The FDA has amended the Emergency Use Authorization for bamlanivimab and etesevimab (administered together) to limit its use to when a patient is likely to have been infected with or exposed to a variant that is susceptible to this treatment.
Because data show that bamlanivimab and etesevimab is highly unlikely to be active against the Omicron variant of COVID-19, it is not authorized for use in any US states, territories, or jurisdictions at this time. Future use may be authorized in certain regions if patients are likely to be infected or exposed to a variant that is susceptible to bamlanivimab and etesevimab.
Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-limits-use-certain-monoclonal-antibodies-treat-covid-19-due-omicron.
The FDA and the Assistant Secretary for Preparedness and Response have announced the authorization of an extension to the shelf-life of Eli Lilly’s etesevimab from 12 months to 18 months. Etesevimab is authorized for emergency use only when administered together with bamlanivimab. Unopened vials of etesevimab injection should be stored under refrigerated temperature at 2 to 8°C (36 to 46°F) and may be stored for an additional 6 months from the labeled date of expiry.
Further information, including batch-specific extended expiration dates, may be found at https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Bamlanivimab-etesevimab/Pages/extension.aspx.
Note: Dosing is based on pharmacokinetic modeling and simulation; the youngest patient in pediatric clinical trials was 10 months of age and weighed 8.6 kg. Consider local prevalence of SARS-CoV-2 variants when evaluating prophylaxis/treatment options; bamlanivimab and etesevimab are not authorized for use in geographic regions where infection or exposure are likely to be due to a nonsusceptible variant (FDA 2022). Further information on variants may be found at: https://covid.cdc.gov/covid-data-tracker/#variant-proportions.
COVID-19, postexposure prophylaxis (FDA 2022):
Note: Only for use in patients who are at high risk for progressing to severe COVID-19 (including hospitalization or death; refer to the FDA fact sheet for health care providers for more information on patients at high risk for progression to severe disease), who are either not fully vaccinated or not expected to mount an adequate response to SARS-CoV-2 vaccination, and who either meet the CDC's criteria for close contact with an individual infected with SARS-CoV-2 or are at high risk of exposure to an individual infected with SARS-CoV-2 in an institutional setting (eg, nursing home, prison).
Neonates weighing ≥1 kg: IV: Bamlanivimab 12 mg/kg and etesevimab 24 mg/kg administered together once as a single infusion; administer as soon as possible following exposure to SARS-CoV-2.
COVID-19, mild to moderate; treatment (FDA 2022): Note: The combination of bamlanivimab and etesevimab is only for use in patients with positive SARS-CoV-2 direct viral testing who are at high risk for progression to severe disease or hospitalization; refer to the FDA fact sheet for health care providers for more information on patients at high risk for progression to severe disease.
Neonates weighing ≥1 kg: IV: Bamlanivimab 12 mg/kg and etesevimab 24 mg/kg administered together once as a single infusion; administer as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset.
Altered kidney function: IV: No dosage adjustment recommended (FDA 2022).
Note: Consider local prevalence of SARS-CoV-2 variants when evaluating prophylaxis/treatment options; bamlanivimab and etesevimab are not authorized for use in geographic regions where infection or exposure are likely to be due to a non-susceptible variant (FDA 2022). Further information on variants may be found at: https://covid.cdc.gov/covid-data-tracker/#variant-proportions. Dosing for patients ≤12 kg is based on pharmacokinetic modeling and simulation; the youngest patient in pediatric clinical trials was 10 months of age and weighed 8.6 kg.
COVID-19, postexposure prophylaxis (FDA 2022):
Note: Only for use in patients who are at high risk for progressing to severe COVID-19 (including hospitalization or death; refer to the FDA fact sheet for health care providers for more information on patients at high risk for progression to severe disease), who are either not fully vaccinated or not expected to mount an adequate response to SARS-CoV-2 vaccination, and who either meet the CDC's criteria for close contact with an individual infected with SARS-CoV-2 or are at high risk of exposure to an individual infected with SARS-CoV-2 in an institutional setting (eg, nursing home, prison).
Infants, Children, and Adolescents: Note: Administer as soon as possible following exposure to SARS-CoV-2.
