ANAVIP [crotalidae immune F(ab')2 (equine)] is a sterile, lyophilized, polyvalent preparation of equine immunoglobulin F(ab')2 fragments, manufactured from the plasma of horses immunized with venom of Bothrops asper and Crotalus simus (formerly Crotalus durissus). The product is obtained by pepsin digestion of horse plasma to remove the Fc portion of immunoglobulin, followed by fractionation and purification steps. The F(ab')2 content is not less than 85%, F(ab') content is not more than 7%, and the product contains less than 5% intact immunoglobulin. Each vial of ANAVIP contains 25.2-56.8 mg of sodium chloride, 47.30 - 91.35 mg of sucrose, and 95.03-183.15 mg of glycine as stabilizers. Trace amounts of pepsin (≤50 ng/vial), cresol (≤0.058 mg/vial), borates (≤1 mg/vial), and sulfates (≤1.7 mg/vial) may be present from the manufacturing process. Each vial contains no more than 120 mg of protein and will be neutralize not less than 780 times the LD50 of Bothrops asper (Terciopelo or fer-de-lance) venom, 790 times the LD50 of Crotalus simus (formerly Crotalus durissus) (Central American Rattlesnake) venom, 244 times the LD50 of Crotalus adamanteus (Eastern Diamondback Rattlesnake) venom, 147 times the LD50 of Crotalus atrox (Western Diamondback Rattlesnake) venom, 185 times the LD50 of Crotalus scutulatus (Mohave Rattlesnake) venom, 28 times the LD50 of Agkistrodon contortrix (Copperhead) venom and 61 times the LD50 of Agkistrodon piscivorus (Cottonmouth or Water Moccasin) venom in a mouse neutralization assay.

The manufacturing procedures that contribute to the reduction of risk of viral transmission include pepsin digestion, ammonium sulfate precipitation/heat treatment and nanofiltration.

In a published non-Good Laboratory Practice study3, ANAVIP and another licensed North American Pit Viper antivenin were tested and cross-reactivity to the venoms of multiple different North American Pit Vipers was demonstrated in rabbits and mice. Animal studies to determine a no observed adverse effect level were unsuccessful due to technical limitations that prevented determination of a systematically toxic dose.

Study 1 was a randomized, prospective, open-label, controlled, comparative, multicenter study was conducted in 12 patients aged 18 to 70 years of age with signs of North American Pit Viper envenomation.6 The subjects received either a licensed North American Pit Viper antivenin as an active control, or ANAVIP. The subjects were dosed until initial control was achieved, followed by maintenance doses. All patients in both treatment groups achieved initial control of local injury and coagulopathy following early antivenin treatment.

In the active control group, at the end of maintenance dosing, 5 of 6 subjects had platelet counts above 150,000/mm3, and all 6 had fibrinogen levels above 150 mg/dL. During the follow-up phase two patients exhibited platelets below 150,000/mm3 and fibrinogen below 150 mg/dL, leading to inpatient management with administration of additional doses (one subject received an additional 6 doses (12 vials) and one subject received an additional 4 doses (8 vials)).

In the ANAVIP arm, at the end of maintenance dosing, 5 of 6 subjects had platelet counts above 150,000/mm3. One subject’s platelets were 114,000/mm3 and were trending upward, and all 6 had fibrinogen levels above 150 mg/dL. During the follow-up phase, 5 of 6 subjects had platelet counts above 150,000/mm3, with no downward trend; 1 subject’s platelet count was 127,000/mm3 on follow-up Day 1, reached 160,000/mm3 on Day 4, and continued trending upward. All 6 subjects in the ANAVIP group had fibrinogen levels above 150 mg/dL during the follow-up phase. None in the ANAVIP group required rehospitalization or retreatment with ANAVIP.

