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Crotalidae Immune F(ab′)2 (Equine)

Class: Antitoxins and Immune Globulins
VA Class: IM300
Brands: Anavip

Medically reviewed by Drugs.com. Last updated on April 27, 2020.

Introduction

Antivenin (antivenom); equine IgG F(ab′)2 fragments capable of binding and neutralizing venom toxins of North American rattlesnakes (pit vipers).1 5 6

Uses for Crotalidae Immune F(ab′)2 (Equine)

North American Rattlesnake Snakebite Envenomation

Treatment of envenomation following snakebites involving North American rattlesnakes (Crotalinae, crotalines, pit vipers; formerly known as Crotalidae or crotalids).1 2 3 9 Designated an orphan drug by FDA for this use.4

Crotalinae subfamily of venomous snakes includes rattlesnakes, copperheads, and cottonmouths or water moccasins.5 6 9

Has been effective in management of envenomation involving various crotaline, including Crotalus, Sistrurus, and Agkistrodon.1 2 3

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 Immune F(ab′)2 (Equine) Dosage and Administration

General

  • Initiate treatment as soon as possible after rattlesnake bite in patients who develop clinically important signs of envenomation (e.g., local injury, coagulation abnormality, systemic signs of envenomation).1

  • Prior to and during treatment, assess CBCs, serum chemistries, and coagulation parameters (e.g., PT, aPTT, serum fibrinogen concentration) to evaluate response to the antivenin.1

  • Monitor closely during and for at least 1 hour after IV infusion of the antivenin to assess for allergic reactions and confirm that local signs of envenomation are not progressing, systemic symptoms of envenomation have resolved, and coagulation abnormalities have normalized or are trending towards normalization.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 immune F(ab′)2 (equine) by adding 10 mL of 0.9% sodium chloride to each vial; mix using continuous gentle swirling (usually dissolves within 1 minute).1 Reconstituted solution should be clear to yellow/green and opalescent;1 do not use if discolored or turbid.1

Immediately after reconstitution, combine contents of appropriate number of reconstituted vials and dilute total dose (total combined reconstituted vials) to a total volume of 250 mL using 0.9% sodium chloride.1 May need to adjust volume of dilution fluid for infants or very small children.1

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

Discard partially used reconstituted vials or unused diluted antivenin.1

Rate of Administration

Administer by IV infusion over 60 minutes.1

Start initial IV infusion using reduced rate of 25–50 mL/hour for first 10 minutes; observe patient closely for sensitivity reactions (including anaphylaxis).1 If reduced rate well tolerated, give remaining initial infusion at rate of 250 mL/hour.1

If sensitivity reaction occurs, immediately discontinue IV infusion and reassess risks and benefits before continuing treatment with the antivenin.1 (See Sensitivity Reactions under Cautions.)

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 for maintenance to sustain envenomation control on individual patient response.1

Age-related dosage adjustments not indicated.1

Pediatric Patients

North American Rattlesnake Snakebite Envenomation
IV

Initially, 10 vials.1 Monitor closely for at least 1 hour after completion of infusion for allergic reaction and to determine if initial envenomation control achieved (i.e., local manifestations not progressing, systemic symptoms resolved, and coagulation abnormalities normalized or trending towards normalization).1

If initial envenomation control not achieved, give additional 10-vial doses every 60 minutes as needed until envenomation controlled.1

After initial envenomation control established, monitor closely for recurrent coagulopathy for at least 18 hours in a healthcare setting.1 If coagulation abnormalities reoccur, give additional 4-vial doses as needed.1

Adults

North American Rattlesnake Snakebite Envenomation
IV

Initially, 10 vials.1 Monitor closely for at least 1 hour after completion of infusion for allergic reaction and to determine if initial envenomation control achieved (i.e., local manifestations not progressing, systemic symptoms resolved, and coagulation abnormalities normalized or trending towards normalization).1

If initial envenomation control not achieved, give additional 10-vial doses every 60 minutes as needed until envenomation controlled.1

After initial envenomation control established, monitor closely for recurrent coagulopathy for at least 18 hours in a healthcare setting.1 If coagulation abnormalities reoccur, give additional 4-vial doses as needed.1

