The FDA has announced Eli Lilly’s bebtelovimab is not currently authorized for emergency use in the United States because it is not expected to neutralize Omicron subvariants BQ.1 and BQ.1.1. The FDA recommends all product be retained in the event that SARS-CoV-2 variants susceptible to bebtelovimab, which are currently circulating at lower prevalence, become more prevalent in the future in the United States. Retained product must be appropriately held in accordance with storage conditions detailed in the Fact Sheet for Health Care Providers and Letter of Authorization for bebtelovimab. Health care providers should use other approved or authorized products that are expected to retain activity against BQ.1 and BQ.1.1.
Further information is available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-announces-bebtelovimab-not-currently-authorized-any-us-region.
COVID-19, outpatients with high risk of progression to severe illness (alternative agent) (off-label use):
Note: Use is not authorized for patients who are hospitalized or require new or increased oxygen therapy due to COVID-19; outcomes may be worse if used in patients requiring high-flow oxygen or mechanical ventilation (FDA 2022).
IV: 175 mg as a single dose; initiate as soon as possible after COVID-19 diagnosis and within 7 days of symptom onset. Note: Consider local prevalence of SARS-CoV-2 variants when evaluating treatment options (FDA 2022; NIH 2022). 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 to severe impairment: There are no dosage adjustments provided (has not been studied) (FDA 2022).
(For additional information see "Bebtelovimab (United States: Distribution paused; refer to 'Special Alerts' field): Pediatric drug information")
Note: Consider local prevalence of SARS-CoV-2 variants when evaluating treatment options; bebtelovimab is not authorized for use in geographic regions where infection is 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, mild to moderate; treatment:
Note: Only for use in patients with positive SARS-CoV-2 direct viral testing who are at high risk for progression to severe disease, including hospitalization or death. In clinical trials, only 3 adolescents received bebtelovimab; emergency use authorization from the FDA is based on likelihood of similar exposure in patients ≥12 years of age weighing ≥40 kg.
Children ≥12 years and Adolescents weighing ≥40 kg: IV: 175 mg as a single dose; administer as soon as possible after positive SARS-CoV-2 test and within 7 days of symptom onset (FDA 2022).
Altered kidney function: Children ≥12 years and Adolescents weighing ≥40 kg: IV: No dosage adjustment necessary (FDA 2022).
Children ≥12 years and Adolescents weighing ≥40 kg:
Mild impairment: No dosage adjustment necessary (FDA 2022).
Moderate or severe impairment: There are no dosage adjustments provided in the fact sheet for health care providers (has not been studied) (FDA 2022).
Refer to adult dosing (FDA 2022).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous [preservative free]:
Generic: 175 mg/2 mL (2 mL [DSC])
Yes
Investigational agent; approved for emergency use authorization by the FDA February 2022.
Bebtelovimab is available under an emergency use authorization (EUA) from the FDA. As part of the EUA, fact sheets pertaining to emergency use of bebtelovimab are required to be available for health care providers and patients/caregivers, and certain mandatory requirements for bebtelovimab 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.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-new-monoclonal-antibody-treatment-covid-19-retains. Additionally, health care providers must track and report all medication errors and serious adverse events potentially associated with bebtelovimab use by either submitting a MedWatch form (https://www.fda.gov/medwatch/report.htm) or FDA form 3500 (health professional) by mail or fax (800-FDA-0178); a copy of all MedWatch forms should also be provided to Eli Lilly and Company, Global Patient Safety: fax: 317-277-0853; email: mailindata_gsmtindy@lilly.com; or phone: 855-545-5921.
Bebtelovimab is purchased directly from the distributor AmerisourceBergen (1-800-746-6273 or c19therapies@amerisourcebergen.com); more information is available at https://www.covid19.lilly.com/bebtelovimab/hcp.
