurred at one single site in southern California compared to Crofab which saw late coagulopathies spread among seven different study sites.  

Overall, the authors concluded Anavip decreased the risk of “subacute coagulopathy and bleeding.” However, as an EM Pharmacist, achieving initial control of envenomation is often our immediate concern. Unfortunately, this outcome was not a reported endpoint. In the text of the manuscript, the authors briefly comment on the number of repeat doses required which may be our best estimation of initial control. Six extra doses were administered in the Anavip/Anavip group, 11 extra doses in the Anavip/Placebo group, and 18 extra doses in the Crofab group. Again, the timing of these doses was not reported but would be extremely helpful in determining if Anavip is efficacious for initial control when compared to Crofab. In light of this unknown, it may be helpful to consider the in-vitro efficacy in an attempt to benchmark Anavip against Crofab.

Figure 1

Importance of Initial Control

In-vitro Data

In 2003, two studies were published in the same issue of Toxicon comparing the in-vitro efficacy of different antivenoms against North American snakes. Of interest, the first study compared the neutralization of hemorrhagic and fibrinolytic activities of eight snake venoms with three different antivenoms.[15] We will focus on the results of two of the three antivenoms, FabO (Crofab) and Fab2H (Antivipmyn ), as the third is not available for use in the US (FabV). While Antivipmyn and Anavip are both produced by the same company with similar snake venoms, it is currently unclear whether they are completely equivalent. For the consideration of comparison, we feel it is reasonable to compare Antivipmyn (as a surrogate for Anavip) to Crofab. 

When comparing the anti-hemorrhagic efficacy of Antivipmyn and Crofab, Antivipmyn was shown to be more efficient and required less antivenom for reversal than Crofab for seven of the eight snake venoms tested, with only the Western Diamondback rattlesnake showing more efficiency with Crofab (see Table 2). Per the authors, [Antivipmyn] “… was capable of neutralizing the hemorrhagic activity of all the venoms while [Crofab] only neutralized 50% of the venoms.” Granted, two of the snake venoms tested are not indigenous to the US (Fer-de-lance and Tropical rattlesnake), but of the snakes found in the US, Antivipmyn was more efficient for all but one venom. 

Table 2: Comparison of anti-hemorrhagic activity of two antivenoms

VenomMHDAntivipmyn AHDCrofab AHD
>> MHD = minimum hemorrhagic dose; lower numbers indicate increased hemorrhagic venom potency
>> AHD = anti-hemorrhagic dose, indicates the amount of antivenom which inhibits 50% of the MHD; lower numbers indicate more efficient antivenom
>> Bolded values represent the antivenom most effective in neutralizing activity
*Species not native to US
Cottonmouth26 ± 1.453 ± 0Partial
Fer-de-lance*5.6 ± 0.5626.5 ± 12.3-
Eastern Diamondback Rattlesnake0.3 ± 0.181 ± 0.24.4 ± 0
Tropical Rattlesnake*50 ± 7.1425 ± 0-
Western Diamondback2.5 ± 026.5 ± 06.6 ± 3
Canebrake Rattlesnake37.5 ± 0.71212 ± 0-
Timber Rattlesnake5.6 ± 0.284.4 ± 06.6 ± 0
Blacktail Rattlesnake12.5 ± 035 ± 0283 ± 0

When comparing the antifibrinolytic effects of the snake venoms, only the Cottonmouth, Fer-de-lance, Tropical rattlesnake, Western Diamondback rattlesnake, and the Blacktail rattlesnake’s venom exhibited fibrinolytic activity (see Table 3). Antivipmyn was more efficient for halting fibrinolysis than Crofab for all snake venoms except the Cottonmouth in which neither antivenom had any effect. Of the two venoms, Crofab was able to exert its antifibrinolytic effects on, only one is found in the US (Western Diamondback rattlesnake). The large gap in antifibrinolytic efficacy is potentially concerning when comparing Crofab to Antivipmyn. 

