# FDA Letter of Authorization > FDA Letter of Authorization | 35 Pages - Interactive version: https://lilly.relayto.com/e/fda-letter-of-authorization-0vi9pyv5qbp5y - Format: PDF document, 35 pages - Published by: [Lilly](https://lilly.relayto.com/) - Last updated: 2020-11-24 - More from this site: https://lilly.relayto.com/llms.txt ## Page 1 November 10, 2020 Eli Lilly and Company Attention: Christine Phillips, PhD, RAC Advisor Global Regulatory Affairs - US Lilly Corporate Center Drop Code 2543 Indianapolis, IN 46285 Dear Ms. Phillips: This letter is in response to Eli Lilly and Company’s (“Lilly”) request that the Food and Drug Administration (FDA) issue an Emergency Use Authorization (EUA) for emergency use of bamlanivimab for the treatment of mild to moderate coronavirus disease 2019 (COVID-19), as described in the Scope of Authorization (Section II) of this letter, pursuant to Section 564 of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. §360bbb-3). On February 4, 2020, pursuant to Section 564(b)(1)(C) of the Act, the Secretary of the Department of Health and Human Services (HHS) determined that there is a public health emergency that has a significant potential to affect national security or the health and security of United States citizens living abroad, and that involves the virus that causes COVID-19.1 On the basis of such determination, the Secretary of HHS on March 27, 2020, declared that circumstances exist justifying the authorization of emergency use of drugs and biological products during the COVID-19 pandemic, pursuant to Section 564 of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 360bbb-3), subject to terms of any authorization issued under that section.2 Bamlanivimab is a neutralizing IgG1 monoclonal antibody that binds to the receptor binding domain of the spike protein of SARS-CoV-2. It is an investigational drug and is not currently approved for any indication. Based on review of the topline data from the planned interim analysis of Trial J2W-MC-PYAB, also called BLAZE-1 (NCT04427501), an ongoing randomized, double-blind, placebo- controlled, Phase 2 dose finding trial of bamlanivimab monotherapy in outpatients with mild to moderate COVID-19, it is reasonable to believe that bamlanivimab may be effective for the treatment of mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization, and that, when 1 U.S. Department of Health and Human Services, Determination of a Public Health Emergency and Declaration that Circumstances Exist Justifying Authorizations Pursuant to Section 564(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3. February 4, 2020. 2 U.S. Department of Health and Human Services, Declaration that Circumstances Exist Justifying Authorizations Pursuant to Section 564(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3, 85 FR 18250 (April 1, 2020). Reference ID: 4699500 ## Page 2 Page 2 – Eli Lilly and Company used under the conditions described in this authorization, the known and potential benefits of bamlanivimab outweigh the known and potential risks of such product. Having concluded that the criteria for issuance of this authorization under Section 564(c) of the Act are met, I am authorizing the emergency use of bamlanivimab for treatment of COVID-19, as described in the Scope of Authorization section of this letter (Section II) and subject to the terms of this authorization. I. Criteria for Issuance of Authorization I have concluded that the emergency use of bamlanivimab for the treatment of COVID-19 when administered as described in the Scope of Authorization (Section II) meets the criteria for issuance of an authorization under Section 564(c) of the Act, because: 1. SARS-CoV-2 can cause a serious or life-threatening disease or condition, including severe respiratory illness, to humans infected by this virus; 2. Based on the totality of scientific evidence available to FDA, it is reasonable to believe that bamlanivimab may be effective in treating mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization, and that, when used under the conditions described in this authorization, the known and potential benefits of bamlanivimab outweigh the known and potential risks of such product; and 3. There is no adequate, approved, and available alternative to the emergency use of bamlanivimab for the treatment of mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization.3 II. Scope of Authorization I have concluded, pursuant to Section 564(d)(1) of the Act, that the scope of this authorization is limited as follows: x Distribution of the authorized bamlanivimab will be controlled by the United States (U.S.) Government for use consistent with the terms and conditions of this EUA. Lilly will supply bamlanivimab to authorized distributors4, who will distribute to healthcare facilities or healthcare providers as directed by the U.S. Government, in collaboration with state and local government authorities, as needed; 3 No other criteria of issuance have been prescribed by regulation under Section 564(c)(4) of the Act. 4 “Authorized Distributor(s)” are identified by Lilly as an entity or entities allowed to distribute authorized bamlanivimab. Reference ID: 4699500 ## Page 3 Page 3 – Eli Lilly and Company x The bamlanivimab covered by this authorization will be used only by healthcare providers to treat mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization; x Bamlanivimab is not authorized for use in the following patient populations5: x Adults or pediatric patients who are hospitalized due to COVID-19, or x Adults or pediatric patients who require oxygen therapy due to COVID- 19, or x Adults or pediatric patients who require an increase in baseline oxygen flow rate due to COVID-19 in those patients on chronic oxygen therapy due to underlying non-COVID-19-related comorbidity. x Bamlanivimab may only be administered in settings in which health care providers have immediate access to medications to treat a severe infusion reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary. x The use of bamlanivimab covered by this authorization must be in accordance with the dosing regimens as detailed in the authorized Fact Sheets. Product Description Bamlanivimab is a neutralizing IgG1 monoclonal antibody that binds to the receptor binding domain of the spike protein of SARS-CoV-2. Bamlanivimab, injection, 700 mg/20 mL, is a sterile, preservative-free aqueous solution that is to be diluted by using a 250 mL prefilled 0.9% Sodium Chloride Injection infusion solution, withdrawing and discarding 70 mL of 0.9% Sodium Chloride Injection from the infusion bag, and then transferring 20mL of 700mg/20mL bamlanivimab to the 0.9% Sodium Chloride Injection infusion bag. The authorized bamlanivimab includes a vial label and/or carton labeling that is clearly marked for “emergency use authorization”. Bamlanivimab, injection, 700 mg/20 mL, vials should be stored in unopened vials under refrigerated temperature at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. Diluted bamlanivimab infusion solution can be stored for up to 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]) or up to 7 hours at room temperature (20°C to 25°C [68°F to 77°F]) including infusion time. 5 Benefit of treatment with bamlanivimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bamlanivimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Reference ID: 4699500 ## Page 4 Page 4 – Eli Lilly and Company Bamlanivimab is authorized for emergency use with the following product-specific information required to be made available to healthcare providers and patients/caregivers, respectively, through Lilly’s website at www.bamlanivimab.com: x Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of Bamlanivimab x Fact Sheet for Patients, Parents and Parent/Caregivers: Emergency Use Authorization (EUA) of Bamlanivimab for Coronavirus Disease 2019 (COVID-19) I have concluded, pursuant to Section 564(d)(2) of the Act, that it is reasonable to believe that the known andpotential benefits of bamlanivimab, when used for the treatment of COVID-19 andusedin accordance with this Scope of Authorization (Section II), outweigh its known and potential risks. I have concluded, pursuant to Section 564(d)(3) of the Act, based on the totality of scientific evidence available to FDA, that it is reasonable to believe that bamlanivimab may be effective for the treatment of COVID-19 when used in accordance with this Scope of Authorization (Section II), pursuant to Section 564(c)(2)(A) of the Act. Having reviewed the scientific information available to FDA, including the information supporting the conclusions described in Section I above, I have concluded that bamlanivimab (as described in this Scope of Authorization (Section II)) meets the criteria set forth in Section 564(c) of the Act concerning