Skip to Content

Crotalidae Polyvalent Immune Fab

Class: Antitoxins and Immune Globulins
ATC Class: J06AA03
VA Class: IM300
Brands: CroFab

Introduction

Antivenin (antivenom); ovine IgG Fab fragments capable of binding and neutralizing venom toxins of Crotalinae (pit vipers, crotalines; formerly known as Crotalidae or crotalids) native to North America.1

Uses for Crotalidae Polyvalent Immune Fab

North American Crotaline Snakebite Envenomation

Treatment of envenomation following snakebites involving North American Crotalinae (pit vipers, Crotalinae, crotalines; formerly known as Crotalidae or crotalids).1 4 5 8 9 18 42 Designated an orphan drug by FDA for this use.14

Crotalinae subfamily of venomous snakes includes rattlesnakes, copperheads, and cottonmouths or water moccasins.1

May be effective in management of minimal, moderate, or severe envenomation involving Crotalus atrox (Western diamondback rattlesnake), C. adamanteus (Eastern diamondback rattlesnake), C. scutulatus (Mojave rattlesnake), Agkistrodon piscivorus (cottonmouth or water moccasin), and other North American crotalines.1 4 6 8 42 49

Consultation with experts experienced in treating snakebites (e.g., regional certified poison control center at 800-222-1222) recommended to guide treatment decisions regarding individual patients.1 5 6

Crotalidae Polyvalent Immune Fab Dosage and Administration

General

  • Initiate treatment as soon as possible after Crotalinae snakebite in patients with signs of progressive envenomation (e.g., worsening local injury, coagulation abnormality, other systemic signs of envenomation).1 6

  • Has been effective in clinical studies when given within 6 hours of snakebite.1

  • Monitor closely during and following administration.1

Administration

IV Administration

Administer by IV infusion.1

Reconstitution and Dilution

Must be reconstituted and diluted prior to administration.1

Reconstitute appropriate number of vials of lyophilized Crotalidae polyvalent immune Fab (ovine) by adding 18 mL of 0.9% sodium chloride injection to each vial; mix by continuously manually inverting vial at a rate of 1 or 2 inversions per second until no solid material is visible in vial.1 Avoid foaming; do not shake.1 Reconstituted solution should be opalescent.1

Combine contents of appropriate number of reconstituted vials and dilute total dose (total combined reconstituted vials) in 250 mL of 0.9% sodium chloride and gently swirl to mix.1 Because of concerns regarding fluid overload, consider lower volume of dilution fluid for children weighing <10 kg.48

Use reconstituted and diluted solution within 4 hours after reconstitution.1 (See Stability.)

Rate of Administration

Administer by IV infusion over 60 minutes.1

Start initial infusion using reduced rate of 25–50 mL/hour for first 10 minutes; observe patient closely for sensitivity or other reactions.1 17 If reduced rate well tolerated, give remaining initial infusion and subsequent infusions at rate of 250 mL/hour.1 17

Dosage

Dosage expressed in terms of the number of vials.1

Base initial dose (number of vials), need for additional initial doses to achieve envenomation control, and number of subsequent doses required to sustain envenomation control on individual patient response.1

Age-related dosage adjustments not indicated.1 6 46 48

Pediatric Patients

North American Crotaline Snakebite Envenomation
Initial Dosage
IV

4–6 vials.1 Manufacturer states initial dose may vary from minimum of 4 vials to maximum of 12 vials based on clinical judgment and severity of envenomation.1 In those with life-threatening symptoms (e.g., shock, serious active bleeding), some experts state consider initial dose of 8–12 vials in consultation with experts experienced in treating crotaline snakebites.6

Monitor closely for up to 1 hour after completion of initial infusion; determine whether initial envenomation control achieved (i.e., local manifestations arrested and not progressing, systemic symptoms resolved, coagulation abnormalities normalized or trending towards normalization).1

If initial envenomation control not achieved, give additional 4- to 6-vial doses until envenomation is controlled.1

