FETROJA- cefiderocol sulfate tosylate_injection, powder, for solution

FETROJA is an antibacterial drug [see Microbiology (12. 4) The percent time of dosing interval that unbound plasma concentrations of cefiderocol exceed the minimum inhibitory concentration (MIC) against the infecting organism best correlates with antibacterial activity in neutropenic murine thigh and lung infection models with E. pneumoniae P. aeruginosa A. baumannii S. maltophilia in vivo Cardiac Electrophysiology At doses 1 and 2 times the maximum recommended dosage, FETROJA does not prolong the QT interval to any clinically relevant extent. Cefiderocol exposures (C max max Table 6 Cefiderocol Exposures Mean (+/-SD) in Patients and Healthy Volunteers with CLcr 60 mL/min or Greater PK Parameters cUTI Patients After multiple (every 8 hours) FETROJA 2-gram doses infused over 3 hours or adjusted based on renal function. HABP/VABP Patients Healthy Volunteers After a single FETROJA 2-gram dose was infused over 3 hours. C max AUC 0-24 hr C max 115 (+/-57) 111 (+/-56) 91. 9) AUC 0-24 hr 1944 (+/-1097) 1773 (+/-990) 1175 (+/-203) Distribution The geometric mean (+/-SD) cefiderocol volume of distribution was 18. Plasma protein binding, primarily to albumin, of cefiderocol is 40% to 60%. Following a FETROJA 2-gram dose (or renal function equivalent dose) at steady state in patients with pneumonia requiring mechanical ventilation with a 3-hour infusion, the cefiderocol concentrations in epithelial lining fluid ranged from 3. 7 mg/L and 7. 9 mg/L at the end of infusion and at 2 hours after the end of infusion, respectively. Elimination Cefiderocol terminal elimination half-life is 2 to 3 hours. The geometric mean (+/-SD) cefiderocol clearance is estimated to be 5. Metabolism Cefiderocol is minimally metabolized [less than 10% of a single radiolabeled cefiderocol dose of 1 gram (0. 5 times the approved recommended dosage) infused over 1 hour]. Excretion Cefiderocol is primarily excreted by the kidneys. After a single radiolabeled cefiderocol 1-gram (0. 5 times the approved recommended dosage) dose infused over 1 hour, 98. 6% of the total radioactivity was excreted in urine (90. 6% unchanged) and 2. 8% in feces. Specific Populations No clinically significant differences in the pharmacokinetics of cefiderocol were observed based on age (18 to 93 years of age), sex, or race. The effect of hepatic impairment on the pharmacokinetics of cefiderocol was not evaluated. Patients with Renal Impairment Approximately 60% of cefiderocol was removed by a 3- to 4-hour hemodialysis session. Cefiderocol AUC fold changes in subjects with renal impairment compared to subjects with CLcr 90 to 119 mL/min are summarized in Table 7. Table 7 Effect of Renal Impairment on the AUC of Cefiderocol After a single FETROJA 1-gram dose (0. 5 times the approved recommended dosage). CLcr (mL/min) Cefiderocol AUC Compared to AUC in subjects with CLcr 90 to 119 mL/min (N = 12). CI = confidence interval. 60 to 89 (N = 6) 1. 62) 30 to 59 (N = 7) 2. 77) 15 to 29 (N = 4) 3. 91) < 15 (N = 6) 4. 56) Patients Receiving CRRT In an in vitro [see Dosage and Administration (2. 2) Patients with CLcr 120 mL/min or Greater Increased cefiderocol clearance has been observed in patients with CLcr 120 mL/min or greater. A FETROJA 2-gram dose every 6 hours infused over 3 hours provided cefiderocol exposures comparable to those in patients with CLcr 90 to 119 mL/min [see Dosage and Administration (2. 