ETESEVIMAB Solution for injection Ref.[10777] Active ingredients: Bamlanivimab and Etesevimab

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

5.1 Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions

Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of bamlanivimab with and without etesevimab. 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 have been observed with administration of bamlanivimab and etesevimab together. 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, dizziness and diaphoresis.

If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care.

5.2 Clinical Worsening After Bamlanivimab Administration

Clinical worsening of COVID-19 after administration of bamlanivimab 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 bamlanivimab 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 bamlanivimab and etesevimab has not been studied in patients hospitalized due to COVID-19. Monoclonal antibodies, such bamlanivimab and etesevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore, bamlanivimab and etesevimab are not authorized for use in patients [see Limitations of Authorized Use]:

• who are hospitalized due to COVID-19, OR
• who require oxygen therapy due to COVID-19, OR
• who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.

OVERALL SAFETY SUMMARY

Approximately 1,500 subjects have been exposed to bamlanivimab and etesevimab administered together in clinical trials in ambulatory (non-hospitalized) subjects at doses of bamlanivimab 700 mg and etesevimab 1,400 mg or higher. More than 3,900 subjects have received bamlanivimab (either alone or with etesevimab) at doses ranging from 700 to 7,000 mg. Bamlanivimab and etesevimab at the authorized doses of 700 mg and 1,400 mg have been administered together to approximately 770 subjects [see Clinical Pharmacology (14.2)].

ADVERSE REACTIONS AND MEDICATION ERRORS REPORTING REQUIREMENTS AND INSTRUCTIONS

Clinical trials evaluating the safety of bamlanivimab and etesevimab are ongoing [see Overall Safety Summary (6)].

Completion of FDA MedWatch Form to report all medication errors and serious adverse events is mandatory. The prescribing healthcare provider and/or the provider’s designee are/is responsible for the mandatory reporting of all medication errors and the following serious adverse events occurring during the use of bamlanivimab and etesevimab and considered to be potentially related to bamlanivimab and etesevimab. These adverse events must be reported within 7 calendar days from the onset of the event:

• 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;
• a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.

If a serious and unexpected adverse event occurs and appears to be associated with the use of bamlanivimab and etesevimab under this EUA, the prescribing healthcare provider and/or the provider’s designee should complete and submit a MedWatch form to FDA using one of the following methods:

• Complete and submit the report online: www.fda.gov/medwatch/report.htm, or
• Use a postage-paid Form FDA 3500 (available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.pdf) and returning by mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787), or by fax (1-800-FDA-0178), or
• Call 1-800-FDA-1088 to request a reporting form

IMPORTANT: When reporting adverse events or medication errors to MedWatch, please complete the entire form with detailed information. It is important that the information reported to FDA be as detailed and complete as possible. Information to include:

• Patient demographics (e.g., patient initials, date of birth)
• Pertinent medical history
• Pertinent details regarding adverse events and course of illness
• Concomitant medications
• Timing of adverse event(s) in relationship to administration of bamlanivimab and etesevimab
• Pertinent laboratory and virology information
• Outcome of the event and any additional follow-up information if it is available at the time of the MedWatch report. Subsequent reporting of follow-up information should be completed if additional details become available.

The following steps are highlighted to provide the necessary information for safety tracking:

• In section A, box 1, provide the patient’s initials in the Patient Identifier
• In section A, box 2, provide the patient’s date of birth
• In section B, box 5, description of the event:
  • Write “bamlanivimab and etesevimab use for COVID-19 under Emergency Use Authorization (EUA)” as the first line
  • Provide a detailed report of medication error and/or adverse event. It is important to provide detailed information regarding the patient and adverse event/medication error for ongoing safety evaluation of this unapproved drug. Please see information to include listed above.
• In section G, box 1, name and address:
  • Provide the name and contact information of the prescribing healthcare provider or institutional designee who is responsible for the report.
  • Provide the address of the treating institution (NOT the healthcare provider’s office address).

OTHER REPORTING REQUIREMENTS

Healthcare facilities and providers must report therapeutics information and utilization data through HHS Protect, Teletracking or National Healthcare Safety Network (NHSN) as directed by the U.S. Department of Health and Human Services.

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 safety of bamlanivimab and etesevimab administered together is based on data from the Phase ⅔ BLAZE-1 trial of ambulatory subjects with COVID-19. The authorized dose is bamlanivimab 700 mg and etesevimab 1,400 mg administered together [see Dosage (2.2)].

