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Formulary Considerations for Use of Fetroja® (cefiderocol) to Treat HABP/VABP, an Investigational Indication

This presentation is intended for a payor, formulary committee, or other similar entities with knowledge and expertise in the area of health care economic analysis, carrying out its responsibilities for the selection of drugs for coverage or reimbursement. Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established.

HABP=hospital-acquired bacterial ; VABP=ventilator-associated bacterial pneumonia.

Please see Important Safety Information on slides 2-4 and Full Prescribing Information for Fetroja.

CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY.

© 2020 Shionogi Inc. Florham Park, NJ 07932. Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. All Rights Reserved. USFET-0158 06/20 Fetroja® (cefiderocol) Is Approved to Treat cUTI1

CURRENT INDICATION1 • Fetroja is currently indicated in patients 18 years of age or older who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: , pneumoniae, , , and complex. Approval of this indication is based on limited clinical safety and efficacy data for Fetroja CURRENT USAGE1 • To reduce the development of drug-resistant and maintain the effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy

CURRENT IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja.

Reference: 1. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2019.

Please see Important Safety Information on slides 2-4 and Full Prescribing Information for Fetroja.

® 2 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Fetroja® (cefiderocol) Important Safety Information (cont’d)

WARNINGS AND PRECAUTIONS Increase in All-Cause Mortality in Patients With Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with Fetroja as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically-ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, , or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin. The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including nonfermenters such as , Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. The safety and efficacy of Fetroja has not been established for the treatment of nosocomial pneumonia, bloodstream infections, or sepsis. Reserve Fetroja for use in patients who have limited or no alternative treatment options for the treatment of cUTI. Closely monitor the clinical response to therapy in patients with cUTI. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in Fetroja clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with . Before therapy with Fetroja is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue Fetroja if an allergic reaction occurs.

Please see Important Safety Information for Fetroja continued on the following slide and Full Prescribing Information for Fetroja.

® 3 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Fetroja® (cefiderocol) Important Safety Information (cont’d)

Clostridioides difficile-Associated Diarrhea (CDAD) Clostridioides difficile-Associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Fetroja. CDAD may range in severity from mild diarrhea to fatal . Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including Fetroja, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust Fetroja dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether Fetroja should be discontinued. Development of Drug-Resistant Bacteria Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and may increase the risk for development of drug-resistant bacteria. ADVERSE REACTIONS The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/cilastatin in clinical trials were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%).

Please see Full Prescribing Information for Fetroja.

® 4 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Fetroja® (cefiderocol) Is Being Investigated as a Treatment for HABP/VABP1

PROPOSED ADDITIONAL INDICATION • In patients ≥18 years of age, treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Burkholderia cepacia complex, koseri, Escherichia coli, Enterobacter cloacae complex, , , , Proteus mirabilis, Pseudomonas aeruginosa, , and Stenotrophomonas maltophilia PROPOSED USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefiderocol and other antibacterial drugs, cefiderocol should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. PROPOSED WARNINGS AND PRECAUTIONS Updated section 5.1. Increase in All-Cause Mortality in Patients With Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin. The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. An increase in mortality was not observed in a multinational, randomized, double-blinded trial in patients with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP) (NCT03032380). Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP.

HABP=hospital-acquired bacterial pneumonia; VABP=ventilator-associated bacterial pneumonia. Reference: 1. Data on file. Shionogi Inc.

Please see Important Safety Information on slides 2-4 and Full Prescribing Information for Fetroja.

® 5 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Important Milestones for Fetroja® (cefiderocol) HABP/VABP Indication1

November 2019 February 2020 March 2020 September 2020* October 2020 FDA approval for Fetroja available FDA filing PDUFA date Anticipated cUTI indication for ordering of application for new-technology HABP/VABP indication add-on payment availability

Fetroja received a Qualified Infectious Disease Product (QIDP) designation, which is granted to antibacterial or antifungal drugs intended to treat serious or life-threatening infections, including those caused by resistant pathogens (including novel or emerging infectious pathogens).2

cUTI=complicated urinary tract infection; HABP=hospital-acquired bacterial pneumonia; PDUFA=Prescription Drug User Fee Act; VABP=ventilator-associated bacterial pneumonia. *Anticipated date as of May 2020 References: 1. Data on file. Shionogi Inc. 2. US Food and Drug Administration. Published January 2018. Accessed May 18, 2020. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM594213.pdf

Please see Important Safety Information on slides 2-4 and Full Prescribing Information for Fetroja.

