NDC 66621-0790 Anavip

Crotalidae Immune F(ab)2(equine)

NDC Product Code 66621-0790

NDC 66621-0790-2

Package Description: 1 VIAL in 1 CARTON > 10 mL in 1 VIAL (66621-0790-1)

NDC Product Information

Anavip with NDC 66621-0790 is a a plasma derivative product labeled by Rare Disease Therapeutics, Inc. The generic name of Anavip is crotalidae immune f(ab)2(equine). The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form.

Labeler Name: Rare Disease Therapeutics, Inc

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Plasma Derivative What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Anavip Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.
  • Intravenous - Administration within or into a vein or veins.

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Rare Disease Therapeutics, Inc
Labeler Code: 66621
FDA Application Number: BLA125488 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-06-2015 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Anavip Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

3 Dosage Forms And Strengths

Anavip is supplied as a sterile, lyophilized powder. Each vial contains not more than 120 milligrams (mg) total protein and not less than the indicated number of mouse LD50 neutralizing units:Snake Species Used for StandardizationMinimum Mouse LD50 Units per VialBothrops asper780Crotalus durissus790

4 Contraindications


5.1 Hypersensitivity

  • Anavip may cause allergic reactions.
  • Patients with known allergies to horse protein are particularly at risk for an anaphylactic reaction. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including urticaria, rash, tightness of the chest, wheezing, hypotension) occur, discontinue immediately and institute appropriate treatment.Monitor patients with follow-up visits for signs and symptoms of delayed allergic reactions or serum sickness (rash, fever, myalgia, arthralgia, pruritus, urticarial rash) and treat appropriately if necessary.

5.2 Transmissible Infectious Agents

Anavip is made from equine (horse) plasma and may therefore carry a risk of transmitting infectious agents, e.g., viruses.

5.3 Reactions To Cresol

Trace amounts of cresol from the manufacturing process are contained in Anavip. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient.

6 Adverse Reactions

The most common adverse reactions observed in more than 2 percent of patients in the clinical trials for Anavip were: pruritus, nausea, rash,
arthralgia, peripheral edema, erythema, headache, myalgia, pain in extremity, and vomiting.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

A total of 86 patients were treated with Anavip, ranging from 2 to 80 years old. The patient population was comprised of 60 males and 26 females.
Patients were monitored for signs and symptoms of adverse reactions including acute hypersensitivity reactions and serum sickness.
Follow-up interviews were conducted at 5, 8, 15 and 22 days after treatment to assess symptoms of ongoing venom effect, serum sickness, and any other adverse reactions.

Table 1 shows the adverse reactions occurring in patients across all clinical trials for Anavip. Seventy six percent (65/86) of patients receiving Anavip reported at least one adverse reaction.

Table 1: Incidence of Adverse Events in Clinical Studies of Anavip by Body SystemAnavip [N=86] n (%)Patients Reporting at Least One Adverse Event65 (76%)Skin and subcutaneous tissue disorders47 (55%)Pruritus37 (43%)Rash10 (12%)Blister4 (5%)Erythema3 (4%)Gastrointestinal disorders28 (33%)Nausea20 (23%)Vomiting5 (6%)Musculoskeletal and connective tissue disorders19 (22%)Arthralgia9 (11%)Myalgia6 (7%)Pain in extremity5 (6%)General disorders and administration site conditions21 (24%)Edema peripheral7 (8%)Chills3 (4%)Pyrexia4 (5%)Nervous system disorders12 (14%)Headache5 (6%)Psychiatric disorders4 (5%)Anxiety2 (2%)Insomnia2 (2%)Metabolism and nutrition disorders4 (5%)Dehydration2 (2%)Respiratory, thoracic and mediastinal disorders5 (6%)Dyspnea1 (1%)Blood and lymphatic system disorders2 (2%)Thrombocytopenia1 (1%)

8.1 Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted with Anavip. It is also not known
whether Anavip can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Anavip should be given to a pregnant woman
only if clearly needed.

8.3 Nursing Mothers

It is not known whether Anavip is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when
Anavip is administered to a nursing woman.

8.4 Pediatric Use

Twenty-four percent (21/86) of patients studied in clinical trials were 16 years of age or younger (6 patients were 2 years of age to 5 years of age, 15 patients ranged from at least 5 years of age to 16 years of age).
None of the pediatric patients in the phase 3 study experienced a recurrent coagulopathic effect. All adverse reactions in the pediatric patients were non-serious. The most frequent adverse reactions among pediatric patients were nausea and vomiting, itching and fever.
Thus, the safety and efficacy in the pediatric population was not different from adults.