1 to 12 kg: IV: Bamlanivimab 12 mg/kg and etesevimab 24 mg/kg administered together once as a single infusion.
>12 to 20 kg: IV: Bamlanivimab 175 mg and etesevimab 350 mg administered together once as a single infusion.
>20 to <40 kg: IV: Bamlanivimab 350 mg and etesevimab 700 mg administered together once as a single infusion.
≥40 kg: IV: Bamlanivimab 700 mg and etesevimab 1,400 mg administered together once as a single infusion.
COVID-19, mild to moderate; treatment (FDA 2022):
Note: Only for use in patients with positive SARS-CoV-2 direct viral testing who are at high risk for progression to severe disease or hospitalization; refer to the FDA fact sheet for health care providers for more information on patients at high risk for progression to severe disease.
Infants, Children, and Adolescents: Note: Administer as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset.
1 to 12 kg: IV: Bamlanivimab 12 mg/kg and etesevimab 24 mg/kg administered together once as a single infusion.
>12 to 20 kg: IV: Bamlanivimab 175 mg and etesevimab 350 mg administered together once as a single infusion.
>20 to <40 kg: IV: Bamlanivimab 350 mg and etesevimab 700 mg administered together once as a single infusion.
≥40 kg: IV: Bamlanivimab 700 mg and etesevimab 1,400 mg administered together once as a single infusion.
Altered kidney function: Infants, Children, and Adolescents: IV: No dosage adjustment recommended (FDA 2022).
Infants, Children, and Adolescents (FDA 2022): IV:
Mild hepatic impairment: No dosage adjustment recommended.
Moderate to severe hepatic impairment: There are no dosage adjustments provided in the fact sheet for health care providers (has not been studied).
(For additional information see "Bamlanivimab and etesevimab (United States: Refer to 'Special Alerts' field for authorized use): Drug information")
COVID-19, postexposure prophylaxis (off-label use):
Note: Reserve for patients with SARS-CoV-2 exposure, or at high risk for exposure, who are not fully vaccinated or are not expected to mount an adequate immune response to complete vaccination and are at high risk for progression to severe disease or hospitalization. Refer to the FDA fact sheet for health care providers for more information on patients at high risk for progression to severe disease. Use is not authorized for preexposure prophylaxis (FDA 2022).
IV: Bamlanivimab 700 mg and etesevimab 1.4 g as a single dose (administered together as a single IV infusion); administer as soon as possible following exposure to SARS-CoV-2. Note: Consider local prevalence of SARS-CoV-2 variants when evaluating postexposure prophylaxis options (FDA 2022).
COVID-19, treatment, mild to moderate (off-label use): Note: Reserve for patients with positive SARS-CoV-2 direct viral testing who are at high risk for progression to severe disease or hospitalization; refer to the FDA fact sheet for health care providers for more information on patients at high risk for progression to severe disease. Use is not authorized for patients who are hospitalized due to COVID-19 or require new or increased oxygen therapy and/or respiratory support due to COVID-19 outside of a clinical trial; outcomes may be worse if used in patients requiring high-flow oxygen or mechanical ventilation (FDA 2022; IDSA [Bhimraj 2021]; NIH 2021).
IV: Bamlanivimab 700 mg and etesevimab 1.4 g as a single dose (administered together as a single IV infusion); administer as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset (FDA 2022; Gottlieb 2021; IDSA [Bhimraj 2021]; NIH 2021). Note: Consider local prevalence of SARS-CoV-2 variants when evaluating treatment options (FDA 2022; IDSA [Bhimraj 2021]; NIH 2021). Further information may be found at: https://covid.cdc.gov/covid-data-tracker/#variant-proportions.
No dosage adjustment recommended (FDA 2022).
Mild impairment: No dosage adjustment recommended (FDA 2022).
Moderate or severe impairment: There are no dosage adjustments provided (has not been studied) (FDA 2022).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Generic: Etesevimab 700 mg/20 mL (20 mL); Bamlanivimab 700 mg/20 mL (20 mL)
Yes
Investigational agents; approved for emergency use authorization by the FDA February 2021.