safety and potential effectiveness. The emergency use of your product under an EUA must be consistent with, and may not exceed, the terms of the Authorization, including the Scope of Authorization (Section II) and the Conditions of Authorization (Section III). Subject to the terms of this EUA and under the circumstances set forth in the Secretary of HHS's determination under Section 564(b)(1)(C) described above and the Secretary of HHS’s corresponding declaration under Section 564(b)(1), bamlanivimab is authorized to treat mild to moderate COVID-19 illness in adults and pediatric patients 12 years of age and older weighing at least 40 kg, who are at high risk for progressing to severe COVID-19 illness and/or hospitalization as described in the Scope of Authorization (Section II) under this EUA, despite the fact that it does not meet certain requirements otherwise required by applicable federal law. III. Conditions of Authorization Pursuant to Section 564 of the Act, I am establishing the following conditions on this authorization: Eli Lilly and Company (Lilly) and Authorized Distributors A. Lilly and authorized distributor(s) will ensure that the authorized bamlanivimab is distributed, as directed by the U.S. government, and the authorized labeling (i.e., Fact Sheets) will be made available to healthcare facilities and/or healthcare providers consistent with the terms of this letter. Reference ID: 4699500 ## Page 5 Page 5 – Eli Lilly and Company B. Lilly and authorized distributor(s) will ensure that appropriate storage and cold chain is maintained until the product is delivered to healthcare facilities and/or healthcare providers. C. Lilly and authorized distributor(s) will ensure that the terms of this EUA are made available to all relevant stakeholders (e.g., U.S. government agencies, state and local government authorities, authorized distributors, healthcare facilities, healthcare providers) involved in distributing or receiving authorized bamlanivimab. Lilly will provide to all relevant stakeholders a copy of this letter of authorization and communicate any subsequent amendments that might be made to this letter of authorization and its authorized accompanying materials (i.e., Fact Sheets). D. Lilly may request changes to this authorization, including to the authorized Fact Sheets for bamlanivimab, that do not alter the analysis of benefits and risks that underlies this authorization and FDA may determine that such changes may be permitted without amendment of this EUA. That determination must be made by joint decision of the Office of Infectious Diseases/Office of New Drugs/Center for Drug Evaluation and Research (CDER),the Counter-Terrorism and Emergency Coordination Staff/Office of the Center Director/CDER, and Office of Counterterrorism and Emerging Threats/Office of the Chief Scientist/Office of the Commissioner. E. Lilly will report to FDA serious adverse events and all medication errors associated with the use of the authorized bamlanivimab that are reported to Lilly using either of the following options. Option 1: Submit reports through the Safety Reporting Portal (SRP)as described on the FDA SRPweb page. Option 2: Submit reports directly through the Electronic Submissions Gateway (ESG) as described on the FAERS electronic submissions web page. Submitted reports under both options should state: “use of bamlanivimab was under an EUA.” For reports submitted under Option 1, include this language at the beginning of the question “Describe Event” for further analysis. For reports submitted under Option 2, include this language at the beginning of the “Case Narrative” field. F. All manufacturing facilities will comply with Current Good Manufacturing Practice requirements. G. Lilly will retain an independent third party (i.e., not affiliated with Lilly) to conduct a review of the batch records and any underlying data and associated discrepancies of bamlanivimab drug substance manufactured at Lilly Branchburg, NJ. x For all batches manufactured prior to the effective date of this authorization, these batches can be released while review is ongoing. x For all batches manufactured after the effective date of this authorization, the third party review can be performed concurrent to Lilly’s batch release process. Reference ID: 4699500 ## Page 6 Page 6 – Eli Lilly and Company If the independent review finds, prior to release, a discrepancy with significant potential to affect critical quality attributes, the product must not be released unless and until the issue is satisfactorily resolved. Any discrepancies found by the independent review, whether prior to or after release, must be reported to the Agency in a summary report, submitted every 14 calendar days, and include Lilly’s corrective and preventive action plans for each discrepancy, including whether market action is required. The plans must include an appropriate evaluation of each discrepancy’s potential impact on any released drug substance and associated drug product. H. Lilly will retain an independent third-party (i.e., not affiliated with Lilly) to conduct laboratory release testing of bamlanivimab drug substance manufactured at Lilly, Branchburg (excluding bioburden and endotoxin testing). Due to implementation timelines, independent third-party potency testing will commence on February 1, 2021. Until February 1, 2021, the Lilly Indianapolis, IN facility may conduct the equivalent of third- party potency testing. Any discrepancies found by Lilly Indianapolis, IN or the independent laboratory must be reported to the Agency in a summary report, submitted every 14 calendar days, and include Lilly’s corrective and preventive action plans for each discrepancy. The plans must include an appropriate evaluation of each discrepancy’s potential impact on any released drug substance and associated drug product. I. Lilly will submit information to the Agency within three working days of receipt of any information concerning any batch of bamlanivimab (whether the batch is distributed or not), as follows: (1) information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article; and (2) information concerning any bacteriological or microscopic contamination, or any significant chemical, physical, or other change in deterioration in the drug product, or any failure of one or more batches of the drug product to meet the established specifications. Lilly will include in its notification to the Agency whether the batch, or batches, in question will be recalled. If FDA requests that these, or any other batches, at any time, be recalled, Lilly must recall them. J. Lilly will not implement any changes to the description of the product, manufacturing process, facilities and equipment, and elements of the associated control strategy that assure process performance and quality of the authorized product without notification to and concurrence by the Agency. K. Lilly will manufacture and test bamlanivimab per the process and methods, including in- process sampling and testing and finishing product testing (release and stability) to meet all specifications as detailed in Lilly’s EUA request. L. Lilly will list bamlanivimab with a unique product NDC under the marketing category of Unapproved Drug- Other. Further, the listing will include each establishment where manufacturing is performed for the drug and the type of operation performed at each such establishment. Reference ID: 4699500 ## Page 7 Page 7 – Eli Lilly and Company M. Through a process of inventory control, Lilly and authorized distributor(s) will maintain records regarding distribution of the authorized bamlanivimab (i.e., lot numbers, quantity, receiving site, receipt date). N. Lilly and authorized distributor(s) will make available to FDA upon request any records maintained in connection with this EUA. Healthcare Facilities to Whom the Authorized BamlanivimabIs Distributedand Healthcare Providers Administering the Authorized Bamlanivimab O. Healthcare facilities and healthcare providers will ensure that they are aware of the letter of authorization, and the terms herein, and that the authorized Fact Sheets are made available to healthcare providers and to patients and caregivers, respectively, through appropriate means, prior to administration of bamlanivimab. P. Healthcare facilities and healthcare providers receiving bamlanivimab will track serious adverse events that are considered to be potentially attributable to bamlanivimab use and must report these to FDA in accordance with the Fact Sheet for Healthcare Providers. Complete and submit a MedWatch form (www.fda.gov/medwatch/report.htm), or Complete and submit FDA Form 3500 (health professional) by fax (1-800-FDA-0178) (these forms can be found via link above). Call 1-800-FDA-1088 for questions. Submitted reports should state, “use of