® 6 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Despite Recent Advancements, There Remains a Need for Novel Treatments That Address Resistant or Uncommon but Clinically Challenging Pathogens1,2

WORLD HEALTH ORGANIZATION CENTERS FOR DISEASE CONTROL Priority 1: (WHO) AND PREVENTION (CDC) Critical Carbapenem-resistant Gram-negative The CDC, in its 2019 Antibiotic Resistance bacteria are identified as “Priority 1: Critical” Threats report, lists carbapenem-resistant in the 2017 WHO global priority list1 Acinetobacter and as urgent public health threats and multidrug-resistant • Acinetobacter baumannii, carbapenem-resistant P aeruginosa as a serious threat2 • Pseudomonas aeruginosa, carbapenem-resistant • Enterobacteriaceae,* carbapenem-resistant, third generation -resistant

The nonfermenter Stenotrophomonas maltophilia is also an emerging pathogen, with intrinsic antibiotic resistance3,4

*Enterobacteriaceae include Klebsiella pneumoniae, Escherichia coli, Enterobacter spp, Serratia spp, Proteus spp, Providencia spp, and Morganella spp. References: 1. World Health Organization. Published February 27, 2017. Accessed May 15, 2020. https://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/ 2. Centers for Disease Control and Prevention. Revised December 2019. Accessed May 15, 2020. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf 3. Brooke JS. Clin Microbial Rev. 2012;25(1):2-41. 4. Chang YT, et al. Front Microbiol. 2015;6:893. doi:10.3389/fmicb.2015.00893

® 7 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Patients With Carbapenem-Nonsusceptible Respiratory Infections Generally Had a Longer LOS*

Median LOS for carbapenem-nonsusceptible respiratory infections1

0 Days 20 Days

A baumannii 14 16

P aeruginosa 15 10

S maltophilia 15 Median length of total hospital stay was longer in the carbapenem-nonsusceptible cohort than in the carbapenem-susceptible K pneumoniae 17 cohort in each instance, except for 14 A baumannii respiratory infections1

E coli 16 12

Carbapenem-nonsusceptible Carbapenem-susceptible

Data were derived from the Premier Research Healthcare Database, which collects anonymized patient-level data from over 700 US hospitals annually. A subset of 180 hospitals provided microbiology test results such as specimen site, pathogen, and drug susceptibility for the period from October 2010 to September 2015. Two cohorts were defined using local hospital carbapenem susceptibility test results.1

LOS=length of stay. *Carbapenem-nonsusceptible P aeruginosa and A baumannii were defined as intermediate or resistant to imipenem or . All S maltophilia were considered carbapenem-resistant. Carbapenem-nonsusceptible K pneumoniae and E coli were defined as being reported as intermediate or resistant to imipenem, meropenem, or ertapenem.1 Reference: 1. Cai B et al. Poster 374. Presented at: IDWeek; San Diego, CA; October 4-8, 2017.

® 8 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Carbapenem-Resistant Respiratory Infections Are Associated With High Rates of Mortality*

In-hospital mortality due to carbapenem-resistant vs carbapenem-susceptible respiratory infections1

0% 30%

A baumannii 26 19.9

P aeruginosa 20.6 14.8

K pneumoniae 25.4 The odds of in-hospital mortality from 20.6 a carbapenem-resistant A baumannii

E coli respiratory infection were statistically 26.7 significant 21.7

Carbapenem-resistant Carbapenem-susceptible

Data were derived from a retrospective study of carbapenem-resistant Gram-negative infections between January 1, 2009 and December 31, 2013 conducted using microbiology data linked with patient-level in-hospital discharge data from the Premier Healthcare Database. The database is an anonymous census of inpatients and hospital-clinic outpatients from geographically diverse hospitals in the United States. Microbiology data were collected from 206 acute care hospitals. The total numbers of pathogen isolates were 173,200 for E coli; 56,552 for K pneumoniae; 56,477 for P aeruginosa; and 6508 for A baumannii.1

*Bacteria were defined as carbapenem-resistant if they were resistant to at least 1 of the carbapenems tested and as carbapenem-susceptible if the pathogen was susceptible to or intermediate for the carbapenems tested. Reference: 1. Cai B, et al. Open Forum Infect Dis. 2017;4(3):ofx176. doi:10.1093/ofid/ofx176

® 9 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Fetroja® (cefiderocol) Is Designed to Help Address These 3 Major Mechanisms of Gram-Negative Resistance1-3

ϐ-lactamase hydrolysis Efflux pump overexpression* Porin channel changes

Inactivates drug4 Expels ϐ-lactams3 Limit drug access3

Stable against all Active against pathogens that known classes of ϐ-lactamases, Active against isolates have decreased or have mutations including serine and with efflux pump overexpression7,8 in porin channels5,7,8 metallo-carbapenemases5,6