Bamlanivimab and etesevimab are not commercially available; they are available as part of ongoing clinical trials and under an emergency use authorization (EUA) from the FDA. The Department of Health and Human Services will determine weekly distribution amounts for each state/territory based on weekly reports of new COVID-19 cases and hospitalizations, in addition to data on inventories and use submitted to the federal government. State and territorial health departments will identify which sites in their respective jurisdictions receive product as well as the amount they will receive.
As part of the EUA, information consistent with fact sheets pertaining to emergency use of bamlanivimab and etesevimab are required to be available for health care providers and patients/caregivers, and certain mandatory requirements for the combination's administration under the EUA must be met as outlined in the FDA EUA letter; the fact sheets and EUA letter may be accessed at https://www.covid19.lilly.com/bam-ete. Additionally, health care providers must track and report all medication errors and serious adverse events potentially associated with bamlanivimab and etesevimab use by either submitting a MedWatch form (https://www.fda.gov/medwatch/report.htm) or FDA Form 3500 (health professional) by mail or fax (1-800-FDA-0178); a copy of all MedWatch forms should also be provided to Eli Lilly and Company.
Note: Although supplied as separate products, both drugs should be prepared in a single infusion bag for administration.
Parenteral: IV: If infusion solution is refrigerated following preparation, allow solution to come to room temperature (~20 minutes) prior to administration. Administer as an IV infusion through a PVC or polyethylene-lined PVC infusion set containing a 0.2 or 0.22 micron in-line or add-on polyethersulfone filter.
Rate of infusion is dependent upon patient weight and size of infusion bag:
Weight <40 kg: Infuse mixed, undiluted solution over ≥16 minutes.
Weight ≥40 kg: Dilute prior to administration.
Diluted in 50 mL bag: Infuse over ≥21 minutes.
Diluted in 100 mL bag: Infuse over ≥31 minutes.
Diluted in 150 mL bag: Infuse over ≥41 minutes.
Diluted in 250 mL bag:
Weight 40 to <50 kg: Infuse over ≥70 minutes.
Weight ≥50 kg: Infuse over ≥60 minutes.
Infuse the entire contents of the bag to avoid underdosage; flush line with NS following completion of infusion to ensure delivery of required dose. Slow or interrupt infusion and treat as appropriate if the patient develops any signs of infusion-associated events (eg, fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia, chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vasovagal reactions, dizziness, diaphoresis); if severe or life-threatening hypersensitivity reactions occur, immediately discontinue infusion and provide emergency care (FDA 2022).
IV: Must be diluted prior to administration. If diluted solution is refrigerated following preparation, allow solution to come to room temperature (~20 minutes) prior to administration. Administer as an IV infusion at a rate of ≤310 mL/hour (≤266 mL/hour for patients <50 kg using the 250 mL prefilled NS infusion bag); infuse entire contents of the bag to avoid underdosage. Administer through a PVC or polyethylene-lined PVC infusion set containing a 0.2 or 0.22 micron in-line or add-on polyethersulfone filter. Slow or stop infusion and treat as appropriate if an infusion-related reaction occurs. Flush infusion line with NS following completion of infusion (FDA 2022).
Store intact vials at 2°C to 8°C (36°F to 46°F); protect from light. Do not freeze, shake, or expose to direct light (FDA 2022).
Solution requires dilution prior to administration when using in patients ≥18 years of age and ≥40 kg. Diluted infusion solution should be administered immediately. If immediate administration is not possible, store diluted infusion solution for up to 24 hours refrigerated at 2°C to 8°C (36°F to 46°F) or up to 7 hours at 20°C to 25°C (68°F to 77°F) including infusion time. If refrigerated, allow infusion solution to warm to room temperature for ~20 minutes prior to administration (FDA 2022).
Treatment: Investigational agent for the treatment of mild to moderate COVID-19 in patients with positive SARS-CoV-2 direct viral testing who are at high risk for progressing to severe COVID-19, including hospitalization or death (FDA issued emergency use authorization [EUA] in all ages).
Postexposure prophylaxis: Investigational agent for postexposure prophylaxis of COVID-19 in patients who are at high risk for progressing to severe COVID-19 (including hospitalization or death), who are either not fully vaccinated or not expected to mount an adequate response to SARS-CoV-2 vaccination, and who either meet the CDC's criteria for close contact with an individual infected with SARS-CoV-2 or are at high risk of exposure to an individual infected with SARS-CoV-2 in an institutional setting (ie, nursing home, prison) (FDA issued EUA in all ages).
