Bebtelovimab: Package Insert and Label Information (Page 2 of 5)

3 DOSAGE FORMS AND STRENGTHS

Bebtelovimab is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow to slightly brown solution available as:

  • Injection: 175 mg/2 mL (87.5 mg/mL) in a single-dose vial

4 CONTRAINDICATIONS

No contraindications have been identified based on the limited available data for the emergency use of bebtelovimab authorized under this EUA.

5 WARNINGS AND PRECAUTIONS

There are limited clinical data available for bebtelovimab. Serious and unexpected adverse events may occur that have not been previously reported with bebtelovimab use.

5.1 Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions

Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of other SARS-CoV-2 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, which may occur up to 24 hours after the injection, have been observed in clinical trials of bebtelovimab when administered with other monoclonal antibodies and may occur with use of bebtelovimab alone. These reactions may be severe or life threatening.

Signs and symptoms of infusion-related reactions may include:

  • fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g., 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 (e.g., pre-syncope, syncope), dizziness and diaphoresis.

Administer appropriate medications and/or supportive care if an infusion-related reaction occurs.

Hypersensitivity reactions occurring more than 24 hours after the injection have also been reported with the use of SARS-CoV-2 monoclonal antibodies under Emergency Use Authorization.

5.2 Clinical Worsening After SARS-CoV-2 Monoclonal Antibody Administration

Clinical worsening of COVID-19 after administration of SARS-CoV-2 monoclonal antibody treatment has been reported and may include signs or symptoms of fever, hypoxia or increased respiratory difficulty, arrhythmia (e.g., atrial fibrillation, sinus tachycardia, bradycardia), fatigue, and altered mental status. 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 progression of COVID-19.

5.3 Limitations of Benefit and Potential for Risk in Patients with Severe COVID 19

Treatment with 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. Therefore, bebtelovimab is not authorized for use in patients, regardless of age, who:

  • are hospitalized due to COVID-19, OR
  • 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.

6 ADVERSE REACTIONS

6.1 Adverse Reactions from Clinical Studies

The following adverse reactions have been observed in the clinical studies of bebtelovimab that supported the EUA. The adverse reaction rates observed in these clinical studies cannot be directly compared to rates in the clinical studies of other products and may not reflect the rates observed in clinical practice. Additional adverse events associated with bebtelovimab may become apparent with more widespread use.

The safety of bebtelovimab is primarily based on exposure of 602 ambulatory (non-hospitalized) subjects who received doses of bebtelovimab, alone or in combination with bamlanivimab and etesevimab, in the phase 1 and phase 2 portions of BLAZE-4, a randomized, single-dose clinical trial.

The following adverse reactions (i.e., adverse events assessed as causally related) have been observed in those who have received bebtelovimab, alone or in combination with bamlanivimab and etesevimab, at the authorized dose or higher:

  • Infusion-related reactions (n=2, 0.3%)
  • Pruritus (n=2, 0.3%)
  • Rash (n=5, 0.8%)

The most common treatment-emergent adverse events observed in subjects treated with bebtelovimab, alone or in combination with bamlanivimab and etesevimab, at the authorized dose or higher, included nausea (0.8%) and vomiting (0.7%).

6.4 Required Reporting for Serious Adverse Events and Medication Errors

The prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory reporting of all serious adverse events* and medication errors potentially related to bebtelovimab within 7 calendar days from the healthcare provider’s awareness of the event, using FDA Form 3500 (for information on how to access this form, see below). The FDA requires that such reports, using FDA Form 3500, include the following:

  • Patient demographics and baseline characteristics (e.g., patient identifier, age or date of birth, gender, weight, ethnicity, and race)
  • A statement “Bebtelovimab use for COVID-19 under Emergency Use Authorization (EUA)” under the “Describe Event, Problem, or Product Use/Medication Error ” heading
  • Information about the serious adverse event or medication error (e.g., signs and symptoms, test/laboratory data, complications, timing of drug initiation in relation to the occurrence of the event, duration of the event, treatments required to mitigate the event, evidence of event improvement/disappearance after stopping or reducing the dosage, evidence of event reappearance after reintroduction, clinical outcomes).
  • Patient’s preexisting medical conditions and use of concomitant products
  • Information about the product (e.g., dosage, route of administration, NDC #).

Submit adverse event and medication error reports, using Form 3500, to FDA MedWatch using one of the following methods:

  • Complete and submit the report online: www.fda.gov/medwatch/report.htm
  • Complete and submit a postage-paid FDA Form 3500 (https://www.fda.gov/media/76299/download) and return by:
    • Mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, or
    • Fax to 1-800-FDA-0178, or
  • Call 1-800-FDA-1088 to request a reporting form

In addition, please provide a copy of all FDA MedWatch forms to:

Eli Lilly and Company, Global Patient Safety
Fax: 1-317-277-0853
E-mail: mailindata_gsmtindy@lilly.com
Or call Eli Lilly and Company at 1-855-LillyC19 (1-855-545-5921) to report adverse events.

The prescribing health care provider and/or the provider’s designee is/are responsible for mandatory responses to requests from FDA for information about adverse events and medication errors following receipt of bebtelovimab.

*Serious adverse events are defined as:

  • Death;
  • A life-threatening adverse event;
  • Inpatient hospitalization or prolongation of existing hospitalization;
  • A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions;
  • A congenital anomaly/birth defect;
  • Other important medical event, which may require a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.

