Mechanism of Action

Fetroja MOA Schematic

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 a siderophore iron uptake mechanism. Cefiderocol exerts bactericidal action by inhibiting cell wall biosynthesis through binding to penicillin-binding proteins (PBPs).

Demonstrated in vitro activity in the presence of resistance mechanisms

β-lactamase hydrolysis Porin channel changes
Certain Enterobacteriaceae 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) Certain P aeruginosa genetically confirmed to contain VIM, GES, and AmpC Certain Acinetobacter baumannii containing OXA-23, OXA-24/40, OXA-51, and OXA-58 Some K pneumoniae isolates with OmpK35/36 porin deletion Some isolates of P aeruginosa with OprD porin deletion
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IN VITRO DATA FOR LISTED ORGANISMS ARE AVAILABLE BUT THEIR CLINICAL SIGNIFICANCE IS UNKNOWN.

Resistance

  • 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 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 10x minimum inhibitory concentration (MIC) ranged from 10-6 to 10-8
  • In vitro, MIC increases that may result in resistance to cefiderocol in Gram-negative bacteria, have been associated with the presence of beta-lactamases including AmpC beta-lactamase overproduction, modifications of penicillin-binding proteins, and mutations of transcriptional regulators that impact siderophore or efflux pump expression
  • 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 isolates with relatively high MICs (range 2 to 256) to cefiderocol

For additional information see full Prescribing Information section 12.4.

Antimicrobial Activity

Fetroja has been shown to be active against the following bacteria, both in vitro and in clinical infections

Gram-negative

  • Escherichia coli
  • Enterobacter cloacae complex
  • Klebsiella pneumoniae
  • Proteus mirabilis
  • Pseudomonas aeruginosa

Cefiderocol demonstrated in vitro activity against the following bacteria, but the clinical significance is unknown

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. However, the efficacy of cefiderocol in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-negative

  • Acinetobacter baumannii
  • Citrobacter freundii complex
  • Citrobacter koseri
  • Klebsiella aerogenes
  • Klebsiella oxytoca
  • Morganella morganii
  • Proteus vulgaris
  • Providencia rettgeri
  • Serratia marcescens
  • Stenotrophomonas maltophilia

Clinical Study

Study design: cUTI, including pyelonephritis

study design study design mobile

TID=three times a day.

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 1g/1g IV every 8 hours (infused over 1 hour) for 7 to 14 days. No switch from IV to oral antibacterial therapy was permitted.

Endpoints

Efficacy was assessed as a composite of microbiological eradication and clinical cure 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 the Test of Cure (TOC) visit in the Micro-ITT population.

Baseline characteristics

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 was 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.

Results

The following table provides the results of a composite of microbiological eradication (all Gram-negative uropathogens found at baseline at ≥105 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 the table below. 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 the second table below 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.

Composite, microbiological, and clinical response rates at the TOC visit—Micro-ITT population

Study endpoint Fetroja
n/N (%)
Imipenem/
Cilastatin
n/N (%)
Treatment difference (95% CI)a
Composite response at TOC 183/252 (72.6%) 65/119 (54.6%) 18.6 (8.2, 28.9)
Microbiologic response TOC 184/252 (73.0%) 67/119 (56.3%) 17.3 (6.9, 27.6)
Clinical response TOC 226/252 (89.7%) 104/119 (87.4%) 2.4 (-4.7, 9.4)
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CI=confidence interval; micro-ITT =microbiological intent-to-treat; TOC=Test of Cure.
a The treatment difference and 95% CI were based on the Cochran-Mantel-Haenszel method.

Composite endpoint of microbiological eradication and clinical response at the TOC visits in the micro-ITT by baseline pathogena subgroups

Baseline pathogen subgroup Fetroja
n/N (%)
Imipenem/Cilastatin
n/N (%)
Escherichia coli 113/152 (74.3) 45/79 (57.0)
Klebsiella pneumoniae 36/48 (75.0) 12/25 (48.0)
Proteus mirabilis 13/17 (76.5) 0/2 (0.0)
Pseudomonas aeruginosa 8/18 (44.4) 3/5 (60.0)
Enterobacter cloacae complex 8/13 (61.5) 3/3 (100.0)
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a Patients may have been infected with 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.