Table 3: Comparison of antifibrinolytic activity of two antivenoms

VenomMFDAntivipmyn AFDCrofab AFD
>> MFD = minimal fibrinolytic dose; lower numbers indicate increasing fibrinolytic potency
>> AFD = anti-fibrinolytic dose, indicates the amount of antivenom which inhibits the degradation of 1 MFD; lower numbers indication more efficient antivenoms
>> Bolded values represent the antivenom most effective in neutralizing fibrinolytic activity
*Species not native to US
Cottonmouth11.2 ± 0--
Fer-de-lance*1.25 ± 05.3 ± 021.2 ±0
Eastern Diamondback Rattlesnaken/an/an/a
Tropical Rattlesnake*4.5 ± 1.510.6 ± 0-
Western Diamondback Rattlesnake5.7 ± 010.6 ± 021.2 ± 0
Canebrake Rattlesnaken/an/an/a
Timber Rattlesnaken/an/an/a
Blacktail Rattlesnake4.7 ± 1.642.5 ± 0-

Overall, Antivipmyn was more efficient in it’s reversal of hemorrhagic and fibrinolytic complications among the snake venoms tested and the authors concluded that Antivipmyn “… was the most effective antivenom in this study.” The authors additionally noted it is unlikely a snake would be able to deliver enough venom to an average sized adult patient in which the patient would expire due to venom-induced hemorrhage. However, rapid neutralization of hemorrhagic and fibrinolytic enzymes is an important consideration for patient recovery time, prevention of tissue necrosis, and dispersal of thrombin-like enzymes.[15] Therefore, while either agent is unlikely to directly decrease mortality due to hemorrhage or fibrinolysis, Antivipmyn’s overall superiority has other downstream non-hemorrhagic benefits.

The second study compared Fab2H (Antivipmyn) against FabO (Crofab) across 15 different North American snakes in terms of anti-hemorrhagic efficacy as well as testing the neutralizing effects of lethal doses of venom in mice.[16] In terms of anti-hemorrhagic efficacy, Antivipmyn was again shown to be more efficient in requiring less protein for the reversal of thirteen of fifteen venoms with Crofab only being more efficient for Western Diamondback rattlesnakes and the Mojave rattlesnake B venom (see Table 4). The authors noted that Antivipmyn neutralized all hemorrhagic venoms while Crofab only neutralized 11 of 14 with gaps in coverage of Canebrake rattlesnake, Northern Pacific rattlesnake, and Broad-banded Copperhead. 

Table 4: Comparison of the anti-hemorrhagic activity of two antivenoms 

VenomMHDAntivipmyn AHDCrofab AHD
>> MHD = minimum hemorrhagic dose; lower numbers indicate increasing hemorrhagic potency
>> AHD = anti-hemorrhagic dose, indicates the amount of antivenom which inhibits 50% of the MHD; lower numbers indicate more efficient antivenoms
>> Bolded values indicate the antivenom that requires less protein for neutralization
Eastern Diamondback rattlesnake0.314
Prairie rattlesnake0.74.44.4
Southern Pacific rattlesnake2.253.313.3
Western Massasauga2.48.813.3
Western Diamondback rattlesnake2.5277
Desert Massasauga3.526.6141.7
Timber rattlesnake5.64.46.5
Mojave rattlesnake B12.228335.4
Blacktail rattlesnake12.535.4283
Western Cottonmouth2970.8141.7
Canebrake rattlesnake37.5212-
Northern Pacific rattlesnake43425-
Broad-banded Copperhead67283-
Southern Copperhead14326.570.8

When assessing the ED50 (“Effective Dose in 50%,” term for the dose or amount of drug that produces a therapeutic response or desired effect in 50% of the subjects taking it) and LD50(“Lethal Dose in 50%,” amount of toxic agent that is sufficient to kill 50% of a population of animals within a certain time) of each antivenom, the authors noted that venoms were collected from juveniles, adults, and both sexes of snakes. This is important as we previously stated that there’s a wide range of variability in the toxic components of venom even between the same species of snake and there are case reports of single snakes producing wildly different venom from each fang.[16] This wide range of venom sources tested is great as it adds to the generalizability of the results which is welcomed given the overall paucity of clinical data with Antivipmyn. Overall, both antivenoms were effective in neutralizing essentially all venoms tested with the exception of Crofab and Blacktail rattlesnake venom (see Table 5).

