FETROJA Powder for solution for injection Ref.[10076] Active ingredients: Cefiderocol

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. coli, K. pneumoniae, P. aeruginosa, A. baumannii, and S. maltophilia. Compared to a 1-hour infusion, a 3-hour infusion increased the percent time of dosing interval that unbound plasma concentrations of cefiderocol exceed the MIC. The in vivo animal pneumonia studies showed that the antibacterial activity of cefiderocol was greater at the human equivalent dosing regimen of 3-hour infusion compared to that of 1-hour infusion.

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 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:

C_max = maximum concentration.
AUC_{0-24 hr} = area under the concentration time curve from 0 to 24 hours.
^* After multiple (every 8 hours) FETROJA 2-gram doses infused over 3 hours or adjusted based on renal function.
^† After a single FETROJA 2-gram dose was infused over 3 hours.

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^*:

CI = confidence interval.
* After a single FETROJA 1-gram dose (0.5 times the approved recommended dosage).
^† Compared to AUC in subjects with CLcr 90 to 119 mL/min (N=12).

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.

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 activity against most Gram-positive bacteria and anaerobic bacteria.

Resistance

In vitro, MIC increases that may result in resistance to cefiderocol in Gram-negative bacteria have been associated with a combination of multiple beta-lactamases, modifications of PBPs, and mutations of transcriptional regulators that impact siderophore expression.

Cefiderocol does not cause induction of AmpC beta-lactamase in P. aeruginosa and E. cloacae. The frequency of resistance development in Gram-negative bacteria including carbapenemase producers exposed to cefiderocol at 10 × minimum inhibitory concentration (MIC) ranged from 10 ^-6 to <10 ^-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 activity against isolates of S. maltophilia and a subset of isolates of Enterobacterales and P. aeruginosa that are resistant to meropenem, ciprofloxacin, amikacin, cefepime, ceftazidime-avibactam, and ceftolozane/tazobactam. Cefiderocol has shown in vitro activity against subset of isolates of A. baumannii complex that are resistant to meropenem, ciprofloxacin, and amikacin. Cefiderocol is active against some colistin-resistant E. coli isolates containing mcr-1.

Cefiderocol demonstrated in vitro activity against a subgroup of Enterobacterales genetically confirmed to contain the following: ESBLs (TEM, SHV, CTX-M, oxacillinase [OXA]), AmpC, AmpC-type ESBL (CMY), serine-carbapenemases (such as KPC, OXA-48), and metallo-carbapenemases (such as NDM and VIM). Cefiderocol demonstrated in vitro activity against a subgroup of P. aeruginosa genetically confirmed to contain VIM, IMP, GES, AmpC, and a subgroup of A. baumannii containing OXA-23, OXA-24/40, OXA-51, OXA-58, and AmpC. Cefiderocol is active in vitro against a subgroup of S. maltophilia containing metallo-carbapenemase (L1) and serine beta-lactamases (L2).

Cefiderocol maintained in vitro activity against K. pneumoniae in the presence of porin channel deletions (OmpK35/36), and against P. aeruginosa in the presence of porin channel deletions (OprD) and efflux pump up-regulation (MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY).

In vitro, the addition of the beta-lactamase inhibitors (such as avibactam, clavulanic acid, and dipicolinic acid) results in the lowering of MICs of some clinical isolates with relatively high MICs (range 2 to 256 mcg/mL) to cefiderocol.

Interaction with Other Antimicrobials

In vitro studies showed no antagonism between cefiderocol and amikacin, ceftazidime/avibactam, ceftolozane/tazobactam, ciprofloxacin, clindamycin, colistin, daptomycin, linezolid, meropenem, metronidazole, tigecycline, or vancomycin against strains of Enterobacterales, P. aeruginosa, and A. 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 1log₁₀ reduction in bacterial burden against most E. coli, K. pneumoniae, A. baumannii, S. maltophilia, and P. aeruginosa including some carbapenemase-producing (KPC, OXA-23, OXA-24/40, OXA-58) isolates with MICs of ≤4 mcg/mL to cefiderocol.

In an immunocompetent rat pneumonia model, reduction in bacterial counts in the lungs of animals infected with K. pneumoniae with MICs ≤8 mcg/mL, A. baumannii with MICs ≤ 2 mcg/mL, and P. aeruginosa with MICs ≤1 mcg/mL including carbapenemase-producing (KPC, NDM, and IMP) isolates was observed using humanized cefiderocol drug exposure.

In an immunocompetent murine urinary tract infection model, cefiderocol reduced bacterial counts in the kidneys of mice infected with E. coli, K. pneumoniae, and P. aeruginosa isolates with MICs ≤1 mcg/mL. In an immunocompromised murine systemic infection model, cefiderocol increased survival in mice infected with E. cloacae, S. maltophilia, and Burkholderia cepacia isolates with MICs ≤0.5 mcg/mL compared to untreated mice. In an immunocompetent murine systemic infection model, cefiderocol increased survival in mice infected with S. marcescens and P. aeruginosa isolates with MICs ≤ 1 mcg/mL compared to untreated mice.

