Atoltivimab, Maftivimab, and Odesivimab-ebgn (Monograph)
Brand name: Inmazeb
Drug class: Monoclonal Antibodies
Introduction
Monoclonal antibodies directed at Zaire ebolavirus glycoprotein.
Uses for Atoltivimab, Maftivimab, and Odesivimab-ebgn
Zaire ebolavirus infection
Treatment of Zaire ebolavirusinfection in adult and pediatric patients, including neonates born to a mother who is reverse transcriptase-polymerase chain reaction (RT-PCR) positive for Zaire ebolavirus infection (designated an orphan drug by FDA for this use).
Efficacy not established for other species of the Ebolavirus and Marburgvirus genera.
Zaire ebolavirus can change over time, and factors such as emergence of resistance or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating Zaire ebolavirus strains when deciding whether to use atoltivimab, maftivimab, and odesivimab-ebgn.
Atoltivimab, maftivimab, and odesivimab-ebgn is among agents recommended by international experts for patients with RT-PCR confirmed Zaire ebolavirusdisease and for neonates ≤7 days of age with unconfirmed Zaire ebolavirusdisease status born to mothers with confirmed Zaire ebolavirusdisease.
Atoltivimab, Maftivimab, and Odesivimab-ebgn Dosage and Administration
General
Patient Monitoring
-
Monitor for hypersensitivity reactions, including infusion-associated reactions, during and post-infusion.
Administration
Administered via IV infusion.
Available as a concentrate for injection; dilute prior to administration.
Supplied in single-dose vials containing 16.67 or 33.33 mg of each antibody per mL.
Solution should be clear to slightly opalescent, and colorless to pale yellow. Discard if cloudy, discolored, or contains particulate matter.
Administer diluted solution through an IV line containing a sterile, in-line or add-on 0.2 micron filter. Do not mix other medications with atoltivimab, maftivimab, and odesivimab-ebgn solution.
Dilution
Determine the number of vials needed based on the calculated dose in volume (mL) and strength of the drug used. Each vial contains 14.5 mL of atoltivimab, maftivimab, and odesivimab-ebgn solution regardless of the strength presentation. If using the preparation containing 16.67 mg of each antibody per mL, the volume of solution needed to prepare the dose will be 3 mL/kg. If using the preparation containing 33.33 mg of each antibody per mL, the volume of solution needed to prepare the dose will be 1.5 mL/kg.
Prior to administration, dilute drug in an IV polyvinyl chloride (PVC) bag containing either 0.9% sodium chloride, 5% dextrose, or lactated Ringer’s. For neonates, dilute in 5% dextrose.
Total volume of the infusion solution to be administered is based on the patient’s body weight (see Table 1). Select a diluent solution infusion bag of appropriate fill volume based on the patient’s body weight. Withdraw and discard from the bag a volume of diluent solution equal to the calculated dose in volume (mL) of the drug. Then add the calculated volume of drug to the bag. Mix by gentle inversion; do not shake.
The recommended infusion volume ensures the final concentration of the diluted solution is 9.5 mg/mL to 23.7 mg/mL for the 16.67 mg/16.67 mg/16.67 mg per mL solution and 9.5 mg/mL to 30 mg/mL for the 33.33 mg/33.33 mg/33.33 mg per mL solution.
|
Body weight (kg) |
Total Infusion Volume After Dilution (mL) |
Infusion Time (hours) |
|---|---|---|
|
0.5 to <1 |
7 |
4 |
|
1–1.9 |
15 |
4 |
|
2–3.9 |
25 |
3 |
|
4–7 |
50 |
3 |
|
8–15 |
100 |
3 |
|
16–38 |
250 |
2 |
|
39–79 |
500 |
2 |
|
80–149 |
1000 |
2 |
|
≥150 |
2000 |
4 |
Administer immediately after preparation when possible; solution does not contain preservatives. Do not mix with other medications. Discard any unused solution.
Rate of Administration
Recommended infusion rate is based on the patient's body weight and the prepared infusion volume (see Table 1). Rate of infusion may be slowed or interrupted if patient develops signs of infusion-associated events or other adverse events.