Table 5: LD50 and ED50 of 15 snake venoms and two antivenoms

 MHDAntivipmyn AHDCrofab AHD
>> LD50 = concentration of venom (mg/kg) required to kill 50% of mice injected with 0.2 ml of venom; lower numbers indicate increased potency
>> ED50 = amount of antivenom required (mg/kg) to neutralize hemorrhagic activity in venoms used in this study(values were determined against 3 x LD50 of venoms)
>> Bolded values indicate which antivenom required less protein for neutralization
VenomLD50Antivipmyn ED50Crofab ED50
Mojave rattlesnake A0.47140.521
Timber rattlesnake0.53111.620.9
Canebrake rattlesnake1.2658.98.9
Prairie rattlesnake1.5693.617.7
Desert Massasauga1.7140226
Eastern Diamondback rattlesnake1.8434.970
Southern Pacific rattlesnake1.946.770
Northern Pacific rattlesnake2.1114.1121
Western Massasauga2.183.178.4
Western Cottonmouth2.75186.855.2
Blacktail rattlesnake4.8493.1-
Western Diamondback rattlesnake5.1295310
Mojave rattlesnake B5.188.4278
Southern Copperhead5.2331.693.7
Broad-banded Copperhead6.8293140.5

Overall, the authors concluded that Antivipmyn “was more effective in neutralizing the hemorrhagic and procoagulant activity of most of the venom used in this study” and both agents were effective in neutralizing venom-induced lethality. As a result the authors stated Antivipmyn “appears to be an excellent choice in the treatment of snakebite envenomations in the US and Canada.”[16]

When comparing the in-vitro data, Antivipmyn appears to be a very “efficient” antivenom for North American Crotalid snakes neutralizing the hemorrhagic and fibrinolytic effects as well as the lethality of a wide variety of snakes. However, “efficiency” does not exactly mean “efficacy” and therefore the in-vitro results should be taken with a bit of caution. While efficiency indicates less antivenom would be required for venom neutralization, we aren’t sure how much antivenom is required for each bite given the vast heterogeneity in venom characteristics and bite severities of different snakes. Therefore, while a more “efficient” antivenom likely increases the chances the initial dose will be sufficient, it is unclear how this translates to cases of higher venom loads and more severe envenomations. At the very least, in severe envenomations, the more “efficient” antivenom would theoretically require fewer doses to achieve initial control. Overall, the authors concluded that Antivipmyn “was more effective in neutralizing the hemorrhagic and procoagulant activity of most of the venom used in this study” and both agents were effective in neutralizing venom-induced lethality. As a result, the authors stated Antivipmyn “appears to be an excellent choice in the treatment of snakebite envenomations in the US and Canada.”[16]

Based on the in-vitro data presented above, the more efficient antivenom was Antivipmyn. However, this did not translate to fewer antivenom requirements when studied in human subjects. The Anavip/Placebo and Crofab arms both utilized a similar amount of antivenom (16  and 14 vials, respectively) while the Anavip/Anavip arm required almost double the amount of antivenom (27 vials). Again, there are a lot of unknown variables such as the severity of envenomations, type of snake, treating physicians, and geographic locations which may have affected the increased use, but until we have more information, this will remain unknown. 

Hospital Formulary Considerations: Cost, Safety, Efficacy

So what do we do with this information when considering the addition of Anavip to our hospital’s formulary? Major points of consideration for P&T usually include the cost of therapy and safety/efficacy against the alternative(s). Additionally, based on data reported by the North American Snakebite Registry, culprit snake envenomations differ greatly depending on geographic location and should also be taken into consideration when evaluating each antivenom (see below).[17]

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We know that Avanip is substantially less expensive per vial compared to Crofab (approximately one-third the price). In the head-to-head study both Anavip groups had a lower treatment cost (based on AWP) than Crofab for a course of treatment (Anavip/Placebo, mean 16 vials = $19,520 vs Anavip/Avavip, mean 27 vials = $32,940 vs Crofab, mean 14 vials = $46,424).[6] 

In terms of safety, there was no difference in the number of adverse events or immune reactions reported between Anavip and Crofab patients, however “serious adverse events” were higher in the Avanip/Anavip group (14.6%) compared to the Anavip/Placebo (2.7%) and Crofab (4.9%) arms.[6] Unfortunately, the definition for “severe adverse events” was not stated in the manuscript, so it remains unclear what these events entailed. While the FDA-approved dosing arm (Anavip/Placebo) showed minimal serious adverse events, the Avanip/Anavip patients (with receipt of a mean of 27 vials of antivenom over the course of therapy) might foreshadow what to expect in severe envenomations in terms of AEs where patients will require multiple rounds of Anavip. 

