Ansuvimab

How Supplied

Ansuvimab Lyophilisate for solution for injection

EBANGA 400mg Powder for Injection (80673-0001) (Ridgeback Biotherapeutics, LP)

Description / Classification

Description

Ansuvimab is an antiviral medication comprised of a recombinant human monoclonal antibody. The drug is approved to treat Ebola virus (species Orthoebolavirus zairense) infection in adult and pediatric patients, including neonates born to mothers who are RT-PCR positive for Orthoebolavirus zairense. Efficacy against other species of the Orthoebolavirus and Orthomarburgvirus genera has not been established. Ansuvimab is administered as a single intravenous infusion. Hypersensitivity and infusion-related reactions, some considered life-threatening, have been reported during and after treatment; therefore, the drug must be prepared and administered under the supervision of a health care provider.^[66201]

Classification

• General Anti-infectives Systemic

  • Antivirals For Systemic Use

    • Antiviral Monoclonal Antibodies for Zaire ebolavirus

Administration Information

General Administration Information

For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

• Injectable Administration

  • Must be prepared and administered under the supervision of a health care provider.

    • Prepare the intravenous infusion using aseptic technique.

    • Visually inspect parenteral products for particulate matter and discoloration prior to drug administration. The reconstituted ansuvimab solution is clear to slightly opalescent and colorless to slightly yellow. Discard the vial if the solution is discolored or contains particulate matter.^[66201]

  • Intravenous Administration Reconstitution * Using the patient's body weight, determine the number of vials needed to produce a 50 mg/kg dose. Each vial contains 400 mg of ansuvimab. * Prior to reconstitution, allow the vial(s) to reach ambient temperature of 15 to 27 degrees C (59 to 81 degrees F) for approximately 20 minutes. If reconstitution cannot proceed immediately upon reaching ambient temperature, the vial(s) that have not been reconstituted may be stored at ambient temperature, protected from light, for no more than 24 hours. * Immediately upon reaching ambient temperature, use a sterile 10 mL syringe and an 18-gauge needle to withdraw 7.7 mL of Sterile Water for Injection, USP. Insert the needle tip into the vial containing ansuvimab. While holding the vial horizontally, angle the needle down at an approximate 45-degree angle above the lyophilized powder. Slowly inject the diluent along the wall of the vial and without any air to avoid foaming and bubbles. * Gently swirl the vial for approximately 10 seconds; do not shake. Then allow the vial to rest for at least 10 seconds. Repeat the gentle swirl until the lyophilized powder is dissolved. This process may take up to 20 minutes. * Upon reconstitution, each vial contains 8 mL of a 50 mg/mL solution (i.e., 400 mg/8 mL). * Storage: Dilute the solution immediately upon reconstitution. If needed, the reconstituted solution in the vial(s) may be stored refrigerated at 2 to 8 degrees C (36 to 46 degrees F), protected from light, for up to 4 hours. This 4-hour window includes the time required for further dilution, which should be administered immediately upon further dilution.^[66201] Dilution* * Use an 18- to 20-gauge, 1- to 1.5-inch needle with an appropriately sized syringe (up to 60 mL) to perform the dilution steps. * For patients weighing 0.5 to less than 2 kg: * Use a 10 mL syringe compatible with the IV infusion pump. * Fill the 10 mL syringe with the appropriate amount of diluent. * Add the calculated volume of reconstituted ansuvimab solution to the 10 mL syringe. * Mix the diluted solution by gentle inversion 3- to 5-times until mixed. Do NOT shake. * For patients weighing 2 kg or more: * Prepare the diluent using either a latex-free, DEHP-free 0.9% Sodium Chloride Injection or 5% Dextrose Injection infusion bag. * Select a diluent solution infusion bag of appropriate fill volume based on the patient's body weight, as described below. * Withdraw and discard from the infusion bag a volume of diluent solution that will leave remaining in the bag the appropriate volume based on the patient's body weight. * Then add the calculated volume of reconstituted ansuvimab solution to the bag based on the patient's body weight. * Gently invert the IV infusion bag 5- to 10-times until the diluted solution is mixed. Do NOT shake. * Dilution based on patient's body weight: * Body weight 0.5 kg: 1 mL/kg of ansuvimab added to 2.5 mL of diluent for a total infusion volume of 3 mL in a 10 mL syringe. * Body weight 1 kg: 1 mL/kg of ansuvimab added to 5 mL of diluent for a total infusion volume of 6 mL in a 10 mL syringe. * Body weight 2 to 10 kg: 1 mL/kg of ansuvimab added to 10 mL of diluent for a total infusion volume of 12 to 20 mL in a 25 mL IV bag. * Body weight 11 to 25 kg: 1 mL/kg of ansuvimab added to 25 mL of diluent for a total infusion volume of 36 to 50 mL in a 50 mL IV bag. * Body weight 26 to 50 kg: 1 mL/kg of ansuvimab added to 50 mL of diluent for a total infusion volume of 76 to 100 mL in a 100 mL IV bag. * Body weight 51 to 100 kg: 1 mL/kg of ansuvimab added to 100 mL of diluent for a total infusion volume of 151 to 200 mL in a 250 mL IV bag. * Body weight 101 kg or more: 1 mL/kg of ansuvimab added to 150 mL of diluent for a total infusion volume of 251 and above in a 500 mL IV bag. * Storage: Infuse the solution immediately upon dilution. If the diluted solution cannot be administered immediately, it may be stored refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 4 hours; do not freeze. This 4-hour window includes the time since reconstitution. * Prepare a medical label including the patient weight in kg and the date and time of the product expiration. * Discard vial(s) and all unused contents**.**^[66201] Intravenous Infusion* * If refrigerated, allow approximately 20 minutes for the diluted solution to come to ambient temperature prior to administration. * Prepare the IV infusion line with a 1.2 micron in-line filter extension set. * Administer over 60 minutes via a central line or peripheral catheter. Do not administer as an IV push or bolus. * Do not mix with or administer as an infusion with other medications. Do not administer simultaneously with other medications through the same infusion line. * Monitor patients during and after the infusion for adverse events. The infusion may be slowed or interrupted if signs of infusion-related or other adverse events develop. For severe or life-threatening reactions, discontinue the infusion immediately and administer appropriate emergency medical care. * At the end of the infusion, flush the line as follows: * If a syringe pump was used, remove the syringe and flush the line with 2 to 5 mL of diluent but do not exceed the total infusion volume. * If an infusion bag was used, replace the empty bag and flush the line by infusing at least 25 mL of the diluent.^[66201]

