FDA Approves FETROJA (Cefiderocol) for the Treatment of Complicated Urinary Tract Infections in Patients 18 Years of age or Older

On November 14, 2019, the U.S. Food and Drug Administration (FDA) approved FETROJA (cefiderocol) 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, in patients 18 years of age or older who have limited or no alternative treatment options. Approval of this indication is based on limited clinical safety and efficacy data for FETROJA. 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.

The approved recommended dosage of FETROJA is 2 grams administered every 8 hours by intravenous infusion over 3 hours in adults with a creatinine clearance (CLcr) of 60 to 119 mL/min. Dosage adjustment is recommended for patients with CLcr less than 60 mL/min or for patients with CLcr 120 mL/min or greater (see below). 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.

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. Additional information regarding dosage and administration, laboratory test interactions, and important warnings and precautions related to increase in all-cause mortality in patients with carbapenem-resistant Gram-negative bacterial infections, hypersensitivity reactions, Clostridioides difficile-associated diarrhea, seizures and other central nervous system adverse reactions, and increase risk for development of drug-resistant bacteria can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

  • MOA: FETROJA is a cephalosporin antibacterial drug.
  • General PK: In cUTI patients with CLcr 60 mL/min or greater, the mean cefiderocol Cmax was 138 mg/L and AUC was 394.7 mg·hr/L (as 1184 mg·hr/L of daily AUC) after multiple (every 8 hours) FETROJA 2-gram doses infused over 1 hour (1/3 of the recommended infusion duration). In healthy volunteers, the mean cefiderocol Cmax and AUC was 89.7 mg/L and 386 mg·hr/L, respectively, after a single FETROJA 2-gram dose was infused over 3 hours. Cefiderocol Cmax and AUC increased proportionally with dose.
  • 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%.
  • 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.
  • PD: 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 Enterobacteriaceae, 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.

Drug Interactions

Drug/Laboratory Test Interactions: 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.

Use in 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

Geometric mean AUC of cefiderocol increases with decreasing renal function. Approximately 60% of cefiderocol was removed by a 3- to 4-hour hemodialysis (HD) session. Dosage adjustment of FETROJA is recommended in patients with CLcr less than 60 mL/min, as follows:

  • Patients with CLcr 30 to 59 mL/min: Adjust FETROJA dosage to 1.5 grams every 8 hours by intravenous infusion over 3 hours.
  • Patients with CLcr 15 to 29 mL/min: Adjust FETROJA dosage to 1 gram every 8 hours by intravenous infusion over 3 hours.
  • Patients with CLcr less than 15 mL/min: Adjust FETROJA dosage to 0.75 gram every 12 hours by intravenous infusion over 3 hours in end-stage renal disease patients (CLcr less than 15 mL/min) with or without intermittent hemodialysis. In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing.

For patients with fluctuating renal function, monitor CLcr and adjust dosage accordingly.

Patients with CLcr 120 mL/min or Greater

Increased cefiderocol clearance has been observed in patients with CLcr 120 mL/min or greater. Adjust FETROJA dosage to 2 grams every 6 hours by intravenous infusion over 3 hours 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.

Efficacy and Safety

Efficacy of FETROJA was evaluated in a randomized, multinational, double-blind trial in adult patients with cUTI (including pyelonephritis). 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 visit in the Micro-ITT population. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most frequently occurring adverse reactions in greater than or equal to 2% of patients treated with FETROJA were diarrhea, infusion site reactions, constipation, rash, candidiasis, cough, elevations in liver tests, headache, hypokalemia, nausea, and vomiting.

Full prescribing information is available at https://go.usa.gov/xpXpR.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.