FDA Label for Anavip

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:

4 Contraindications

None.

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.

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 F_c 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.

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.

   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).

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.

   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 °C (77 °F)). Brief temperature excursions are permitted up to 40 °C (104°F).
• 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.⁵
• 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.⁴




Manufactured by:

Instituto Bioclon S.A. de C.V.

Mexico D.F., Mexico

www.bioclon.com.mx





Manufactured for:

Rare Disease Therapeutics, Inc.

2550 Meridian Blvd., Suite 150

Franklin, TN 37067

www.raretx.com





Distributed by:

AnovoRx Distribution, LLC

1710 North Shelby Oaks Drive

Suite 6

Memphis, TN 38134





U.S. License No. 1860





RDT Part No. Anavip PI002






PACKAGE LABEL