Note: Infuse in an environment equipped to monitor for and manage hypersensitivity and infusion-related reactions (eg, fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia, chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, dizziness, diaphoresis); if severe or life-threatening hypersensitivity reactions, including anaphylaxis, occur, immediately discontinue infusion and provide emergency care (FDA 2022).
IV: Remove vial from refrigerator and allow to come to room temperature for ~20 minutes; do not expose to direct heat; do not shake. The solution should be clear to opalescent and colorless to slightly yellow or slightly brown; discard if solution is cloudy, discolored, or contains particulate matter. Withdraw dose using a disposable polypropylene syringe; discard any product remaining in vial. Administer dose immediately after withdrawing if possible; if dose is refrigerated, allow syringe to come to room temperature prior to administration (~20 minutes). If used, attach and prime IV extension set made of polyethylene or PVC with or without diethylhexylphthalate (Note: Prior to March 2022, use of an IV extension set was required; however, as of March 2022 the use of an IV extension set is now optional). Administer IV over ≥30 seconds; following administration, flush the injection line with NS to ensure delivery of entire dose (FDA 2022).
Note: Infuse in an environment equipped to monitor for and manage hypersensitivity and infusion-related reactions (eg, fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia, chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, dizziness, diaphoresis); if severe or life-threatening hypersensitivity reactions including anaphylaxis occur, immediately discontinue infusion and provide emergency care (FDA 2022).
Parenteral: IV: Remove vial from refrigerator and allow to come to room temperature for ~20 minutes; do not expose to direct heat; do not shake. The solution should be clear to opalescent and colorless to slightly yellow or slightly brown; discard if solution is cloudy, discolored, or contains particulate matter. Withdraw dose using a disposable polypropylene syringe; discard any product remaining in vial. Administer dose immediately after withdrawing if possible; if dose is refrigerated, allow syringe to come to room temperature prior to administration (~20 minutes). Use of IV extension set is optional (extension set was required prior to March 2022). If using IV extension set, must use IV extension set made of polyethylene or PVC with or without diethylhexylphthalate (DEHP); attach and prime IV extension set. Administer IV over ≥30 seconds; following administration, flush the injection line with NS to ensure delivery of entire dose (FDA 2022).
See “Use: Off-Label.”
COVID-19, outpatients with high risk of progression to severe illness
Infusion related reactions have rarely been reported with bebtelovimab. 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, throat irritation, and vasovagal reactions (presyncope, syncope) with infusion related reactions. Hypersensitivity reactions, including anaphylaxis, have been reported with other SARS-CoV-2 monoclonal antibodies and could also occur with bebtelovimab.
Onset: Rapid; infusion reactions may occur during and ≤24 hours after administration and hypersensitivity reactions may occur >24 hours after administration.
Bebtelovimab is currently under investigation for use in the treatment of COVID-19. Serious or unexpected adverse reactions not previously reported may occur; refer to emergency use authorization (EUA) for information regarding reporting serious adverse reactions (FDA 2022). Adverse reactions reported for monotherapy and combination therapy with etesevimab in adolescents and adults for the authorized dose and unauthorized higher dose.
<1%:
Dermatologic: Pruritus, skin rash
Gastrointestinal: Nausea, vomiting
Miscellaneous: Infusion related reaction
There are no contraindications listed in the emergency use authorization.
Concerns related to adverse effects:
• Hypersensitivity: Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of other SARS-CoV-2 human immunoglobulin G1 (IgG1) monoclonal antibodies and could occur with administration of bebtelovimab. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care. Infusion-related reactions (eg, fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia [eg, atrial fibrillation, sinus tachycardia, bradycardia], chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash, including urticaria, pruritus, myalgia, vasovagal reactions [eg, presyncope, syncope], dizziness, diaphoresis) have been observed with administration of bebtelovimab and up to 24 hours after the infusion. Monitor patients after administration for ≥1 hour; if an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care (FDA 2022).
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See fact sheet for health care providers.