Adverse Reactions

Please see Warnings and Precautions in the Important Safety Information below including:

  • Increase in all-cause mortality in patients with carbapenem-resistant Gram-negative bacterial infections
  • Hypersensitivity reactions
  • Clostridioides difficile-associated diarrhea (CDAD)
  • Seizures and other central nervous system adverse reactions

Serious adverse reactions and adverse reactions leading to discontinuation

In Trial 1, a total of 14/300 (4.7%) patients treated with Fetroja and 12/148 (8.1%) of 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

Selected adverse reactions occurring in ≥2% of patients receiving Fetroja in the cUTI trial

Adverse reaction Fetrojaa (N=300) Imipenem/
Cilastatinb (N=148)
Diarrhea 4% 6%
Infusion site reactionsc 4% 5%
Constipation 3% 4%
Rashd 3% <1%
Candidiasise 2% 3%
Cough 2% <1%
Elevations in liver testsf 2% <1%
Headache 2% 5%
Hypokalemiag 2% 3%
Nausea 2% 4%
Vomiting 2% 1%
cUTI=complicated urinary tract infection.
a 2 grams IV over 1 hour every 8 hours (with dosing adjustment based on renal function).
b 1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight).
c Infusion site reactions include infusion site erythema, inflammation, pain, pruritis, injection site pain, and phlebitis.
d Rash includes rash macular, rash maculopapular, erythema, skin irritation.
e Candidiasis includes oral or vulvovaginal candidiasis, candiduria.
f Elevations in liver tests include alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, blood alkaline phosphatase, hepatic enzyme increased.
g Hypokalemia includes blood potassium decreased.

For more on Adverse Reactions, see full Prescribing Information.

Dosing

Recommended dosage

The recommended duration of treatment with Fetroja is 7 to 14 days. The duration of therapy should be guided by the severity of infection and the patient’s clinical status for up to 14 days.

Recommended dosage and dosage adjustments of Fetroja for adult patients

Estimated creatinine clearance (CLcr)a
dose icon Dose
frequency icon Frequency
infusion time icon Infusion time
60 to 119 mL/min (Recommended dosage) 2 grams Every 8 hours 3 hours
30 to 59 mL/min 1.5 grams Every 8 hours 3 hours
15 to 29 mL/min 1 gram Every 8 hours 3 hours
<15 mL/min
(ESRD patients with or without intermittent HDb)
0.75 gram Every 12 hours 3 hours
≥120 mL/min 2 grams Every 6 hours 3 hours
a CLcr=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.
ESRD=end-stage renal disease; HD=hemodialysis.
  • For patients with fluctuating renal function, monitor CLcr and adjust dosage accordingly

Renal impairment

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

Dose adjustment is required in patients with CLcr 15 to 59 mL/min, and in patients with end-stage renal disease or who are receiving hemodialysis (HD). In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing. Monitor renal function regularly and adjust the dosage of Fetroja accordingly as renal function may change during the course of therapy.

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. Monitor renal function regularly and adjust the dosage of Fetroja accordingly as renal function may change during the course of therapy.

Fetroja Packaging

Fetroja vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. Store in the carton until time of use. Reconstituted and diluted solutions of Fetroja can be stored at room temperature (see Dosage and Administration).

Preparation and Administration

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.

1

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.

2

Allow the vial(s) to stand until the foaming generated on the surface has disappeared (typically within 2 minutes). The final volume of the reconstituted solution will be approximately 11.2 mL. The reconstituted solution is for intravenous infusion only after dilution in an appropriate infusion solution.

3

To prepare the required doses, withdraw the appropriate volume of reconstituted solution from the vial according to the table below.

4

Add the withdrawn volume to an infusion bag containing 100 mL of 0.9% sodium chloride injection, USP or 5% dextrose injection, USP.

5

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 below).

Fetroja solution for administration is compatible with: 0.9% sodium chloride injection, USP and 5% dextrose injection, USP. The compatibility of Fetroja solution for administration with solutions containing other drugs or other diluents has not been established.

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 at least 100 mL
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
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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. Discard any unused reconstituted solution.

Diluted Fetroja infusion solution

The diluted Fetroja infusion solution in the infusion bags is stable for up to 4 hours at room temperature.

For more on dosing, see the full Prescribing Information.
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Formulary Resources

A variety of resources are available to help formulary decision makers review Fetroja.

Access the Fetroja Digital Formulary Kit.

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.

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, 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 in patients with infections caused by Gram-negative organisms, including nonfermenters such as Acinetobacter baumannii, 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 cephalosporins. 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.

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 colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. 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%).

Indication

Fetroja® (cefiderocol) is 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: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.

Approval of this indication is based on limited clinical safety and efficacy data for Fetroja.

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.

Please see Full Prescribing Information for Fetroja.

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