8.5 Geriatric Use

Over 9 percent (8/86) of patients studied in clinical trials were over 65 years of age. The efficacy of Anavip in the geriatric population appears comparable to the overall population.

11 Description

Anavip [Crotalidae Immune F(ab')2 (Equine)] is a sterile, lyophilized, polyvalent preparation of equine immunoglobulin F(ab')2 fragments,
manufactured from plasma of horses immunized with venom of
Bothrops asper and 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, 18.2 - 85.8 mg of sucrose, and 16.2-51.8 mg of glycine as stabilizers. Trace amounts of pepsin (≤160 ng/vial), cresol (≤0.99 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 venom and 790 times the LD50 of Crotalus durissus 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.

12.1 Mechanism Of Action

Anavip contains venom-specific F(ab')2 fragments of immunoglobulin G (IgG) that bind and neutralize venom toxins, facilitating
redistribution away from target tissues and elimination from the body.1,2

12.3 Pharmacokinetics

Fourteen healthy volunteers each received one vial of intravenous (IV) doses (one vial = 81.86 mg) of an antivenin comparable to Anavip both in composition and manufacturing.
On the first day of antivenin administration, blood samples were collected from all subjects at 16 specific time points: 0 (prior to drug infusion), 5, 10, 20, 30, 45, 60, 120, and 480 minutes after drug infusion.
Additional samples were drawn just prior to discharge (Day 1), and on days 3, 5, 7, 9, 11, and 21. A two-compartment model best described the concentration-time data. The pharmacokinetic parameters of the antivenin are summarized in Table 2.Table 2. Pharmacokinetic Parameters of Anavip Antivenin Following a Single IV Dose to Healthy Volunteers (n=13)UnitsMeanSDArea under plasma concentration vs time curveAUC0-∞(µg•h/mL)4144670Steady-state volume of distributionVss (L)3.30.9Mean residence timeMRT (h)15740Elimination half-lifeBeta-HL (h)13353Total ClearanceCL (mL/h)227

13 Nonclinical Toxicology

In a published non-GLP study3, Anavip and another licensed pit viper antivenin were tested and cross-reactivity to the venoms of multiple different pit vipers including rattlesnakes was demonstrated in rabbits and mice.
Animal studies to determine an NOAEL were unsuccessful due to technical limitations that prevented determination of a systematically toxic dose.

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 pit viper envenomation6.
The subjects received either a licensed 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 counts 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 pit viper antivenin (comparator) conducted in patients with 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], 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 coagulopathic effect as measured on Study Day 5 or Study Day 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 coagulopathic effect is summarized by treatment group in Table 3.
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 rattlesnake envenomation.

Table 3. Comparison of Coagulopathic Effect Rates on Study Day 5 or Study Day 8Experienced Coagulopathic Effect on Either Day 5 or Day 8Group 1 (n=39) Anavip/AnavipGroup 2 (n=38) Anavip/PlaceboGroup 3 (n=37) Comparator product  Yes No4 (10.3%)35 (89.7%)2 (5.3%)36 (94.7%)11 (29.7%)26 (70.3%)Treatment Group (vs. Group 3)  Odds Ratio (95% Cl)0.275(0.058, 1.048)0.135(0.014, 0.686)
   Cl= 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 CroFab/CroFab (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 4).
Table 4. Coagulopathy by Treatment Group and Baseline CoagulopathyBaseline coagulopathyExperienced coagulopathy on either Day 5 or 8Anavip/AnavipAnavip/PlaceboComparator productTotalYesNumber 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 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 5). This analysis provides supportive evidence of the efficacy of Anavip.Table 5. Comparison Coagulopathic Effect Rates Adjusted for Baseline CoagulopathyGroup 1 (N=39) Anavip/AnavipGroup 2 (N=38) Anavip/PlaceboTreatment Group (vs Comparator product)Odds ration (95% Cl1)0.184 (0.033, 0.794)0.121 (0.010, 0.764)
   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.
Efficacy outcomes could not be evaluated in the copperhead snake bite subgroup due to these limited coagulopathic effects.

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-use 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 780 times the LD50 of Bothrops asper venom and 790 times the LD50 of Crotalus durissus
  • 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.Discard partially used vials.

17 Patient Counseling Information

  • 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.5Advise 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.4Manufactured by:Instituto Bioclon S.A. de C.V.Mexico D.F., Mexicowww.bioclon.com.mxManufactured for:Rare Disease Therapeutics, Inc.2550 Meridian Blvd., Suite 150Franklin, TN 37067www.raretx.comDistributed by:AnovoRx Distribution, LLC1710 North Shelby Oaks DriveSuite 6Memphis, TN 38134U.S. License No. 1860RDT Part No. Anavip PI002PACKAGE LABEL

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