2) Drug Interaction Studies Clinical Studies No clinically significant differences in the pharmacokinetics of furosemide (an organic anion transporter [OAT]1 and OAT3 substrate), metformin (an organic cation transporter [OCT]1, OCT2, and multidrug and toxin extrusion [MATE]2-K substrate), and rosuvastatin (an organic anion transporting polypeptide [OATP]1B3 substrate) were observed when coadministered with cefiderocol. In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically Cytochrome P450 (CYP) Enzymes Transporter Systems Mechanism of Action FETROJA is a cephalosporin antibacterial with activity against Gram-negative aerobic bacteria. Cefiderocol functions as a siderophore and binds to extracellular free (ferric) iron. In addition to passive diffusion via porin channels, cefiderocol is actively transported across the outer cell membrane of bacteria into the periplasmic space using the bacterial siderophore iron uptake mechanism. Cefiderocol exerts bactericidal action by inhibiting cell wall biosynthesis through binding to penicillin-binding proteins (PBPs). Cefiderocol has no clinically relevant in vitro Resistance In vitro, Cefiderocol does not cause induction of AmpC beta-lactamase in P. aeruginosa E. cloacae -6 -8 Cross-resistance with other classes of antibacterial drugs has not been identified; therefore, isolates resistant to other antibacterial drugs may be susceptible to cefiderocol. Cefiderocol has shown in vitro S. maltophilia P. coli mcr-1 Cefiderocol demonstrated in vitro in vitro P. baumannii in vitro S. maltophilia Cefiderocol maintained in vitro K. aeruginosa In vitro, Interaction with Other Antimicrobials In vitro P. baumannii Activity against Bacteria in Animal Infection Models In a neutropenic murine thigh infection model using a humanized dose (2 grams every 8 hours), cefiderocol demonstrated 1log 10 E. pneumoniae A. maltophilia, P. aeruginosa In an immunocompetent rat pneumonia model, reduction in bacterial counts in the lungs of animals infected with K. baumannii , P. aeruginosa In an immunocompetent murine urinary tract infection model, cefiderocol reduced bacterial counts in the kidneys of mice infected with E. maltophilia Burkholderia cepacia S. marcescens P. aeruginosa The clinical significance of the above findings in animal infection models is not known. Antimicrobial Activity FETROJA has been shown to be active against the following bacteria, both in vitro [see Indications and Usage (1) Complicated Urinary Tract Infections, Including Pyelonephritis Gram-negative Bacteria Escherichia coli Enterobacter cloacae Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) Gram-negative Bacteria Acinetobacter baumannii Escherichia coli Enterobacter cloacae Klebsiella pneumoniae Pseudomonas aeruginosa Serratia marcescens The following in vitro in vitro Gram-negative Bacteria Achromobacter spp. Burkholderia cepacia Citrobacter freundii Citrobacter koseri Klebsiella aerogenes Klebsiella oxytoca Morganella morganii Proteus vulgaris Providencia rettgeri Stenotrophomonas maltophilia Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see https://www.

FETROJA is a cephalosporin antibacterial indicated in patients 18 years of age or older for the treatment of the following infections caused by susceptible Gram-negative microorganisms: Complicated Urinary Tract Infections (cUTI), including Pyelonephritis ( 1. 1 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) ( 1. 2 To reduce the development of drug-resistant bacteria 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 bacteria. 3 FETROJA registered Escherichia coli Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Enterobacter cloacae [see Clinical Studies (14. 1) FETROJA is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii Escherichia coli Enterobacter cloacae Klebsiella pneumoniae Pseudomonas aeruginosa Serratia marcescens [see Clinical Studies (14. 2) To reduce the development of drug-resistant bacteria 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.