*Mechanism newly included in proposed labeling9

Cefiderocol is active against isolates resistant to cephalosporins or carbapenems due to any one or a combination of these mechanisms5-7,9

References: 1. Ito-Horiyama T, et al. Antimicrob Agents Chemother. 2016;60(7):4384-4386. 2. Aoki T, et al. Eur J Med Chem. 2018;155:847-868. 3. Fernandez L, Hancock REW. Clin Microbiol Rev. 2012;25(4):661-681. 4. Ruppé É, et al. Ann Intensive Care. 2015;5(1):61. doi:10.1186/s13613-015-0061-0 5. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2019. 6. Kazmierczak KM, et al. Int J Antimicrob Agents. 2019;53(2):177-184. 7. Ito A, et al. Antimicrob Agents Chemother. 2018;62(1):e01454-17. doi:10.1128/AAC.01454-17 8. Iregui A, et al. Microbial Drug Resist. Posted online February 7, 2020. doi:10.1089/mdr.2019.0298 9. Data on file. Shionogi Inc.

Please see Important Safety Information on slides 2-4 and Full Prescribing Information for Fetroja.

® 10 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Fetroja® (cefiderocol) Has a Unique Structure

Fetroja gains entry into bacteria cells by linking a siderophore with a cephalosporin1,2

S cephalosporin iron-binding O siderophore H N H 2 • To obtain iron for growth, bacteria produce N S siderophores, which bind to iron, and then N O CI actively transport the siderophore-bound iron into their cells to proliferate3 + OH N N N N • Fetroja is a unique cephalosporin with an O H attached catechol side-chain (siderophore) O Fe and uses iron to actively enter bacterial cells, in O addition to passive entry via porin channels4-6 O OH OH

O catechol side-chain

References: 1. Aoki T, et al. Eur J Med Chem. 2018;155:847-868. 2. Portsmouth S, et al. Lancet Infect Dis. 2018;18(12):1319-1328. 3. Ellermann M, et al. Free Radic Biol Med. 2017;105:68-78. 4. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2019. 5. Zhanel GG, et al. Drugs. 2019;79(3):271-289. 6. Ito A, et al. Antimicrob Agents Chemother. 2016;60(12):7396-7401.

Please see Important Safety Information on slides 2-4 and Full Prescribing Information for Fetroja.

® 11 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. High-Priority and Challenging Pathogens (US Isolates) Are Highly Susceptible to Fetroja® (cefiderocol) In Vitro1

In vitro activity does not necessarily correlate with clinical efficacy Fetroja in vitro susceptibility using FDA-approved breakpoints* Study Design: Clinical isolates of Gram-negative bacteria were collected in the United States from 2014-2018 for 99% 91% Enterobacterales one study that included Enterobacterales‡ and § (n =10,186) overall (n=162) carbapenem-nonsusceptible non-fermenter strains. The Proteeae study isolates were collected from 2013-2016 and were tested centrally (IHMA Inc., Schaumburg, IL, USA). Fetroja MICs were determined by microbroth dilution using iron-depleted P aeruginosa P aeruginosa cation-adjusted Mueller-Hinton broth (ID-CAMHB) 98% 97% as approved by the Clinical and Laboratory Standards (n=2445) overall (n=468) carbapenem-nonsusceptible Institute (CLSI) subcommittee on antimicrobial susceptibility testing in January 2016. FDA breakpoints were used for Enterobacterales MIC ≤2 μg/mL and Fetroja in vitro susceptibility using CLSI investigational breakpoints† P aeruginosa MIC ≤1 μg/mL, whereas CLSI investigational breakpoint was used for A baumannii and S maltophilia 98% A baumannii 96% A baumannii 99% S maltophilia MIC ≤4 μg/mL. Carbapenem-nonsusceptible strain (n=1049) overall (n=548) carbapenem- (n=596) overall was defined as meropenem MIC≥ 2 μg/mL for nonsusceptible (inherently carbapenem-resistant)2,3 Enterobacterales (including Proteeae) strains and MIC ≥4 μg/mL for P aeruginosa and A baumannii.