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 and in clinical infections [see Indications and Usage (1)].

Complicated Urinary Tract Infections, Including Pyelonephritis

Gram-negative Bacteria:

Escherichia coli
Enterobacter cloacae complex
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa

Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

Gram-negative Bacteria:

Acinetobacter baumannii complex
Escherichia coli
Enterobacter cloacae complex
Klebsiella pneumoniae
Pseudomonas aeruginosa
Serratia marcescens

The following in vitro data are available, but their clinical significance is not known. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for FETROJA against isolates of similar genus or organism group. However, the efficacy of FETROJA in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-negative Bacteria:

Achromobacter spp.
Burkholderia cepacia complex
Citrobacter freundii complex
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.fda.gov/STIC.

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 and E. coli and did not induce mutations in V79 Chinese hamster lung cells. Cefiderocol was positive in a chromosomal aberration test in cultured TK6 human lymphoblasts and increased mutation frequency in L5178Y mouse lymphoma cells. Cefiderocol was negative in an in vivo rat micronucleus test and a rat comet assay at the highest doses of 2000 and 1500 mg/kg/day, respectively.

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.

14.1 Complicated Urinary Tract Infections, Including Pyelonephritis

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. coli and K. pneumoniae.

Table 8 provides the results of a composite of microbiological eradication (all Gram-negative uropathogens found at baseline at ≥10 ⁵ CFU/mL reduced to <10⁴ CFU/mL) and clinical response (resolution or improvement of cUTI symptoms and no new symptoms assessed by the investigator) at the TOC visit, 7+/-2 days after the last dose of study drug. The response rates for the composite endpoint of microbiological eradication and clinical response at the TOC visit were higher in the FETROJA arm compared with imipenem/cilastatin, as shown in Table 8. Clinical response rates at the TOC visit were similar between FETROJA and imipenem/cilastatin. Most patients with microbiological failure at the TOC visit in either treatment arm did not require further antibacterial drug treatment. Subgroup analyses examining composite outcomes by baseline pathogen are shown in Table 9 and demonstrated responses consistent with the overall population. Subgroup analyses examining outcomes by age, gender, and/or outcomes in patients with renal impairment, concomitant bacteremia, complicated UTI with or without pyelonephritis, or acute uncomplicated pyelonephritis demonstrated responses were consistent with the overall population.

Table 8. Composite, Microbiological, and Clinical Response Rates at the TOC Visit in cUTI Patients (Micro-ITT Population) in Trial 1:

CI = confidence interval; Micro-ITT = microbiological intent-to-treat; TOC = Test of Cure.
* The treatment difference and 95% CI were based on the Cochran-Mantel-Haenszel method.

Table 9. Composite Endpoint of Microbiological Eradication and Clinical Response at the TOC Visit in cUTI Patients (Micro-ITT Population) by Baseline Pathogen^* Subgroups:

* Patients may have had more than one pathogen in the baseline urine culture.

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.

14.2 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

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:

CI = confidence interval; TOC = Test of Cure.
* 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.

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 complex at baseline, of which 17 (33.3%) patients had isolates susceptible to meropenem (MIC ≤8 mcg/mL, based on meropenem 2 grams every 8 hours). Among 51 patients with A. baumannii complex at baseline, all-cause mortality at Day 14 was 5/26 (19.2%) in FETROJA and 4/25 (16.0%) in the meropenem treatment group and at Day 28 was 9/26 (34.6%) in FETROJA and 6/25 (24.0%) in the meropenem treatment group. The clinical cure rates at the TOC visit were 14/26 (53.8%) in the FETROJA and 15/25 (60.0%) in the meropenem treatment group.

Table 11. All-cause Mortality by Baseline Pathogens Susceptible to Meropenem^* in HABP/VABP Patients (mITT Population) in Trial 2:

Each cell excludes subjects in whom baseline pathogen had meropenem MIC >8 mcg/mL or where MIC was unknown. Subjects with unknown survival status were considered deaths.

^* Susceptible defined as MIC of ≤8 mcg/mL to meropenem.
^† Includes A. baumannii, A. nosocomialis, and A. pittii.
^‡ Includes Enterobacter cloacae complex (E. cloacae, E. asburiae, and E. kobei) and Serratia marcescens.

Table 12 Clinical Cure Rates by Baseline Pathogen Susceptible to Meropenem^* at the TOC Visit in HABP/VABP (mITT Population) in Trial 2:

Each cell excludes subjects whose pathogen-specific meropenem MIC was >8 mcg/mL or where MIC was unknown.

^* Susceptible defined as MIC of ≤8 mcg/mL to meropenem.
^† Includes A. baumannii, A. nosocomialis, and A. pittii.
^‡ Includes Enterobacter cloacae complex (E. cloacae, E. asburiae, and E. kobei) and Serratia marcescens.

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.