bamlanivimab was under an EUA” at the beginning of the question “Describe Event” for further analysis. Q. Healthcare facilities and healthcare providers will ensure that appropriate storage and cold chain is maintained until the product is administered consistent with the terms of this letter. R. Through a process of inventory control, healthcare facilities will maintain records regarding the dispensed authorized bamlanivimab (i.e., lot numbers, quantity, receiving site, receipt date), product storage, and maintain patient information (e.g., patient name, age, disease manifestation, number of doses administered per patient, other drugs administered). S. Healthcare facilities will ensure that any records associated with this EUA are maintained until notified by Lilly and/or FDA. Such records will be made available to Lilly, HHS, and FDA for inspection upon request. Conditions Related to Printed Matter, Advertising and Promotion T. All descriptive printed matter, as well as advertising and promotional material, relating to the use of the bamlanivimab under this authorization shall be consistent with the authorized labeling, as well as the terms set forth in this EUA and the applicable requirements set forth in the Act and FDA regulations. U. No descriptive printed matter, as well as advertising or promotional material, relating to the use of bamlanivimab may represent or suggest that such products are safe or effective when used for the treatment of mild to moderate COVID-19 in adults and pediatric patients with Reference ID: 4699500 ## Page 8 Page 8 – Eli Lilly and Company positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization. V. All descriptive printed matter, as well as advertising and promotional material, relating to the use of the bamlanivimab clearly and conspicuously shall state that: x the bamlanivimab has not been approved, but has been authorized for emergency use by FDA, to treat mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization. x the bamlanivimab is authorized for the treatment of mild to moderate COVID- 19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of the bamlanivimab under Section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner. IV. Durationof Authorization This EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic is terminated under Section 564(b)(2) of the Act or the EUA is revoked under Section 564(g) of the Act. Sincerely, Digitally signed by Denise M. Denise M. Hinton -S3 Hinton -S3 Date: 2020.11.10 12:38:07 -05'00' ____________________________ RADM Denise M. Hinton Chief Scientist Food and Drug Administration Reference ID: 4699500 ## Page 9 FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF BAMLANIVIMAB AUTHORIZED USE The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to permit the emergency use of the unapproved product bamlanivimab for the treatment of mild to moderate coronavirus disease 2019 (COVID- 19) in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization. LIMITATIONS OF AUTHORIZED USE • Bamlanivimab is not authorized for use in patients: o who are hospitalized due to COVID-19, OR o who require oxygen therapy due to COVID-19, OR o 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. • Benefit of treatment with bamlanivimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bamlanivimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Bamlanivimab has been authorized by FDA for the emergency uses described above. Bamlanivimab is not FDA-approved for these uses. Bamlanivimab is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of bamlanivimab under section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner. This EUA is for the use of the unapproved product bamlanivimab for the treatment of mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization [see Limitations of Authorized Use]. High risk is defined as patients who meet at least one of the following criteria: • Have a body mass index (BMI) ≥35 • Have chronic kidney disease • Have diabetes • Have immunosuppressive disease • Are currently receiving immunosuppressive treatment • Are ≥65 years of age 1 Reference ID: 4699500 ## Page 10 • Are ≥55 years of age AND have o cardiovascular disease, OR o hypertension, OR o chronic obstructive pulmonary disease/other chronic respiratory disease. • Are 12 – 17 years of age AND have o BMI ≥85th percentile for their age and gender based on CDC growth , OR charts, https://www.cdc.gov/growthcharts/clinical_charts.htm o sickle cell disease, OR o congenital or acquired heart disease, OR o neurodevelopmental disorders, for example, cerebral palsy, OR o a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), OR o asthma, reactive airway or other chronic respiratory disease that requires daily medication for control. Bamlanivimab must be administered by intravenous (IV) infusion. Bamlanivimab may only be administered in settings in which health care providers have immediate access to medications to treat a severe infusion reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary. Health care providers must submit a report on all medication errors and ALL SERIOUS ADVERSE EVENTS potentially related to bamlanivimab. See Sections 8 and 9 of the Full EUA Prescribing Information for reporting instructions below. • The authorized dosage for bamlanivimab is a single intravenous (IV) infusion of 700 mg administered as soon as possible after positive viral test for SARS-CoV- 2 and within 10 days of symptom onset. • Bamlanivimab is available as concentrated solution and must be diluted prior to administration. • Administer bamlanivimab 700 mg via IV infusion over at least 60 minutes via pump or gravity. • Clinically monitor patients during infusion and observe patients for at least 1 hour after infusion is complete. • Patients treated with bamlanivimab should 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, and frequent handwashing) according to CDC guidelines. The authorized dosage may be updated as additional data from clinical trials becomes available. For information on clinical trials that are testing the use of bamlanivimab in COVID- 19, please see www.clinicaltrials.gov. 2 Reference ID: 4699500 ## Page 11 Contraindications None. Dosing Patient Selection and Treatment Initiation This section provides essential information on the unapproved product bamlanivimab for the treatment of mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization [see Limitations of Authorized Use]. High risk is defined as patients who meet at least one of the following criteria: • Have a body mass index (BMI) ≥35 • Have chronic kidney disease • Have diabetes • Have immunosuppressive disease • Are currently receiving immunosuppressive treatment • Are ≥65 years of age • Are ≥55 years of age AND have o cardiovascular disease, OR o hypertension, OR o chronic obstructive pulmonary disease/other chronic respiratory disease. • Are 12 – 17 years of age AND have o BMI ≥85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinical_charts.htm, OR o sickle cell disease, OR o congenital or acquired heart disease, OR o neurodevelopmental disorders, for example, cerebral palsy, OR o a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), OR o asthma, reactive airway or other chronic respiratory disease that requires daily medication for control. Dosage The dosage of bamlanivimab in adults and pediatric patients 12 years of age and older weighing at least 40 kg is a single IV infusion of 700 mg bamlanivimab administered over at least 60 minutes. Bamlanivimab should be given as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 10 days of symptom onset. Dosage Adjustment in Specific Populations No dosage adjustment is recommended based on age, sex, race, body weight, renal or mild hepatic impairment, during pregnancy or while lactating, or for disease severity or inflammation [see Full EUA Prescribing Information, Use in Specific Populations (11)]. Preparation and Administration Preparation Bamlanivimab solution for infusion should be prepared by a qualified healthcare professional using aseptic technique: • Remove the bamlanivimab vial from refrigerated storage and allow to equilibrate to room temperature for approximately 20 minutes before preparation. Do not expose to direct heat. 3 Reference ID: 4699500 ## Page 12 • Inspect bamlanivimab visually for particulate matter and discoloration. o Bamlanivimab is a clear to slightly opalescent and colorless to slightly yellow to slightly brown solution. • Gently invert vial by hand approximately 10 times. Do not shake. • Dilute bamlanivimab using a 250 mL prefilled 0.9% Sodium Chloride Injection bag for intravenous infusion according to Table 1. o Withdraw and discard required volume of 0.9% Sodium Chloride Injection from infusion bag. o Withdraw required volume of bamlanivimab from the vial using