Administer 2 grams of FETROJA for injection every 8 hours by intravenous (IV) infusion over 3 hours in patients with creatinine clearance (CLcr) 60 to 119 mL/min. 1 Dose adjustments are required for patients with CLcr less than 60 mL/min, (including patients receiving intermittent hemodialysis (HD) or continuous renal replacement therapy (CRRT)), and for patients with CLcr 120 mL/min or greater. 2 See full prescribing information for instructions on preparation of FETROJA doses. 3 See full prescribing information for drug compatibilities. 4 The recommended dosage of FETROJA is 2 grams administered every 8 hours by intravenous (IV) infusion over 3 hours in adults with a creatinine clearance (CLcr) of 60 to 119 mL/min. Dosage adjustment of FETROJA is recommended for patients with CLcr less than 60 mL/min, including patients receiving intermittent hemodialysis (HD) or continuous renal replacement therapy (CRRT), and for patients with CLcr 120 mL/min or greater [see Dosage and Administration (2. 2) Dosage Adjustments in Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dosage adjustment of FETROJA is recommended in patients with CLcr less than 60 mL/min (Table 1). For patients undergoing intermittent HD, start the dosing of FETROJA immediately after the completion of HD. For patients with fluctuating renal function, monitor CLcr and adjust dosage accordingly. Table 1 Recommended Dosage of FETROJA for Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Estimated Creatinine Clearance (CLcr) CLcr = creatinine clearance estimated by Cockcroft-Gault equation. Dose Frequency Infusion Time HD = hemodialysis. CLcr 30 to 59 mL/min 1. 5 grams Every 8 hours 3 hours CLcr 15 to 29 mL/min 1 gram Every 8 hours 3 hours CLcr less than 15 mL/min, with or without intermittent HD Cefiderocol is removed by HD; administer FETROJA immediately after HD for patients receiving intermittent HD. 75 grams Every 12 hours 3 hours Dosage Adjustments in Patients Receiving CRRT For patients receiving CRRT, including continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF), the dosage of FETROJA should be based on the effluent flow rate in CRRT (see Table 2 [see Use in Specific Populations (8. 6) Table 2 Recommended Dosage of FETROJA for Patients Receiving CRRT Effluent Flow Rate Ultrafiltrate flow rate for CVVH, dialysis flow rate for CVVHD, ultrafiltrate flow rate plus dialysis flow rate for CVVHDF. Recommended Dosage of FETROJA CRRT = continuous renal replacement therapy. 2 L/hr or less 1. 5 grams every 12 hours 2. 1 to 3 L/hr 2 grams every 12 hours 3. 1 to 4 L/hr 1. 5 grams every 8 hours 4. 1 L/hr or greater 2 grams every 8 hours Dosage Adjustments in Patients with CLcr 120 mL/min or Greater For patients with CLcr greater than or equal to 120 mL/min, FETROJA 2 grams administered every 6 hours by IV infusion over 3 hours is recommended [see Use in Specific Populations (8. 6) FETROJA is supplied as a sterile, lyophilized powder that must be reconstituted and subsequently diluted using aseptic technique prior to intravenous infusion. Preparation of Doses Reconstitute the powder for injection in the FETROJA vial with 10 mL of either 0. 9% sodium chloride injection, USP or 5% dextrose injection, USP and gently shake to dissolve. Allow the vial(s) to stand until the foaming generated on the surface has disappeared (typically within 2 minutes). The reconstituted solution will have a final volume of approximately 11. 2 mL and concentration of 0. 089 gram/mL. The reconstituted solution is for intravenous infusion only after dilution in an appropriate infusion solution. To prepare the required doses, withdraw the appropriate volume of reconstituted solution from the vial according to Table 3 below. Add the withdrawn volume to a 100 mL infusion bag containing 0. 9% sodium chloride injection, USP or 5% dextrose injection, USP [see Dosage and Administration (2. 4) Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. FETROJA infusions are clear, colorless solutions. Discard any unused FETROJA solution in the vial (see Table 3 Table 3 Preparation of FETROJA Doses FETROJA Dose Number of 1-gram FETROJA Vials to be Reconstituted Volume to Withdraw from Reconstituted Vial(s) Total Volume of FETROJA Reconstituted Solution for Further Dilution into a 100 mL Infusion Bag 2 grams 2 vials 11. 2 mL (entire contents) of each vial 22. 5 grams 2 vials 11. 2 mL (entire contents) of first vial AND 5. 6 mL from second vial 16. 8 mL 1 gram 1 vial 11. 2 mL (entire contents) 11. 75 gram 1 vial 8. 4 mL FETROJA solution for administration is compatible with: 0. 9% sodium chloride injection, USP 5% dextrose injection, USP The compatibility of FETROJA solution for administration with solutions containing other drugs or other diluents has not been established. Reconstituted FETROJA Upon reconstitution with the appropriate diluent, the reconstituted FETROJA solution in the vial should be immediately transferred and diluted into the infusion bag. Reconstituted FETROJA can be stored for up to 1 hour at room temperature in the vial. Discard any unused reconstituted solution. Diluted FETROJA Infusion Solution The diluted FETROJA infusion solution in the infusion bag is stable for up to 6 hours at room temperature. The diluted FETROJA infusion solution in the infusion bag may also be refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours, protected from light; and then the infusion should be completed within 6 hours at room temperature.

