ANAVIP: Package Insert and Label Information

ANAVIP- pit viper (crotalinae) immune globulin antivenin (equine) injection, powder, lyophilized, for solution
Rare Disease Therapeutics, Inc

1 INDICATIONS AND USAGE

ANAVIP [crotalidae immune F(ab’)2 (equine)] is an equine-derived antivenin indicated for the management of adult and pediatric patients with North American Pit Viper envenomation.

2 DOSAGE AND ADMINISTRATION

For Intravenous use only.

Administer ANAVIP as soon as possible after North American Pit Viper bite in patients who develop any signs of envenomation (e.g., local injury, coagulation abnormality, or systemic signs of envenomation).
The amount of antivenin required to treat a snake bitten patient is highly variable owing in part to the venom burden, the potency of the venom and the time to health care presentation. Use supportive measures to treat certain manifestations of North American Pit Viper envenomation, such as pain, swelling, hypotension, and wound infection. Contact the local poison control centers for additional individual treatment advice.Prior to initiating treatment, perform laboratory analyses, including complete blood count, platelet count, PT, PTT, serum fibrinogen level, and routine serum chemistries. Repeat testing at regular intervals to gauge response to therapy and anticipate additional dosing.

Initial Dose: 10 vials

  • The initial dose of ANAVIP is 10 vials.
  • Reconstitute the contents of each vial with 10 milliliters (mL) of sterile normal saline (0.9% NaCl). Average reconstitution time is 11.8 seconds (range 8-26 seconds) per vial when using continuous gentle swirling.
  • Inspect the solution visually for particulate matter and discoloration prior to administration. The solution is expected to be clear to yellow/green and opalescent. Do not use if otherwise discolored or turbid.
  • Combine the contents of the reconstituted vials promptly and further dilute to a total volume of 250 mL with sterile normal saline (0.9% NaCl). Fluid volumes may need to be adjusted for very small children or infants. Use reconstituted and diluted product within 6 hours. Discard partially or unused reconstituted and diluted product.
  • Infuse intravenously over 60 minutes.
  • For the first 10 minutes infuse at a 25-50 mL/hour rate, carefully monitoring for any allergic reactions, including any anaphylactic reactions. Discontinue the infusion if any allergic reaction occurs and institute appropriate emergency treatment. Reassess the risk to benefit before continuing the infusion.
  • If no reactions occur, the infusion rate may be incrementally increased to the full 250 mL/hour rate until completion. If there is any allergic reaction at any time, stop the infusion, treat accordingly, and reassess the need to continue ANAVIP.
  • Following the completion of infusion, monitor the patient for at least 60 minutes for any allergic reaction and to determine that local signs of envenomation are not progressing (leading edge of local injury not progressing), systemic symptoms are resolved and coagulation parameters have normalized or are trending toward normal.

Additional Dosing to Achieve Initial Control

  • Administer additional 10 vial doses if needed to arrest the progressive symptoms and repeat every hour until local signs of envenomation are not progressing, systemic symptoms are resolved and coagulation parameters have normalized or are trending toward normal. There is no known maximum dose.
  • Prepare additional loading doses as described above for initial dose.
  • Once initial control has been achieved, observe the patient to determine any need for further dosing, as described below.

Observation and late Dosing

  • Monitor patients in a health care setting at least 18 hours following initial control of signs and symptoms. Re-emerging symptoms including coagulopathies may be suppressed with additional 4 vial doses of ANAVIP as needed. Reconstitute each vial with 10 mL of sterile normal saline (0.9% NaCl). Combine and further dilute to a total of 250 mL. Infuse intravenously over 60 minutes.

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:

Table 1. Minimum Potency Units per Vial in Mouse LD50 Units
Snake Species Used for Standardization Minimum Mouse LD50 Units per Vial
Bothrops asper (Terciopelo or fer-de-lance)1 780
Crotalus simus (formerly Crotalus durissus) (Central American Rattlesnake)1 790
Crotalus adamanteus (Eastern Diamondback Rattlesnake) 244
Crotalus atrox (Western Diamondback Rattlesnake) 147
Crotalus scutulatus (Mohave Rattlesnake)2 185
Agkistrodon contortrix (Copperhead) 28
Agkistrodon piscivorus (Cottonmouth or Water Moccasin) 61

1 The venom of these species is used in the manufacture of ANAVIP.

2 The Mohave phenotype A is used for standardization.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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.4

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 (2%) 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 2 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 2: Incidence of Adverse Reactions in Clinical Trials of ANAVIP by Body System
Adverse Reaction ANAVIP [N=86] (%)
Patients Reporting at Least One Adverse Reactions 65 (76%)
Skin and subcutaneous tissue disorders 47 (55%)
Pruritus 37 (43%)
Rash 10 (12%)
Blister 4 (5%)
Erythema 3 (4%)
Gastrointestinal disorders 28 (33%)
Nausea 20 (23%)
Vomiting 5 (6%)
Musculoskeletal and connective tissue disorders 19 (22%)
Arthralgia 9 (11%)
Myalgia 6 (7%)
Pain in extremity 5 (6%)
General disorders and administration site conditions 21 (24%)
Edema peripheral 7 (8%)
Chills 3 (4%)
Pyrexia 4 (5%)
Nervous system disorders 12 (14%)
Headache 5 (6%)
Psychiatric disorders 4 (5%)
Anxiety 2 (2%)
Insomnia 2 (2%)
Metabolism and nutrition disorders 4 (5%)
Dehydration 2 (2%)
Respiratory, thoracic and mediastinal disorders 5 (6%)
Dyspnea 1 (1%)
Blood and lymphatic system disorders 2 (2%)
Thrombocytopenia 1 (1%)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of ANAVIP. Because these reactions are reported as monotherapy or in combination with other drugs and voluntarily from a global population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Chest Pain/Discomfort
  • Flushing
  • Hypersensitivity
  • Late Thrombocytopenia
  • Necrosis
  • Prolonged Prothrombin Time
  • Tachycardia
  • Treatment failure resulting in death
  • Urticaria

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively.

8.2 Lactation

Risk Summary
There is no information regarding the presence of ANAVIP in human milk, its effects on the breastfed infant, or its effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ANAVIP and any potential adverse effects on the breastfed infant from ANAVIP or from the underlying material condition.

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 nine percent (9%; 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 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, 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 (≤0.058 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.

12 CLINICAL PHARMACOLOGY

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

12.2 Pharmacodynamics

No pharmacodynamic studies were conducted on ANAVIP.

12.3 Pharmacokinetics

Thirteen healthy volunteers each received an intravenous (IV) dose of one vial (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 3.

Table 3. Pharmacokinetic Parameters of the ANAVIP Antivenin Following a Single IV Dose to Healthy Volunteers (n=13)
Parameters Units Mean SD
Area under plasma concentration vs time curve AUC0-∞ (µg•h/mL) 4144 670
Steady-state volume of distribution Vss (L) 3.3 0.9
Mean residence time MRT (h) 157 40
Elimination half-life Beta-HL (h) 133 53
Total clearance CL (mL/h) 22 7
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