an appropriately sized syringe. o Transfer bamlanivimab to the 0.9% Sodium Chloride Injection infusion bag. o Discard any product remaining in the vial. • Gently invert IV bag by hand approximately 10 times to mix. Do not shake. • This product is preservative-free and therefore, the diluted infusion solution should be administered immediately. If immediate administration is not possible, store the diluted bamlanivimab infusion solution for up to 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]) or up to 7 hours at room temperature (20°C to 25°C [68°F to 77°F]) including infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 20 minutes prior to administration. Table 1: Recommended Dilution and Administration Instructions for Bamlanivimab Treatment Dose/Volume of Volume of Total Minimum Minimum Bamlanivimab 0.9% sodium Volume Infusion Infusion (# of vials) chloride to for Rate Time Discard from a Infusion 250 mL IV bag Bamlanivimab 700 mg/20 mL 70 mL 200 mL 200 mL/hr 60 minutes (1 vial) Administration Bamlanivimab infusion solution should be administered by a qualified healthcare professional. • Gather the recommended materials for infusion: o Polyvinylchloride (PVC) infusion set containing a 0.20/0.22 micron in-line polyethersulfone (PES) filter. • Attach the infusion set to the IV bag. • Prime the infusion set. • Administer the infusion solution via pump or gravity over at least 60 minutes (see Table 1). • Once infusion is complete, flush the infusion line to ensure delivery of the required dose. • Discard unused product. • Clinically monitor patients during administration and observe patients for at least 1 hour after infusion is complete. 4 Reference ID: 4699500 ## Page 13 Storage Refrigerate unopened vials at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze, shake, or expose to direct light. Warnings There are limited clinical data available for bamlanivimab. Serious and unexpected adverse events may occur that have not been previously reported with bamlanivimab use. Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions There is a potential for serious hypersensitivity reaction, including anaphylaxis, with administration of bamlanivimab. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive therapy. Infusion-related reactions have been observed with administration of bamlanivimab. Signs and symptoms of infusion related reactions may include: • fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, dizziness. If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care. Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19 Benefit of treatment with bamlanivimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bamlanivimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore, bamlanivimab is not authorized for use in patients [see Limitations of Authorized Use]: o who are hospitalized due to COVID-19, OR o who require oxygen therapy due to COVID-19, OR o 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. Side Effects Adverse events have been reported with bamlanivimab [see Full EUA Prescribing Information, Clinical Trials Experience (6.1)]. Additional adverse events associated with the drug may become apparent with more widespread use. INSTRUCTIONS FOR HEALTHCARE PROVIDERS As the healthcare provider, you must communicate to your patient or parent/caregiver, as age appropriate, information consistent with the “Fact Sheet for Patients, Parents and Caregivers” (and provide a copy of the Fact Sheet) prior to the patient receiving bamlanivimab, including: • FDA has authorized the emergency use of bamlanivimab for the treatment of mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at 5 Reference ID: 4699500 ## Page 14 least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization [see Limitations of Authorized Use]. • The patient or parent/caregiver has the option to accept or refuse bamlanivimab. • The significant known and potential risks and benefits of bamlanivimab, and the extent to which such potential risks and benefits are unknown. • Information on available alternative treatments and the risks and benefits of those alternatives, including clinical trials. • Patients treated with bamlanivimab should 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, and frequent handwashing) according to CDC guidelines. For information on clinical trials that are testing the use of bamlanivimab for COVID-19, . please see www.clinicaltrials.gov MANDATORY REQUIREMENTS FOR BAMLANIVIMAB ADMINISTRATION UNDER EMERGENCY USE AUTHORIZATION: In order to mitigate the risks of using this unapproved product under the EUA and to optimize the potential benefit of bamlanivimab, the following items are required. Use of bamlanivimab under this EUA is limited to the following (all requirements must be met): 1. Treatment of mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization [see Limitations of Authorized Use]. 2. As the healthcare provider, communicate to your patient or parent/caregiver, as age appropriate, information consistent with the “Fact Sheet for Patients, Parents and Caregivers” prior to the patient receiving bamlanivimab. Healthcare providers (to the extent practicable given the circumstances of the emergency) must document in the patient’s medical record that the patient/caregiver has been: a. Given the “Fact Sheet for Patients, Parents and Caregivers”, b. Informed of alternatives to receiving authorized bamlanivimab, and c. Informed that bamlanivimab is an unapproved drug that is authorized for use under this Emergency Use Authorization. 3. Patients with known hypersensitivity to any ingredient of bamlanivimab must not receive bamlanivimab. 4. The prescribing health care provider and/or the provider’s designee are/is responsible for mandatory reporting of all medication errors and serious adverse events* potentially related to bamlanivimab treatment within 7 calendar days from the onset of the event. The reports should include unique identifiers and the words “Bamlanivimab treatment under Emergency Use Authorization (EUA)” in the description section of the report. • Submit adverse event reports to FDA MedWatch using one of the following methods:  Complete and submit the report online: , or www.fda.gov/medwatch/report.htm 6 Reference ID: 4699500 ## Page 15  By using a postage-paid Form FDA 3500 (available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/For ms/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  Submitted reports should include in the field name, “Describe Event, Problem, or Product Use/Medication Error” the statement “Bamlanivimab treatment under Emergency Use Authorization (EUA)” *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; • a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly. 5. The prescribing health care provider and/or the provider’s designee are/is to provide mandatory responses to requests from FDA for information about adverse events and medication errors following receipt of bamlanivimab. 6. OTHER REPORTING REQUIREMENTS 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. APPROVED AVAILABLE ALTERNATIVES There is no adequate, approved and available alternative to bamlanivimab for patients who have mild to moderate COVID-19 who are at high risk for progressing to severe COVID-19 and/or hospitalization. Additional information on COVID-19 treatments can be found at https://www.cdc.gov/coronavirus/2019-ncov/index.html. The health care provider should visit https://clinicaltrials.gov/ to determine whether the patient may be eligible for enrollment in a clinical trial. AUTHORITY FOR ISSUANCE OF THE EUA The Secretary of the Department of Health and Human Services (HHS) has declared a public health emergency that justifies the emergency use of drugs and biological products during the COVID-19 pandemic. FDA has issued this EUA, requested by Eli Lilly and Company for the unapproved product bamlanivimab for the treatment of mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS- CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who 7 Reference ID: 4699500 ## Page 16 1 are at high risk for progressing to severe COVID-19 and/or hospitalization. As a health care provider, you must comply with the mandatory requirements of the EUA (see above). Although limited scientific information is available, based on the totality of the scientific evidence available to date, it is reasonable to believe that bamlanivimab may be effective for the treatment of mild to moderate COVID-19 in certain high-risk patients as specified in this Fact Sheet. You may be contacted and asked to provide information to help with the assessment of the use of the product during this emergency. This EUA for bamlanivimab will end when the Secretary determines that the circumstances justifying the EUA no longer exist or when there is a change in the approval