Source: FDA, National Drug Code (US) Revision Year: 2020
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 [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
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 non-fermenters such as Acinetobacter baumannii complex, 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.
Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP.
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-treated patients in clinical trials [see Adverse Reactions (6.1)]. 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) 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.
Cephalosporins, including FETROJA, have been implicated in triggering seizures [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.2)]. 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.
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 increases the risk of the development of drug-resistant bacteria [see Indications and Usage (1.3)].
The following serious adverse reactions are described in greater detail in the Warnings and Precautions section:
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.
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.
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%).
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* (N=300) | Imipenem/Cilastatin† (N=148) |
|---|---|---|
| Diarrhea | 4% | 6% |
| Infusion site reactions‡ | 4% | 5% |
| Constipation | 3% | 4% |
| Rash§ | 3% | <1% |
| Candidiasis¶ | 2% | 3% |
| Cough | 2% | < 1% |
| Elevations in liver tests# | 2% | <1% |
| Headache | 2% | 5% |
| HypokalemiaÞ | 2% | 3% |
| Nausea | 2% | 4% |
| Vomiting | 2% | 1% |
cUTI = complicated urinary tract infection.
* 2 grams IV over 1 hour every 8 hours (with dosing adjustment based on renal function).
† 1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight).
‡ Infusion site reactions include infusion site erythema, inflammation, pain, pruritis, injection site pain, and phlebitis.
§ Rash includes rash macular, rash maculopapular, erythema, skin irritation.
¶ Candidiasis includes oral or vulvovaginal candidiasis, candiduria.
# Elevations in liver tests include alanine aminotransferase, aspartate aminotransferase, gammaglutamyl transferase, blood alkaline phosphatase, hepatic enzyme increased.
Þ Hypokalemia includes blood potassium decreased.
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
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.
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.
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* N = 148 | Meropenem† N = 150 |
|---|---|---|
| Elevations in liver tests‡ | 16% | 16% |
| Hypokalemia§ | 11% | 15% |
| Diarrhea | 9% | 9% |
| Hypomagnesemia | 5% | < 1% |
| Atrial fibrillation | 5% | 3% |
HABP/VABP = hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia.
* 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function).
† 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function).
‡ 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.
§ Hypokalemia includes blood potassium decreased.
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
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.
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 (see Data).
Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 0.9 times (rats) or 1.3 times (mice) higher than the average observed in patients receiving the maximum recommended daily dose.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.
Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice). No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 0.9 times (rats) and 1.3 times (mice) the daily mean plasma exposure in patients that received 2 grams of cefiderocol infused intravenously every 8 hours.
In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from Day 6 of pregnancy until weaning. No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed.
In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (<0.5%) of the dose.
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.
Cefiderocol-derived radioactivity was detected in milk following intravenous administration to lactating rats. The peak level in rat milk was approximately 6% of the peak plasma level.
Safety and effectiveness of FETROJA in pediatric patients younger than 18 years of age have not been established.
Of the 300 patients treated with FETROJA in the cUTI trial, 158 (52.7%) were 65 years of age and older, and 67 (22.3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these patients and younger patients.
Of the 148 patients treated with FETROJA in the HABP/VABP trial, 83 (56.1%) were 65 years of age and older, and 40 (27%) were 75 years of age and older.
The incidence of adverse reactions in patients treated with FETROJA was similar in patients under 65 years of age as compared to older patients (65 years of age and older and 75 years of age and older). The incidence of adverse reactions in older patients (65 years of age and older and 75 years of age and older) was also similar between treatment groups.
Clinical cure rates at the Test-of-Cure visit (TOC) in FETROJA-treated adult patients younger than 65 years of age, 65 years of age to younger than 75 years of age, and 75 years of age and older were 60%, 77.5%, and 60%, respectively. In comparison, the clinical cure rates at the TOC visit in the meropenem-treated patients for each of these subgroups were 65.5%, 64.4%, and 70.5%, respectively. The observed all-cause mortality rates at Day 14 in the FETROJA-treated patients for each of these subgroups were 12.3%, 7.5%, and 17.5%, respectively. In comparison, in the meropenem-treated patients for each of these subgroups, they were 10.3%, 17.8%, and 9.1%, respectively.
FETROJA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
No dosage adjustment of FETROJA is recommended in patients with CLcr 60 to 89 mL/min.
Dose adjustment is required in patients with CLcr less than 60 mL/min, and in patients who are receiving HD. In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.
A total of 16 patients treated with FETROJA received CRRT in clinical trials. Dosage adjustment of FETROJA is required in patients receiving CRRT including CVVH, CVVHD, and CVVHDF. Dosage of FETROJA should be based on the effluent flow rate in patients receiving CRRT [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. While on CRRT, a patient’s residual renal function may change. Improvements or reductions in residual renal function may warrant a change in FETROJA dosage.
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 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.
The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol. Dosage adjustments are not necessary in patients with impaired hepatic function.
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