Dosage
Pediatric Patients
Zaire ebolavirus infection
IV
50 mg atoltivimab, 50 mg maftivimab, and 50 mg odesivimab per kg diluted and administered as a single IV infusion. Dosing regimen includes neonates born to a mother who is RT-PCR positive for Zaire ebolavirus infection.
Adults
Zaire ebolavirus infection
IV
50 mg atoltivimab, 50 mg maftivimab, and 50 mg odesivimab per kg diluted and administered as a single IV infusion.
Special Populations
Hepatic Impairment
No specific dosage recommendations.
Renal Impairment
No specific dosage recommendations.
Geriatric Use
No specific dosage recommendations.
Cautions for Atoltivimab, Maftivimab, and Odesivimab-ebgn
Contraindications
-
None.
Warnings/Precautions
Hypersensitivity Reactions Including Infusion-associated Events
Hypersensitivity reactions (including infusion-associated events) reported during and after infusion. Reactions may be acute and life-threatening.
Monitor all patients for signs and symptoms of hypersensitivity reactions (e.g., hypotension, chills, elevation of fever) during and following infusion. If a severe or life-threatening hypersensitivity reaction occurs, discontinue immediately and administer appropriate emergency care. Rate of infusion may be slowed or interrupted if infusion-associated events or other adverse events develop.
Immunogenicity
Immunogenic responses not detected at baseline or through 168 days post-dose.
Specific Populations
Pregnancy
Data are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal/fetal outcome. Human monoclonal antibodies, such as atoltivimab, maftivimab, and odesivimab-ebgn, are transported across the placenta; therefore, atoltivimab, maftivimab, and odesivimab-ebgn has the potential to be transferred from the mother to the developing fetus.
Maternal, fetal, and neonatal outcomes are poor among pregnant women infected with Zaire ebolavirus. The majority of such pregnancies result in maternal death with miscarriage, stillbirth, or neonatal death. Zaire ebolavirus infection is life-threatening for both mother and fetus, and treatment should not be withheld due to pregnancy.
Lactation
The CDC recommends that patients with confirmed Zaire ebolavirus not breast-feed their infants to reduce the risk of postnatalZaire ebolavirus transmission.
No data available on the presence of atoltivimab, maftivimab, and odesivimab-ebgn in human milk, the effects on the breast-fed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. Effects of local GI exposure and limited systemic exposure in the breast-fed infant unknown.
Pediatric Use
Safety and effectiveness of atoltivimab, maftivimab, and odesivimab-ebgn established in pediatric patients from birth to <18 years of age.
Geriatric Use
Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. Limited clinical experience has not identified differences in responses between elderly and younger patients.
Hepatic Impairment
Effects on pharmacokinetics of atoltivimab, maftivimab, and odesivimab unknown.
Renal Impairment
Effects on pharmacokinetics of atoltivimab, maftivimab, and odesivimab unknown.
Common Adverse Effects
Most common adverse reactions (≥20%) are pyrexia, chills, tachycardia, tachypnea, vomiting.
Drug Interactions
No formal drug interaction studies conducted.
Specific Drugs
|
Drug |
Interaction |
Comments |
|---|---|---|
|
Live vaccines against Zaire ebolavirus |
Atoltivimab, maftivimab, and odesivimab may inhibit replication of live vaccine virus and reduce efficacy; no vaccine-therapeutic interaction studies conducted Efficacy of atoltivimab, maftivimab, and odesivimab-ebgn not affected by prior receipt of recombinant live vaccine |
Avoid administration of live vaccine during treatment with atoltivimab, maftivimab, and odesivimab-ebgn; follow current vaccination guidelines to determine interval between treatment with atoltivimab, maftivimab, and odesivimab-ebgn and live vaccination |
Atoltivimab, Maftivimab, and Odesivimab-ebgn Pharmacokinetics
Absorption
Bioavailability
Pharmacokinetics are linear and dose-proportional following a single IV infusion containing 1–50 mg/kg of each drug component.
Special Populations
Effect of age (<21 years or >60 years) on pharmacokinetics unknown.
Distribution
Extent
Distribution into human milk unknown; maternal IgG is known to be present in human milk.
Elimination
Half-life
Atoltivimab: 21.2 days
Maftivimab: 22.3 days
Odesivimab: 25.3 days
Stability
Storage
Parenteral
Concentrate, for IV infusion
Prior to dilution, store vial in original carton refrigerated at 2–8°C. Protect from light; do not freeze or shake.