status of the product such that an EUA is no longer needed. CONTACT INFORMATION For additional information visit www.bamlanivimab.com If you have questions, please contact 1-855-LillyC19 (1-855-545-5921) ______________________________________________________________________ END SHORT VERSION FACT SHEET Long Version Begins on Next Page 1 The health care provider should visit clinicaltrials.gov to determine whether there is an active clinical trial for the product in this disease/condition and whether enrollment of the patient(s) in a clinical trial is more appropriate than product use under this EUA. 8 Reference ID: 4699500 ## Page 17 FULL EUA PRESCRIBING INFORMATION FULL EUA PRESCRIBING INFORMATION: CONTENTS* 11.3 Pediatric Use 1 AUTHORIZED USE 11.4 Geriatric Use 2 DOSAGE AND ADMINISTRATION 11.5 Renal Impairment 2.1 Patient Selection 11.6 Hepatic Impairment 2.2 Dosage 11.7 Other Specific Populations 2.3 Dosage Adjustment in Specific Populations 12 OVERDOSAGE 2.4 Dose Preparation and Administration 13 DESCRIPTION 3 DOSAGE FORMS AND STRENGTHS 14 CLINICAL PHARMACOLOGY 4 CONTRAINDICATIONS 14.1 Mechanism of Action 5 WARNINGS AND PRECAUTIONS 14.2 Pharmacodynamics 5.1 Hypersensitivity Including Anaphylaxis and Infusion- 14.3 Pharmacokinetics Related Reactions 15 MICROBIOLOGY/RESISTANCE INFORMATION 5.2 Limitations of Benefit and Potential for Risk in Patients 16 NONCLINICAL TOXICOLOGY with Severe COVID-19 17 ANIMAL PHARMACOLOGIC AND EFFICACY DATA 6 OVERALL SAFETY SUMMARY 18 CLINICAL TRIAL RESULTS AND SUPPORTING DATA 6.1 Clinical Trials Experience FOR EUA 7 PATIENT MONITORING RECOMMENDATIONS 18.1 Mild to Moderate COVID-19 (BLAZE-1) 8 ADVERSE REACTIONS AND MEDICATION ERRORS 19 HOW SUPPLIED/STORAGE AND HANDLING REPORTING REQUIREMENTS AND INSTRUCTIONS 20 PATIENT COUNSELING INFORMATION 9 OTHER REPORTING REQUIREMENTS 21 CONTACT INFORMATION 10 DRUG INTERACTIONS * Sections or subsections omitted from the full prescribing 11 USE IN SPECIFIC POPULATIONS information are not listed. 11.1 Pregnancy 11.2 Lactation 1 AUTHORIZED USE Bamlanivimab is authorized for use under an EUA for treatment of mild to moderate COVID-19 in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization. LIMITATIONS OF AUTHORIZED USE • Bamlanivimab is not authorized for use in patients: o who are hospitalized due to COVID-19, OR o who require oxygen therapy due to COVID-19, OR o 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. • Benefit of treatment with bamlanivimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bamlanivimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation [see Warnings and Precautions (5.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Bamlanivimab should be administered as soon as possible after positive viral test for SARS-CoV-2 and within 10 days of symptom onset in adults and pediatric patients 12 9 Reference ID: 4699500 ## Page 18 years of age and older weighing at least 40 kg who are at high risk for progressing to severe COVID-19 and/or hospitalization. High risk is defined as patients who meet at least one of the following criteria: • Have a body mass index (BMI) ≥35 • Have chronic kidney disease • Have diabetes • Have immunosuppressive disease • Are currently receiving immunosuppressive treatment • Are ≥65 years of age • Are ≥55 years of age AND have • cardiovascular disease, OR • hypertension, OR • chronic obstructive pulmonary disease/other chronic respiratory disease. • Are 12 – 17 years of age AND have • BMI ≥85th percentile for their age and gender based on CDC growth , OR charts, https://www.cdc.gov/growthcharts/clinical_charts.htm • sickle cell disease, OR • congenital or acquired heart disease, OR • neurodevelopmental disorders, for example, cerebral palsy, OR • a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), OR • asthma, reactive airway or other chronic respiratory disease that requires daily medication for control. 2.2 Dosage The dosage of bamlanivimab in adults and pediatric patients 12 years of age and older weighing at least 40 kg is a single intravenous (IV) infusion of 700 mg bamlanivimab administered over at least 60 minutes. Bamlanivimab should be administered as soon as possible after positive viral test for SARS-CoV-2 and within 10 days of symptom onset. 2.3 Dosage Adjustment in Specific Populations Pregnancy or Lactation No dosage adjustment is recommended in pregnant or lactating women [see Use in Specific Populations (11.1, 11.2)]. Pediatric Use No dosage adjustment is recommended in pediatric patients who weigh at least 40 kg. Bamlanivimab is not authorized for patients weighing less than 40 kg [see Use in Specific Populations (11.3)]. Geriatric Use No dosage adjustment is recommended in geriatric patients [see Use in Specific Populations (11.4)]. 10 Reference ID: 4699500 ## Page 19 Renal Impairment No dosage adjustment is recommended in patients with renal impairment [see Use in Specific Populations (11.5)]. Hepatic Impairment No dosage adjustment is recommended in patients with mild hepatic impairment. Bamlanivimab has not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (11.6)]. 2.4 Dose Preparation and Administration Preparation Bamlanivimab infusion solution should be prepared by a qualified healthcare professional using aseptic technique: • Remove bamlanivimab vial from refrigerated storage and allow to equilibrate to room temperature for approximately 20 minutes before preparation. Do not expose to direct heat. • Inspect bamlanivimab visually for particulate matter and discoloration. o Bamlanivimab is a clear to slightly opalescent and colorless to slightly yellow to slightly brown solution. • Gently invert vial by hand approximately 10 times. Do not shake. • Dilute bamlanivimab using a 250 mL prefilled 0.9% Sodium Chloride Injection bag for intravenous infusion according to Table 1. o Withdraw and discard required volume of 0.9% Sodium Chloride Injection from the infusion bag. o Withdraw required volume of bamlanivimab from the vial using an appropriately sized syringe. o Transfer bamlanivimab to the 0.9% Sodium Chloride Injection infusion bag. o Discard any product remaining in the vial. • Gently invert IV bag by hand approximately 10 times to mix. Do not shake. • This product is preservative-free and therefore, the diluted infusion solution should be administered immediately. If immediate administration is not possible, store the diluted bamlanivimab infusion solution for up to 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]) or up to 7 hours at room temperature (20°C to 25°C [68°F to 77°F]) including infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 20 minutes prior to administration. Table 1: Recommended Dilution and Administration Instructions for Bamlanivimab Treatment Dose/Volume Volume of Total Minimum Minimum of 0.9% sodium Volume Infusion Infusion Bamlanivimab chloride to for Rate Time (# of vials) Discard from Infusion a 250 mL IV bag Bamlanivimab 700 mg/20 mL 70 mL 200 mL 200 mL/hr 60 minutes (1 vial) 11 Reference ID: 4699500 ## Page 20 Administration Bamlanivimab solution should be administered by a qualified healthcare professional. • Gather the recommended materials for infusion: o Polyvinylchloride (PVC) infusion set containing a 0.20/0.22 micron in-line polyethersulfone (PES) filter. • Attach the infusion set to the IV bag. • Prime the infusion set. • Administer the infusion solution via pump or gravity over at least 60 minutes (see Table 1). • Once infusion is complete, flush the infusion line to ensure delivery of the required dose. • Discard unused product. • Clinically monitor patients during infusion and observe patients for at least 1 hour after infusion is complete. Storage This product is preservative-free and therefore, the diluted infusion solution should be administered immediately. If immediate administration is not possible, store the diluted bamlanivimab solution for up to 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]) or up to 7 hours at room temperature (20°C to 25°C [68°F to 77°F]) including infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 20 minutes prior to administration. 3 DOSAGE FORMS AND STRENGTHS Injection: 700 mg/20 mL (35 mg/mL) as a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow to slightly brown solution in a single-dose vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS There are limited clinical data available for bamlanivimab. Serious and unexpected adverse events may occur that have not been previously reported with bamlanivimab use. 5.1 Hypersensitivity Including Anaphylaxis and Infusion-Related Reactions There is a potential for serious hypersensitivity reaction, including anaphylaxis, with administration of bamlanivimab. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care. 12 Reference ID: 4699500 ## Page 21 Infusion-related reactions have been observed with administration of bamlanivimab. Signs and symptoms of infusion related reactions may include: • fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, dizziness. If an infusion-related reaction occurs, consider slowing or stopping the infusion and administer appropriate medications and/or supportive care. 5.2 Limitations of Benefit and Potential for Risk in Patients with Severe COVID-19 Benefit of treatment with bamlanivimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bamlanivimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation. Therefore, bamlanivimab is not authorized for use in patients [see Limitations of Authorized Use]: o who are hospitalized due to COVID-19, OR o who require oxygen therapy due to COVID-19, OR o 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. 6 OVERALL SAFETY SUMMARY Over 850 subjects have been exposed to bamlanivimab in clinical trials in both hospitalized and non-hospitalized patients. 6.1 Clinical Trials Experience The safety of bamlanivimab is based on interim data from one Phase 2 trial of 465 ambulatory (non-hospitalized) subjects with COVID-19. 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. Subjects were treated with a single infusion of bamlanivimab at doses of 700 mg (N=101), 2,800 mg (N=107), or 7,000 mg (N=101) or placebo (N=156). Based on data from 309 bamlanivimab-treated subjects followed for at least 28 days after treatment, adverse events occurred in 23% bamlanivimab-treated subjects and 26% of placebo-treated subjects. Serious adverse events occurred in 1 placebo-treated subject (1%) and in no bamlanivimab-treated subjects. The most commonly reported adverse event was nausea. Table 2 shows adverse events reported in at least 1% of patients in any treatment group. Bamlanivimab is not authorized at doses of 2,800 mg or 7,000 mg. 13 Reference ID: 4699500 ## Page 22 Table 2: Treatment-emergent Adverse Events Reported in at Least 1% of All Subjects in BLAZE-1 Preferred Placebo Bamlanivimab term N=156 700 mg 2,800 mg 7,000 mg Total % N=101 N=107 N=101 N=309 % % % % Nausea 4% 3% 4% 5% 4% Diarrhea 5% 1% 2% 7% 3% Dizziness 2% 3% 3% 3% 3% Headache 2% 3% 2% 0% 2% Pruritus 1% 2% 3% 0% 2% Vomiting 3% 1% 3% 1% 2% Hypersensitivity Including Anaphylaxis and Infusion-related Reactions: One anaphylaxis reaction and one serious infusion-related reaction were reported during infusion of bamlanivimab in ongoing, blinded trials. The infusions were stopped. Both reactions required treatment, one required epinephrine. Both events resolved. Immediate non-serious hypersensitivity events were noted for 2% of bamlanivimab- treated subjects and 1% of placebo-treated subjects in BLAZE-1. Reported events of pruritus, flushing and hypersensitivity were mild with one case of face swelling which was moderate. All events resolved [see Warnings and Precautions (5.1)]. 7 PATIENT MONITORING RECOMMENDATIONS Clinically monitor patients during infusion and observe patients for at least 1 hour after infusion is complete [see Warnings and Precautions (5.1) and Clinical Trials Experience (6.1)]. 8 ADVERSE REACTIONS AND MEDICATION ERRORS REPORTING REQUIREMENTS AND INSTRUCTIONS Clinical trials evaluating the safety of bamlanivimab 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 selected serious adverse events occurring during bamlanivimab use and considered to be potentially related to bamlanivimab. 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. 14 Reference ID: 4699500 ## Page 23 If a serious and unexpected adverse event occurs and appears to be associated with the use of bamlanivimab, 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/UCM163 919.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 • 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: o Write “Bamlanivimab treatment under Emergency Use Authorization (EUA)” as the first line o 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: o Provide the name and contact information of the prescribing healthcare provider or institutional designee who is responsible for the report. o Provide the address of the treating institution (NOT the healthcare provider’s office address). 9 OTHER REPORTING REQUIREMENTS 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. 15 Reference ID: 4699500 ## Page 24 10 DRUG INTERACTIONS Bamlanivimab 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. 11 USE IN SPECIFIC POPULATIONS 11.1 Pregnancy Risk Summary There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Bamlanivimab 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. In a tissue cross reactivity study with bamlanivimab using human fetal tissues, no binding of clinical concern was detected. Human immunoglobulin G1 (IgG1) antibodies are known to cross the placental barrier; therefore, bamlanivimab has the potential to be transferred from the mother to the developing fetus. It is unknown whether the potential transfer of bamlanivimab 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. 11.2 Lactation Risk Summary There are no available data on the presence of bamlanivimab 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 any potential adverse effects on the breastfed child from bamlanivimab 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. 11.3 Pediatric Use The safety and effectiveness of bamlanivimab have not been assessed in pediatric patients. The recommended dosing regimen is expected to result in comparable serum exposures of bamlanivimab 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. 16 Reference ID: 4699500 ## Page 25 11.4 Geriatric Use Of the 309 patients receiving bamlanivimab in BLAZE-1, 11% were 65 years of age and older and 3% were 75 years of age and older. Based on population PK analyses, there is no difference in PK in geriatric patients compared to younger patients. 11.5 Renal Impairment Bamlanivimab is not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of bamlanivimab. 11.6 Hepatic Impairment Based on population PK analysis, patients with mild hepatic impairment had approximately 20% higher clearance than patients with normal hepatic function. This effect is statistically significant, but not clinically meaningful. Bamlanivimab has 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 was not affected by sex, race, and disease severity or inflammation. Body weight had no clinically relevant effect on the PK of bamlanivimab in adults with COVID-19 over the body weight range of 41 kg to 173 kg. 12 OVERDOSAGE Doses up to 7,000 mg (10 times the recommended dose) have been administered in clinical trials without dose-limiting toxicity. Treatment of overdose with bamlanivimab 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 bamlanivimab. 13 DESCRIPTION Bamlanivimab is a human immunoglobulin G-1 (IgG1 variant) monoclonal antibody consisting of 2 identical light chain polypeptides composed of 214 amino acids each and 2 identical heavy chain polypeptides composed of 455 amino acids produced by a Chinese Hamster Ovary (CHO) cell line and molecular weight of 146 kDa. Bamlanivimab injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow to slightly brown solution in a single-dose vial for intravenous infusion after dilution. Each mL contains 35 mg of bamlanivimab, and 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 bamlanivimab solution has a pH range of 5.5-6.5. 17 Reference ID: 4699500 ## Page 26 14 CLINICAL PHARMACOLOGY 14.1 Mechanism of Action Bamlanivimab is a recombinant neutralizing human IgG1κ monoclonal antibody (mAb) to the spike protein of SARS-CoV-2, and is unmodified in the Fc region. Bamlanivimab binds to spike protein with a dissociation constant K = 0.071 nM and blocks spike D protein attachment to the human ACE2 receptor with an IC value of 0.025 µg/mL. 50 14.2 Pharmacodynamics A Phase 2 trial evaluated bamlanivimab over a dose range of 1 to 10 times the recommended dose (700 to 7000 mg) of bamlanivimab in patients with mild to moderate COVID-19. A flat exposure-response relationship for efficacy was identified for bamlanivimab within this dose range, based on viral load and clinical outcomes. 14.3 Pharmacokinetics Pharmacokinetic profile of bamlanivimab is expected to be consistent with the profile of other IgG1 monoclonal antibodies. Special Populations: The PK of bamlanivimab was not affected by age, sex, race, disease severity or inflammation based on a population PK analysis. Body weight had no clinically relevant effect on the PK of bamlanivimab in adults with COVID-19 over the body weight range of 41 kg to 173 kg [see Use in Specific Populations (11.4, 11.7)]. Pediatric population The PK of bamlanivimab in pediatric patients have not been evaluated. Using modeling and simulation, the recommended dosing regimen is expected to result in comparable plasma exposures of bamlanivimab in pediatric patients ages 12 years of age or older who weigh at least 40 kg as observed in adult patients [see Use in Specific Populations (11.3)]. Patients with renal impairment Bamlanivimab is not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of bamlanivimab [see Use in Specific Populations (11.5)]. Patients with hepatic impairment Based on population PK analysis, patients with mild hepatic impairment had approximately 20% higher clearance than patients with normal hepatic function. This effect is statistically significant, but not clinically meaningful. Bamlanivimab has not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (11.6)]. Drug interactions: Bamlanivimab 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 [see Drug Interactions (10)]. 