Maintenance Dosage
IV

After initial envenomation control established, give 2-vial doses every 6 hours for up to 18 hours to maintain response.1 Use of scheduled dosage regimen after initial control may provide best control of subsequent envenomation symptoms, especially coagulopathies, that may result from continued venom release from depot sites.1

After initial 18-hour scheduled maintenance dosage regimen, may give additional 2-vial doses if considered necessary based on patient’s clinical course.1 Optimum dosage schedule not established for these additional maintenance doses after 18-hour regimen.1 4

Adults

North American Crotaline Snakebite Envenomation
Initial Dosage
IV

4–6 vials.1 Manufacturer states initial doses may vary from minimum of 4 vials to maximum of 12 vials based on clinical judgment and severity of envenomation.1 In those with life-threatening symptoms (e.g., shock, serious active bleeding), some experts state consider initial dose of 8–12 vials in consultation with experts experienced in treating crotaline snakebites.6

Monitor closely for up to 1 hour after completion of infusion; determine whether initial envenomation control is achieved (i.e., local manifestations arrested and not progressing, systemic symptoms resolved, coagulation abnormalities normalized or trending towards normalization).1

If initial envenomation control not achieved, give additional 4- to 6-vial doses until envenomation is controlled.1

Maintenance Dosage
IV

After initial envenomation control established, give 2-vial doses every 6 hours for up to 18 hours to maintain response.1 Use of scheduled dosage regimen after initial control may provide best control of subsequent envenomation symptoms, especially coagulopathies, that may result from continued venom release from depot sites.1

After initial 18-hour scheduled maintenance dosage regimen, may give additional 2-vial doses if considered necessary based on patient’s clinical course.1 Optimum dosage schedule not established for these additional maintenance doses after 18-hour regimen.1 4

Prescribing Limits

Pediatric Patients

North American Crotaline Snakebite Envenomation
IV

Maximum dose and maximum total dosage not known; total dosage of up to 18 vials used in clinical trials without toxic effects.1 17

Adults

North American Crotaline Snakebite Envenomation
IV

Maximum dose and maximum total dosage not known; total dosage of up to 18 vials used in clinical trials without toxic effects.1 17

Special Populations

No special population dosage recommendations.1

Cautions for Crotalidae Polyvalent Immune Fab

Contraindications

  • Known hypersensitivity to papaya or papain is a contraindication, unless benefits outweigh risks and appropriate drugs and equipment for management of anaphylactic reactions are readily available.1 (See Papain Hypersensitivity under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Contains purified immunoglobulin fragments from blood of sheep immunized with snake venom.1 (See Actions.) Heterologous animal proteins can cause severe acute hypersensitivity reactions (anaphylaxis, anaphylactoid reactions), delayed hypersensitivity reactions (late serum reaction, serum sickness), or possible febrile responses to immune complexes formed by animal antibodies and neutralized venom components.1

Skin sensitivity testing not considered necessary and not recommended.1 6

Use caution if repeat course is indicated for a subsequent envenomation episode since patients may become sensitized to the antivenin.1

Anaphylaxis and Anaphylactoid Reactions

Acute allergic reactions, including anaphylaxis and anaphylactoid reactions, may occur during or shortly after IV infusion of Crotalidae polyvalent immune Fab (ovine).1 17 19 43 44

Immediate hypersensitivity reactions, including hypotension, tongue swelling, chest discomfort, angioedema, bronchospasm, wheezing, tracheal edema, dyspnea, and/or lip swelling, reported in 0.1–6% of patients.1 6 43 44 49 Rarely, immediate hypersensitivity reaction appeared to be anaphylactoid reaction related to extremely rapid IV infusion rate (i.e., 640 mL/hour).19

Monitor closely for signs and symptoms of acute hypersensitivity (e.g., urticaria, pruritus, erythema, angioedema, bronchospasm with wheezing or cough, stridor, laryngeal edema, hypotension, tachycardia).1