7 DRUG INTERACTIONS

Bebtelovimab is not renally excreted or metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Severe hypersensitivity reactions and infusion-related reactions, have been observed with administration of bebtelovimab, including in pregnant patients [see Warnings and Precautions (5.1)]. There are risks to the mother and fetus associated with untreated COVID-19 in pregnancy as well as potential risks to the fetus associated with severe maternal hypersensitivity and infusion-related reactions (see Clinical Considerations).

There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Bebtelovimab should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the fetus. There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations).

Data

Nonclinical reproductive toxicity studies have not been performed with bebtelovimab. In tissue cross reactivity studies using human fetal tissues, no binding of clinical concern was detected for bebtelovimab. Human immunoglobulin G1 (IgG1) antibodies are known to cross the placental barrier; therefore, bebtelovimab has the potential to be transferred from the mother to the developing fetus. It is unknown whether the potential transfer of bebtelovimab provides any treatment benefit or risk to the developing fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo-fetal risk

COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.

Maternal Adverse Reactions

Pregnant patients who develop severe hypersensitivity and infusion-related reactions should be managed appropriately, including obstetrical care [see Warnings and Precautions (5.1)].

8.2 Lactation

Risk Summary

There are no available data on the presence of bebtelovimab in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for bebtelovimab and any potential adverse effects on the breastfed child from bebtelovimab or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

8.4 Pediatric Use

Bebtelovimab is not authorized for use in pediatric individuals under 12 years of age or weighing less than 40 kg. The safety and effectiveness of bebtelovimab have not been assessed in pediatric patients. The recommended dosing regimen in patients 12 years to less than 18 years of age, weighing at least 40 kg, is expected to result in comparable serum exposures of bebtelovimab as those observed in adults.

8.5 Geriatric Use

Of the 602 patients receiving bebtelovimab in BLAZE-4, 10.5% were 65 years of age and older and 3.3% were 75 years of age and older. Based on population PK analyses of samples from 573 patients over an age range of 14 to 89 years, there was no impact of age on PK. Therefore, there is no difference in the PK of bebtelovimab in geriatric patients compared to younger patients.

10 OVERDOSAGE

Doses up to 1750 mg of bebtelovimab (10 times the authorized dose of bebtelovimab) have been administered in clinical trials without dose-limiting toxicity. Treatment of overdose with bebtelovimab should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with bebtelovimab.

11 DESCRIPTION

Bebtelovimab is a human immunoglobulin G-1 (IgG1 variant) monoclonal antibody consisting of 2 identical light chain polypeptides composed of 215 amino acids each and 2 identical heavy chain polypeptides composed of 449 amino acids produced by a Chinese Hamster Ovary (CHO) stable bulk culture or cell line with a molecular weight of 144 kDa.

Bebtelovimab injection is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow to slightly brown solution in a single-dose vial for intravenous injection.

Each mL contains 87.5 mg of bebtelovimab, L-histidine (0.4 mg), L-histidine hydrochloride monohydrate (0.6 mg), sodium chloride (2.9 mg), sucrose (60 mg), polysorbate 80 (0.5 mg), and Water for Injection. The bebtelovimab solution has a pH range of 5.5-6.5.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Bebtelovimab is a recombinant neutralizing human IgG1λ monoclonal antibody (mAb) to the spike protein of SARS-CoV-2 and is unmodified in the Fc region. Bebtelovimab binds the spike protein with a dissociation constant KD = 0.046 to 0.075 nM and blocks spike protein attachment to the human ACE2 receptor with an IC50 value of 0.39 nM (0.056 mcg/mL).

12.2 Pharmacodynamics

The exposure-response relationships of bebtelovimab for viral loads and clinical outcomes are unknown.

12.3 Pharmacokinetics

A summary of PK parameters of bebtelovimab following administration of a single dose of 175 mg bebtelovimab is provided in Table 1.

Table 1: Pharmacokinetic Parameters of Bebtelovimab Administered IV in Adults and Pediatric Patients (12 years of age and older weighing at least 40 kg)

Abbreviations: CV = coefficient of variation; Cmax = maximum concentration; Cday,29 = drug concentration on day 29; AUCinf = area under the concentration versus time curve from zero to infinity; Vss = steady-state volume of distribution.

Bebtelovimab (175 mg) N=585
Systemic Exposure
Geometric Mean (%CV) Cmax , mcg/mL 59.9 (31.9)
Geometric Mean (%CV) Cday 29 , mcg/mL 4.55 (70.9)
Geometric Mean (%CV) AUCinf , mcg day/mL 539 (41.5)
Distribution
Geometric Mean (%CV) Vss (L) 4.55 (25.8)
Elimination
Geometric Mean (%CV) Elimination Half-Life (day) 11.5 (27.0)
Geometric Mean (%CV) Clearance (L/day) 0.325 (41.5)

Specific Populations:

The PK profile of bebtelovimab was not affected by age, sex, race, or baseline viral load based on a population PK analysis. Body weight had no clinically relevant effect on the PK of bebtelovimab in adults with COVID-19 over the body weight range of 45 kg to 194 kg.

Patients with renal impairment

Renal impairment is not expected to impact the PK of bebtelovimab, since mAbs with molecular weight >69 kDa are known not to undergo renal elimination. Similarly, dialysis is not expected to impact the PK of bebtelovimab.

Patients with hepatic impairment

Bebtelovimab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as other IgG monoclonal antibodies and human endogenous IgG antibodies.

Based on population PK analysis, there is no significant difference in PK of bebtelovimab in patients with mild hepatic impairment compared to patients with normal hepatic function. Bebtelovimab has not been studied in patients with moderate or severe hepatic impairment.

Drug Interactions:

Bebtelovimab is not renally excreted or metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2022. All Rights Reserved.