Prescribing Limits

Pediatric Patients

North American Rattlesnake Snakebite Envenomation
IV

Maximum dosage not known.1

Adults

North American Rattlesnake Snakebite Envenomation
IV

Maximum dosage not known.1

Special Populations

No special population dosage recommendations.1

Cautions for Crotalidae Immune F(ab′)2 (Equine)

Contraindications

  • Manufacturer states none.1

Warnings/Precautions

Sensitivity Reactions

Anaphylaxis and Other Severe Hypersensitivity Reactions

Severe hypersensitivity reactions, including anaphylaxis, may occur.1

Patients with history of sensitivity to equine protein are at increased risk for anaphylactic reactions to Crotalidae immune F(ab′)2 (equine).1

Monitor closely for signs and symptoms of acute hypersensitivity (e.g., urticaria, rash, bronchospasm with wheezing or cough, hypotension) during IV infusion.1

If hypersensitivity reaction occurs, immediately discontinue IV infusion and initiate appropriate emergency medical care.1 Carefully weigh potential risks and benefits of restarting Crotalidae immune F(ab′)2 (equine) infusion.1

Delayed Hypersensitivity or Serum Sickness Reactions.

Delayed hypersensitivity or serum sickness reactions may occur.1 2

Usually manifest as fever, rash, urticaria, pruritus, myalgia, arthralgia, and lymphadenopathy;1 5 may occur 7–21 days after antivenin treatment.5

Monitor for signs and symptoms of delayed allergic reactions or serum sickness.1 If such reactions suspected, administer appropriate medical care.1

Coagulopathy

Coagulopathic effects, such as thrombocytopenia (platelet counts <150,000/mm3), hypofibrinogenemia (fibrinogen concentrations <150 mg/dL), and prolonged PT and PTT, are a complication in many snakebite victims (especially those with severe envenomation).1 2 3 5 6 7

Recurrent coagulopathy, characterized by thrombocytopenia, hypofibrinogenemia, and prolonged PT, can occur after successful initial control of envenomation.6 There is some evidence that recurrent coagulopathy may occur less frequently in patients treated with Crotalidae immune F(ab′)2 (equine) than in those treated with Crotalidae polyvalent immune Fab (ovine);1 2 3 may be related in part to pharmacokinetics of Crotalidae immune F(ab′)2 (equine).2 3

Monitor for signs and symptoms of recurrent coagulopathy.1 6 Manufacturer recommends that, after initial control of envenomation achieved with Crotalidae immune F(ab′)2 (equine), monitor closely for reoccurrence of coagulation abnormalities for at least 18 hours in a healthcare setting.1 (See Dosage under Dosage and Administration.) 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 antivenin administration and as clinically indicated.6

Risk of Transmissible Infectious Agents

Prepared from equine plasma;1 potentially may transmit infectious agents (e.g., viruses).1

Several steps in manufacturing process (e.g., pepsin digestion, ammonium sulfate precipitation/heat treatment, nanofiltration) reduce risk of transmission of viruses.1

Cresol Content

Contains trace amounts of cresol (<0.058 mg per vial) from manufacturing process.1

Localized reactions and generalized myalgia reported when cresol used as an injectable excipient.1

Specific Populations

Pregnancy

Use during pregnancy only when clearly needed.1

Not known whether Crotalidae immune F(ab′)2 (equine) can cause fetal harm if administered to a pregnant woman or affect fertility.1 No animal reproduction studies performed.1

Lactation

Not known whether distributed into milk.1

Use with caution in nursing women.1

Pediatric Use

Efficacy and safety in pediatric patients comparable to that in adults.1 In clinical trials, 24% of patients were children 2–16 years of age.1

Age-related dosage adjustments not indicated since venom dose following snakebite is expected to be similar in children and adults.6 However, fluid volume used to dilute the antivenin may need to be adjusted in infants or small children.1 (See Reconstitution and Dilution under Dosage and Administration.)