18 Reference ID: 4699500 ## Page 27 15 MICROBIOLOGY/RESISTANCE INFORMATION Antiviral Activity The cell culture neutralization activity of bamlanivimab against SARS-CoV-2 was measured in a dose-response model using cultured Vero E6 cells. Bamlanivimab neutralized SARS-CoV-2 with an estimated EC value = 0.03 µg/mL and an estimated 50 EC value = 0.09 µg/mL. 90 Bamlanivimab demonstrated antibody-dependent cell-mediated cytotoxicity on reporter Jurkat cells expressing FcγRIIIa following engagement with target cells expressing spike protein. Bamlanivimab did not elicit complement-dependent cytotoxicity activity in cell- based assays. Antibody Dependent Enhancement (ADE) of Infection The risk that bamlanivimab could mediate viral uptake and replication by immune cells was studied in THP-1 and Raji cell lines and primary human macrophages. This experiment did not demonstrate productive viral infection in immune cells exposed to SARS CoV-2 at concentrations of bamlanivimab down to 100-fold below the EC value. 50 Antiviral Resistance There is a potential risk of treatment failure due to the development of viral variants that are resistant to bamlanivimab. Non-clinical studies using serial passage of SARS-CoV-2 and directed evolution of the spike protein identified E484K, F490S, Q493R and S494P, amino acid substitutions in the spike protein receptor binding domain, that had reduced susceptibility to bamlanivimab as determined in neutralization assays using SARS-CoV-2 (F490S and S494P: >485-fold and >71-fold reduction, respectively) and/or vesicular stomatitis virus- based pseudovirus (all variants >100-fold reduction). Genotypic and phenotypic testing are ongoing to monitor for potential bamlanivimab- resistance-associated spike variations in clinical trials. Known bamlanivimab-resistant variants at baseline were observed at a frequency of 0.27% (1/375) in Part A of clinical trial BLAZE-1. In the same trial, treatment-emergent variants were detected at spike protein amino acid positions E484, F490 and S494, and included E484A/D/G/K/Q/V, F490L/S/V and S494L/P; only E484K/Q, F490S and S494P have been assessed phenotypically to date. Considering all variants detected at positions E484, F490 and S494, 9.2% (9/98) and 6.1% (6/98) of participants in the 700 mg bamlanivimab arm harbored such a variant post-baseline at ≥15% and ≥50% allele fractions, respectively, compared with 8.2% (8/97) and 4.1% (4/97), respectively, of participants in the placebo arm. Most of these variants were first detected on Day 7 following treatment initiation and many were detected only at a single time point (700 mg arm: 5/9 and 2/6 at ≥15% and ≥50% allele fractions, respectively; placebo arm: 8/8 and 4/4, respectively). For the 700 mg bamlanivimab arm, these variants were detected more frequently in high-risk participants (14.0% [6/43] and 9.3% [4/43] at ≥15% and ≥50% allele fractions, respectively, vs 2.4% [1/41] and 0% [0/41], respectively, in the placebo arm). The clinical relevance of these findings is not known. It is possible that bamlanivimab resistance-associated variants could have cross- The resistance to other mAbs targeting the receptor binding domain of SARS-CoV-2. clinical impact is not known. 19 Reference ID: 4699500 ## Page 28 Immune Response Attenuation There is a theoretical risk that antibody administration may attenuate the endogenous immune response to SARS-CoV-2 and make patients more susceptible to re-infection. 16 NONCLINICAL TOXICOLOGY Carcinogenesis, mutagenesis, and reproductive toxicology studies with bamlanivimab have not been conducted. In toxicology studies in rats, bamlanivimab had no adverse effects when administered intravenously. Non-adverse increases in neutrophils were observed. In tissue cross reactivity studies using human adult and fetal tissues, no binding of clinical concern was detected. 17 ANIMAL PHARMACOLOGIC AND EFFICACY DATA In Vivo Efficacy Pharmacology Prophylactic administration of bamlanivimab to female Rhesus macaques (n=3 or 4 per group) resulted in 1 to 4 log10 decreases in viral load (genomic RNA) and viral replication (sub-genomic RNA) in bronchoalveolar lavage samples relative to control animals, but less of an impact on viral RNA in throat and nasal swabs following SARS-CoV-2 inoculation. The applicability of these findings to a prophylaxis or treatment setting is not known. 18 CLINICAL TRIAL RESULTS AND SUPPORTING DATA FOR EUA 18.1 Mild to Moderate COVID-19 (BLAZE-1) The data supporting this EUA are based on an interim analysis from Part A of BLAZE-1 that occurred after all enrolled subjects completed at least Day 29 of the trial. BLAZE-1 Part A is a randomized, double-blind, placebo-controlled clinical trial studying bamlanivimab for the treatment of subjects with mild to moderate COVID-19 (subjects with COVID-19 symptoms who are not hospitalized). BLAZE-1 enrolled adult patients who were not hospitalized and had at least 1 or more COVID-19 symptoms that were at least mild in severity. Treatment was initiated within 3 days of obtaining the clinical sample for the first positive SARS-CoV-2 viral infection determination. Subjects were treated with a single infusion of bamlanivimab (at doses of 700 mg [N=101], 2,800 mg [N=107], or 7,000 mg [N=101]) or placebo (N=156). At baseline, median age was 45 years (with 12% of subjects aged 65 or older); 55% of subjects were female, 88% were White, 44% were Hispanic or Latino, and 6% were Black; 44% of subjects were considered high risk (as defined in Section 2). Subjects had mild (76%) to moderate COVID-19 (24%); the mean duration of symptoms was 5 days; mean viral load by cycle threshold (CT) was 24 at baseline. The baseline demographics and disease characteristics were well balanced across bamlanivimab and placebo treatment groups. 20 Reference ID: 4699500 ## Page 29 The pre-specified primary endpoint in this Phase 2 trial was change in viral load from baseline to Day 11 for bamlanivimab versus placebo. Most subjects, including those receiving placebo, effectively cleared virus by Day 11 (Figure 1). Figure 1: SARS-CoV-2 viral load change from baseline by visit. While viral load was used to define the primary endpoint in this Phase 2 trial, the most important evidence that bamlanivimab may be effective came from the predefined secondary endpoint of COVID-19-related hospitalizations or emergency room visits within 28 days after treatment. A lower proportion of bamlanivimab-treated subjects progressed to COVID-19-related hospitalization or emergency room visits compared to placebo-treated subjects (Table 3). Results for this endpoint were suggestive of a relatively flat dose-response relationship. Table 3: Proportion of Subjects with Events of Hospitalization or Emergency Room Visits within 28 Days After Treatment Proportion of a Treatment N Events Subjects % Placebo 156 9 6% bamlanivimab 700 mg 101 1 1% bamlanivimab 2800 mg 107 2 2% bamlanivimab 7000 mg 101 2 2% All bamlanivimab doses 309 5 2% a N = number of treated patients in analysis. 21 Reference ID: 4699500 ## Page 30 The absolute risk reduction for bamlanivimab compared to placebo is greater in subjects at higher risk of hospitalization according to the high risk criteria (Table 4). Table 4: Proportion of Subjects with Events of Hospitalization or Emergency Room Visits for Subjects at Higher Risk of Hospitalization Proportion of a Treatment N Events Subjects % Placebo 69 7 10% bamlanivimab 700 mg 46 1 2% bamlanivimab 2800 mg 46 1 2% bamlanivimab 7000 mg 44 2 5% All bamlanivimab doses 136 4 3% a N = number of treated patients in analysis. The median time to symptom improvement as recorded in a trial specific daily symptom diary was 6 days for bamlanivimab-treated subjects, as compared with 8 days for placebo-treated subjects. Symptoms assessed were cough, shortness of breath, feeling feverish, fatigue, body aches and pains, sore throat, chills, and headache. Symptom improvement was defined as symptoms scored as moderate or severe at baseline being scored as mild or absent, and symptoms scored as mild or absent at baseline being scored as absent. 