Efficacy comparisons between the antivenoms require a wide range of considerations. Although Anavip was shown to decrease late coagulopathies, this may be an overall less clinically relevant endpoint. Two studies of note have investigated the clinical significance of late coagulopathies. The first, from 2011, reviewed patients from two centers in Phoenix, Arizona and reported 31% of their patients (21 out of 66) were found to have late coagulopathy (prothrombin time > 14 seconds), hypofibrinogenemia (fibrinogen < 70 mg/dL), or thrombocytopenia (platelets < 120,000/mm^3). Severe late hematologic toxicity (fibrinogen < 35 mg/dL, prothrombin time > 100 seconds, or platelets < 50,000/mm^3) developed in five of 66 patients (8%). No deaths were reported, and one patient required retreatment with an additional course of 20 vials Crofab for late severe thrombocytopenia.[18] Second, a meta-analysis published in 2014, found late bleeding occurred in 9 of 1,017 patients (0.5%), 5 of which had medically significant late bleeding. Three patients required red blood cell transfusions, but no deaths or permanent sequelae were reported. The authors noted that of the nine patients with late bleeding, eight were the result of rattlesnake bites, while the ninth was an unidentified snake.[19] It’s clear late coagulopathy is not a completely benign phenomenon, however as an EM pharmacist, initial control is still our primary concern. 

Anavip does not appear to be less effective for initial control based solely on repeat dosing requirements (which itself is not a great maker for this outcome), but again, there’s a lot of missing information and only a handful of patients to draw a meaningful conclusion from. In-vitro data would suggest that Antivipmyn is as effective, if not more effective, than Crofab for a wide range of snake venoms with Antivipmyn reacting against all venoms tested compared to Crofab which had multiple gaps in efficacy in neutralizing the hemorrhagic and fibrinolytic effects of several different snake venoms. However, in likely the most important measure of efficacy, reducing lethality (in mice), both antivenoms produced favorable results with some subtle variances in “efficiency.” 

In our opinion, there’s no one right answer in regards to the addition or omission of Avanip to your hospital’s formulary. Additionally, the correct answer may be different depending on your area of the country. Several options are available, and may include (in no particular order): 

  1. Add Anavip to formulary to replace Crofab
    • Rationale: 
      • A substantial decrease in drug costs per treatment course
      • Likely as effective as Crofab with in-vitro and in-vivo data to support Anavip’s overall efficacy across a wide range of snakes
      • Overall equivalent safety profile compared to Crofab with standard Anavip dosing
    • Caveats: 
      • Limited Copperhead populations in the local area 
        • Unfortunately, the Anavip vs Crofab study authors were unable to analyze coagulopathy reversal among Copperhead bites given the very low amount of coagulopathies seen among those patients. It does not mean Avavip doesn’t work against Copperhead venom, but rather we don’t have the in-vivo evidence to confirm it works as well as Crofab
        • Additionally, the in-vitro evidence presented above it might be strong enough for some clinicians to use Anavip given that it neutralized all venoms tested, but Crofab was shown to be more efficient than Antivipmyn in terms of lethal venom neutralization for Copperhead snakes. Again, “efficiency” does not mean “efficacy,” but may indicate that additional caution and vigilance should be exercised when treating Copperhead bites with Anavip
        • Additional time and experience with Anavip in humans will shed more light on this issue
  2. Do NOT add Anavip to the formulary, continue Crofab
    • Rationale: 
      • Limited human data (81 patients) with a less-than-ideal primary outcome of “late coagulopathy” 
      • Unclear if “initial control” is sufficient with Anavip vs Crofab
      • Local snakes most commonly seen in clinical practice have better in-vitro data with Crofab or limited in-vivo data with Avavip (e.g., very high rates of Copperhead snakes).
      • Although in-vitro data appears equivalent to Crofab, Anavip is still very new and more human-driven efficacy and safety data would be required before adding to the formulary. Can reevaluate when early adopters publish additional data in the next 1-2 years 
  3. Add Anavip to formulary with restrictions, keep Crofab on the formulary
    • Rationale:
      • Anavip appears equally efficacious based on one small head-to-head comparison against Crofab
      • However, in-vitro data suggests one particular antivenom might be more “efficacious” depending on the culprit snake 
      • Can reduce antivenom drug costs by utilizing Anavip where appropriate instead of Crofab 
      • Restrictions for use based on local snake populations and identification of culprit snake for each patient 
    • Caveats: 
      • Anavip use restricted to confirmed bites via Desert Massasauga, Western Diamondback rattlesnake, Eastern Diamondback rattlesnake, Southern Pacific rattlesnake, Northern Pacific rattlesnake, Blacktail rattlesnake, and Mojave B rattlesnake
      • Crofab reserved for unknown pit viper envenomations or confirmed bites via Timber rattlesnake, Canebrake rattlesnake, Western Massasauga, Western Cottonmouth, Southern Copperhead, Broad-banded Copperhead, and Mojave A rattlesnake