MIC=minimum inhibitory concentration. *FDA breakpoints used for Enterobacterales MIC ≤2 μg/mL and P aeruginosa MIC ≤1 μg/mL †CLSI investigational breakpoint used for A baumannii and S maltophilia MIC ≤4 μg/mL ‡E coli, K pneumoniae, other Klebsiella spp, Enterobacter spp, Serratia spp, and Citrobacter spp §Morganella morganii, Proteus mirabilis, , and References: 1. Data on file. Shionogi Inc. 2. Brooke JS. Clin Microbiol Rev. 2012;25(1):2-41. 3. Ruppé E, et al. Ann Intensive Care. 2015;5(1):61. doi:10.1186/s13613-015-0061-0

® 12 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Cefiderocol Activity Against Gram-Negative Bacteria Implicated in HABP/VABP

Cefiderocol both in vitro and in clinical infections1 Cefiderocol in vitro activity1

Cefiderocol has been shown to be active against the following Gram-negative Cefiderocol demonstrated in vitro activity against the following bacteria, both in vitro and in clinical infections Gram-negative bacteria, but the clinical significance is unknown*

Acinetobacter baumannii complex Achromobacter spp Burkholderia cepacia complex Burkholderia pseudomallei complex Escherichia coli Morganella morganii Enterobacter cloacae complex Proteus vulgaris Klebsiella aerogenes Providencia rettgeri Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Serratia marcescens Stenotrophomonas maltophilia

Bacteria that are newly included in the proposed HABP/VABP indication *At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefiderocol.

Note: The efficacy of cefiderocol in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

HABP=hospital-acquired bacterial pneumonia; VABP=ventilator-associated bacterial pneumonia. Reference: 1. Data on file. Shionogi Inc.

Please see Important Safety Information on slides 2-4 and Full Prescribing Information for Fetroja.

® 13 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. APEKS-NP: Cefiderocol vs High-Dose, Extended-Infusion Meropenem Was Studied in Patients With HABP or VABP

A multicenter, randomized, double-blind, parallel-group, phase 3 efficacy trial in adults with nosocomial pneumonia caused by Gram-negative pathogens1-3

Cefiderocol 2 g IV over 3 h q8h + LZD for at least 5 days Randomized End of Test of End of Follow-up 1:1 Treatment Cure Study Meropenem N~300 2 g IV over 3 h q8h + LZD for at least 5 days

Day 1 Days 3-4 Up to EOT EOT EOT Day 21 +7 days +14 days +28 days Early Assessment

• Key inclusion: Clinical diagnosis for HABP, VABP, and HCABP; suspected Gram-negative infection involving the lower respiratory tract; confirmed clinical and microbiologic failure for patients failing empiric therapy2 Primary Endpoint: all-cause mortality at • Key exclusion: CAP, atypical/viral/chemical pneumonia; infection due Day 14 in modified ITT population1,2 to carbapenem-resistant pathogen; neutropenia; APACHE II >35; receipt of effective antibiotic therapy >24 h within previous 72 h2,4

APACHE=acute physiology and chronic health evaluation; APEKS-NP=Acinetobacter, Pseudomonas, Escherichia coli, Klebsiella, Stenotrophomonas–nosocomial pneumonia; CAP=community-acquired pneumonia; EOT=end of treatment; HABP=hospital-acquired bacterial pneumonia; HCABP=healthcare-associated bacterial pneumonia; ITT=intention-to-treat; LZD=linezolid; q8h=every 8 hours; VABP=ventilator-associated bacterial pneumonia. *Modified ITT population includes all patients who received at least 1 dose of study treatment and had evidence of a Gram-negative infection of the lower respiratory tract.4

References: 1. Wunderink RG, et al. Presented at: IDWeek 2019; October 2-6, 2019; Washington, DC. 2. Matsunaga Y, et al. Poster A3290. Presented at: American Thoracic Society Conference 2018; May 18-23, 2018; San Diego, CA. 3. US Food and Drug Administration. Presented at: Antimicrobial Drugs Advisory Committee Meeting; October 16, 2019; Silver Spring, MD. Accessed May 15, 2020. https://www.fda.gov/advisory-committees/advisory-committee-calendar/ october-16-2019-antimicrobial-drugs-advisory-committee-meeting-announcement-10162019-10162019#event-materials 4. Data on file. Shionogi Inc.

