Atoltivimab; Maftivimab; Odesivimab

How Supplied

Atoltivimab, Maftivimab, Odesivimab Solution for injection

INMAZEB 241.7mg-241.7mg-241.7mg/14.5mL Solution for Injection (61755-0018) (Regeneron Pharmaceuticals Inc.)

Description / Classification

Description

Atoltivimab; maftivimab; odesivimab is an antiviral medication comprised of three recombinant human monoclonal antibodies. The drug is indicated for the treatment of Ebola virus (species Orthoebolavirus zairense) infection in adult and pediatric patients and is given as a single intravenous infusion. Efficacy against other species of the Orthoebolavirus and Orthomarburgvirus genera has not been established. 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 healthcare provider. Atoltivimab; maftivimab; odesivimab was approved by the FDA in October 2020.^[66032]

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 healthcare provider.

    • Visually inspect parenteral products for particulate matter and discoloration prior to drug administration. Atoltivimab; maftivimab; odesivimab is a clear to slightly opalescent, colorless to pale yellow solution that is free from visible particulates. Discard the vial if the solution is cloudy, discolored, or contains particulate matter.^[66032]

  • Intravenous Administration Preparation and Dilution * Product available as two different strength formulations, one containing 16.67 mg of each antibody per mL and the other containing 33.33 mg of each antibody per mL. * Using the patient's body weight, determine the number of vials needed based on the calculated dose in volume (mL). Both strength formulations contain 14.5 mL of atoltivimab; maftivimab; odesivimab solution per vial; thus, the number of vials needed depends on the strength formulation used: * 16.67 mg atoltivimab; 16.67 mg maftivimab; 16.67 mg odesivimab per mL solution = 241.7 mg atoltivimab; 241.7 mg maftivimab; 241.7 mg odesivimab per 14.5 mL vial * Withdraw 3 mL of solution per kg to prepare the dose. * 33.33 mg atoltivimab; 33.33 mg maftivimab; 33.33 mg odesivimab per mL solution = 483.3 mg atoltivimab; 483.3 mg maftivimab; 483.3 mg odesivimab per 14.5 mL vial * Withdraw 1.5 mL of solution per kg to prepare the dose. * Do not shake the vial(s) during the preparation and dilution process. * The atoltivimab; maftivimab; odesivimab solution must be diluted in a PVC infusion bag containing either 0.9% Sodium Chloride for Injection, 5% Dextrose Injection, or Lactated Ringer's Injection. For neonates, use only 5% Dextrose Injection as the diluent. * 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 bag a volume of diluent solution equal to the calculated dose volume. Then add the calculated volume of atoltivimab; maftivimab; odesivimab solution from the vial(s) to the bag. * body weight, 0.5 to less than 1 kg: give a total infusion volume after dilution of 7 mL * body weight, 1 to 1.9 kg: give a total infusion volume after dilution of 15 mL * body weight, 2 to 3.9 kg: give a total infusion volume after dilution of 25 mL * body weight, 4 to 7 kg: give a total infusion volume after dilution of 50 mL * body weight, 8 to 15 kg: give a total infusion volume after dilution of 100 mL * body weight, 16 to 38 kg: give a total infusion volume after dilution of 250 mL * body weight, 39 to 79 kg: give a total infusion volume after dilution of 500 mL * body weight, 80 to 149 kg: give a total infusion volume after dilution of 1,000 mL * body weight, 150 kg or more: give a total infusion volume after dilution of 2,000 mL * Mix the diluted solution by gentle inversion. Do not shake. * Administer immediately after preparation whenever possible. * Storage: * Solution diluted with 0.9% Sodium Chloride Injection may be stored at room temperature up to 25 degrees C (77 degrees F) for no more than 8 hours or under refrigeration at 2 to 8 degrees C (36 to 46 degrees F) for no more than 24 hours. Do not freeze the diluted solution. * Solution diluted with 5% Dextrose may be stored at room temperature up to 25 degrees C (77 degrees F) for no more than 4 hours or under refrigeration at 2 to 8 degrees C (36 to 46 degrees F) for no more than 24 hours. Do not freeze the diluted solution. * Solution diluted with Lactated Ringer's Injection may be stored for no more than 4 hours, whether kept at room temperature up to 25 degrees C (77 degrees F) or under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). Do not freeze the diluted solution. * Discard any unused product.^[66032] Intravenous Infusion* * Allow the diluted solution to come to room temperature before administration. * Solution diluted with 5% Dextrose can be infused at temperatures up to 35 degrees C (95 degrees F); however, when temperatures are higher than 25 degrees C (77 degrees F), administration must occur immediately after the dose has been prepared. * Administer the diluted solution intravenously through an intravenous line containing a sterile, in-line or add-on 0.2-micron filter. * The infusion rate is based on the patient's body weight and prepared infusion volume, as described below. * body weight, 0.5 to 1.9 kg: infuse over 4 hours * body weight, 2 to 15 kg: infuse over 3 hours * body weight, 16 to 149 kg: infuse over 2 hours * body weight, 150 kg or more: infuse over 4 hours * 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. * Do not mix the diluted solution with other medications. Compatibility studies with other medications administered simultaneously through the same infusion line have not been performed.^[66032]