Study 2 was a randomized, prospective, blinded, controlled, comparative, multicenter study, comparing two ANAVIP regimens with a licensed North American Pit Viper antivenin (comparator) conducted in patients with North American Pit Viper envenomation at 16 sites in the United States. The study had an in-hospital Acute Treatment Phase that included screening and baseline assessments, initial and maintenance dosing, and an outpatient Follow-up Phase that included 4 follow-up visits on Days 5, 8, 15 and 22.

Patients were randomized in a 1:1:1 ratio to one of three groups: ANAVIP with ANAVIP maintenance therapy (Group 1), ANAVIP with placebo maintenance therapy (Group 2), or Comparator product with Comparator product maintenance therapy (Group 3).

Initial dosing consisted of sequential intravenous (IV) doses infused to achieve initial control. If initial control of envenomation was not achieved, treatment was repeated until initial control was attained. Maintenance dosing (4 vials of ANAVIP or placebo [normal saline (0.9% NaCl)], or 2 vials of comparator product) was initiated 6 hours after the start of the last dose required to achieve initial control, and continued every 6 hours for 3 doses.

The Follow-up Phase began immediately after the third maintenance dose. Patients returned to the clinical site on Days 5, 8, and 15 for scheduled follow-up visits. Patients with ongoing signs of envenomation received 4 vials of ANAVIP or 2 vials of Comparator product. Dosing was provided as needed until the patient was stabilized. One hundred twenty-one (121) patients received blinded study drug and were analyzed for safety and efficacy.

The efficacy endpoint was the proportion of patients experiencing a coagulopathic effect as measured on Study Day 5 or 8. Patients were assessed as experiencing a coagulopathic effect if they had any one of the following: absolute platelet levels < 150,000/mm3 as measured on either Study Day 5 (±1 day) or 8 (±1 day); absolute fibrinogen levels <150 mg/dL as measured on either Study Day 5 (±1 day) or 8 (±1 day); or clinical coagulopathy between end of maintenance dosing and Study Day 5 requiring additional antivenin. The comparison of coagulopathic effect proportions between treatment groups was tested using an exact logistic regression model with terms for treatment and region. Comparisons of the proportion of coagulopathic effect for two levels of ANAVIP versus Comparator product were performed in the following order: ANAVIP with ANAVIP maintenance dose versus Comparator product; then ANAVIP with Placebo maintenance dose versus Comparator product. The number and percentage of patients who experienced a coagulopathic effect is summarized by treatment group in Table 5. The efficacy analysis did not meet the pre-specified statistically defined superiority criterion. However, the percentages of subjects showing prespecified criteria for coagulopathic effect on either Day 5 and/or Day 8 were 10.3% and 5.3% in the Groups 1 and 2 when compared to 29.7% in Group 3 indicating efficacy of ANAVIP in management of coagulopathic effect in patients with North American Pit Viper envenomation.

1Cl= confidence interval

FDA conducted a post hoc analysis to assess the outcomes of the patients who presented with or without baseline coagulopathic effect in the three treatment groups. Using the pre-specified criteria for coagulopathic effect, it was found that ANAVIP/ANAVIP (Group 1) had the highest percentage of baseline coagulopathic subjects among the three groups [41.5% compared with 17.5% and 32.5% for the ANAVIP/Placebo (Group 2) and Comparator product (Group 3), respectively]. Thirty-three percent (33%) of all baseline coagulopathic subjects also experienced coagulopathic effect on either Day 5 or 8, compared to only 6% for baseline non-coagulopathic subjects. Only 18% of the subjects with baseline coagulopathic effect in Group 1 continued to remain coagulopathic at Days 5 or 8 compared to 58% in Group 3 (Table 6).

An exact logistic regression analysis adjusting for baseline coagulopathic effect and region was conducted and showed that treatment effect for both Groups 1 and 2 is statistically significant (Table 7). This analysis provides supportive evidence of the efficacy of ANAVIP.

1Cl= confidence interval

Analysis by snakebite type was performed but was limited due to the number of unknown snakebite types (n=43). However, 57 subjects who were envenomated by rattlesnakes showed more severe coagulopathic effects and resolution of these effects after treatment with ANAVIP as compared to 21 subjects who were envenomated by copperhead snakes. Due to limited coagulopathic effects in the copperhead snake bite subgroup, efficacy outcomes for late coagulopathies could not be evaluated.