BLAZE-1 is a randomized, double-blind, placebo-controlled clinical trial in ambulatory adults with mild to moderate COVID-19 symptoms who had sample collection for the first positive SARS-CoV-2 viral infection determination within 3 days prior to the start of the infusion.

Phase 2 Data from BLAZE-1

Five hundred seventy-seven (577) subjects were treated with a single infusion of bamlanivimab 2,800 mg and etesevimab 2,800 mg (N=112), bamlanivimab alone at doses of 700 mg (N=101), 2,800 mg (N=107), or 7,000 mg (N=101) or placebo (N=156).

Based on Phase 2 data from BLAZE-1 subjects followed for at least 28 days after treatment, adverse events occurred in 18% of subjects treated with both bamlanivimab and etesevimab and 28% of placebo-treated subjects.

Nausea was the most commonly reported adverse event, reported by 4% of subjects treated with bamlanivimab and etesevimab together and 4% treated with placebo. Pruritus and pyrexia were more frequently reported from subjects treated with both bamlanivimab and etesevimab (2% and 1%) compared to placebo (1% and 0%, respectively).

Phase 3 Data from BLAZE-1

Five hundred eighteen (518) subjects were treated with a single infusion of bamlanivimab 2,800 mg and etesevimab 2,800 mg together and 517 subjects were treated with a single infusion of placebo in Arms 7 and 8, respectively, of the BLAZE-1 Phase 3 trial. Adverse events occurred in 13% of subjects who received 2,800 mg of bamlanivimab and 2,800 mg etesevimab together, and in 12% of placebo-treated subjects. The most common adverse events were nausea, dizziness, and rash. These events each occurred in 1% of subjects treated with bamlanivimab and etesevimab and in 1% of placebo subjects.

Hypersensitivity Including Anaphylaxis and Infusion-related Reactions

Across ongoing, blinded clinical trials, a case of anaphylaxis and other cases of serious infusion-related reactions were reported with infusion of bamlanivimab with and without etesevimab. The infusions were stopped. All reactions required treatment, one required epinephrine. All events resolved.

Other Immediate Hypersensitivity Events

In the phase 2 portion of BLAZE-1, 2% of subjects treated with bamlanivimab and etesevimab, and 1% of placebo-treated subjects experienced immediate hypersensitivity events. Reported events of pruritus, flushing and hypersensitivity were mild and one case of face swelling was moderate.

In the phase 3 portion of BLAZE-1, 1% of subjects treated with bamlanivimab and etesevimab experienced immediate hypersensitivity events, including 2 infusion-related reactions (moderate severity), 2 cases of rash (1 mild, 1 moderate), 1 infusion site rash (mild), and 1 mild case of pruritus. All events resolved [see Warnings and Precautions (5.1)].

Bamlanivimab and etesevimab are 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.

Risk Summary

There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Bamlanivimab and etesevimab should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the fetus.

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

Risk Summary

There are no available data on the presence of bamlanivimab or etesevimab 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 bamlanivimab and etesevimab and any potential adverse effects on the breastfed child from bamlanivimab and etesevimab 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.

The safety and effectiveness of bamlanivimab and etesevimab administered together are being assessed in adolescent patients in ongoing clinical trials. The recommended dosing regimen is expected to result in comparable serum exposures of bamlanivimab and etesevimab in patients 12 years of age and older and weighing at least 40 kg as observed in adults, based on a pharmacokinetic (PK) modeling approach which accounted for effect of body weight changes associated with age on clearance and volume of distribution.

Of the 112 patients receiving bamlanivimab and etesevimab in BLAZE-1, 12% were 65 years of age and older and 2% were 75 years of age and older. Based on population PK analyses, there is no difference in PK of bamlanivimab or etesevimab in geriatric patients compared to younger patients.

Bamlanivimab and etesevimab are not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of bamlanivimab or etesevimab.

Based on population PK analysis, there is no difference in PK of bamlanivimab or etesevimab in patients with mild hepatic impairment compared to patients with normal hepatic function. Bamlanivimab and etesevimab have not been studied in patients with moderate or severe hepatic impairment.

11.7 Other Specific Populations

Based on population PK analysis, the PK of bamlanivimab and etesevimab was not affected by sex, race, or disease severity. Body weight had no clinically relevant effect on the PK of bamlanivimab and etesevimab in adults with COVID-19 over the body weight range of 41 kg to 173 kg.