Adverse Reactions

Severe

• hyperkalemia

Moderate

• elevated hepatic enzymes

• hypernatremia

• hypokalemia

• hyponatremia

• hypotension

• hypoxia

• sinus tachycardia

• tachypnea

• infusion-related reactions

Mild

• abdominal pain

• diarrhea

• fever

• vomiting

• chills

Hypersensitivity and infusion-related reactions, some considered life-threatening, have been reported during and after treatment with ansuvimab. In the clinical trial, adverse events that occurred during the infusion included fever (17%), sinus tachycardia (9%), diarrhea (9%), vomiting (8%), hypotension (8%), tachypnea (6%), chills (5%), and hypoxia (3%). Monitor all drug recipients for signs of adverse events. If a patient develops an adverse reaction during the infusion, consider slowing the infusion rate or interrupting the infusion. If the reaction is deemed severe or life-threatening, discontinue the infusion immediately and administer appropriate emergency medical care. During clinical trials, two patients (1% of total drug recipients) were unable to complete treatment due to infusion-related adverse events. In 8 patients (5% of total drug recipients) the infusion rate was decreased due to an adverse reaction. Pre-specified symptoms that were assessed daily during the clinical trial and occurred in 40% or more of drug recipients included diarrhea, fever, abdominal pain, and vomiting. Evaluation of these pre-specified symptoms may have been confounded by the underlying infection.^[66201]

Laboratory abnormalities (worsening to Grade 3 or 4 as compared to baseline) that developed in patients treated with ansuvimab during the clinical trial include hypernatremia (154 mmol/L or more; 5%), hyponatremia (less than 125 mmol/L; 7%), hyperkalemia (6.5 mmol/L or more; 15%), hypokalemia (less than 2.5 mmol/L; 6%), elevated creatinine (more than 1.8-times ULN; 27%), and elevated hepatic enzymes (at least 5-times ULN; 12% to 13%).^[66201]

Contraindications / Precautions

• breast-feeding

• pregnancy

The coadministration of certain medications may lead to harm and require avoidance or therapy modification; review all drug interactions prior to concomitant use of other medications.

This medication is contraindicated in patients with a history of hypersensitivity to it or any of its components.

Data regarding the use of ansuvimab during pregnancy are insufficient to determine a drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. Additionally, animal reproductive studies with ansuvimab have not been conducted. However, since Ebola virus (species Orthoebolavirus zairense) infection is a life-threatening disease for both the pregnant person and fetus, treatment should not be withheld due to pregnancy. Available data from pregnant individuals who have received ansuvimab for Ebola virus (species Orthoebolavirus zairense) infection found the maternal and fetal/neonatal morbidity rate to be consistent with published literature describing the risk associated with underlying maternal Ebola virus (species Orthoebolavirus zairense) infection. Ansuvimab is a monoclonal antibody; human monoclonal antibodies are known to be transported across the placenta.^[66201]

The Centers for Disease Control and Prevention recommend all lactating individuals with a confirmed Ebola virus (species Orthoebolavirus zairense) infection avoid breast-feeding to reduce the risk of postnatal transmission. Although maternal IgG is known to be present in human milk, there are no data on the presence of ansuvimab in human milk, the effects on a breast-fed infant, or the effects on milk production.^[66201]