The following serious adverse reactions are described in greater detail in the Warnings and Precautions section: Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections [see Warnings and Precautions (5. 1) Hypersensitivity Reactions [see Warnings and Precautions (5. 2) Clostridioides difficile [see Warnings and Precautions (5. 3) Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions (5. 1 HABP/VABP: 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Shionogi Inc. at 1-800-849-9707 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA was evaluated in an active-controlled, randomized clinical trial in patients with cUTI, including pyelonephritis (Trial 1). In this trial, 300 patients received FETROJA 2 grams every 8 hours infused over 1 hour (or a renally-adjusted dose), and 148 patients were treated with imipenem/cilastatin 1gram/1gram every 8 hours infused over 1 hour (or a renally-adjusted dose). The median age of treated patients across treatment arms was 65 years (range 18 to 93 years), with approximately 53% of patients aged greater than or equal to 65. Approximately 96% of patients were White, most were from Europe, and 55% were female. Patients across treatment arms received treatment for a median duration of 9 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 1, a total of 14/300 (4. 7%) cUTI patients treated with FETROJA and 12/148 (8. 1%) of cUTI patients treated with imipenem/cilastatin experienced serious adverse reactions. One death (0. 3%) occurred in 300 patients treated with FETROJA as compared to none treated with imipenem/cilastatin. Discontinuation of treatment due to any adverse reaction occurred in 5/300 (1. 7%) of patients treated with FETROJA and 3/148 (2. 0%) of patients treated with imipenem/cilastatin. Specific adverse reactions leading to treatment discontinuation in patients who received FETROJA included diarrhea (0. 3%), drug hypersensitivity (0. 3%), and increased hepatic enzymes (0. Common Adverse Reactions Table 4 lists the most common selected adverse reactions occurring in >= 2% of cUTI patients receiving FETROJA in Trial 1. Table 4 Selected Adverse Reactions Occurring in >= 2% of cUTI Patients Receiving FETROJA in Trial 1 Adverse Reaction FETROJA 2 grams IV over 1 hour every 8 hours (with dosing adjustment based on renal function). Imipenem/Cilastatin 1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight). cUTI = complicated urinary tract infection. Diarrhea 4% 6% Infusion site reactions Infusion site reactions include infusion site erythema, inflammation, pain, pruritis, injection site pain, and phlebitis. 4% 5% Constipation 3% 4% Rash Rash includes rash macular, rash maculopapular, erythema, skin irritation. 3% < 1% Candidiasis Candidiasis includes oral or vulvovaginal candidiasis, candiduria. 2% 3% Cough 2% < 1% Elevations in liver tests Elevations in liver tests include alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, blood alkaline phosphatase, hepatic enzyme increased. 2% < 1% Headache 2% 5% Hypokalemia Hypokalemia includes blood potassium decreased. 