Cefiderocol Sulfate Tosylate

1 INDICATIONS AND USAGE 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. ( 1.3 ) 1.1 Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA ® is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Pseudomonas aeruginosa , and Enterobacter cloacae complex [see Clinical Studies (14.1) ] . 1.2 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) 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 complex, Escherichia coli , Enterobacter cloacae complex, Klebsiella pneumoniae , Pseudomonas aeruginosa , and Serratia marcescens [see Clinical Studies (14.2) ]. 1.3 Usage 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.

2 DOSAGE AND ADMINISTRATION 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. ( 2.1 ) 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. ( 2.2 ) See full prescribing information for instructions on preparation of FETROJA doses. ( 2.3 ) See full prescribing information for drug compatibilities. ( 2.4 ) 2.1 Recommended Dosage 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) ]. The recommended duration of treatment with FETROJA is 7 to 14 days. The duration of therapy should be guided by the patient's clinical status. 2.2 Dosage Adjustments in Patients with CLcr Less Than 60 mL/min (Including Patients Undergoing Intermittent HD or CRRT), and CLcr 120 mL/min or Greater 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. 0.75 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 ). These recommendations are intended to provide initial dosing in patients receiving CRRT. Dosing regimens may need to be tailored based on residual renal function and patient's clinical status [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) ] . 2.3 Preparation of FETROJA Solution for Administration 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 22.4 mL 1.5 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) 11.2 mL 0.75 gram 1 vial 8.4 mL 8.4 mL 2.4 Drug Compatibility 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. 2.5 Storage of Reconstituted Solutions 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.

6 ADVERSE REACTIONS 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 -associated Diarrhea (CDAD) [see Warnings and Precautions (5.3) ] Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions (5.4) ] cUTI: The most frequently occurring adverse reactions in greater than or equal to 2% of cUTI patients treated with FETROJA were diarrhea, infusion site reactions, constipation, rash, candidiasis, cough, elevations in liver tests, headache, hypokalemia, nausea, and vomiting. ( 6.1 ) HABP/VABP: The most frequently occurring adverse reactions in greater than or equal to 4% of HABP/VABP patients treated with FETROJA were elevations in liver tests, hypokalemia, diarrhea, hypomagnesemia, and atrial fibrillation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Shionogi Inc. at 1-800-849-9707 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 (0.3%). 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). (N = 300) Imipenem/Cilastatin 1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight). (N = 148) 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 : thrombocytosis Cardiac disorders : congestive heart failure, bradycardia, atrial fibrillation Gastrointestinal disorders : abdominal pain, dry mouth, stomatitis General system disorders : pyrexia, peripheral edema Hepatobiliary disorders : cholelithiasis, cholecystitis, gallbladder pain Immune system disorders : drug hypersensitivity Infections and infestations : C. difficile infection Laboratory investigations : prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), red blood cells urine positive, creatine phosphokinase increase Metabolism and nutrition disorders : decreased appetite, hypocalcemia, fluid overload Nervous system disorders : dysgeusia, seizure Respiratory, thoracic, and mediastinal disorders : dyspnea, pleural effusion Skin and subcutaneous tissue disorders : pruritis Psychiatric disorders : insomnia, restlessness 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). N = 148 Meropenem 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). N = 150 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 : thrombocytopenia, thrombocytosis Cardiac disorders : myocardial infarction, atrial flutter Gastrointestinal disorders : nausea, vomiting, abdominal pain Hepatobiliary disorders : cholecystitis, cholestasis Infections and infestations : C. difficile infection, oral candidiasis Laboratory investigations : prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) Metabolism and nutrition disorders : hypocalcemia, hyperkalemia Nervous system disorders : seizure Renal and genitourinary disorders : acute interstitial nephritis Respiratory, thoracic, and mediastinal disorders : cough Skin and subcutaneous tissue disorders : rash including rash erythematous 6.2 Postmarketing Experience 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 : neutropenia Renal and urinary disorders : chromaturia

12.3 Pharmacokinetics Cefiderocol exposures (C max and daily AUC) in cUTI patients, HABP/VABP patients, and healthy volunteers are summarized in Table 6. Cefiderocol C max and AUC increased proportionally with dose. 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. (N = 21) HABP/VABP Patients (N = 146) Healthy Volunteers After a single FETROJA 2-gram dose was infused over 3 hours. (N = 43) C max = maximum concentration. AUC 0-24 hr = area under the concentration time curve from 0 to 24 hours. C max (mg/L) 115 (±57) 111 (±56) 91.4 (±17.9) AUC 0-24 hr (mg∙hr/L) 1944 (±1097) 1773 (±990) 1175 (±203) Distribution The geometric mean (±SD) cefiderocol volume of distribution was 18.0 (±3.36) L. 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 3.1 to 20.7 mg/L and 7.2 to 15.9 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 5.18 (±0.89) L/hr. 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 Geometric Mean Ratios (90% CI) Compared to AUC in subjects with CLcr 90 to 119 mL/min (N = 12). CI = confidence interval. 60 to 89 (N = 6) 1.37 (1.15, 1.62) 30 to 59 (N = 7) 2.35 (2.00, 2.77) 15 to 29 (N = 4) 3.21 (2.64, 3.91) < 15 (N = 6) 4.69 (3.95, 5.56) Patients Receiving CRRT In an in vitro study, effluent flow rate was the major determinant of cefiderocol clearance by CRRT. Variables examined included effluent flow rate, CRRT mode (CVVH or CVVHD), filter type and point of dilution (pre- or post-filter dilution). The effluent flow rate-based dosing recommendations in Table 2 are predicted to provide cefiderocol exposures similar to those achieved with a dose of 2 grams given every 8 hours in patients not receiving CRRT [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 : Cefiderocol is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Cefiderocol is not an inducer of CYP1A2, CYP2B6, or CYP3A4. Transporter Systems : Cefiderocol is not an inhibitor of OATP1B1, MATE1, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or bile salt export pump transporters. Cefiderocol is not a substrate of OAT1, OAT3, OCT2, MATE1, MATE2-K, P-gp, or BCRP.