19 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Bamlanivimab injection, 700 mg/20 mL (35 mg/mL), is a sterile, preservative-free clear to slightly opalescent and colorless to slightly yellow to slightly brown solution supplied as one single-dose vial per carton. NDC 0002-7910-01 Storage and Handling Bamlanivimab is preservative-free. Discard unused portion. Store unopened vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. DO NOT FREEZE, SHAKE, OR EXPOSE TO DIRECT LIGHT. Solution in vial requires dilution prior to administration. The prepared infusion solution is intended to be used immediately. If immediate administration is not possible, store diluted bamlanivimab infusion solution in the refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at room temperature (20°C to 25°C [68°F to 77°F]) for up to 7 hours, including infusion time. If refrigerated, allow the infusion solution to equilibrate to room temperature prior to administration. 20 PATIENT COUNSELING INFORMATION Patients treated with bamlanivimab should continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal 22 Reference ID: 4699500 ## Page 31 items, clean and disinfect “high touch” surfaces, and frequent handwashing) according to CDC guidelines. Also see Fact Sheet for Patients, Parents and Caregivers. 21 CONTACT INFORMATION For additional information visit: www.bamlanivimab.com If you have questions, please contact: 1-855-LillyC19 (1-855-545-5921) Literature issued November 2020 Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2020, Eli Lilly and Company. All rights reserved. 9.0-BAM-0000-EUA HCP-2020-11-09 23 Reference ID: 4699500 ## Page 32 Fact Sheet for Patients, Parents and Caregivers Emergency Use Authorization (EUA) of Bamlanivimab for Coronavirus Disease 2019 (COVID-19) You are being given a medicine called bamlanivimab for the treatment of coronavirus disease 2019 (COVID- 19). This Fact Sheet contains information to help you understand the potential risks and potential benefits of taking bamlanivimab, which you may receive. Receiving bamlanivimab may benefit certain people with COVID-19. Read this Fact Sheet for information about bamlanivimab. Talk to your healthcare provider if you have questions. It is your choice to receive bamlanivimab or stop it at any time. What is COVID-19? COVID-19 is caused by a virus called a coronavirus. People can get COVID-19 through contact with another person who has the virus. COVID-19 illnesses have ranged from very mild (including some with no reported symptoms) to severe, including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, serious illness can happen and may cause some of your other medical conditions to become worse. People of all ages with severe, long-lasting (chronic) medical conditions like heart disease, lung disease, and diabetes, for example, seem to be at higher risk of being hospitalized for COVID-19. What are the symptoms of COVID-19? The symptoms of COVID-19 include fever, cough, and shortness of breath, which may appear 2 to 14 days after exposure. Serious illness including breathing problems can occur and may cause your other medical conditions to become worse. What is bamlanivimab? Bamlanivimab is an investigational medicine used for the treatment of COVID-19 in non-hospitalized adults and adolescents 12 years of age and older with mild to moderate symptoms who weigh 88 pounds (40 kg) or more, and who are at high risk for developing severe COVID-19 symptoms or the need for hospitalization. Bamlanivimab is investigational because it is still being studied. There is limited information known about the safety or effectiveness of using bamlanivimab to treat people with COVID-19. The FDA has authorized the emergency use of bamlanivimab for the treatment of COVID-19 under an Emergency Use Authorization (EUA). For more information on EUA, see the section “What is an Emergency Use Authorization (EUA)?” at the end of this Fact Sheet. What should I tell my healthcare provider before I receive bamlanivimab? Tell your healthcare provider about all of your medical conditions, including if you: • Have any allergies • Are pregnant or plan to become pregnant • Are breastfeeding or plan to breastfeed • Have any serious illnesses • Are taking any medications (prescription, over-the-counter, vitamins, and herbal products) How will I receive bamlanivimab? • Bamlanivimab is given to you through a vein (intravenous or IV) for at least 1 hour. • You will receive one dose of bamlanivimab by IV infusion. What are the important possible side effects of bamlanivimab? Possible side effects of bamlanivimab are: • Allergic reactions. Allergic reactions can happen during and after infusion with bamlanivimab. Tell your healthcare provider right away if you get any of the following signs and symptoms of allergic reactions: fever, 1 Reference ID: 4699500 ## Page 33 chills, nausea, headache, shortness of breath, low blood pressure, wheezing, swelling of your lips, face, or throat, rash including hives, itching, muscle aches, and dizziness. The side effects of getting any medicine by vein may include brief pain, bleeding, bruising of the skin, soreness, swelling, and possible infection at the infusion site. These are not all the possible side effects of bamlanivimab. Not a lot of people have been given bamlanivimab. Serious and unexpected side effects may happen. Bamlanivimab is still being studied so it is possible that all of the risks are not known at this time. It is possible that bamlanivimab could interfere with your body's own ability to fight off a future infection of SARS-CoV-2. Similarly, bamlanivimab may reduce your body’s immune response to a vaccine for SARS-CoV-2. Specific studies have not been conducted to address these possible risks. Talk to your healthcare provider if you have any questions. What other treatment choices are there? Like bamlanivimab, FDA may allow for the emergency use of other medicines to treat people with COVID-19. Go to https://www.covid19treatmentguidelines.nih.gov/ for information on the emergency use of other medicines that are not approved by FDA to treat people with COVID-19. Your healthcare provider may talk with you about clinical trials you may be eligible for. It is your choice to be treated or not to be treated with bamlanivimab. Should you decide not to receive bamlanivimab or stop it at any time, it will not change your standard medical care. What if I am pregnant or breastfeeding? There is limited experience treating pregnant women or breastfeeding mothers with bamlanivimab. For a mother and unborn baby, the benefit of receiving bamlanivimab may be greater than the risk from the treatment. If you are pregnant or breastfeeding, discuss your options and specific situation with your healthcare provider. How do I report side effects with bamlanivimab? Tell your healthcare provider right away if you have any side effect that bothers you or does not go away. Report side effects to FDA MedWatch at www.fda.gov/medwatch, call 1-800-FDA-1088, or contact Eli Lilly and Company at 1-855-LillyC19 (1-855-545-5921). How can I learn more? • Ask your healthcare provider • Visit www.bamlanivimab.com • Visit https://www.covid19treatmentguidelines.nih.gov/ • Contact your local or state public health department What is an Emergency Use Authorization (EUA)? The United States FDA has made bamlanivimab available under an emergency access mechanism called an EUA. The EUA is supported by a Secretary of Health and Human Service (HHS) declaration that circumstances exist to justify the emergency use of drugs and biological products during the COVID-19 pandemic. Bamlanivimab has not undergone the same type of review as an FDA-approved or cleared product. The FDA may issue an EUA when certain criteria are met, which includes that there are no adequate, approved, and available alternatives. In addition, the FDA decision is based on the totality of scientific evidence available showing that it is reasonable to believe that the product meets certain criteria for safety, performance, and labeling and may be effective in treatment of patients during the COVID-19 pandemic. All of these criteria must be met to allow for the product to be used in the treatment of patients during the COVID-19 pandemic. 2 Reference ID: 4699500 ## Page 34 The EUA for bamlanivimab is in effect for the duration of the COVID-19 declaration justifying emergency use of these products, unless terminated or revoked (after which the product may no longer be used). Literature issued November 2020 Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2020, Eli Lilly and Company. All rights reserved. 5.0-BAM-0000-EUA PAT-20201109 3 Reference ID: 4699500 ## Page 35 Signature Page 1 of 1 -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ LINDA C AKUNNE 11/09/2020 06:13:37 PM Reference ID: 4699500