TRANSFORM HOW YOU USE DRUG INFORMATION

NOTE: Bamlanivimab and etesevimab are NOT authorized for treatment or post-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in geographic regions where infection or exposure is likely to have been caused by a non-susceptible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant. Omicron SARS-CoV-2 variant (B.1.1.529) has become the dominant variant in the United States; antiviral resistance data show that bamlanivimab and etesevimab are unlikely to retain activity against Omicron. The FDA will monitor conditions to determine whether use in a geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility, and CDC regional variant frequency data available at: covid.cdc.gov/covid-data-tracker/#variant-proportions.[65314][66394]

Individuals are deemed to be at high risk for progressing to severe COVID-19 if they meet at least 1 of the following criteria:

• Elderly (65 years or older)
• Younger than 1 year of age
• Obesity or overweight
• Pregnancy
• Chronic kidney disease
• Diabetes
• Immunosuppressive disease or receiving immunosuppressive therapy
• Cardiovascular disease (including congential heart disease) or hypertension
• Chronic lung disease (e.g., chronic obstructive pulmonary disease, moderate-to-severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension)
• Sickle cell disease
• Neurodevelopmental disorder (e.g., cerebral palsy) or other conditions that confer medical complexity (e.g., genetic or metabolic syndromes, severe congential anomalies)
• Medical-related technological dependency (e.g., tracheostomy, gastrostomy, positive pressure ventilation) not related to COVID-19

In addition, other medical conditions or factors (e.g., race, ethnicity) may also place individual patients at high risk, and authorization of bamlanivimab and etesevimab under the EUA is not limited to only those medical conditions or factors listed above. Health care providers are advised to consider the benefit-to-risk of an individual patient.[66394]

NOTE: Bamlanivimab and etesevimab MUST be administered in combination. Neither drug is authorized for administration as a single agent (i.e., monotherapy).

NOTE: There may be logistical or supply constraints that make it impossible to offer the available therapy to all eligible patients, making patient triage necessary. Health care providers should prioritize their use for patients at highest risk of clinical progression. Information on which individuals might receive the greatest benefit from anti-SARS-CoV-2 therapeutics for treatment or prevention can be obtained from www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies. Health care providers are advised to consider the benefit-risk for each individual patient.[65314]

No dosage adjustments are needed for patients with mild hepatic impairment. Use in patients with moderate to severe hepatic impairment has not been evaluated.[66394]

No dosage adjustments are needed.[66394]

NOTE: Bamlanivimab and etesevimab are NOT authorized for treatment or post-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in geographic regions where infection or exposure is likely to have been caused by a non-susceptible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant. Omicron SARS-CoV-2 variant (B.1.1.529) has become the dominant variant in the United States; and antiviral resistance data show that bamlanivimab and etesevimab are unlikely to retain activity against Omicron. The FDA will monitor conditions to determine whether use in a geographic region is consistent with this scope of authorization, referring to available information, including information on variant susceptibility, and CDC regional variant frequency data available at: covid.cdc.gov/covid-data-tracker/#variant-proportions.[65314][66394]

Bamlanivimab and etesevimab are investigational human immunoglobulin G-1 (IgG1) monoclonal antibodies with activity against SARS-CoV-2. They are not FDA-approved drugs; however, their use in combination has been authorized by the FDA for emergency treatment of mild to moderate COVID-19 in adults and pediatric patients, including neonates, with positive SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19, including hospitalization or death. They are also authorized for use as post-exposure prophylaxis of COVID-19 in adults and pediatric patients, including neonates, exposed to SARS-CoV-2 who are at high risk for progressing to severe COVID-19 and are not fully vaccinated or are not expected to mount an adequate immune response to the complete COVID-19 vaccination. These drugs are NOT authorized for treatment of patients 2 years and older who are hospitalized due to COVID-19, who require oxygen therapy and/or respiratory support for COVID-19, or who require an increase in baseline oxygen flow rate and/or respiratory support due to COVID-19 if already on chronic oxygen therapy for an underlying condition. The reasons for hospital admission may be different and the threshold for hospital admission may be lower for neonates, young infants, and toddlers with COVID-19 compared to older children and adults. The authorization allows for young children (i.e., birth to 2 years of age) who are hospitalized with mild to moderate COVID-19 at the time of treatment to receive bamlanivimab and etesevimab. Use of these drugs in hospitalized patients with COVID-19 who require high flow oxygen or mechanical ventilation may be associated with worsening clinical outcomes. Additionally, the combination is not authorized for pre-exposure prophylaxis, nor should it be used as a substitute for the COVID-19 vaccines.[66394]

The National Institutes of Health (NIH) COVID-19 guidelines recommend individuals who have recently been exposed to SARS-CoV-2 and have symptoms consistent with COVID-19 be evaluated for SARS-CoV-2 infection.