Which option would the authors choose? 

Not surprisingly, each one of us chose a different option for what we would recommend to our P&T’s. This is a complicated topic and the answer varies depending on a wide range of factors specific to your hospital and geographic location. Our recommendation is to look into what snakes are most prevalent in your area, your antivenom drug use and yearly costs, and then compare Anavip to Crofab using the information above to determine which option would be most beneficial to the hospital and your patients. 

 

Comments from the Editor:

After this post was published, Ryan and I were contacted by Boston Scientific/BTG with additional information and clarification regarding the in-vitro data described above. Understanding the inherent conflict, but also wanting to provide accurate information, as a group we chose to provide the clarification here at the end of the text rather than change the integrity of the post.

In the aforementioned papers, outcome measures including anti-hemorrhagic dose, minimum hemorrhagic dose, minimal fibrinolytic dose, and anti-fibrinolytic dose should be viewed with the proper limitations in mind. In one respect, these tests could be viewed as surrogate markers of different components of antivenom “efficacy” which would allow other hypotheses to develop. In contrast, Effective Dose in 50%, (ED50) describes the dose or amount of drug that produces a therapeutic response or desired effect in 50% of the subjects taking it. It’s relative, the  LD50, Lethal Dose in 50%, describes the amount of toxic agent that is sufficient to kill 50% of a population of animals within a certain time. These outcome measures might be better predictors of antivenom efficacy compared to measures such as hemorrhagic or fibrinolytic assays. However, given that mortality from North American Crotalid envenomations is relatively low, the totality of in-vitro data can be used to compile a complete picture of each antivenom’s overall efficacy in terms of morbidity and mortality with potentially a higher weight given to LD50/ED50 results.

 

References

  1. Ruha A, Kleinschmidt KC, Green S, et al. The epidemiology, clinical course, and management of snakebites in the North American Snakebite Registry. J Med Toxicol. 2017;13:309-320
  2. Berling I, Isbister GK, Hematologic effects and complications of snake envenomating. Transf Med Rev. 2015;29:82-89
  3. Tasoulis T, Isbister GK. A review and database of snake venom proteomes. Toxins. 2017:18(9):E290 
  4. Dart RC, McNally J. Efficacy, safety, and use of snake antivenoms in the  United States. Ann Emerg Med. 2001;37(2):181-188
  5. Crofab (crotalidae polyvalent immune fab) [package insert]. BTG International Inc, West Conshohocken, PA. May 21017. 
  6. Anavip (crotalidae immune F(ab’)2) [package insert]. Instituto Bioclon S.A. de C.V. Mexico D.F., Mexico
  7. Gerring D, King TR, Branton R. Validating a faster method for reconstitution of cortalidae polyvalent immune fab (ovine). Toxicon. 2013;69:42-49
  8. Mazer-Amarshahi M, Stolbach A, Nelson LS. ACMT position statement: addressing the rising cost of prescription antidotes. J Med Toxicol. 2018;14(2):168-171
  9. Leffers P, Ferreira J, Sollee D, Schuaben J. Thromboelastography in the management of snakebite-induced coagulopathy: a case series and literature review. Blood Coag Fibrinolysis. 2018;29:656-660
  10. Boyer LV, Chase PB, Degan JA, et al. Subacute coagulopathy in a randomized, comparative trial of Fab and F(ab’)2 antivenoms. Toxicon. 2013 Nov;74:101-8
  11. Bush SP, Ruha AM, Seifert SA, et al. Comparison of F(ab’)2 vesus Fab antivenom for pit viper envenomation: a prospective, randomized, blinded, multicenter, randomized clinical trial. Clin Tox. 2015;53:37-45
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