® 14 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Patient Demographics and Baseline Characteristics (ITT Population)1

Cefiderocol Meropenem Baseline Characteristics N=148 N=150 Statistic/Category (%) (%)

Gender (Male) 68.2 69.3

Age (mean) 64.7 65.6 ≥75 years 27.0 31.3 <75 years 73.0 68.7

Clinical diagnosis VABP 40.5 43.3 HABP 40.5 40.7

Ventilation status at randomization Ventilated 61.5 58.0

APACHE II score ≤15 50.7 52.0 ≥16 49.3 48.0

APACHE=acute physiology and chronic health evaluation; HABP=hospital-acquired bacterial pneumonia; ITT=intention-to-treat; VABP=ventilator-associated bacterial pneumonia. Reference: 1. US Food and Drug Administration. Presented at: Antimicrobial Drugs Advisory Committee Meeting; October 16, 2019; Silver Spring, MD. Accessed May 15, 2020. https://www.fda.gov/advisory-committees/advisory-committee-calendar/ october-16-2019-antimicrobial-drugs-advisory-committee-meeting-announcement-10162019-10162019#event-materials

® 15 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Baseline Pathogens (ITT Population)1

Cefiderocol Meropenem Baseline Characteristics N=148 N=150 Statistic/Category (%) (%)

Baseline pathogens Gram-negative pathogen only 76.4 70.0 Mixed Gram-negative and Gram-positive 7.4 14.7 pathogens

Gram-negative subtotal 83.8 84.7

Culture negative 8.1 5.3 Gram-positive pathogen only 2.0 2.0

Top 4 baseline pathogens K pneumoniae 32.4 29.3 P aeruginosa 16.2 16.0 A baumannii 15.5 16.0 E coli 12.8 14.7

Positive Gram-negative blood culture 5.4 6.7

Reference: 1. Data on file. Shionogi Inc.

® 16 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. All-Cause Mortality (mITT Population)1

Cefiderocol Meropenema Treatment Comparison Time Point (%) n/N (%) n/N Difference (%) 95% CI

Day 14 12.4 11.6 0.8 -6.6, 8.2 (Primary Endpoint) 18/145 17/146

Day 28 21.0 20.5 0.5 - 8.7, 9.8 30/143 30/146

End of Study2 26.8 23.3 3.6 -6.3, 13.4 38/142 34/146

Primary endpoint achieved: cefiderocol demonstrated noninferiority to high-dose, extended-infusion meropenem

CI=confidence interval; mITT=modified intention-to-treat. a High-dose (2 g), extended-infusion (3 hours) meropenem was used as comparator to optimize Gram-negative activity.2 References: 1. US Food and Drug Administration. Presented at: Antimicrobial Drugs Advisory Committee Meeting; October 16, 2019; Silver Spring, MD. Accessed May 15, 2020. https://www.fda.gov/advisory-committees/advisory-committee- calendar/october-16-2019-antimicrobial-drugs-advisory-committee-meeting-announcement-10162019-10162019#event-materials 2. Data on file. Shionogi Inc.

® 17 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. All-Cause Mortality and Clinical Cure by Pathogen1

Day 14 All-Cause Mortality Day 28 All-Cause Mortality Clinical Cure at TOC Baseline Group or Pathogen Cefiderocol Meropenem Cefiderocol Meropenem Cefiderocol Meropenem n/N (%) n/N (%) n/N (%) n/N (%) n/N (%) n/N (%)

K pneumoniae 5/48 (10.4) 5 / 4 4 (11.4 ) 11/ 4 8 (22.9 ) 12 / 4 4 (27.3 ) 31/48 (64.6) 29/44 (65.9)

P aeruginosa 2/24 (8.3) 3/23 (13.0) 2/24 (8.3) 6 /23 (26.1) 16/24 (66.7) 17/24 (70.8)

A baumannii complex 5/26 (19.2) 4/25 (16.0) 8/25 (32.0) 6/25 (24.0) 14/26 (53.8) 15/25 (60.0)

E coli 4 /19 (21.1) 3/22 (13.6) 6/19 (31.6) 4/22 (18.2) 12/19 (63.2) 13 /22 (59.1)

• In the cefiderocol treatment group, 45 (31%) patients had ESBL-producing bacterial isolates compared with 42 (28.6%) patients in the meropenem treatment group

• All-cause mortality at Day 14 and Day 28 in these subsets of patients was consistent with overall trial results

ESBL=extended-spectrum beta-lactamases; TOC=Test of Cure. Reference: 1. Data on file. Shionogi Inc.