Mechanism Of Action

Ansuvimab is an antiviral medication comprised of a recombinant human IgG1 monoclonal antibody that targets the receptor binding domain (RBD) of Orthoebolavirus zairense glycoprotein (EBOV GP). This glycoprotein mediates viral attachment and membrane fusion to host cell membranes. By binding to the RBD of Orthoebolavirus zairense, ansuvimab prevents the viral glycoprotein from interacting with the host cell receptor protein, Niemann-Pick C1 (NPC1); and thus blocks viral entry into the cell. Ansuvimab targets a highly conserved epitope in the RBD region, which may have a lower risk for causing ebolavirus mutations. Also, ansuvimab is able to bind RBD in both physiologic and low pH intracellular environments, which allows for antiviral activity during multiple steps of the viral life cycle.^{[66201][66202][66203]}

Ansuvimab is active against Orthoebolavirus zairense; efficacy against other species of the Orthoebolavirus and Orthomarburgvirus genera has not been established. In cell culture resistance studies, 7 amino acid substitutions were identified in the EBOV GP. Of these 7 substitutions, 2 (P116H and T144M) exhibited resistance to ansuvimab with a more than 56-fold reduction in susceptibility for each substitution as compared with the wild type EBOV GP. Two additional EBOV GP substitutions (G118E and G118R) have been reported in the literature from other cell culture studies. The reduction in ansuvimab susceptibility for these substitutions was more than 29-fold for G118E and more than 34-fold for G118R. Of the 4 resistant substitutions identified under selective pressure in cell culture, only G118R has been identified in naturally infected Ebola virus disease patients in low frequency through NGS sequencing. In vivo studies specifically evaluating resistance to ansuvimab have not been conducted. Consider the possibility of resistance in patients who either fail to respond to treatment or who develop relapse of the disease after initial response.^[66201]

Pharmacokinetics

Ansuvimab is administered via a single intravenous infusion. No pharmacokinetic data are available in patients with Ebola virus (species Orthoebolavirus zairense) infection; however, limited data from 18 healthy subjects ages 22 to 56 years indicate that the pharmacokinetic profile is consistent with other IgG1 monoclonal antibodies. These subjects received a single dose of 5 mg/kg, 25 mg/kg, or 50 mg/kg. Half-life calculations were performed on 9 of the subjects with at least 56 days of pharmacokinetic data; the average half-life of ansuvimab for all dose levels was 24.2 +/- 1.8 days.^{[66201][66202]}

Affected cytochrome P450 isoenzymes: none

•Route-Specific Pharmacokinetics*

Intravenous Route*

Data from healthy subjects, ages 22 to 56 years, showed the pharmacokinetics of ansuvimab to be linear and dose-proportional over a range of 5 mg/kg to 50 mg/kg (0.1- to 1-times the approved recommended dose). At the recommended dose of 50 mg/kg, the mean maximum serum concentration (Cmax) was 1,961 +/- 340 mcg/mL, which occurred approximately 2.8 hours post dose. The average concentration over the first 28 days after the 50 mg/kg dose was 664 +/- 130 mcg/mL; the mean Day 28 serum concentration was 427 +/- 88 mcg/mL. The pharmacokinetics of ansuvimab were predictable with low variability in drug concentrations observed between drug recipients at Days 14 and 28.^[66202]

Pregnancy / Breast-Feeding

Pregnancy

Data regarding the use of ansuvimab during pregnancy are insufficient to determine a drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. Additionally, animal reproductive studies with ansuvimab have not been conducted. However, since Ebola virus (species Orthoebolavirus zairense) infection is a life-threatening disease for both the pregnant person and fetus, treatment should not be withheld due to pregnancy. Available data from pregnant individuals who have received ansuvimab for Ebola virus (species Orthoebolavirus zairense) infection found the maternal and fetal/neonatal morbidity rate to be consistent with published literature describing the risk associated with underlying maternal Ebola virus (species Orthoebolavirus zairense) infection. Ansuvimab is a monoclonal antibody; human monoclonal antibodies are known to be transported across the placenta.^[66201]

Breast Feeding

The Centers for Disease Control and Prevention recommend all lactating individuals with a confirmed Ebola virus (species Orthoebolavirus zairense) infection avoid breast-feeding to reduce the risk of postnatal transmission. Although maternal IgG is known to be present in human milk, there are no data on the presence of ansuvimab in human milk, the effects on a breast-fed infant, or the effects on milk production.^[66201]

Interactions

• Ebola Zaire Vaccine, Live

Ebola Zaire Vaccine, Live: (Major) Avoid administration of the ebola Zaire vaccine, live with ebolavirus monoclonal antibodies (i.e., ansuvimab and atoltivimab; maftivimab; odesivimab), as use of these drugs together may reduce the effectiveness of the vaccine. Ebolavirus monoclonal antibodies have activity against Zaire ebolavirus. These antibodies, if given with the vaccine, may inhibit the replication of the vaccine virus. No vaccine-therapeutic interaction studies have been conducted. According to the Advisory Committee on Immunization Practices (ACIP), the length of time that an antibody-containing product may interfere with a live virus vaccine depends on the amount of antigen-specific antibody contained in the product; also, after an antibody-containing product is received, live vaccines should be delayed until the passive antibody has degraded. If the vaccine is administered too soon after an antibody-containing product, a repeat dose of the vaccine may be needed. ^{[43236] [64868] [66032] [66201]}

Monitoring Parameters

• laboratory monitoring not necessary

US Drug Names

• EBANGA