If anaphylaxis or any severe hypersensitivity reaction occurs, immediately discontinue IV infusion and initiate appropriate therapy (e.g., epinephrine, corticosteroids, maintenance of adequate airway, oxygen, IV fluids, IV antihistamines, albuterol, maintenance of BP) as indicated.1

Delayed Hypersensitivity or Serum Reactions

Delayed hypersensitivity or serum reactions may occur.1 20

Late serum reactions (rash, pruritus, urticaria, or serum sickness consisting of severe rash and pruritus) reported in 14% (6/42) of patients in initial clinical trials;1 in other studies, delayed hypersensitivity or serum sickness reported in 5–11% of patients.1 6 49

Most common signs and symptoms are rash and fever.1 Generally mild and respond to treatment with antihistamines and corticosteroids.1 6

Monitor for signs and symptoms of delayed hypersensitivity reactions or serum sickness (e.g., rash, fever, myalgia, arthralgia) for up to 2–3 weeks; initiate appropriate treatment if necessary.1 17

Papain Hypersensitivity

Traces of papain or inactivated papain residues may be present in the Crotalidae polyvalent immune Fab (ovine);1 papain is used in manufacturing process.1

Individuals allergic to papain, chymopapain, other papaya extracts, or the pineapple enzyme bromelain may be at risk of hypersensitivity reaction to the antivenin.1 Patients allergic to dust mites or latex may also be allergic to papain.1 (See Contraindications under Cautions.)

Coagulopathy

Coagulopathic effects, such as thrombocytopenia (platelet counts <150,000/mm3), hypofibrinogenemia (fibrinogen concentrations <150 mg/dL), and prolonged PT and PTT, are common in many snakebite victims (especially those with severe envenomation)1 5 6 7 40 and occur because snake venom can activate or inhibit activity of various coagulation factors and interfere with blood coagulation cascade.1 6 40

Recurrent coagulopathy, characterized by thrombocytopenia, hypofibrinogenemia, and prolonged PT, can occur 2–7 days or longer after successful initial envenomation control and may persist for 1–2 weeks or longer.1 4 6 18 40 41 42 50 55

Recurrent coagulation abnormalities reported in 7–32% of patients treated with Crotalidae polyvalent immune Fab (ovine).1 6 40 Reported in clinical studies only in patients who experienced coagulation abnormalities during initial hospitalization,1 4 but can initially appear at any time before, during, or after treatment.1

Clinical importance of recurrent coagulopathy and most appropriate strategies for prevention or management unknown.1 6 41 42 49 50 Optimum dosage schedule of the antivenin to prevent recurrent coagulopathy not determined.1 4 6 18 55 Because the antivenin may be cleared from circulation while crotaline venoms continue to be released from depot sites, repeated antivenin doses may be necessary to prevent and/or treat recurrence of venom effects.1 4 6 18 55 (See Dosage under Dosage and Administration.)

Monitor for signs and symptoms of recurrent coagulopathy for up to 1 week or longer; carefully assess need for retreatment with the antivenin and use of any type of anticoagulant or antiplatelet drug.1 17 Some clinicians suggest that follow-up in patients treated with antivenin should include platelet counts, fibrinogen concentrations, hemoglobin, and PT at 2–3 days and 5–7 days after administration of antivenin and as clinically indicated.6 Avoid use of any drug that may decrease platelet function or prolong PT or PTT.17

Consider other causes of persistent coagulation abnormalities, including cancer, collagen disease, CHF, diarrhea, elevated temperature, hepatic disorders, hyperthyroidism, poor nutritional state, steatorrhea, and vitamin K deficiency.1 17

Infusion Reactions

Monitor closely during IV infusion.1 Based on experience with antibody therapies, infusion reactions (fever, low back pain, wheezing, nausea) may be related to infusion rate and can be controlled by decreasing rate.1 (See Rate of Administration under Dosage and Administration.)