® 18 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. HABP/VABP Trial Safety Results (Safety Population)1

Cefiderocol (2 g, q8h) Meropenem (2 g, q8h) Adverse Event Category N=148 N=150 n (%) n (%)

TEAEs 87.8 86.0

Drug-related TEAEs 9.5 11.3

Treatment-emergent SAEs 36.5 30.0

Drug-related SAEs 2.0 3.3

Discontinuation due to TEAEs 8.1 9.3

Discontinuation due to drug-related TEAEs 1.4 1.3

TEAEs leading to death 26.4 23.3

Selected adverse reactions occurring in ≥2% of patients receiving cefiderocola

Elevations in liver testsb 22 (14.9%) 24 (16%)

Diarrhea 13 (8.8%) 13 (8.7%)

Clostridioides difficile infection 4 (2.7%) 3 (2%)

Nausea 4 (2.7%) 2 (1.3%)

HABP=hospital-acquired bacterial pneumonia; q8h=every 8 hours; SAEs=selected adverse events; TEAEs=treatment-emergent adverse events; VABP=ventilator-associated bacterial pneumonia. a Dosing for both cefiderocol and meropenem: 2 g IV over 3 hours every 8 hours (with dosing adjustment based on renal function) b Elevations in liver tests include the following terms: alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hepatic enzyme increased, liver function test increased, liver function test abnormal, transaminases increased. Reference: 1. Data on file. Shionogi Inc.

® 19 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Anemia-Related TEAEs (Safety Population)1

Cefiderocol Meropenem System Organ Class N=148 N=150 Preferred Term n (%) n (%)

Blood and lymphatic system disorders 27 (18.2) 28 (18.7) Anemia 12 (8.1) 12 (8.0) Anemia of chronic disease 2 (1.4) 0 Hemorrhagic anemia 0 2 (1.3) Iron deficiency anemia 3 (2.0) 0 Nephrogenic anemia 0 1 (0.7) Normochromic normocytic anemia 1 (0.7) 0

Investigations 32 (21.6) 29 (19.3) Hemoglobin decreased 1 (0.7) 0 Red blood cell count decreased 1 (0.7) 0

TEAEs=treatment-emergent adverse events. Reference: 1. Data on file. Shionogi Inc.

® 20 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Proposed Dosage and Administration for HABP/VABP

The proposed dosages, frequency, and adjustments for HABP/VABP are consistent with the recommended dosing for cUTI1

Estimated Creatinine Clearance (CLcr)a Dose Frequency Infusion Time • The recommended duration 60 to 119 mL/min (recommended dosage) 2 g Every 8 hours 3 hours of treatment for HABP/VABP is 7 to 14 days* 30 to 59 mL/min 1.5 g Every 8 hours 3 hours • The duration of therapy should be guided by the severity of infection and the patient’s clinical status for 15 to 29 mL/min 1 g Every 8 hours 3 hours up to 21 days† <15 mL/min (ESRD patients with or without 0.75 g Every 12 hours 3 hours • No dosage adjustments intermittent HDb) recommended in patients with hepatic impairment ≥120 mL/min 2 g Every 6 hours 3 hours

For patients receiving continuous renal replacement therapy (CRRT) including continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF), dosage of cefiderocol needs to be adjusted according to the effluent flow rate in CRRT.

Recommended dosage of cefiderocol for patients receiving CRRT

Effluent Flow Ratec 1 L/h or Less 1.1 to 2 L/h 2.1 to 3 L/h 3.1 L/h or Greater

Dosage of cefiderocol 1.5 g every 12 hours 2 g every 12 hours 1.5 g every 8 hours 2 g every 8 hours

cUTI=complicated urinary tract infection; ESRD=end-stage renal disease; HABP=hospital-acquired bacterial pneumonia; HD=hemodialysis; VABP=ventilator-associated bacterial pneumonia. aCLcr=creatinine clearance estimated by Cockcroft-Gault equation b Cefiderocol is removed by HD; thus, complete HD at the latest possible time before the start of cefiderocol dosing. cUltrafiltrate flow rate for CVVH, dialysis flow rate for CVVHD, ultrafiltrate flow rate + dialysis flow rate for CVVHDF *For cUTI, the recommended duration of treatment is 7 to 14 days.2 † For cUTI, the duration of therapy should be guided by the severity of infection and the patient’s clinical status for up to 14 days.2 References: 1. Data on file. Shionogi Inc.2. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2019.

® 21 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Ongoing Clinical Trials

Study Design Study Population Objectives

Phase 2 study in healthcare- Randomized, parallel-group, Adult patients with a bloodstream To compare the 14, 30, and associated and hospital- open-label, active-controlled infection from a Gram-negative 90-day mortality from day of acquired Gram-negative BSI organism randomization of cefiderocol versus (NCT03869437; recruiting)1 standard of care

Phase 2 study in aerobic Randomized, parallel-group, Hospitalized children 3 months Safety, tolerability, and Gram-negative bacterial open-label to <12 years with suspected or pharmacokinetics infections and cUTI confirmed aerobic Gram-negative (NCT04215991; recruiting)2 bacterial infections, and children 3 months to <18 years with cUTI

