ANAVIP: Package Insert and Label Information (Page 2 of 3)

13 NONCLINICAL TOXICOLOGY

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.

13.2 Animal Toxicology and/or Pharmacology

ANAVIP is standardized by its ability to neutralize the lethal action of each of the 7 venom immunogens following intravenous injection in mice. The potency of the product will vary from batch to batch; however, a minimum number of mouse LD50 neutralizing units against each of the 7 venoms is included in every vial of final product, as shown in Table 1 [see Dosage Forms and Strengths (3)]. ANAVIP was effective in neutralizing the venoms of 7 clinically important North American Pit Vipers in a murine lethality model see Table 1 [see Dosage Forms and Strengths(3)]. The ED50 data demonstrate the number of milligrams of antivenom necessary to neutralize a milligram of venom.

The amount of Anavip necessary to neutralize one milligram of venom was determined in a murine model. The dynamic between the venom and antivenom in a murine model provides a controlled environment to test the cross reactivity of antivenom against a variety of different snake venoms. Unlike the potency assays performed, as shown in Table 1 [see Dosage Forms and Strengths (3)] , the effective dose study provides a mg per mg comparison for venoms from 7 species commonly associated with North American Pit Viper envenomations. The results for each species are shown in Table 4.

Table 4. Average ED50 Values for ANAVIP in a Mouse Model When Administered Three LD50 of Venom
Challenge Venom ED50 (mg antivenin/mg venom)
B. asper (Terciopelo or fer-de-lance) 1.7
C. simus (formerly C. durissus) (Central American Rattlesnake) 3.4
C. adamanteus (Eastern Diamondback Rattlesnake) 2.4
C. atrox (Western Diamondback Rattlesnake) 2.9
C. scutulatus A1 (Mohave Rattlesnake) 14.6
A. contortrix (Copperhead) 8.0
A. piscivorus (Cottonmouth or Water Moccasin) 5.0

1 C. scutulatus A is the Mohave phenotype containing neurotoxic venom

14 CLINICAL STUDIES

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.

Table 5. Comparison of Coagulopathic Effect Rates on Study Day 5 or Study Day 8
Experienced Coagulopathic Effect on Either Day 5 or Day 8 Group 1 ANAVIP/ANAVIP (n=39) Group 2 ANAVIP/Placebo (n=38) Group 3 Comparator product (n=37)
Yes 4 (10.3%) 2 (5.3%) 11 (29.7%)
No 35 (89.7%) 36 (94.7%) 26 (70.3%)
Treatment Group (vs. Group 3) Odds Ratio (95% Cl1) 0.275 (0.058, 1.048) 0.135 (0.014, 0.686)

1 Cl= confidence intervalFDA 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).

Table 6. Coagulopathy by Treatment Group and Baseline Coagulopathy
Baseline Coagulopathy and Experienced coagulopathy on either Day 5 or 8 Group 1 ANAVIP/ANAVIP Group 2 ANAVIP/Placebo Group 3 Comparator product Total
Number of subjects n=17 n=7 n=12 n=36
Yes 3 (17.65%) 2 (28.57%) 7 (58.33%) 12 (33.3%)
No 14 (82.35%) 5 (71.43%) 5 (41.67%) 24 (66.7%)
No Baseline Coagulopathy and Experienced coagulopathy on either Day 5 or 8 Group 1 ANAVIP/ANAVIP Group 2 ANAVIP/Placebo Group 3 Comparator product Total
Number of Subjects n=22 n=31 n=25 n=78
Yes 1 (4.55%) 0 (0%) 4 (16%) 5 (6.4%)
No 21 (95.45%) 31 (100%) 21 (84%) 73 (93.6%)

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.

Table 7. Comparison Coagulopathic Effect Rates Adjusted for Baseline Coagulopathy
Group 1 ANAVIP/ANAVIP (n=39) Group 2 ANAVIP/Placebo (n=38)
Treatment Group (vs Comparator product)Odds ration (95% Cl1) 0.184 (0.033, 0.794) 0.121 (0.010, 0.764)

1 Cl= 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.

15 REFERENCES

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

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.

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