After dilution, use immediately when possible; otherwise, diluted solution may be stored as specified in Table 2. Allow diluted solution to come to room temperature before administration. When diluted in 5% dextrose, the drug may be administered at temperatures up to 35ºC; if temperature is >25ºC, administer solution diluted with 5% dextrose immediately after completion of dose preparation.
|
Diluent Used to Prepare Solution for Infusion |
Diluted Solution Storage Conditions |
|---|---|
|
0.9% sodium chloride |
Store at room temperature (up to 25ºC) for no more than 8 hours or refrigerated at 2–8ºC for no more than 24 hours. |
|
5% dextrose |
Store at room temperature (up to 25ºC) for no more than 4 hours or refrigerated at 2–8ºC for no more than 24 hours. |
|
Lactated Ringer's |
Store at room temperature (up to 25ºC) for no more than 4 hours or refrigerated at 2–8ºC for no more than 4 hours. |
Actions
-
Comprised of 3 recombinant human IgG1 monoclonal antibodies that target and simultaneously bind to the Zaire ebolavirus glycoprotein at non-overlapping epitopes.
-
Zaire ebolavirus glycoprotein mediates virus attachment and membrane fusion; it is also expressed on the surface of infected host cells.
-
Maftivimab is a neutralizing antibody that blocks entry of the virus into susceptible cells.
-
Odesivimab is a non-neutralizing antibody that induces antibody-dependent effector function through Fc gamma receptor type IIIa (FcγRIIIa) signaling and binds to the soluble glycoprotein form.
-
Atoltivimab combines both neutralization and FcγRIIIa signaling activities.
-
In a live virus infection assay, maftivimab neutralized Mayinga, Kikwit, and Makona strains of Zaire ebolavirus; atoltivimab and odesivimab did not demonstrate neutralizing activity. Effector function activity was assessed with a cell line expressing ebolavirus Makona glycoprotein and Jurkat/nuclear factor of activated T cells (NFAT)-luciferase/FcγRIIIa reporter effector cells; atoltivimab and odesivimab exhibited FcγRIIIa signaling activity at tested concentrations, while maftivimab did not.
-
No clinical data available on the development of ebolavirus resistance to atoltivimab, maftivimab, and odesivimab; cell culture development of resistance not assessed.
-
In vitro binding activity and/or neutralization activity of the individual components of atoltivimab, maftivimab, and odesivimab-ebgn may be affected by amino acid substitutions in viral glycoprotein. However, no glycoprotein substitution impacted the binding affinity of the combination of the 3 antibodies by >2.5-fold, and no glycoprotein substitutions had a substantial impact on the neutralization potency of the combination of the 3 antibodies.
Advice to Patients
-
Inform patients that hypersensitivity reactions including infusion-associated events have been reported during and after infusion of atoltivimab, maftivimab, and odesivimab-ebgn. Advise patients to immediately report any symptoms of systemic hypersensitivity.
-
Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Instruct patients with Zaire ebolavirus infection not to breast-feed because of the risk of passing Zaire ebolavirus to the infant.
-
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, and any concomitant illnesses.
-
Advise patients of other important precautionary information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Atoltivimab, maftivimab, and odesivimab-ebgn is stored in the US Strategic National Stockpile (SNS) and is not commercially available in the US. To request a drug from the SNS, state health departments can contact the US Centers for Disease Control and Prevention (CDC) Emergency Operations Center at 770-488-7100 or the HHS Secretary's Operations Center at 202-619-7800.
|
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
|---|---|---|---|---|
|
Parenteral |
Concentrate, for IV infusion |
241.7 mg atoltivimab, 241.7 mg maftivimab, and 241.7 mg odesivimab per 14.5 mL (16.67 mg/16.67 mg/16.67 mg per mL) |
Inmazeb (single-dose vial) |
|
|
483.3 mg atoltivimab, 483.3 mg maftivimab, and 483.3 mg odesivimab per 14.5 mL (33.33 mg/33.33 mg/33.33 mg per mL) |
Inmazeb (single-dose vial) |
Regeneron |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions December 14, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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