2% 3% Nausea 2% 4% Vomiting 2% 1% Other Adverse Reactions of FETROJA in the cUTI Patients (Trial 1) The following selected adverse reactions were reported in FETROJA-treated cUTI patients at a rate of less than 2% in Trial 1: Blood and lymphatic disorders Cardiac disorders Gastrointestinal disorders General system disorders Hepatobiliary disorders Immune system disorders Infections and infestations C. difficile Laboratory investigations Metabolism and nutrition disorders Nervous system disorders Respiratory, thoracic, and mediastinal disorders Skin and subcutaneous tissue disorders Psychiatric disorders Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA was evaluated in an active-controlled clinical trial in patients with HABP/VABP (Trial 2). In this trial, 148 patients received FETROJA 2 grams every 8 hours infused over 3 hours, and 150 patients received meropenem 2 grams every 8 hours infused over 3 hours. Doses of study treatments were adjusted based on renal function. The median age was 67 years, approximately 59% of patients were 65 years of age and older, 69% were male, and 68% were White. Overall, approximately 60% were ventilated at randomization, including 41% with VABP and 14% with ventilated HABP. The mean Acute Physiology And Chronic Health Evaluation (APACHE II) score was 16. All patients received empiric treatment for Gram-positive organisms with linezolid for at least 5 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 2, serious adverse reactions occurred in 54/148 (36. 5%) HABP/VABP patients treated with FETROJA and 45/150 (30%) of HABP/VABP patients treated with meropenem. Adverse reactions leading to death were reported in 39/148 (26. 4%) patients treated with FETROJA and 35/150 (23. 3%) patients treated with meropenem. Adverse reactions leading to discontinuation of treatment occurred in 12/148 (8. 1%) of patients treated with FETROJA and 14/150 (9. 3%) of patients treated with meropenem. The most common adverse reactions leading to discontinuation in both treatment groups were elevated liver tests. Common Adverse Reactions Table 5 lists the most common selected adverse reactions occurring in >= 4% of patients receiving FETROJA in the HABP/VABP trial. Table 5 Selected Adverse Reactions Occurring in >= 4% of HABP/VABP Patients Receiving FETROJA in Trial 2 Adverse Reaction FETROJA 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). Meropenem 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). HABP/VABP = hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. Elevations in liver tests Elevations in liver tests include the following terms: aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyl transferase increased, liver function test increased, liver function test abnormal, hepatic enzyme increased, transaminases increased, hypertransaminesemia. 16% 16% Hypokalemia Hypokalemia includes blood potassium decreased. 11% 15% Diarrhea 9% 9% Hypomagnesemia 5% < 1% Atrial fibrillation 5% 3% Other Adverse Reactions of FETROJA in HABP/VABP Patients in Trial 2 The following selected adverse reactions were reported in FETROJA-treated HABP/VABP patients at a rate of less than 4% in Trial 2: Blood and lymphatic disorders Cardiac disorders Gastrointestinal disorders Hepatobiliary disorders Infections and infestations C. difficile Laboratory investigations Metabolism and nutrition disorders Nervous system disorders Renal and genitourinary disorders Respiratory, thoracic, and mediastinal disorders Skin and subcutaneous tissue disorders The following adverse reactions have been identified during postapproval use of FETROJA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders Renal and urinary disorders.

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 [see Warnings and Precautions (5. 2) Adverse Reactions (6. 1) FETROJA is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol and other beta-lactam antibacterial drugs or other components of FETROJA.