Phase 2 study in aerobic Multicenter, single-group, Hospitalized children 3 months Safety, tolerability, and Gram-negative bacterial open-label, single- and to <18 years with suspected or pharmacokinetics infections (NCT04335539; multiple-dose confirmed aerobic Gram-negative not yet recruiting)3 bacterial infections

BSI=bloodstream infection; cUTI=complicated urinary tract infection. References: 1. ClinicalTrials.gov. Updated November 25, 2019. Accessed May 19, 2020. https://clinicaltrials.gov/ct2/show/NCT03869437?term=cefiderocol&draw=2&rank=3 2. ClinicalTrials.gov. Updated March 20, 2020. Accessed May 19, 2020. https://clinicaltrials.gov/ct2/show/NCT04215991?term=cefiderocol&draw=2&rank=5 3. ClinicalTrials.gov. Updated April 6, 2020. Accessed May 19, 2020. https://clinicaltrials.gov/ct2/show/NCT04335539?term=cefiderocol&draw=2&rank=4

® 22 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Educational Resources for Institutions and Staff

Conference presentations Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment and published articles* of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319-1328.

Cai B, Echols R, Magee G, et al. Prevalence of carbapenem-resistant Gram-negative infections in the United States predominated by Acinetobacter baumannii and Pseudomonas aeruginosa. Open Forum Infect Dis. 2017;4(3):ofx176. doi:10.1093/ofid/ofx176

For a list of additional publications, please see the Appendix at the end of this presentation.

Meetings with Shionogi Speaker programs Medical Science Liaisons

Other resources to aid in formulary Online Formulary Kit at https://www.fetroja.com/fetroja-login decision-making available upon request Other resources to aid in formulary decision-making available upon request

*Federal and/or State transparency reporting obligations (e.g., Sunshine) may apply.

® 23 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Fetroja® (cefiderocol)Formulary Considerations for Proposed New Indication in HABP/VABP

Fetroja is approved for the treatment of cUTI, including pyelonephritis, caused by susceptible Gram-negative microorganisms in adult patients1

The drug is under investigation for an additional indication for the treatment of HABP/VABP2

Fetroja overcomes resistance through multiple mechanisms and has been shown to be active against Gram-negative bacteria implicated in HABP/VABP, both in vitro and in clinical infections2

In a clinical trial, cefiderocol demonstrated noninferiority vs high-dose, extended-infusion meropenem in patients with HABP or VABP3

NTAP reimbursement is anticipated for FY 2021 (October 1, 2020)

Fetroja is available through all usual distribution channels and supported with a targeted commercialization program

Proposed HABP/VABP indication2: • In patients ≥18 years of age, treatment of hospital-acquired bacterial pneumonia • To reduce the development of drug-resistant bacteria and maintain the and ventilator-associated bacterial pneumonia caused by the following susceptible effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only Gram-negative microorganisms: Acinetobacter baumannii complex, Burkholderia to treat or prevent infections that are proven or strongly suspected to be caused by cepacia complex, Citrobacter koseri, Escherichia coli, Enterobacter cloacae complex, susceptible bacteria. When culture and susceptibility information are available, they Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, should be considered in selecting or modifying antibacterial therapy. In the absence Pseudomonas aeruginosa, Serratia marcescens, and Stenotrophomonas maltophilia of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy cUTI=complicated urinary tract infection; FY=fiscal year; HABP=hospital-acquired bacterial pneumonia; NTAP=new technology add-on payment; VABP=ventilator-associated bacterial pneumonia. References: 1. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2019. 2. Data on file. Shionogi Inc. 3. US Food and Drug Administration. Presented at: Antimicrobial Drugs Advisory Committee Meeting; October 16, 2019; Silver Spring, MD. Accessed May 15, 2020. https://www.fda.gov/advisory-committees/advisory-committee-calendar/october-16-2019-antimicrobial-drugs-advisory-committee-meeting-announcement-10162019-10162019#event-materials Please see Important Safety Information on slides 2-4 and Full Prescribing Information for Fetroja.

® 24 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Discussion

How does the proposed HABP/VABP indication impact your review of Fetroja® (cefiderocol)?

How large a concern are carbapenem-resistant Gram-negative HABP/VABP infections in your network?

What is your typical approach to adopting antibiotic treatments for HABP/VABP upon FDA approval?

What types of access controls or protocols do you use to manage antibiotic usage for HABP/VABP?

What will be your formulary review process for use of Fetroja for HABP/VABP?

How does the Fetroja cUTI indication impact your review of the investigational indication for HABP/VABP?