• If test results are positive for SARS-CoV-2, the NIH recommends against the use of bamlanivimab and etesevimab for treatment of high-risk, nonhospitalized patients with mild to moderate COVID-19. This recommendation is based on the Omicron SARS-CoV-2 variant (B.1.1.529) becoming the dominant variant in the United States and real-time testing to identify rare, non-Omicron variants not being routinely available.
• If test results are negative for SARS-CoV-2, the NIH recommends against the use of bamlanivimab and etesevimab as post-exposure prophylaxis in adults who would be at high risk of clinical progression if infected (as defined by the EUA) and who are not fully vaccinated or are fully vaccinated but not expected to mount an adequate immune response. This recommendation is based on the Omicron SARS-CoV-2 variant (B.1.1.529) becoming the dominant variant in the United States.

The use and timing of anti-SARS-CoV-2 antibodies should not be affected by prior exposure to the COVID-19 vaccine.[65314] Similarly, the Centers for Disease Control and Prevention (CDC) state that although some reduction in vaccine-induced antibody titers have been observed in persons who previously received antibody products, the benefits versus risks favor proceeding with vaccination; and thus, COVID-19 vaccination does not need to be delayed following receipt of anti-SARS-CoV-2 antibodies.[66175]

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

NOTE: Bamlanivimab and etesevimab MUST be administered in combination. Neither drug is authorized for administration as a single agent (i.e., monotherapy).

NOTE: Bamlanivimab and etesevimab are not FDA-approved medications; however, they have been authorized for use under an Emergency Use Authorization (EUA) to treat mild to moderate COVID-19 in patients with positive SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19, including hospitalization or death. They are also authorized for use as post-exposure prophylaxis of COVID-19 in persons exposed to SARS-CoV-2 who are at high risk for progressing to severe COVID-19 and are not fully vaccinated or are not expected to mount an adequate immune response to the complete COVID-19 vaccination. Under the EUA, health care providers are required to communicate to the patient, parent, or caregiver information consistent with the "Fact Sheet for Patients, Parents and Caregivers" prior to the patient receiving treatment; such information includes the following:

• The option to accept or refuse bamlanivimab and etesevimab
• The significant known and potential risks and benefits of bamlanivimab and etesevimab, and the extent to which such potential risks and benefits are unknown
• Available alternative treatments and the risk and benefits of those alternatives
• The need to continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal items, clean and disinfect "high touch" surfaces, frequent handwashing) according to CDC guidelines

NOTE: Under the EUA, health care providers are required to report all medication errors and serious adverse events potentially related to bamlanivimab and etesevimab therapy within 7 calendar days from the onset of the event.[66394]

Clinical worsening of COVID-19 has been reported after administration of bamlanivimab and etesevimab together. Signs and symptoms included fever, hypoxia or increased respiratory difficulty, arrythmia exacerbation (e.g., atrial fibrillation, sinus tachycardia, bradycardia), fatigue, and altered mental status. Some of these events have required hospitalization. It is not known if these events were related to bamlanivimab and etesevimab treatment or were due to the progression of COVID-19. Additionally, monoclonal antibodies (such as bamlanivimab and etesevimab) may be associated with worsening clinical outcomes when administered to hospitalized patients with COVID-19 who require high flow oxygen or mechanical ventilation. Therefore, these drugs are not authorized for use in patients who are hospitalized due to COVID-19, who require oxygen therapy for COVID-19, or who require an increase in baseline oxygen flow rate due to COVID-19 if already on chronic oxygen therapy for an underlying condition.[66394]