Per the EUA, the following, in addition to other potential factors (eg, race, ethnicity), may place patients at higher risk for progressing to severe COVID-19 (FDA 2022):
• Age <1 year
• Older age (eg, ≥65 years)
• Overweight or obesity
• Pregnancy
• Chronic kidney disease
• Diabetes
• Immunosuppression (due to treatment or underlying disease)
• Cardiovascular disease (including congenital heart disease) or hypertension
• Chronic lung diseases (eg, chronic obstructive pulmonary disease, moderate to severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension)
• Sickle cell disease
• Neurodevelopmental disorders (eg, cerebral palsy) or other conditions that confer medical complexity (eg, genetic or metabolic syndromes, severe congenital anomalies)
• Medical technology dependence (eg, tracheostomy, gastrostomy, positive pressure ventilation [not related to COVID-19])
Bamlanivimab and etesevimab are NOT authorized for use in patients ≥2 years of age who are hospitalized due to COVID-19, for patients of any age who require new or increased oxygen therapy or respiratory support due to COVID-19, or for use in geographic regions where infection or exposure are likely to be due to a nonsusceptible variant (FDA 2022).
Bamlanivimab may be confused with belimumab.
Hypersensitivity reactions, including anaphylaxis and infusion related reaction, have been reported with bamlanivimab and etesevimab. Patients may experience altered mental status, angioedema, asthenia, bronchospasm, cardiac arrhythmia (including atrial fibrillation, sinus tachycardia, bradycardia), chest pain or discomfort, chills, diaphoresis, dizziness, dyspnea, fatigue, fever, headache, hypertension, hypotension, myalgia, nausea, pruritus, rash (including urticaria), reduced oxygen saturation, and throat irritation with infusion related reactions, but most reactions were mild in severity (Ref). Slower infusion rates may be considered. All reactions were reversible; severe reactions required discontinuation and treatment (Ref).
Onset: Rapid; most infusion related reactions occurred during infusion (Ref).
The following adverse reactions and incidences are derived from the FDA-issued emergency use authorization (EUA), unless otherwise specified. Refer to EUA for information regarding reporting adverse reactions (FDA 2021).
1% to 10%: Miscellaneous: Infusion related reaction (1%: including severe infusion related reaction)
<1%:
Dermatologic: Pruritus
Gastrointestinal: Nausea
Hypersensitivity: Anaphylaxis, hypersensitivity reaction (including type 1 hypersensitivity reaction, flushing, facial swelling, rash at injection site, skin rash)
Nervous system: Dizziness
Miscellaneous: Fever (Gottlieb 2021)
There are no contraindications listed in the FDA emergency use authorization (EUA) fact sheet for health care providers.
Other warnings/precautions:
• Antiviral resistance: Development of SARS-CoV-2 variants with reduced susceptibility to bamlanivimab and etesevimab may increase risk of treatment failure; consider local prevalence of SARS-CoV-2 variants when evaluating treatment options (FDA 2022).
• Clinical worsening: Clinical worsening of COVID-19, including signs or symptoms of altered mental status, arrhythmia (atrial fibrillation, bradycardia, tachycardia), fatigue, fever, hypoxia, or increased respiratory difficulty, has been reported after administration of bamlanivimab and etesevimab; some of these events required hospitalization. It is not known if these events were related to bamlanivimab and etesevimab or were due to COVID-19 progression (FDA 2022).
• Limitations of use: Bamlanivimab and etesevimab are not authorized for use in patients ≥2 years of age who are hospitalized due to COVID-19, or patients of any age who require oxygen therapy and/or respiratory support due to COVID-19, or require an increase in baseline oxygen flow rate and/or respiratory support due to COVID-19 and are on chronic oxygen therapy and/or respiratory support due to underlying non–COVID-19 related comorbidity. Monoclonal antibodies, such as bamlanivimab and etesevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen therapy or mechanical ventilation (FDA 2022).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Bamlanivimab and etesevimab (administered in combination) is currently available under FDA emergency use authorization (EUA) for the treatment and postexposure prophylaxis of COVID-19 (FDA 2022). The original clinical trials required male and female patients of reproductive potential to use effective contraception during the study (Gottlieb 2021).