Risk Summary There are no available data on FETROJA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 0. 9 times (rats) or 1. 3 times (mice) higher than the average observed in patients receiving the maximum recommended daily dose. 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. 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. Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice). No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 0. 9 times (rats) and 1. 3 times (mice) the daily mean plasma exposure in patients that received 2 grams of cefiderocol infused intravenously every 8 hours. In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from Day 6 of pregnancy until weaning. No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed. In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (< 0. 5%) of the dose. Risk Summary It is not known whether cefiderocol is excreted into human milk; however, cefiderocol-derived radioactivity was detected in the milk of lactating rats that received the drug intravenously. When a drug is present in animal milk, it is likely that the drug will be present in human milk. No information is available on the effects of FETROJA on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FETROJA and any potential adverse effects on the breastfed child from FETROJA or from the underlying maternal condition. Data Cefiderocol-derived radioactivity was detected in milk following intravenous administration to lactating rats. The peak level in rat milk was approximately 6% of the peak plasma level. Safety and effectiveness of FETROJA in pediatric patients younger than 18 years of age have not been established. cUTI Of the 300 patients treated with FETROJA in the cUTI trial, 158 (52. 7%) were 65 years of age and older, and 67 (22. 3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these patients and younger patients. HABP/VABP Of the 148 patients treated with FETROJA in the HABP/VABP trial, 83 (56. 1%) were 65 years of age and older, and 40 (27%) were 75 years of age and older. The incidence of adverse reactions in patients treated with FETROJA was similar in patients under 65 years of age as compared to older patients (65 years of age and older and 75 years of age and older). The incidence of adverse reactions in older patients (65 years of age and older and 75 years of age and older) was also similar between treatment groups. Clinical cure rates at the Test-of-Cure visit (TOC) in FETROJA-treated adult patients younger than 65 years of age, 65 years of age to younger than 75 years of age, and 75 years of age and older were 60%, 77. 5%, and 60%, respectively. In comparison, the clinical cure rates at the TOC visit in the meropenem-treated patients for each of these subgroups were 65. 5%, respectively. The observed all-cause mortality rates at Day 14 in the FETROJA-treated patients for each of these subgroups were 12. In comparison, in the meropenem-treated patients for each of these subgroups, they were 10. 1%, respectively. cUTI and HABP/VABP FETROJA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2. 2) Use in Specific Populations (8. 6) Clinical Pharmacology (12. 3) Patients with CLcr 60 to 89 mL/min No dosage adjustment of FETROJA is recommended in patients with CLcr 60 to 89 mL/min. Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dose adjustment is required in patients with CLcr less than 60 mL/min, and in patients who are receiving HD. In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing [see Dosage and Administration (2. 2) Clinical Pharmacology (12. 3) Patients Receiving CRRT A total of 16 patients treated with FETROJA received CRRT in clinical trials. Dosage adjustment of FETROJA is required in patients receiving CRRT including CVVH, CVVHD, and CVVHDF. Dosage of FETROJA should be based on the effluent flow rate in patients receiving CRRT [see Dosage and Administration (2. 3) Patients with CLcr 120 mL/min or Greater CLcr 120 mL/min or greater may be seen in seriously ill patients, who are receiving intravenous fluid resuscitation. Dosage adjustment of FETROJA is required in patients with CLcr 120 mL/min or greater [see Dosage and Administration (2. 3) The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol. Dosage adjustments are not necessary in patients with impaired hepatic function.

Use alternate testing methods to confirm positive results of dipstick tests (urine protein, ketones, or occult blood). 1 Cefiderocol may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests.

OVERDOSAGE
There is no information on clinical signs and symptoms associated with an overdose of FETROJA. Patients who receive doses greater than the recommended dose regimen and have unexpected adverse reactions possibly associated with FETROJA should be carefully observed and given supportive treatment, and discontinuation or interruption of treatment should be considered. Approximately 60% of cefiderocol is removed by a 3- to 4-hour hemodialysis session [see Clinical Pharmacology (12.3)
NONCLINICAL TOXICOLOGY
Carcinogenesis Carcinogenicity studies in animals have not been conducted with cefiderocol. Mutagenesis Cefiderocol was negative for genotoxicity in a reverse mutation test with S. typhimurium E. coli in vivo Impairment of Fertility Cefiderocol did not affect fertility in adult male or female rats when administered intravenously at doses up to 1000 mg/kg/day. The AUC at this dose is approximately 0. 9 times the mean daily cefiderocol exposure in patients who received the maximum recommended clinical dose of 2 grams every 8 hours.