Other warnings/precautions:
• Antiviral resistance: Development of SARS-CoV-2 variants with reduced susceptibility to bebtelovimab may potentially increase risk of treatment failure; consider local prevalence of SARS-CoV-2 variants, if available, when evaluating treatment options (FDA 2022; NIH 2022).
• Clinical worsening: Clinical worsening of COVID-19, including signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrhythmia (eg, atrial fibrillation, bradycardia, tachycardia), fatigue, and altered mental status, has been reported after administration of SARS-CoV-2 monoclonal antibodies; some of these events required hospitalization. It is not known if these events were related to SARS-CoV-2 monoclonal antibody use or were due to COVID-19 progression (FDA 2022).
• Limitations of use: Bebtelovimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bebtelovimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen or mechanical ventilation. Bebtelovimab is not authorized for use in patients who are hospitalized due to COVID-19, 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 (FDA 2022).
None known.
There are no known significant interactions.
Reproductive toxicity studies have not been conducted (FDA 2022).
Bebtelovimab is currently available under FDA emergency use authorization (EUA) for the treatment of COVID-19. Reproductive toxicity studies have not been conducted (FDA 2022).
Bebtelovimab is a humanized monoclonal antibody (IgG1). Human IgG crosses the placenta. Exposure is dependent upon the IgG subclass, maternal serum concentrations, placental integrity, newborn birth weight, and GA, 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). The potential benefits or risks of in utero exposure of bebtelovimab 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-19. 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). Use may be considered in nonhospitalized, COVID-19–positive, pregnant patients who have mild to moderate symptoms, especially patients with 1 or more additional risk factors (eg, BMI >25, cardiovascular disease, chronic kidney disease, diabetes mellitus) (ACOG 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/).
It is not known if bebtelovimab is present in breast milk.
Bebtelovimab is a humanized monoclonal antibody (IgG1). Human IgG is present in breast milk; concentrations are dependent upon IgG subclass and postpartum age (Anderson 2021).
Bebtelovimab is currently available under FDA emergency use authorization (EUA) for the treatment of COVID-19. Dose adjustments are not recommended for lactating patients. According to the EUA, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother (FDA 2022).
Lactating patients with one or more risk factors for severe illness from COVID-10 infection may be treated with monoclonal antibodies when otherwise clinically indicated. Breastfeeding does not need to be discontinued. Breast milk has not been found to contain infectious materials from SARS-CoV-2, and maternal infection is not a contraindication to breastfeeding. However, lactating patients with COVID-19 infection should take all precautions to avoid spreading the virus to the infant (eg, hand hygiene, mask wearing) and the infant should be isolated with the mother; alternatively, breast milk can be expressed and fed to the infant by someone without confirmed or suspected COVID-19 (ACOG 2022).
Interim guidance is available from the CDC for the care of lactating patients who are diagnosed with COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/care-for-breastfeeding-women.html). Information related to COVID-19 and breastfeeding is also available from the World Health Organization (https://www.who.int/news/item/28-04-2020-new-faqs-address-healthcare-workers-questions-on-breastfeeding-and-covid-19).
Monitor for ≥1 hour after injection for infusion-related reactions (FDA 2022).
Bebtelovimab is a recombinant human IgG1λ monoclonal antibody to the spike protein of SARS-CoV-2. Bebtelovimab binds the spike protein and blocks attachment to the human ACE2 receptor (FDA 2022).
Distribution: Vd (steady state): 4.61 L (coefficient of variation, 25.3%).
Half-life elimination: 11.5 days (coefficient of variation, 25%).
Excretion: 0.335 L/day (coefficient of variation, 39.3%).
Pediatric: In clinical trials, only 3 adolescents received bebtelovimab; serum exposures in patients ≥12 years of age and weighing ≥40 kg are expected to be similar to those observed in adults (FDA 2022).
Solution (Bebtelovimab Intravenous)
175 mg/2 mL (per mL): $1,260.00
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