Geriatric Use

Efficacy in geriatric patients comparable to that in overall patient population.1 In clinical trials, >9% of patients were >65 years of age.1

Common Adverse Effects

Pruritus, nausea, rash, arthralgia, myalgia, peripheral edema, headache, extremity pain, vomiting, pyrexia, blister, erythema, chills, anxiety, insomnia, dehydration.1

Interactions for Crotalidae Immune F(ab′)2 (Equine)

No formal drug interaction studies.1

Crotalidae Immune F(ab′)2 (Equine) Pharmacokinetics

Elimination

Half-life

Mean elimination half-life following single IV dose: Approximately 5.5 days in healthy (nonenvenomed) adults.1

Stability

Storage

Parenteral

For Injection, for IV Use

Lyophilized powder: Room temperature (up to 25°C); may briefly expose to temperatures up to 40°C.1 Do not freeze.1

Reconstituted and diluted solution: Use within 4 hours after reconstitution;1 discard partially used reconstituted vials and unused diluted solutions.1

Compatibility

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

Parenteral

Solution Compatibility1

Compatible

Sodium chloride 0.9%

Actions

  • Crotalidae immune F(ab′)2 (equine) is a polyvalent antivenin (antivenom) preparation of venom-specific F(ab′)2 fragments of equine IgG that bind and neutralize venom toxins of Crotalinae (rattlesnakes; genera Crotalus and Sistrurus) native to North America.1

  • Following IV administration, the F(ab′)2 fragments in Crotalidae immune F(ab′)2 (equine) bind to venom components, facilitating redistribution of venom away from target tissues and elimination from the body.1

  • Manufactured from plasma of horses immunized with venom of Bothrops asper and Crotalus durissus.1 Antivenin obtained by pepsin digestion of equine plasma to remove the Fc portion of the equine IgG, followed by fractionation and purification to isolate the venom-specific F(ab′)2 fragments.1 The antivenin is stabilized with sodium chloride, sucrose, and glycine; may contain trace amounts of pepsin, cresol, borates, and sulfates from the manufacturing process.1

  • Standardized by ability to neutralize B. asper and C. durissus venom in mice (mouse LD50 neutralizing units).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

  • Importance of immediately contacting clinician or seeking emergency treatment if manifestations of a hypersensitivity reaction or anaphylaxis (e.g., urticaria, rash, tightness of the chest, wheezing, hypotension) occur.1

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

  • Importance of women informing clinicians if they are pregnant or breast-feeding.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.

FDA has extended the expiration date on all lots of Crotalidae immune F(ab′)2 (equine) from 24 months to 36 months (based on an evaluation of stability data).10 Anavip lot B-8G-33 (labeled with an expiration date of July 31, 2020) now has an expiration date of July 31, 2021; lot B-9B-33 (labeled with an expiration date of February 28, 2021) now has an expiration date of February 28, 2022; and lot B-9E-35 (labeled with an expiration date of June 30, 2021) now has an expiration date of June 30, 2022.10 These products may be retained until their new expiration dates.10

Crotalidae Immune F(ab′)2 (Equine)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

≥780 mouse LD50 neutralizing units of Bothrops asper antivenin (equine) and ≥790 mouse LD50 neutralizing units of Crotalus durissus antivenin (equine) per vial

Anavip

Rare Disease Therapeutics

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. Rare Disease Therapeutics. Anavip (Crotalidae Immune F(ab′)2 [Equine]) for injection prescribing information. Franklin, TN; 2019 Jun.

2. Boyer LV, Chase PB, Degan JA et al. Subacute coagulopathy in a randomized, comparative trial of Fab and F(ab')2 antivenoms. Toxicon. 2013; 74:101-8. http://www.ncbi.nlm.nih.gov/pubmed/23948058?dopt=AbstractPlus

3. Bush SP, Ruha AM, Seifert SA et al. Comparison of F(ab')2 versus Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial. Clin Toxicol (Phila). 2015; 53:37-45. http://www.ncbi.nlm.nih.gov/pubmed/25361165?dopt=AbstractPlus

4. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2019 Jul 18. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=177503

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

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

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

10. Food and Drug Administration. Biologics safety and availability communication. Expiration date extension for Anavip (Crotalidae Immune F(ab′)2 [Equine]): Lot B-8G-33 through July 31, 2021; Lot B-9B-33 through February 28, 2022; and Lot B-9E-35 through June 30, 2022. From FDA website. Accessed 2020 Apr 2. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/expiration-date-extension-anavip-crotalidae-immune-fab2-equine-lot-b-8g-33-through-july-31-2021-lot