CLINICAL STUDIES
A total of 448 adults hospitalized with cUTI (including pyelonephritis) were randomized in a 2:1 ratio and received study medications in a multinational, double-blind trial (Trial 1) (NCT02321800) comparing FETROJA 2 grams intravenously (IV) every 8 hours (infused over 1 hour) to imipenem/cilastatin 1gram/1gram IV every 8 hours (infused over 1 hour) for 7 to 14 days. No switch from IV to oral antibacterial therapy was permitted. Efficacy was assessed as a composite of microbiological eradication and clinical cure at the Test-of-Cure visit (TOC) in the microbiological intent-to-treat (Micro-ITT) population, which included all patients who received at least a single dose of study medication and had at least one baseline Gram-negative uropathogen. Other efficacy endpoints included the microbiological eradication rate and the clinical response rate at TOC in the Micro-ITT population. The Micro-ITT population consisted of 371 patients of whom 25% had cUTI with pyelonephritis, 48% had cUTI without pyelonephritis, and 27% had acute uncomplicated pyelonephritis. Complicating conditions included obstructive uropathy, catheterization, and renal stones. The median age was 66 years, with 24% of patients over the age of 75 years, and 55% of the population were female. The median duration of therapy in both treatment groups was 9 days (range 1-14 days). Of the 371 patients, 32% had CLcr > 50-80 mL/min, 17% had CLcr 30-50 mL/min, and 3% had CLcr < 30 mL/min at baseline. Concomitant Gram-negative bacteremia was identified in 7% of patients. In the Micro-ITT population, the most common baseline pathogens were E. pneumoniae Table 8 provides the results of a composite of microbiological eradication (all Gram-negative uropathogens found at baseline at >= 10 5 4 Table 8 Composite, Microbiological, and Clinical Response Rates at the TOC Visit in cUTI Patients (Micro-ITT Population) in Trial 1 Study Endpoint FETROJA Imipenem/Cilastatin Treatment Difference The treatment difference and 95% CI were based on the Cochran-Mantel-Haenszel method. CI = confidence interval; Micro-ITT = microbiological intent-to-treat; TOC = Test of Cure. Composite response at TOC 183/252 (72. 6%) 65/119 (54. 9) Microbiologic response TOC 184/252 (73. 0%) 67/119 (56. 6) Clinical response TOC 226/252 (89. 7%) 104/119 (87. 4) Table 9 Composite Endpoint of Microbiological Eradication and Clinical Response at the TOC Visit in cUTI Patients (Micro-ITT Population) by Baseline Pathogen Patients may have had more than one pathogen in the baseline urine culture. Baseline Pathogen Subgroup FETROJA Imipenem/Cilastatin Escherichia coli 113/152 (74. 3) 45/79 (57. 0) Klebsiella pneumoniae 36/48 (75. 0) 12/25 (48. 0) Proteus mirabilis 13/17 (76. 0) Pseudomonas aeruginosa 8/18 (44. 0) Enterobacter cloacae 8/13 (61. 5) 3/3 (100. 0) In the FETROJA treatment group, 61 (24. 2%) bacterial isolates were ESBL producers compared with 32 (26. 9%) in the imipenem/cilastatin group. The composite response rate of patients with these ESBL isolates at the TOC visit was consistent with the overall results. A total of 298 hospitalized adults with HABP/VABP received study medications in a multicenter, randomized, double-blind trial (Trial 2) (NCT03032380) comparing FETROJA 2 grams administered intravenously every 8 hours as a 3-hour infusion to meropenem (2 grams every 8 hours infused over 3 hours). Dosing was adjusted for renal function. Patients in both treatment arms received linezolid 600 mg every 12 hours for at least 5 days for empiric treatment of Gram-positive organisms. The trial protocol permitted administration of potentially active prior antibacterial therapy for no more than 24 hours within 72 hours prior to randomization and disallowed systemic concomitant antibacterial therapy until the Test-of-Cure visit (TOC, 7 days after end of treatment). The analysis population was the modified intent-to-treat (mITT) population, which included all randomized patients who received study medication and had evidence of bacterial pneumonia, except those with only anaerobic or Gram-positive aerobic infections. Of the 292 patients in the mITT population, the median age was 67 years, and 58% of the population was 65 years of age and older, with 29% of the population 75 years of age and older. The majority of patients were male (68%), White (69%), and were from Europe (67%). Approximately 4% (11/292) were from the United States. The median baseline APACHE II score was 15, and 29% of patients had a baseline APACHE II score of greater than or equal to 20. At randomization, 68% of patients were in the ICU, and 60% were mechanically ventilated. 