Adverse Reactions

Severe

• hyperkalemia

Moderate

• elevated hepatic enzymes

• hypotension

• hypoxia

• infusion-related reactions

• sinus tachycardia

• tachypnea

• hypernatremia

• hypokalemia

• hyponatremia

• antibody formation

Mild

• chills

• diarrhea

• fever

• vomiting

Hypersensitivity and infusion-related reactions, some considered life-threatening, have been reported during and after treatment with atoltivimab; maftivimab; odesivimab. In the clinical trial, adverse events that occurred during the infusion included fever (54%), chills (39%), sinus tachycardia (20%), tachypnea (19%), vomiting (19%), hypotension (15%), diarrhea (11%), and hypoxia (10%). 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. One of the 2 patients stopped treatment as a result of elevated fever. Pre-specified symptoms that were assessed daily during the clinical trial and occurred in 40% or more of drug recipients included diarrhea, fever, and vomiting. Evaluation of these pre-specified symptoms may have been confounded by the underlying infection.^[66032]

Laboratory abnormalities (worsening to Grade 3 or 4 as compared to baseline) that developed in patients treated with atoltivimab; maftivimab; odesivimab during the clinical trial include hypernatremia (154 mmol/L or more; 9%), hyponatremia (less than 125 mmol/L; 7%), hyperkalemia (6.5 mmol/L or more; 13%), hypokalemia (less than 2.5 mmol/L; 9%), elevated creatinine (at least 1.8-times ULN; 15%), and elevated hepatic enzymes (at least 5-times ULN; 10% to 21%).^[66032]

Antibody formation against atoltivimab, maftivimab, and odesivimab was evaluated in 24 healthy adults who received a single dose. In this study, there was no immunogenic response against atoltivimab, maftivimab, or odesivimab detected at baseline or through 168 days post-dose in any subject.^[66032]

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 atoltivimab; maftivimab; odesivimab during pregnancy are insufficient to determine a drug-associated risk for major birth defects, miscarriages, or adverse outcomes; animal reproductive studies have not been conducted. However, since Orthoebolavirus zairense infection is a life-threatening disease for both the patient and fetus, treatment should not be withheld due to pregnancy. Available data from pregnant patients who have received atoltivimab; maftivimab; odesivimab for Orthoebolavirus zairense infection found the patient and fetal or neonatal morbidity rates to be consistent with published literature describing the risk associated with underlying patient infection. Atoltivimab; maftivimab; odesivimab is a combination product consisting of 3 monoclonal antibodies; human monoclonal antibodies are known to be transported across the placenta.^[66032]

Advise patients to avoid breast-feeding while taking atoltivimab; maftivimab; odesivimab. The Centers for Disease Control and Prevention recommend all individuals with a confirmed Orthoebolavirus zairense infection to avoid breast-feeding as a method of preventing postnatal transmission. Although IgG is known to be present in human milk, there are no data on the presence of atoltivimab, maftivimab, or odesivimab in human milk, the effects on a breast-fed child, or the effects on milk production.^[66032]