How does COVID-19 impact your review of Fetroja?

What additional information would be helpful to facilitate your internal review process?

cUTI=complicated urinary tract infection; HABP=hospital-acquired bacterial pneumonia; VABP=ventilator-associated bacterial pneumonia. Please see Important Safety Information on slides 2-4 and Full Prescribing Information for Fetroja.

® 25 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Appendix: List of Select Publications

• Cai B, Echols R, Magee G, et al. Prevalence of carbapenem-resistant Gram-negative infections in the United States predominated by Acinetobacter baumannii and Pseudomonas aeruginosa. Open Forum Infect Dis. 2017;4 (3):ofx176. doi:10.1093/ofid /ofx176

• Chen IH, Kidd JM, Abdekraouf K, Nicolau DP. Comparative in vivo antibacterial activity of human-simulated exposures of cefiderocol and ceftazidime against Stenotrophomonas maltophilia in the murine thigh model. Preprint. Posted online October 7, 2019. Antimicrob Agents Chemother. doi:10.1128/AAC.01558-19

• Choi JJ, McCarthy MW. Cefiderocol: a novel siderophore cephalosporin. Expert Opin Investig Drugs. 2018;27(2):193-197.

• Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. In vitro activity of the siderophore cephalosporin, cefiderocol, against carbapenem-nonsusceptible and multidrug-resistant isolates of Gram-negative bacilli collected worldwide in 2014 to 2016. Antimicrob Agents Chemother. 2018;62(2):e01968-17. doi:10.1128/AAC.01968-17

• Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseuodmonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Preprint. Posted online February 7, 2020. Microb Drug Resist. doi:10.1089/mdr.2019.0298

• Karlowsky JA, Hackel MA, Tsuji M, Yamano Y, Echols R, Sahm DF. In vitro activity of cefiderocol, a siderophore cephalosporin, against Gram-negative bacilli isolated by clinical laboratories in North America and Europe in 2015-2016: SIDERO-WT-2015. Int J Antimicrob Agents. 2019;53(4):456-466.

• Katsube T, Miyazaki S, Narukawa Y, Hernandez-Illas M, Wajima T. Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters. Eur J Clin Pharmacol. 2018;74(7):931-938.

• Katsube T, Saisho Y, Shimada J, Furuie H. Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects. J Antimicrob Chemother. 2019;74(7):1971-1974.

• Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, Echols R. Pharmacokinetic/pharmacodynamic modeling and simulation of cefiderocol, a parenteral siderophore cephalosporin, for dose adjustment based on renal function. Antimicrob Agents Chemother. 2017;61(1):e01381-16.

• Kazmierczak KM, Tsuji M, Wise MG, et al. In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-nonsusceptible Gram-negative bacilli, including serine carbapenemase- and metallo-lactamase-producing isolates (SIDERO-WT-2014 Study). Int J Antimicrob Agents. 2019;53:177-184.

® 26 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY. Appendix: List of Select Publications (cont’d)

• Portsmouth S, van Veenuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18 (12):1319-1328.

• Saisho Y, Katsube T, White S, Fukase H, Shimada J. Pharmacokinetics, safety, and tolerability of cefiderocol, a novel siderophore cephalosporin for Gram-negative bacteria, in healthy subjects. Antimicrob Agents Chemother. 2018;62(3)e02163-17. doi:10.1128/AAC.02163-17

• Sanabria C, Migoya E, Mason JW, et al. Effect of cefiderocol, a siderophore cephalosporin, on QT/QTc interval in healthy adult subjects. Preprint. Posted online August 1, 2019. Clin Ther. doi:10.1016/j.clinthera.2019.07.006

• Tillotson GS. Trojan horse –a novel way to circumvent Gram-negative bacterial resistance? Infect Dis (Auckl). 2016;9:45-52.

• Wunderink RG, Matsunaga Y, Ariyasu M, et al. Efficacy and safety of cefiderocol versus high-dose meropenem in patients with nosocomial pneumonia – results of a phase 3 randomized, multicenter, double-blind, non-inferiority study. Presented at: ID Week 2019; October 2-6, 2019; Washington, DC. Accessed May 20, 2020. https://www.eventscribe.com/2019/IDWeek/fsPopup.asp?Mode=presInfo&PresentationID=633899

• Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs. 2019;79(3):271-289.

® 27 Fetroja (cefiderocol) is not approved by the FDA for treatment of HABP/VABP, and the safety or effectiveness of the product for this use has not been established. CONFIDENTIAL: FOR PAYOR COMMUNICATIONS ONLY.