1. Seifert SA and Boyer LV: Recurrence phenomena after immunoglobulin therapy for snake envenomation: Part 1. Pharmacokinetics and pharmacodynamics of immunoglobulin antivenoms and related antibodies. Annals of Emergency Medicine 37(2):189-195; 2001.

2. Boyer LV, Seifert SA and Cain JS: Recurrence phenomena after immunoglobulin therapy for snake envenomation: Part 2. Guidelines for clinical management with crotaline Fab antivenom. Annals of Emergency Medicine 37(2):196-201; 2001.

3. Sanchez EE, Galan JA, Perez JC, et al. The efficacy of two antivenoms against the venom of North American snakes, Toxicon 41: 357-365; 2003.

4. Gold BS, Dart RC and Barish RA: Bites of venomous snakes. New England Journal of Medicine 347(5):347-56; 2002.

5. Boyer LV, Seifert SA, Clark RF, et al: Recurrent and persistent coagulopathy following Pit Viper envenomation. Archives of Internal Medicine 159:706-710; 1999.

6. Boyer LV, Chase PB, Degan JA, et al: Subacute coagulopathy in a randomized, comparative trial of Fab and F(ab’)2 antivenoms. Toxicon 74: 101-108; 2013.

ANAVIP is supplied as a sterile, lyophilized preparation in a single-dose vial. When reconstituted with 10 mL of 0.9% NaCl solution, each vial contains not more than 12 mg per mL of protein, and will neutralize not less than 780 times the LD50 of Bothrops asper (Terciopelo or fer-de-lance) venom and 790 times the LD50 of Crotalus simus (formerly Crotalus durissus) (Central American Rattlesnake) venom, 244 times the LD50 of Crotalus adamanteus (Eastern Diamondback Rattlesnake) venom, 147 times the LD50 of Crotalus atrox (Western Diamondback Rattlesnake) venom, 185 times the LD50 of Crotalus scutulatus (Mohave Rattlesnake) venom, 28 times the LD50 of Agkistrodon contortrix (Copperhead) venom and 61 times the LD50 of Agkistrodon piscivorus (Cottonmouth or Water Moccasin) venom in a mouse neutralization assay.

Each carton NDC 66621-0790-2 contains 1 vial of ANAVIP NDC 66621-0790-1.

• Store at room temperature (up to 25 ºC (77 ºF)). Brief temperature excursions are permitted up to 40 ºC (104ºF).
• DO NOT FREEZE.
• Use within 6 hours after reconstitution.
• Discard partially used vials.

• Advise patients to contact their physician immediately if they experience unusual bruising or bleeding (e.g., nosebleeds, excessive bleeding after brushing teeth, the appearance of blood in stools or urine, excessive menstrual bleeding, petechiae, excessive bruising or persistent oozing from superficial injuries) after hospital discharge.5
• Serious Allergic Reactions
       o Advise patients to contact their physician immediately if they experience any signs and symptoms of delayed allergic reactions or serum sickness (e.g., rash, fever, myalgias, arthralgia, pruritus, urticaria) after hospital discharge [see Hypersensitivity (5.1)].4

Manufactured by:
Laboratorios Silanes S.A. de C.V.
Toluca, Estado de Mexico, Mexico
Silanes® and the Silanes logo are registered trademarks in Mexico of Laboratorios Silanes, S.A. de C.V.

Manufactured for:
Rare Disease Therapeutics, Inc.
2550 Meridian Blvd., Suite 150
Franklin, TN 37067
www.raretx.com
RDT® and the RDT logo are registered trademarks of Rare Disease Therapeutics, Inc.

U.S. License No. 1860

RDT Part No. ANV-PI-009

Silanes Part number: 360893-8

PACKAGE LABEL

Anavip Carton label

Serialization Example of Anavip Carton label

Anavip Vial label