Specific Populations

Pregnancy

Use during pregnancy only if clearly needed.1

Not known whether Crotalidae polyvalent immune Fab (ovine) can cause fetal harm if administered to a pregnant woman or whether it can affect reproduction capacity.1 No animal reproduction studies conducted.1

Lactation

Not known whether distributed into milk.1

Use with caution in nursing women.1

Pediatric Use

Efficacy and safety in pediatric patients similar to that in adults.1 Data from postmarketing retrospective study indicate 32% (78/247) of patients were ≤16 years of age (median age: 8.5 years).1 Has been used in children as young as 14 months of age without unusual adverse effects.18 45 47 48

Age-related dosage adjustments not indicated since venom dose following snakebite is expected to be similar in children and adults.1 6 46 48 To avoid fluid overload, fluid volume used to dilute the antivenin may need to be adjusted in children weighing <10 kg.48 (See Reconstitution and Dilution under Dosage and Administration.)

Geriatric Use

Efficacy and safety in geriatric patients appears comparable to that in overall patient population.1 Data from postmarketing retrospective study indicate 5% (13/247) of patients were >65 years of age (median age: 72 years).1

Common Adverse Effects

Urticaria, rash, pruritus, nausea, coagulation disorder, back pain.1 4

Interactions for Crotalidae Polyvalent Immune Fab

No formal drug interaction studies.1

Crotalidae Polyvalent Immune Fab Pharmacokinetics

Elimination

Half-life

Limited data indicate distribution half-life of approximately 2.5 hours55 and elimination half-life of approximately 12–30 hours.1 4 55

Stability

Storage

Parenteral

For Injection, for IV Infusion

Lyophilized powder: 2–8°C; if necessary, may be exposed to temperatures ranging from −20° to 25°C for up to 7 days.1 Do not freeze.1

Reconstituted and diluted solution: Use within 4 hours after reconstitution.1 17 Should be refrigerated, but may be stored at room temperature if necessary.17

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Sodium chloride 0.9%

Actions

  • Crotalidae polyvalent immune Fab (ovine) is an antivenin (antivenom) preparation of venom-specific Fab fragments of ovine IgG that bind and neutralize venom toxins of Crotalinae (pit vipers, crotalines; formerly known as Crotalidae or crotalids) native to North America.1

  • Following IV administration, the Fab fragments in Crotalidae polyvalent immune Fab (ovine) bind to venom components, facilitating redistribution of venom away from target tissues and elimination from the body.1

  • Mixture of 4 different monospecific antivenins derived from serum of healthy sheep immunized with one of the following North American snake venoms: C. atrox (Western diamondback rattlesnake), C. adamanteus (Eastern diamondback rattlesnake), C. scutulatus (Mojave rattlesnake), or A. piscivorus (cottonmouth or water moccasin).1 Each monospecific antivenin is prepared by fractionating IgG from the ovine serum, digesting it with papain, and isolating venom-specific Fab fragments using ion exchange and affinity chromatography columns and then mixed together.1

  • Standardized by ability to neutralize lethal action of the 4 crotaline venoms following IV injection in mice (mouse LD50 neutralizing units).1 One neutralizing unit is determined as the amount of mixed monospecific Fab proteins necessary to neutralize one LD50 of each of the 4 venoms, where the LD50 is amount of venom that would be lethal in 50% of mice.1

  • Murine lethality tests indicate that the antivenin has cross-neutralizing ability with venoms from some other clinically important North American crotalines, including venoms from C. horridus atricaudatus (Canebrake rattlesnake), A. contortrix contortrix (Southern copperhead), Sistrurus miliarius barbouri (Southeastern pygmy rattlesnake), and C. horridus horridus (Timber rattlesnake), but is less potent against venoms from C. viridis helleri (Southern Pacific rattlesnake) and C. molossus molossus (Mexican black-tailed rattlesnake).1

Advice to Patients

  • Importance of immediately contacting a clinician if any unusual bruising or bleeding (e.g., nosebleeds, excessive bleeding after brushing teeth, blood in stools or urine, excessive menstrual bleeding, petechiae, excessive bruising or persistent oozing from superficial injuries) occurs after hospital discharge.1 Advise patients that such bruising or bleeding may occur for 1 week or longer following initial treatment of envenomation.1