60% of patients had CLcr less than or equal to 80 mL/min at baseline; among these, 34% had CLcr less than or equal to 50 mL/min, and 14% had a CLcr less than 30 mL/min. Augmented renal clearance (CLcr greater than 120 mL/min) was present in 16% of patients. Gram-negative bacteremia was present at baseline in 6% of patients. In both treatment groups, most patients (70%) received between 7 and 14 days of study medication and 18% between 15 and 21 days. Table 10 shows the Day 14 and Day 28 all-cause mortality rates, as well as clinical cure at the TOC visit. FETROJA was noninferior to meropenem with regard to the primary efficacy endpoint (Day 14 all-cause mortality in the mITT population). Clinical cure was defined as resolution or substantial improvement in signs and symptoms associated with pneumonia, such that no additional antibacterial therapy was required for the treatment of the current infection through the TOC visit. Table 10 All-cause Mortality and Clinical Cure at the TOC Visit in HABP/VABP Patients (mITT Population) in Trial 2 Endpoint FETROJA Meropenem Treatment Difference The adjusted treatment difference (FETROJA minus meropenem) and associated 95% CI were based on the Cochran-Mantel-Haenszel stratum-weighted method. Subjects with unknown survival status were considered deaths. For Day 14 All-cause Mortality, 1 meropenem subject had unknown status; for Day 28 All-cause Mortality, 1 meropenem subject and 2 FETROJA subjects had unknown status. CI = confidence interval; TOC = Test of Cure. Day 14 All-cause Mortality 18/145 (12. 4) 18/147 (12. 7) Day 28 All-cause Mortality 32/145 (22. 1) 31/147 (21. 4) Clinical Cure at TOC 94/145 (64. 8) 98/147 (66. 5) The Day 14 and Day 28 all-cause mortality rates by pathogen in patients in the mITT population who had a baseline LRT pathogen that was susceptible to meropenem are shown in Table 11; the clinical outcome at the TOC visit is shown in Table 12. There were 51 patients with A. baumannii A. baumannii Table 11 All-cause Mortality by Baseline Pathogens Susceptible to Meropenem Susceptible defined as MIC of <= 8 mcg/mL to meropenem. Baseline Pathogen Day 14 All-cause Mortality Day 28 All-cause Mortality FETROJA Meropenem FETROJA Meropenem Each cell excludes subjects in whom baseline pathogen had meropenem MIC > 8 mcg/mL or where MIC was unknown. Klebsiella pneumoniae 4/38 (10. 5) 4/36 (11. 1) 8/38 (21. 1) 9/36 (25. 0) Pseudomonas aeruginosa 2/20 (10. 0) 4/17 (23. 5) 2/20 (10. 0) 5/17 (29. 4) Acinetobacter baumannii Includes A. baumannii, A. nosocomialis, and A. 0) Escherichia coli 3/18 (16. 7) 3/21 (14. 3) 5/18 (27. 8) 4/21 (19. 0) Other Enterobacterales Includes Enterobacter cloacae complex ( E. asburiae, and E. kobei) and Serratia marcescens. 5) 2/14 (14. 3) 4/16 (25. 0) 3/14 (21. 4) Table 12 Clinical Cure Rates by Baseline Pathogen Susceptible to Meropenem Susceptible defined as MIC of <= 8 mcg/mL to meropenem. Baseline Pathogen Clinical Cure FETROJA Meropenem Each cell excludes subjects whose pathogen-specific meropenem MIC was > 8 mcg/mL or where MIC was unknown. Klebsiella pneumoniae 24/38 (63. 2) 23/36 (63. 9) Pseudomonas aeruginosa 13/20 (65. 0) 13/17 (76. 5) Acinetobacter baumannii Includes A. 8) Escherichia coli 12/18 (66. 7) 13/21 (61. 9) Other Enterobacterales Includes Enterobacter cloacae complex ( E. 5) 8/14 (57. 1) In the FETROJA 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 of patients with these ESBL-producing bacterial isolates was consistent with the overall results.

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FETROJA- cefiderocol sulfate tosylate_injection, powder, for solution Product manual source documgent