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What is Fetroja (cefiderocol), and how does it work?
Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis
Fetroja (cefiderocol) 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.
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.
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.
What are the side effects of Fetroja?
Serious Allergic Reactions
Advise patients and their families that
allergic reactions, including serious allergic reactions, could occur with
Fetroja and that serious reactions require immediate treatment. Ask patients
about any previous hypersensitivity reactions to Fetroja, other beta-lactams
(including cephalosporins), or other allergens.
Potentially Serious Diarrhea
Advise patients and their families that diarrhea is a common problem caused by
antibacterial drugs, including Fetroja. Sometimes, frequent watery or bloody
diarrhea may occur and may be a sign of a more serious intestinal infection. If
severe watery or bloody diarrhea develops, tell patient to contact his or her
healthcare provider.
Seizures
Counsel patients on the implication of cephalosporins, including Fetroja, in
triggering seizures, particularly in patients with renal impairment when the
dosage was not reduced and in patients with a history of epilepsy.
Antibacterial Resistance
Patients should be counseled that antibacterial drugs including Fetroja should
only be used to treat bacterial infections. They do not treat viral infections
(e.g., influenza, common cold). When Fetroja is prescribed to treat a bacterial
infection, patients should be told that although it is common to feel better
early in the course of therapy, the medication should be taken exactly as
directed. Skipping doses or not completing the full course of therapy may (1)
decrease the effectiveness of the immediate treatment and (2) increase the
likelihood that bacteria will develop resistance and will not be treatable by
Fetroja or other antibacterial drugs in the future.
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 1 gram/1 gram 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 ReactionFetrojaa(N = 300)Imipenem/Cilastatinb
(N = 148)Diarrhea4%6%Infusion site reactionsc4%5%Constipation3%4%Rashd3%< 1%Candidiasise2%3%Cough2%< 1%Elevations in liver testsf2%< 1%Headache2%5%Hypokalemiag2%3%Nausea2%4%Vomiting2%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.
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 ReactionFetrojaaN = 148Meropenemb
N = 150Elevations in liver testsc16%16%Hypokalemiad11%15%Diarrhea9%9%Hypomagnesemia5%< 1%Atrial fibrillation5%3%HABP/VABP = hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia.
a 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function).
b 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function).
c 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.
d Hypokalemia includes blood potassium decreased.
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), and 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
What is the dosage for Fetroja?
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. 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.
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)aDoseFrequencyInfusion TimeCLcr 30 to 59 mL/min1.5 gramsEvery 8 hours3 hoursCLcr 15 to 29 mL/min1 gramEvery 8 hours3 hoursCLcr less than 15 mL/min, with or without intermittent HDb0.75 gramsEvery 12 hours3 hoursHD = hemodialysis.a CLcr = creatinine clearance estimated by Cockcroft-Gault equation.
b Cefiderocol is removed by HD; administer Fetroja immediately after HD for patients receiving intermittent HD.
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].
Table 2 : Recommended Dosage of Fetroja for Patients Receiving CRRT
Effluent Flow RateaRecommended Dosage of Fetroja2 L/hr or less1.5 grams every 12 hours2.1 to 3 L/hr2 grams every 12 hours3.1 to 4 L/hr1.5 grams every 8 hours4.1 L/hr or greater2 grams every 8 hoursCRRT = continuous renal replacement therapy.a Ultrafiltrate flow rate for CVVH, dialysis flow rate for CVVHD, ultrafiltrate flow rate plus dialysis flow rate for CVVHDF.
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.
QUESTION
Bowel regularity means a bowel movement every day.
See Answer
What drugs interact with Fetroja?
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.
Is Fetroja safe to use while pregnant or breastfeeding?
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.
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.