The use of bamlanivimab in combination with etesevimab is currently available under FDA emergency use authorization (EUA) for the treatment and postexposure prophylaxis of COVID-19. Nonclinical reproductive toxicity studies have not been conducted (FDA 2022).
Bamlanivimab and etesevimab are humanized monoclonal antibodies (IgG1). Human IgG crosses the placenta. Fetal exposure is dependent upon the IgG subclass, maternal serum concentrations, placental integrity, newborn birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis and the highest during the third trimester (Clements 2020; Palmeira 2012; Pentsuk 2009).
Outcome data following maternal use of bamlanivimab and etesevimab during pregnancy are limited (Richley 2022). The original clinical trials of bamlanivimab in combination with etesevimab did not include pregnant patients (Gottlieb 2021). The potential benefits or risks of in utero exposure to bamlanivimab and etesevimab to the fetus are not known (FDA 2022).
The risk of severe illness from COVID-19 infection is increased in symptomatic pregnant patients compared to nonpregnant patients. Pregnant and recently pregnant patients with moderate or severe infection are at increased risk of complications such as hypertensive disorders of pregnancy, postpartum hemorrhage, or other infections compared to pregnant patients without COVID. Pregnant patients with symptoms may require ICU admission, mechanical ventilation, or ventilatory support (ECMO) compared to symptomatic nonpregnant patients. Other adverse pregnancy outcomes include preterm birth and stillbirth. The risk of coagulopathy, cesarean delivery, and maternal death may be increased; neonates have an increased risk for NICU admission. Maternal age and comorbidities such as diabetes, hypertension, lung disease, and obesity may also increase the risk of severe illness in pregnant and recently pregnant patients (ACOG 2022; NIH 2022).
In general, the treatment of COVID-19 infection during pregnancy is the same as in nonpregnant patients (NIH 2022). Monoclonal antibodies should not be withheld from pregnant patients when otherwise appropriate (ACOG 2022; NIH 2022). Pregnancy is one of the medical conditions listed in the EUA eligibility criteria for bamlanivimab in combination with etesevimab. Use may be considered in nonhospitalized, COVID-19–positive pregnant patients who have mild to moderate symptoms, especially patients with one or more additional risk factors (eg, BMI >25, cardiovascular disease, chronic kidney disease, diabetes mellitus) (ACOG 2022; FDA 2022; NIH 2022). According to the EUA, dose adjustments are not recommended for patients who are pregnant (FDA 2022). Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.
Data collection to monitor maternal and infant outcomes following exposure to COVID-19 during pregnancy is ongoing. Health care providers are encouraged to enroll patients exposed to COVID-19 during pregnancy in the Organization of Teratology Information Specialists pregnancy registry (877-311-8972; https://mothertobaby.org/join-study/).
Monitor for infusion-related reactions (eg, fever, chills, hypotension, rash, pruritus) and hypersensitivity/anaphylaxis during infusion and for 1 hour following infusion completion (FDA 2022).
Bamlanivimab and etesevimab are both recombinant neutralizing human IgG1k monoclonal antibodies to the spike protein of SARS-CoV-2. They bind to different, but overlapping receptors, thus blocking the spike protein attachment to the human ACE2 receptor. Use of the combination is expected to reduce the risk of viral resistance (FDA 2022).
Absorption:
Cmax:
Bamlanivimab (700 mg): 196 mg/L.
Etesevimab (1.4 g): 504 mg/L.
Distribution:
Vd:
Bamlanivimab: 2.87 L (central); 2.71 L (peripheral).
Etesevimab: 2.38 L (central); 1.98 L (peripheral).
Metabolism: Bamlanivimab and etesevimab are expected to be degraded into small peptides and component amino acids via catabolic pathways in the same manner as endogenous IgG antibodies.
Half-life elimination:
Bamlanivimab: 17.6 days.
Etesevimab: 25.1 days.
Solution (Etesevimab Intravenous)
700 mg/20 mL (per mL): $0.00
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