  • Importance of immediately contacting a clinician if any manifestations of delayed allergic reactions or serum sickness (e.g., rash, pruritus, urticaria) occur after hospital discharge.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Crotalidae Polyvalent Immune Fab (Ovine)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

≥1270 mouse LD50 neutralizing units of Crotalus atrox, ≥420 mouse LD50 neutralizing units of C. adamanteus, ≥5570 mouse LD50 neutralizing units of C. scutulatus, and ≥780 mouse LD50 neutralizing units of Agkistrodon piscivorus antivenins (equine) per vial

CroFab

BTG

AHFS DI Essentials™. © Copyright 2021, Selected Revisions April 27, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. BTG International. Crofab (Crotalidae polyvalent immune fab [ovine]) prescribing information. West Conshohocken, PA; 2018 Jan.

2. Dart RC, McNally J. Efficacy, safety, and use of snake antivenoms in the United States. Ann Emerg Med. 2001;37:181-8.

3. Hill RE, Bogdan GM, Dart RC. Time to reconstitution: purified Fab antivenom vs. unpurified IgG antivenom. Toxicon. 2001;39:729-31.

4. Dart RC,, Seifert SA, Boyer LV et al. A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States. Arch Intern Med. 2001; 161:2030-6. http://www.ncbi.nlm.nih.gov/pubmed/11525706?dopt=AbstractPlus

5. Gold BS, Dart RC, Barish RA. Bites of venomous snakes. N Engl J Med. 2002; 347:347-56. http://www.ncbi.nlm.nih.gov/pubmed/12151473?dopt=AbstractPlus

6. Lavonas EJ, Ruha AM, Banner W et al. Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop. BMC Emerg Med. 2011; 11:2. http://www.ncbi.nlm.nih.gov/pubmed/21291549?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3042971&blobtype=pdf

7. Ruha AM, Kleinschmidt KC, Greene S et al. The Epidemiology, Clinical Course, and Management of Snakebites in the North American Snakebite Registry. J Med Toxicol. 2017; 13:309-320. http://www.ncbi.nlm.nih.gov/pubmed/28975491?dopt=AbstractPlus

8. Dart RC, Seifert SA, Carroll L et al. Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid venom poisoning. Ann Emerg Med. 1997;30:33-9.

9. Cocchio C, Johnson J, Clifton S. Review of North American pit viper antivenoms. Am J Health Syst Pharm. 2020; 77:175-187. http://www.ncbi.nlm.nih.gov/pubmed/31974558?dopt=AbstractPlus

14. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2020 Jan 10. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=78993

17. Protherics Inc, Brentwood, TN: Personal communication

18. Ruha AM, Curry SC, Beuhler M et al. Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake envenomation. Ann Emerg Med. 2002; 39:609-15. http://www.ncbi.nlm.nih.gov/pubmed/12023703?dopt=AbstractPlus

19. Holstege CP, Wu J, Baer AB. Immediate hypersensitivity reaction associated with the rapid infusion of Crotalidae polyvalent immune Fab (ovine). Ann Emerg Med. 2002; 39:677-9. http://www.ncbi.nlm.nih.gov/pubmed/12023715?dopt=AbstractPlus

20. Clark RF, McKinney PE, Chase PB et al. Immediate and delayed allergic reactions to Crotalidae polyvalent immune Fab (ovine) antivenom. Ann Emerg Med. 2002; 39:671-6. http://www.ncbi.nlm.nih.gov/pubmed/12023714?dopt=AbstractPlus

40. Ruha AM, Curry SC, Albrecht C et al. Late hematologic toxicity following treatment of rattlesnake envenomation with crotalidae polyvalent immune Fab antivenom. Toxicon. 2011; 57:53-9. http://www.ncbi.nlm.nih.gov/pubmed/20920516?dopt=AbstractPlus