Mechanism Of Action

Atoltivimab; maftivimab; odesivimab is an antiviral medication comprised of three recombinant human IgG monoclonal antibodies, each targeting the Orthoebolavirus zairense glycoprotein (EBOV GP). This glycoprotein is the sole envelope protein that mediates viral attachment and membrane fusion to host cell membranes. The glycoprotein is also present on the surface of host cells that have been infected with Orthoebolavirus zairense. Atoltivimab, maftivimab, and odesivimab bind to three non-overlapping epitopes on the glycoprotein and all three antibodies can simultaneously bind to the glycoprotein. Maftivimab is a neutralizing antibody that blocks entry of the virus into susceptible host cells. Odesivimab is a non-neutralizing antibody that, when bound to the target, induces antibody-dependent effector function through Fc-gamma receptor signaling (specifically Fc-gammaRIIIA). Odesivimab also binds to the soluble form of Orthoebolavirus zairense glycoprotein. Atoltivimab is both a neutralizing antibody and a Fc-gammaRIIIA signaling antibody.

Atoltivimab; maftivimab; odesivimab is active against Orthoebolavirus zairense; efficacy against other species of the Orthoebolavirus or Orthomarburgvirus genera has not been established. Clinical data regarding resistance to atoltivimab; maftivimab; odesivimab are not available. However, amino acid substitutions in EBOV GP have been identified and assessed for activity in binding, neutralization, and antibody-dependent cellular cytotoxicity (ADCC). The clinical significance of these substitutions is not known.^[66032]

Pharmacokinetics

Atoltivimab; maftivimab; odesivimab is administered via a single intravenous infusion. No pharmacokinetic data are available in patients with Orthoebolavirus zairense infection; however, the pharmacokinetic parameters were evaluated in 18 healthy subjects ages 21 to 60 years. In healthy subjects and at the recommended dose of 50 mg/kg, the mean steady-state volume of distribution for atoltivimab, maftivimab, and odesivimab was 58.2 mL/kg, 57.6 mL/kg, and 56 mL/kg, respectively. The mean elimination half-lives were reported as follows: 21.2 days for atoltivimab, 22.3 days for maftivimab, and 25.3 days for odesivimab. The mean clearances were reported to be 3.08 mL/day/kg for atoltivimab, 2.78 mL/day/kg for maftivimab, and 2.02 mL/day/kg for odesivimab.^[66032]

Affected cytochrome P450 isoenzymes: none

•Route-Specific Pharmacokinetics*

Intravenous Route*

In 18 healthy subjects, ages 21 to 60 years, the pharmacokinetics of atoltivimab, maftivimab, and odesivimab were linear and dose-proportional over a range of 1 mg/kg to 50 mg/kg (0.02- to 1-times the approved recommended dose). At the recommended dose of 50 mg/kg, the mean maximum plasma concentration (Cmax) for atoltivimab, maftivimab, and odesivimab was 1,220 mg/L, 1,280 mg/L, and 1,260 mg/L, respectively. The mean systemic exposure (AUC) was 17,100 mg x day/L for atoltivimab, 18,700 mg x day/L for maftivimab, and 25,600 mg x day/L for odesivimab.^[66032]

Pregnancy / Breast-Feeding

Pregnancy

Data regarding the use of atoltivimab; maftivimab; odesivimab during pregnancy are insufficient to determine a drug-associated risk for major birth defects, miscarriages, or adverse outcomes; animal reproductive studies have not been conducted. However, since Orthoebolavirus zairense infection is a life-threatening disease for both the patient and fetus, treatment should not be withheld due to pregnancy. Available data from pregnant patients who have received atoltivimab; maftivimab; odesivimab for Orthoebolavirus zairense infection found the patient and fetal or neonatal morbidity rates to be consistent with published literature describing the risk associated with underlying patient infection. Atoltivimab; maftivimab; odesivimab is a combination product consisting of 3 monoclonal antibodies; human monoclonal antibodies are known to be transported across the placenta.^[66032]

Breast Feeding

Advise patients to avoid breast-feeding while taking atoltivimab; maftivimab; odesivimab. The Centers for Disease Control and Prevention recommend all individuals with a confirmed Orthoebolavirus zairense infection to avoid breast-feeding as a method of preventing postnatal transmission. Although IgG is known to be present in human milk, there are no data on the presence of atoltivimab, maftivimab, or odesivimab in human milk, the effects on a breast-fed child, or the effects on milk production.^[66032]

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

• Inmazeb