Bamlanivimab and etesevimab are recombinant human immunoglobulin G-1 (IgG1) monoclonal antibodies used in combination as an antiviral medication against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Both bamlanivimab and etesevimab target the spike protein of SARS-CoV-2; however, they bind to different but overlapping epitopes in the receptor binding domain (RBD) of the S-protein. By binding to the spike protein, these monoclonal antibodies block the attachment of SARS-CoV-2 to the human ACE2 receptor. Both bamlanivimab and etesevimab are neutralizing antibodies. Bamlanivimab demonstrates antibody-dependent cell-mediated cytotoxicity, but does not elicit complement-dependent cytotoxicity activity. Etesevimab does not demonstrate detectable antibody-dependent cell-mediated cytotoxicity or elicit complement-dependent cytotoxicity. The estimated 50% effective concentration (EC₅₀) against SARS-CoV-2 in Vero cells of bamlanivimab, etesevimab, and a 1:1 ratio of bamlanivimab and etesevimab is 0.02 mcg/mL, 0.14 mcg/mL, and 0.02 mcg/mL, respectively.[66394]

There is a potential for treatment failure due to the development of viral variants that are resistant to the combination of bamlanivimab and etesevimab. Antiviral resistance data show that bamlanivimab and etesevimab are unlikely to retain activity against the Omicron SARS-CoV-2 variant (B.1.1.529/BA.1). Health care providers are advised to consider the prevalence of SARS-CoV-2 variants in their area when considering treatment options. Other anti-SARS-CoV-2 antibodies should be considered. Data from non-clinical studies have associated E484D/K/Q, F490S, Q493R, and S494P amino acid substitutions in the spike protein with reduced susceptibility to bamlanivimab. Viral variants with reduced susceptibility to etesevimab include substitutions K417N, D420N, and N460K/S/T/Y. All variants maintained susceptibility to bamlanivimab and etesevimab together, except for those with E484D, E484K, E484Q, and Q493R substitutions, which had reduced susceptibilities of 145-fold, 24-fold, 17-fold, and 1,054-fold, respectively. An evaluation of susceptibility data from SARS-CoV-2 variants identified through global surveillance in patients treated with bamlanivimab and etesevimab is ongoing. As of December 2021, neutralization data for variant substitutions with bamlanivimab and etesevimab together show:

• United Kingdom B.1.1.7 variant (Alpha):
• Key substitution: N501Y
• No change or less than 5-fold reduction in susceptibility
• South Africa B1.1.529/BA.1 (Omicron)
• Key substitutions: G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H
• More than 2,938-fold reduced susceptibility; bamlanivimab and etesevimab are unlikely to be active against this variant
• South Africa B.1.351 variant (Beta):
• Key substitutions: K417N + E484K + N501Y
• More than 325- to 431-fold reduced susceptibility; bamlanivimab and etesevimab are unlikely to be active against this variant
• Brazil P.1 variant (Gamma):
• Key substitutions: K417T + E484K + N501Y
• 252-fold reduced susceptibility; bamlanivimab and etesevimab are unlikely to be active against this variant
• California B.1.427/B.1.429 variant (Epsilon):
• Key substitution: L452R
• 9- to 11-fold reduced susceptibility; etesevimab retains activity against this variant
• New York B.1.526 variant (Iota):
• Key substitution: E484K (not all New York B.1.526 isolates harbored the E484K substitution)
• 11- to 30-fold reduced susceptibility
• India B.1.617.2/AY.3 variant (Delta)
• Key substitutions: L452R + T478K
• No change or less than 5-fold reduction in susceptibility
• India B.1.617.2/AY.1/AY.2 variant (Delta Plus)
• Key substitutions: L452R + T478K + K417N
• 1,235-fold reduced susceptibility; bamlanivimab and etesevimab are unlikely to be active against this variant
• India B.1.617.1 variant (Kappa)
• Key substitutions: L452R + E484Q
• 6-fold reduced susceptibility; etesevimab retains activity against this variant
• Peru C.37 variant (Lambda)
• Key substitutions: L452Q + F490S
• No change or less than 5-fold reduction in susceptibility
• Colombia B.1.621 variant (Mu)
• Key substitutions: R346K + E484K + N501Y
• 116-fold reduced susceptibility; bamlanivimab and etesevimab are unlikely to be active against this variant[66394]