41. Miller AD, Young MC, DeMott MC et al. Recurrent coagulopathy and thrombocytopenia in children treated with crotalidae polyvalent immune fab: a case series. Pediatr Emerg Care. 2010; 26:576-82. http://www.ncbi.nlm.nih.gov/pubmed/20693856?dopt=AbstractPlus

42. Lavonas EJ, Schaeffer TH, Kokko J et al. Crotaline Fab antivenom appears to be effective in cases of severe North American pit viper envenomation: an integrative review. BMC Emerg Med. 2009; 9:13. http://www.ncbi.nlm.nih.gov/pubmed/19545426?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2713980&blobtype=pdf

43. Cannon R, Ruha AM, Kashani J. Acute hypersensitivity reactions associated with administration of crotalidae polyvalent immune Fab antivenom. Ann Emerg Med. 2008; 51:407-11. http://www.ncbi.nlm.nih.gov/pubmed/18191286?dopt=AbstractPlus

44. Schaeffer TH, Khatri V, Reifler LM et al. Incidence of Immediate Hypersensitivity Reaction and Serum Sickness Following Administration of Crotalidae Polyvalent Immune Fab Antivenom: A Meta-analysis. Acad Emerg Med. 2012; 19:121-31. http://www.ncbi.nlm.nih.gov/pubmed/22320362?dopt=AbstractPlus

45. Pizon AF, Riley BD, LoVecchio F et al. Safety and efficacy of Crotalidae Polyvalent Immune Fab in pediatric crotaline envenomations. Acad Emerg Med. 2007; 14:373-6. http://www.ncbi.nlm.nih.gov/pubmed/17296804?dopt=AbstractPlus

46. Behm MO, Kearns GL. Crotaline Fab antivenom for treatment of children with rattlesnake envenomation. Pediatrics. 2003; 112:1458-9; author reply 1458-9. http://www.ncbi.nlm.nih.gov/pubmed/14654633?dopt=AbstractPlus

47. Richardson WH, Barry JD, Tong TC et al. Rattlesnake envenomation to the face of an infant. Pediatr Emerg Care. 2005; 21:173-6. http://www.ncbi.nlm.nih.gov/pubmed/15744196?dopt=AbstractPlus

48. Offerman SR, Bush SP, Moynihan JA et al. Crotaline Fab antivenom for the treatment of children with rattlesnake envenomation. Pediatrics. 2002; 110:968-71. http://www.ncbi.nlm.nih.gov/pubmed/12415038?dopt=AbstractPlus

49. Lavonas EJ, Kokko J, Schaeffer TH et al. Short-term outcomes after Fab antivenom therapy for severe crotaline snakebite. Ann Emerg Med. 2011; 57:128-137.e3. http://www.ncbi.nlm.nih.gov/pubmed/20952098?dopt=AbstractPlus

50. Camilleri C, Offerman S, Gosselin R et al. Conservative management of delayed, multicomponent coagulopathy following rattlesnake envenomation. Clin Toxicol (Phila). 2005; 43:201-6. http://www.ncbi.nlm.nih.gov/pubmed/15902796?dopt=AbstractPlus

51. Johnson PN, McGoodwin L, Banner W. Utilisation of Crotalidae polyvalent immune fab (ovine) for Viperidae envenomations in children. Emerg Med J. 2008; 25:793-8. http://www.ncbi.nlm.nih.gov/pubmed/19033492?dopt=AbstractPlus

52. LaMonica GE, Seifert SA, Rayburn WF. Rattlesnake bites in pregnant women. J Reprod Med. 2010 Nov-Dec; 55:520-2.

54. Seifert SA, Boyer LV. Recurrence phenomena after immunoglobulin therapy for snake envenomations: Part 1. Pharmacokinetics and pharmacodynamics of immunoglobulin antivenoms and related antibodies. Ann Emerg Med. 2001; 37:189-95. http://www.ncbi.nlm.nih.gov/pubmed/11174238?dopt=AbstractPlus

55. 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; 37:196-201. http://www.ncbi.nlm.nih.gov/pubmed/11174239?dopt=AbstractPlus